December 2010, Vol 3, No 8 by The Oncology Pharmacist

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DECEMBER 2010

www.TheOncologyPharmacist.com

VOL 3, NO 8

The Official Newspaper for the Hem/Onc Pharmacist

PHARMACY PRACTICE

CANCER CENTER PROFILE

Geisinger Medical Center’s Cancer Institute Joins the NCCCP By Dawn Lagrosa

Bar Coding: An Effective Strategy for Preventing Medication Errors By Eric G. Poon, MD, MPh Director of Clinical Informatics, Brigham and Women’s Hospital; Assistant Professor of Medicine, Harvard Medical School, Boston

edication safety is an ongoing challenge for hospitals, healthcare providers, and healthcare delivery systems. Medication errors in hospitals are common1,2 and can lead to patient harm. A study by Leape and colleagues found that serious medication errors occurred most often in physician ordering (39%) and nurse administration (38%). The remaining 23% occurred during transcription (12%) and pharmacy dispensing (11%).3 Strategies are needed to reduce pre-

ventable adverse drug events (ADEs), and the implementation of healthcare information technology (HIT) has been touted as a promising strategy for preventing medication errors. Computerized physician order entry (CPOE) has been shown to decrease serious medication errors by 55%.4 Bar code technology, which is widely adopted in industries outside of healthcare because of its ease of use and reliability, has been shown to prevent errors in dispensing drugs from the pharContinued on page 4

HEALTHCARE REFORM Mammography technologist Jessica Davis, RT(R) (M), is part of a multidisciplinary breast cancer care team working to improve access to screening, treatment, and research.

Cancer Society Science Officer Calls for Logic in Healthcare By Laird Harrison

his past April, Geisinger Medical Center’s (GMC) Cancer Institute became one of 14 sites added to the National Cancer Institute Community Cancer Centers Program (NCCCP). Joining this national network of community cancer centers offers GMC the opportunity to expand its state-of-the-art cancer care and research in northeast Pennsylvania. GMC is a part of Geisinger Health System (Geisinger), which serves a mostly rural population and has cancer centers in Danville, WilkesBarre, State College, and Hazleton. Geisinger takes pride in its innovative approach to healthcare delivery to this population, which also includes many elderly patients. In addition, a significant portion is underserved because of socioeconomic status and transportation problems. Thanjavur Ravikumar, MD, FACS, director of the Center for Surgical Innovation, and co-chair of the oncology service line at

Continued on page 24

Inside Continuing Education Implications of Recent Guideline Updates on the Management of Chemotherapy-induced Nausea and Vomiting Page 10

Hematologic Cancers Lymphoma Expert Outlines Recent Reﬁnements in Diagnosis and Treatment Page 26 Oncology Congress PARP Inhibitors Show Promise in Trials

SAN FRANCISCO—America must take a more logical approach to healthcare, or the whole system for providing it will collapse, warned Otis W. Brawley, MD, chief medicine and science officer at the American Cancer Society. “I spend a lot of time talking about the rational use of healthcare, not the rationing,” said Brawley, who also serves as an Emory University professor of oncology, hematology, and medicine. He treated his audience at a plenary session of the sixth annual Oncology Congress to a blizzard of statistics suggest-

ESMO For Breakthrough Cancer Pain, Fentanyl Nasal Spray Easily Titratable and Eﬀective Sex and the Cancer Patient: Still a Problem with Targeted Agents Page 32

ing that awareness and prevention could dramatically reduce suffering and death. The United States spent $2.53 trillion for healthcare in 2009, twice as much per capita as Switzerland, the next-biggest spender, he said. Yet the United States is only 29th in life expectancy. And healthcare expenditures are growing at a rapid rate, he warned. Currently they account for 17.3% of gross domestic product, but they are expected to reach 25% by 2025. “We’re not getting what we pay for,” he said. Continued on page 6

Fostering a Dialogue to Improve Patient Care & Outcomes

Submit your cases online today at www.myelomacases.com

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Editorial Board EDITOR-INCHIEF Patrick J. Medina, PharmD, BCOP The University of Oklahoma College of Pharmacy Tulsa, OK

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Jim Koeller, MS University of Texas at Austin San Antonio, TX

Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA

Christopher J. Lowe, PharmD

John M. Valgus, PharmD, BCOP

Novant Health Winston-Salem, NC

University of North Carolina Hospitals and Clinics Chapel Hill, NC

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

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

Gary C. Yee, PharmD, FCCP, BCOP

Betty M. Chan, PharmD, BCOP

David C. Gammon, BS Pharm

Laura Boehnke Michaud, PharmD, BCOP, FASHP

John F. Aforismo, BSc Pharm, RPh, FASCP

Christopher Fausel, PharmD, BCPS, BCOP

RJ Health Systems International, LLC Wethersfield, CT

Indiana University Simon Cancer Center Indianapolis, IN

David Baribeault, RPh, BCOP

USC/Norris Cancer Hospital Los Angeles, CA

Women and Infant’s Hospital Providence, RI

University of Nebraska College of Pharmacy Omaha, NE

Burt Zweigenhaft, BS BioPharma Partners LLC New York, NY

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

Marlo Blazer, RPh, PharmD Steven L. D’Amato, RPh, BCOP

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

James Cancer Hospital & Solove Research Institute Columbus, OH

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

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Steve Stricker, PharmD, MS, BCOP

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

Samford University McWhorter School of Pharmacy Birmingham, AL

www.TheOncologyPharmacist.com

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

December 2010 I VOL 3, NO 8

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FROM THE EDITOR

The Official Newspaper for the Hem/Onc Pharmacist

ncluded with this issue is the inaugural issue of the new peer-reviewed Journal of Hema tology Oncology Pharmacy. The journal complements the coverage of oncology-related news and events in The Oncology Pharmacist by providing original research, indepth review articles, and articles addressing clinical controversies and practice management issues, Patrick Medina, all of which will undergo rigorous PharmD, BCOP review by our distinguished editoEditor-in-Chief rial board members and reviewers. We hope you will find this new publication a valuable addition to the oncology pharmacy literature and consider submitting manuscripts to it. Ensuring medication safety is a major issue for pharmacists and other healthcare providers, and various technologies are being used in an effort to prevent medication errors. Bar coding is one approach that many institutions are now using or are considering, but implementing the technology can present challenges. The article by Dr Eric G. Poon describes how one hospital successfully used bar code technology to reduce

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com Editorial Director Karen Rosenberg karen@greenhillhc.com Associate Editor Dawn Lagrosa dawn@greenhillhc.com Director, Client Services John W. Hennessy john@greenhillhc.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

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the rate of medication errors, and the commentary by Dr Mahro Ershadi provides a pharmacist’s perspective on practical considerations in integrating the technology in clinical practice. Another challenge to healthcare professionals is providing high-quality care to underserved populations, including minority groups and those in rural areas. Overcoming healthcare disparities is one of the central pillars of the National Cancer Institute’s Community Cancer Centers Program (NCCCP). The profile in this issue showcases the innovative strategies employed by one of the new NCCCP sites, Geisinger Medical Center in northeast Pennsylvania, to extend state-of-the-art cancer care to its largely rural population. Also in this issue are reports from several recent national and international meetings and an update on the management of lymphoma by Dr Owen A. O’Connor, one of the leading experts in this field. Speaking at one of these meetings, Dr Otis A. Brawley of the American Cancer Society called for “rational use of healthcare.” The recent elections have intensified debate about healthcare reform, but given the huge costs of healthcare in general and cancer in particular, we can all agree that a logical approach to use of available resources is necessary. ●

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2010 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare 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.

CONTENTS

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

PERSONAL FINANCE

December 2010 I VOL 3, NO 8

December 2010 • VOL 3, NO 8

CONTINUING EDUCATION

10 Implications of recent guideline updates on the management of chemotherapyinduced nausea and vomiting

HEMATOLOGIC CANCERS

26 Lymphoma expert outlines recent refinements in diagnosis and treatment 28 The golden years: are you financially prepared? CONFERENCE NEWS: ONCOLOGY CONGRESS

30 PARP inhibitors show promise in trials CONFERENCE NEWS: ESMO

32 For breakthrough cancer pain, fentanyl nasal spray easily titratable and effective Sex and the cancer patient: still a problem with targeted agents

34 Prolonging chemotherapy in metastatic breast cancer improves survival DEPARTMENTS

18 24 30 34 37

Oncology Drug Codes Recent FDA Approval News Notes International News Meetings

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

www.TheOncologyPharmacist.com www.TheOncologyPharmacist.com

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www.BioOncology.com

A pioneer in cancer innovation — exploring new directions

At Genentech BioOncology, we’re leading the fight against cancer with innovative science and are working to transform cancer treatment. A family of firsts — Our proven therapeutics are standards of care in 5 of the 6 leading causes of cancer mortality in the United States. A robust pipeline — Our molecules in development target the fundamental mechanisms of cancer growth and include a HER dimerization inhibitor, a Hedgehog pathway inhibitor, an antibody–drug conjugate, and antibodies targeting cancer cell-surface antigens. A commitment to patients — We actively pursue ways to ensure patient access to therapeutics through a variety of patient support programs so healthcare providers can remain focused on patient care. Our goal is to fundamentally change the way cancer is treated — not just with incremental advances, but with new standards of care.

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Pharmacy Practice

Bar Coding: An Effective Strategy... macy.5 At the bedside, the use of bar code technology to verify a patient’s identity and the medication to be administered has been shown to be an effective strategy for preventing medication errors, and its use has been increasing. The US Department of Veterans Affairs, for example, pioneered the way by instituting a national bar coding program in 1999 in its hospital system.6,7 Bar code medication verification at the bedside is usually implemented in conjunction with an electronic medication administration record (eMAR). This combination of technologies allows nurses to automatically document the administration of drugs by scanning their bar codes6 to ensure the correct medication is administered in the correct dose at the correct time to the correct patient. Because the eMAR imports drug orders electronically from the physician’s order entry or the pharmacy system, its implementation may reduce transcription errors.6 Bar code plus eMAR technology is not without its drawbacks. One study

found that although medication management improved, the system studied was difficult to implement.8 Furthermore, other studies have highlighted certain unintended consequences of eMAR implementation, such as hospital staff relying too heavily on the technology, bypassing some of the hospital’s safety processes, or overriding the system’s alerts, thus increasing the risk for new errors.9,10 Study examines efficacy and safety of bar code technology in hospital setting Given the uncertainties with bar code plus eMAR technology, my colleagues and I at Brigham and Women’s Hospital evaluated its implementation in 35 adult medical, surgical, and intensive care units in our 735-bed tertiary academic medical center to assess its effects on administration and transcription errors, as well as associated potential ADEs.6 During the 9-month study, we compared 6723 medication administrations

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on patient units before the bar code plus eMAR technology was introduced with 7318 medication administrations after the technology was introduced. We also reviewed order transcriptions in both time frames.6 Results Of the 1272 nontiming errors observed, 776 occurred in medication administration on units without the bar code plus eMAR system (an 11.5% error rate) compared with 495 such errors on units that used it (a 6.8% error rate), corresponding to a 41.4% relative reduction in errors (P <.001). The rate of potential ADEs (associated with nontiming errors) fell from 3.1% without the use of the bar code plus eMAR system to 1.6% with its use, representing a 50.8% relative reduction (P <.001). A 27.3% (P <.001) reduction was seen in the rate of timing errors in medication administration, but the rate of potential ADEs associated with timing errors did not differ significantly.6 Transcription errors also were re-

duced with the bar code plus eMAR system. Of the 3082 transcription orders reviewed, 1799 orders were on units without the technology. We found 110 transcription errors, of which 53 were potential ADEs, corresponding to 6.1 transcription errors and 2.9 potential ADEs per 100 medication orders transcribed. In the 1282 medication orders reviewed on units with the bar code plus eMAR system, transcription errors were completely eliminated.6 Clinical implications of bar code technology This study demonstrates that bar code plus eMAR technology can be an important intervention to improve medication safety. Because the study hospital administers approximately 5.9 million doses of medications per year, use of the bar code plus eMAR is expected to prevent approximately 95,000 potential ADEs at the point of medication administration every year in this medical center. The electronic Continued on page 6

COMMENTARY

Bar Code Medication Administration and Computerized Physician Order Entry: A Pharmacist’s Perspective By Mahro Ershadi, PharmD Director of Pharmacy, Suburban Hospital Healthcare System, Bethesda, Maryland

lthough bar code technology has been used widely in the pharmacy for dispensing medications, many new challenges are faced when the bar code technology and computerized physician order entry (CPOE) are used for medication administration at the patient’s bedside. This new technology requires every medication dispensed from the pharmacy to have a bar code that identifies the medication. The bar code allows for the correct medication to be dispensed based on an order in the CPOE. Most important, the bar code will identify the right patient for administering the prescribed medication. All this must be done in an effort to ensure patient safety.1,2 Obtaining medications with a manufacturer’s label that includes an identifying bar code is essential, when possible.3,4 However, many products do not come from the manufacturer with a bar code, for example, compounded products or admixtures. In addition,

December 2010 I VOL 3, NO 8

there are many instances when the manufacturer’s bar code is not readable by the facility’s scanner. The pharmacy also must be able to produce bar-coded labels when needed. It is essential to have an automated packager to produce bar-coded packages/labels for oral medication. For products that are compounded by the pharmacy (such as intravenous admixtures), a computergenerated label with bar code must be used.3-5 One of the challenges faced with bar coding is when the medication is switched from one manufacturer to another, which results in a change of the bar code and the information programmed for that specific medication. Thus, it becomes essential that as medications change, either due to manufacturer switch or shortage, the computer system is updated so the order entered via CPOE is linked to the right medication available in the pharmacy.3,4 Another challenge many pharmacies face is the readability of the bar

codes. All bar codes must be readable by the scanner the hospital chooses.3-5 Studies have found that manufacturers’ bar codes are sometimes the hardest to read.3 It is critical that the bar codes be readable; otherwise manual overrides at the patient’s bedside become the norm, as nurses cannot get bar codes to read properly and regularly. To ensure successful bar code implementation, the pharmacy must ensure that the following steps are taken: • Have resources to extemporaneously package and repackage products that are not available with bar-coded unit-dose packages • Ensure that all products leaving the pharmacy to patient care areas are bar coded • All automated systems for dispensing medications must be able to apply a bar code • The bar-coded labels must be attached carefully to avoid curvature of the container or crinkles

that would not allow the complete bar code to be scanned • Ensure that all products received from the manufacturer or distributor are scanned before adding the items to the inventory. This will assure that all items received match current products on the shelf • Ensure that each medication has a bar code linked to it in the computer system so it can be scanned. References 1. Traynor K. Details matter in bedside bar-code scanning. Am J Health Syst Pharm. 2004;61:1987-1988. 2. Section on Pharmacy Informatics and Technology, American Society of Health-System Pharmacists. ASHP statement on bar-code-enabled medication administration technology. Am J Health Syst Pharm. 2009;66:588-590. 3. Mims E, Tucker C, Carlson R, et al. Quality-monitoring program for bar-code-assisted medication administration. Am J Health Syst Pharm. 2009;66:1125-1131. 4. Paoletti RD, Seuss TM, Lesko MG, et al. Using barcode technology and medication observation methodology for safer medication administration. Am J Health Syst Pharm. 2007;64:536-543. 5. Helmons PJ, Wargel, LN, Daniels CE. Effect of barcode-assisted medication administration on medication administration errors and accuracy in multiple patient care areas. Am J Health Syst Pharm. 2009;66:1202-1210.

www.TheOncologyPharmacist.com

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Pharmacy Practice

Bar Coding: An Effective Strategy... order-entry system processed about 1.69 million medication orders during the study period. As a result, the system is also expected to prevent approximately 50,000 potential ADEs related to transcription errors.6 Whereas nurses and pharmacists often intercept errors made by physicians during the medication-ordering stage, errors made during the administration stage and, to a lesser extent, during the medication transcription stage often go undetected.3 This finding underscores the need for highly reliable strategies, such as bar code technology, to act as an additional safety component in medication administration and order transcription.6 Pharmacists’ role in dispensing medications is crucial in hospitals. The close integration of order-entry, pharmacy, and medication administration systems ensures that nurses administer medications only after pharmacists have reviewed the orders, providing patients with the added benefit of the pharmacists’ clinical knowledge.6 Preventing transcription errors is also vital. Factoring in the high number of doses administered and orders transcribed in acute care hospitals, implementation of a bar code plus eMAR system could significantly improve medication safety.6 The results of this study were similar to Bates and colleagues’ findings on CPOE, which reduced serious medication errors at the ordering stage by more

than 50%.4 Decision support embedded within CPOE systems is more likely to prevent errors that result from poor judgment, lack of knowledge, or incomplete clinical information when choosing a therapeutic plan. In contrast, a bar code plus eMAR system is more likely to prevent errors associated with memory lapses or mental slips in executing a therapeutic plan.6 My colleagues and I have suggested that these two technologies could play complementary roles in

The rate of potential ADEs (associated with nontiming errors) fell from 3.1% without the use of the bar code plus eMAR system to 1.6% with its use. improving medication safety in acute care. More research is needed to determine which of these two technologies should be implemented first, if an organization has to make that choice.6 In the current study, the rate of medication administration errors fell significantly, but not all the errors were eliminated. We offer two possible reasons. Patient safety technology is effective if it is used as intended. Whereas the study hospital expended substantial resources in the training of end users, 20% of the

Continued from page 4

drugs administered on units with the bar code plus eMAR technology were administered without the bar code scanning step during the study period. In addition, the study hospital used an early version of the software; several important improvements have been made since this study was conducted. In light of these issues, we recommend that deployment of HIT should be envisioned not as a single event in time but rather as an ongoing process that requires modifications and improvements.6 Multiple limitations of this study, however, warrant consideration. The study findings reflect the experience of one hospital that already has fully implemented CPOE for physicians and bar code verification for pharmacy staff. Hospitals considering implementation of a bar code plus eMAR technology without CPOE, pharmacy bar code verification, or both may observe a different outcome on the effect on administration errors. The study also examined potential ADEs, not actual ADEs. Furthermore, the study hospital worked closely with users and clinical leaders who were willing to support a significant change in workflow to improve the overall medication process.6 Healthcare organizations interested in using a bar code plus eMAR technology should take into account these factors and find strategies to implement the technology in the most cost-effective way.6 Bar code plus eMAR technology, in

my opinion, improves medication safety by reducing administration and transcription errors, providing support for its inclusion as a 2013 criterion for meaningful use of HIT under the American Recovery and Reinvestment Act of 2009. ● References 1. Brennan TA, Leape LL, Laird NM, et al. Incidence of adverse events and negligence in hospitalized patients: results of the Harvard Medical Practice Study I. N Engl J Med. 1991;324:370-376. 2. Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. JAMA. 1995;274:29-34. 3. Leape LL, Bates DW, Cullen CJ, et al. Systems analysis of adverse drug events. ADE Prevention Study Group. JAMA. 1995;274:35-43. 4. Bates DW, Leape LL, Cullen DJ, et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. JAMA. 1998;280:1311-1316. 5. Poon EG, Cina JL, Churchill W, et al. Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy. Ann Intern Med. 2006;145:426-434. 6. Poon EG, Keohane CA, Yoon CS, et al. Effect of barcode technology on the safety of medication administration. N Engl J Med. 2010;362:1698-1707. 7. Wright AA, Katz IT. Bar coding for patient safety. N Engl J Med. 2005;353:329-331. 8. Puckett F. Medication-management component of a point-of-care information system. Am J Health Syst Pharm. 1995;52:1305-1309. 9. McDonald CJ. Computerization can create safety hazards: a bar-coding near miss. Ann Intern Med. 2006; 144:510-516. 10. Koppel R, Wetterneck T, Telles JL, Karsh BT. Workarounds to barcode medication administration systems: their occurrences, causes, and threats to patient safety. J Am Med Inform Assoc. 2008;15:408-423.

Eileen Koutnik-Fotopoulos contributed to the preparation of this article.

HEALTHCARE REFORM

Cancer Society Science Officer... “Our life expectancy is starting to go age of the population. down in this country.” More attention needs to be focused Much of the money that goes to can- on lifestyle factors, he said. “Many peocer treatment could be saved, he said. ple don’t realize that obesity, a high Part of the problem is that increased caloric intake, and lack of physical screening is leading to canactivity causes cancer.” The cer diagnoses in patients United States faces a “tsunawho would otherwise be mi” of disease because of the untroubled by the disease. obesity epidemic, which is For example, many prostate particularly alarming among cancers progress so slowly children. “One in five kids they will never bother the aged 6 to 11 is obese,” he patient. “We are curing cansaid. “This is so important cer we don’t need to cure,” because obese kids hardly he said. ever lose weight.” He called for more supAs an example of how port for genetic and genomwell prevention can work, Otis W. Brawley, MD ic studies aimed at identifyBrawley cited lung cancer. ing the types of cancer most likely to About half of all men smoked in the metastasize. 1960s, and now the rate has dropped to Worldwide, the number of cancers about a quarter (women’s smoking rates diagnosed (currently about 11 million increased with women’s liberation in new cases per year) is increasing due to the 1960s and 1970s), as a result, morthree factors, said Brawley: better tality from lung cancer has declined detection, the adoption of a Western 14.3% since 1992. lifestyle, and the increasing size and The incidence of melanoma is increas-

December 2010 I VOL 3, NO 8

Continued from cover

ing, but sun avoidance and widebrimmed hats could cut it in half, Brawley said. He called for caution about sunscreen, however, because it may only prevent sunburn and not cancer. The incidence of colorectal cancer is declining. Fecal adult blood testing is the most important test for this cancer, said Brawley. Stool blood testing decreases the risk of death by 35%, he said, but very few people are getting this test. Still, people should get whatever kind of screening they can for this cancer. Surprising factors have affected other disease. For example, refrigeration has lowered stomach cancer rates because Americans are eating less meat preserved with salt, he said. Liver cancer, however, is increasing because one of 20 US men who served in Vietnam ended up positive for hepatitis B, said Brawley. Breast cancer deaths are also decreasing because better screening is catching this cancer earlier, and because treatments have improved, he said.

He stepped into the controversy over mammography, arguing in favor of the cancer society’s recommendation of screening all women older than 40. Women should be informed about the problem of false positives, but still get screened, he said. “If a third of women in their 40s don’t get screened, that means 4100 lives will be lost needlessly,” he said. He noted, however, that “breast self-exams will save more lives than mammography.” He pointed out that the disparity in survival rates between blacks and whites with both breast cancer and colon cancer had only emerged in the 1980s when better treatments became available. “This disparity is heavily driven by a disparity in treatment,” he said. So how can we wring the illogic out of healthcare? “I think we need to stress awareness,” Brawley said. “It’s a whole transformation of how we view healthcare.” ●

www.TheOncologyPharmacist.com

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The Official Newspaper for the Hem/Onc Pharmacist

Whoâ&#x20AC;&#x2122;s Your Nominee for

TOP

Pharmacist? The Oncology Pharmacist is pleased to announce the inaugural T.O.P. Pharmacist award. The award will recognize an oncology pharmacist nominated by his/her peers for an outstanding contribution to oncology pharmacy practice, research, or education in 2010. The four leading nominees will be profiled in the February issue of The Oncology Pharmacist. Readers will have an opportunity to vote for the winner online at www.TheOncologyPharmacist. com/award or by visiting The Oncology Pharmacist booth at the 2011 HOPA meeting. The winner will be announced in the April issue of The Oncology Pharmacist.

Nominate a pharmacist online at

www.TheOncologyPharmacist.com/award

TOP_December 2010_v4_TOP 11/16/10 3:03 PM Page 8

ARE YOU PREPARED?

TWO PRICE OPTIONS AVAILABLE

Totect® Kit (dexrazoxane) for injection is for intravenous infusion only. Totect is indicated for the treatment of extravasation resulting from intravenous anthracycline chemotherapy.

First and only FDA approved treatment for anthracycline extravasation. Supplied as a convenient and accessible complete three day treatment kit for single patient use, which should be proactively stocked on-site and infused as soon as possible and within 6 hours of an anthracycline extravasation. Demonstrates 98% overall efficacy based on two biopsy-confirmed clinical trials1,2 in reducing or avoiding surgical intervention (i.e., surgical debridement, plastic surgery and their related costs), thereby reducing postponement of a patient’s chemotherapy treatments and the avoidance of long-term consequences. Cited in nursing guidelines.3,4 Extravasation management is now a chemotherapy administration safety standard.5

For more information, call 866-478-8274 or visit our website at www.totect.com To order Totect®, contact one of our authorized distributors. ASD Healthcare Cardinal Specialty McKesson/OTN Oncology Supply US Oncology (800) 482-6700 (800) 633-7555 (888) 987-6679 (800) 746-6273 (866) 677-4844 1

Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane). Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550. 2 Totect® package insert. 3 Polovich M, White JM, Olsen, M (eds.). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (ed 3). Pittsburgh, PA, Oncology Nursing Society, 2009. 4 Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R. (eds). Infusion Nurses Society Infusion Nursing an Evidence-Based Approach (ed 3). Boston, MA, Infusion Nurses Society, 2009. 5 Jacobsen J., et al. American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards. Oncology Nursing Forum, 2009; 36:651-658. © 2010 Topotarget USA. All rights reserved. TOT0111/7-10 Totect and its logo mark are registered trademarks of Topotarget A/S Image is copyright © Photo Researchers, Inc. Pharma Chemo Ad 11x14FINAL 4 26 10 indd 1

7/21/10 10:56:51 AM

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Totect® – Brief prescribing information Please refer to the package insert for full prescribing information. Each Totect carton contains 10 vials of Totect® (dexrazoxane for injection) 500 mg and 10 vials of 50 mL diluent. Indication: Treatment of extravasation resulting from IV anthracycline chemotherapy. Dosage and administration: Totect is a cytotoxic drug. Vial contents must be mixed and diluted before use. Totect should not be mixed or administered with any other drug during the infusion. Administration of Totect should begin as soon as possible and within 6 hours following the anthracycline extravasation. Totect should be given as an intravenous (IV) infusion once daily for 3 consecutive days. The dose of Totect is based on the patient’s body surface area: day one, 1000 mg/m2; day two, 1000 mg/m2; day three, 500 mg/m2. For patients with a body surface area of > 2 m2, a dose of 2000 mg should be given on days 1 and 2, and a dose of 1000 mg should be given on day 3. Treatment on Day 2 and Day 3 should start at the same hour (+/- 3 hours) as on the first day. The Totect dose should be reduced 50% for patients with creatinine clearance values of <40 mL/minute. Cooling procedures such as ice packs should be removed from the affected area at least 15 minutes prior to Totect administration. Totect (dexrazoxane for injection) must be reconstituted with diluent supplied in the carton. The patient’s Totect dose is diluted in 0.9% 1000 mL NaCl prior to administration. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.3-5 Direct contact of Totect® with the skin or mucous membranes prior to and following reconstitution should be avoided. If contact occurs, wash immediately and thoroughly with water. Contraindications: None. Warnings and Precautions: Myelosuppression: treatment with Totect is associated with leukopenia, neutropenia, and thrombocytopenia. Hematological monitoring should be performed. Use in Pregnancy: Pregnancy Category D. Totect can cause fetal harm when administered to a pregnant woman. There is no adequate information about the use of Totect in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Adverse reactions: The most common adverse reactions (≥ 16%) are nausea, pyrexia, injection site pain and vomiting.

www.totect.com

Rx only

Totect® is a registered trademark of Topotarget A/S US Patent No. 6,727,253B2 NDC 38423-110-01

Drug Interactions: No drug interactions have been identified. Based on anecdotal reports concurrent use of topical dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the benefit of Totect. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treatment with topical DMSO decreases the efficacy of systemic dexrazoxane. Use in Specific Populations: Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. Renal Impairment: Reduce the Totect dose by 50% In patients with creatinine clearance values <40 mL/min. Pediatric Use: The safety and effectiveness of Totect in pediatric patients have not been established. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdosage: There are no data on overdosage. There is no known antidote for dexrazoxane. Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/m2 basis).

Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Hameln Pharmaceuticals GmbH 31789 Hameln Germany

Manufactured for: Topotarget A/S Fruebjergvej 3 DK-2100 Copenhagen Denmark

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CONTINUING EDUCATION PROGRAM P10060 • RELEASE DATE: SEPTEMBER 15, 2010 • EXPIRATION DATE: SEPTEMBER 15, 2011 ESTIMATED TIME TO COMPLETE: 1.0 HOUR

Implications of Recent Guideline Updates on the Management of Chemotherapy-induced Nausea and Vomiting TARGET AUDIENCE

This activity was developed for pharmacists who wish to enhance their competence concerning the treatment of patients with chemotherapy-induced nausea and vomiting (CINV). LEARNING OBJECTIVES

Upon completion of this activity, participants will be able to: • Describe recent advances and emerging therapies in the treatment of patients with CINV • Compare key recommendations from updated clinical practice guidelines for the management of CINV, including those established by ASCO, NCCN, MASCC, and ONS • Examine effective treatment strategies for preventing CINV and improving patient outcomes

hemotherapy, the mainstay of treatment for many patients with cancer, has prolonged countless lives, but is also associated with potentially serious side effects, including nausea and vomiting. Although chemotherapy-induced nausea and vomiting (CINV) is preventable in the majority of patients receiving emetogenic chemotherapy, approximately 70% to 80% still experience some form of symptoms.1 Uncontrolled CINV can impose a substantial burden on patients, affecting their daily functional activity and overall quality of life.2 It may also lead to poor treatment adherence, delays in life-saving therapy, and increased healthcare costs and resource utilization.1,2 PHARMACISTS DESIGNATION

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 04689999-10-042-H01-P. INSTRUCTIONS FOR CREDIT

1. Read the article in its entirety 2. Log on to www.TheOncologyPharmacist.com 3. Select “Continuing Education” 4. Click on this article’s title from the list shown 5. Select “Click here to complete the posttest and obtain a CE certificate online” 6. Complete and submit the CE posttest and CE Activity Evaluation 7. Print your Statement of Completion

December 2010 I VOL 3, NO 8

There are several barriers to the optimal control of CINV that must be identified and addressed. An ongoing challenge is the tendency of health providers to underestimate the incidence of CINV, particularly with regard to delayed symptoms.3,4 There also appears to be a gap in knowledge regarding the latest evidence-based CINV guidelines from organizations such as the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN), and the Multinational Association of Sup portive Care in Cancer (MASCC).3 Although these recommendations have limitations, they provide an important framework for delivering high-quality supportive care and are often linked to Medicare reimbursement or other thirdparty payment.5 To improve patient outcomes, clinicians must be aware of the most recent CINV guidelines, as well as safety and efficacy data regarding novel antiemetic agents and regimens. This knowledge, combined with the implementation of accurate patient-assessment tools and careful consideration of cost and reimbursement issues, will allow for prudent evidence-based decisions that will minimize complications, thereby reducing the burden and cost of uncontrolled CINV. Burden and cost of CINV CINV can negatively impact a patient’s quality of life and lead to potenThis activity is provided free of charge to participants. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. FACULTY DISCLOSURES

Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. The associates of Medical Learning Institute, Inc., and Center of Excellence Media, LLC, have no financial relationships to disclose. Sally Barbour, PharmD, BCOP, CPP, has nothing to disclose.*

tially serious physiologic consequences, including metabolic imbalances, nutrient depletion, anorexia, esophageal tears, wound dehiscence, and degeneration of functional ability and self-care.1 Furthermore, uncontrolled CINV may result in diminished adherence to chemotherapy treatment and delays in, or withdrawal from, potentially beneficial or curative anticancer therapy.1,2 In a recent study of patients receiving cisplatin-based chemotherapy, more than 90% of those who experienced both acute and delayed CINV reported that it had an impact on their daily lives.6 According to a report by Shih and colleagues, working-age patients with

CINV can negatively impact a patient’s quality of life and lead to potentially serious physiologic consequences. uncontrolled CINV lost nearly 3 more work days than patients with controlled CINV, and incurred direct medical costs per patient per month of more than $1300 (30% higher) than patients with controlled CINV.7 In addition, indirect monthly costs per patient were $433 higher for those in the uncontrolled CINV group.7

Furthermore, a 4-year retrospective cohort study based on data from 19,139 patients treated at 256 outpatient hospital facilities was conducted to determine CINV-associated costs and healthcare visits following an initial cycle of highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC).8 All patients received at least one antiemetic agent on the chemotherapy administration visit, per the inclusion criteria. Results of this study revealed that 2641 patients (13.8%) required a CINV-related follow-up hospital visit after the first cycle of HEC or MEC.8 The estimated mean cost of the hospital visit was $5300 (or $750 when averaged across all patients with and without a visit), and costs were highest for patients receiving HEC. Moreover, nearly all hospital visits took place during the delayed CINV phase following chemotherapy. Uncontrolled CINV not only imposes a significant clinical and economic burden on patients, but it also has an adverse economic impact on oncology practices, as demonstrated in a study by Vanscoy and colleagues.9 Their analysis of data from 20 community oncologist practices showed that managing one extreme CINV event required an average of 255 minutes of labor time—the equivalent of approximately $175 (2005 dollars).9 In this study, the definition of an extreme CINV event included: nausea or vomiting coded as a grade 2 or higher toxicity; visits to the oncol-

Carrie Tompkins Stricker, PhD, RN, has nothing to disclose.*

COMMERCIAL SUPPORT ACKNOWLEDGMENT

*Content will include non–FDA-approved uses.

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

PEER REVIEWER

Jayshree Shah, RN, APN-C, MSN, BSN, BS, is on the speaker’s bureau for Bristol-Myers Squibb, Celgene, Merck, and Novartis, and is on the advisory board for Bristol-Myers Squibb and Novartis. DISCLAIMER

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. SPONSOR

FACULTY

Sally Barbour, PharmD, BCOP, CPP Clinical Oncology Pharmacist Duke Comprehensive Cancer Center Pharmaceutical Research Service/Duke Cancer Care Research Program Durham, NC Carrie Tompkins Stricker, PhD, RN Oncology Nurse Practitioner Clinical Assistant Professor of Nursing Abramson Cancer Center University of Pennsylvania Philadelphia, PA

This activity is jointly sponsored by Medical Learning Institute, Inc., a non-profit medical accreditation company, and Center of Excellence Media, LLC.

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www.TheOncologyPharmacist.com ogy practice for rescue medication within 2 to 5 days postchemotherapy; unscheduled hydration or office visits due to CINV; phone calls complaining of symptoms; or documented switching of outpatient antiemetics on days 2 to 5 after chemotherapy.9 Challenges in the treatment of CINV Investigators have identified several barriers to optimal CINV control, including the underestimation of CINV

may not remember to bring their prescribed oral therapies on the scheduled day of chemotherapy. It is important for providers to have the ability to administer IV antiemetics in such situations.12 Coverage and clinical decisions should support the antiemetic formulation that most effectively prevents CINV at the outset, thereby potentially reducing delayed adverse outcomes and associated costs. In this respect, clinicians play an important role in address-

Coverage decisions that limit the discretion of healthcare providers to prescribe specific formulations of antiemetics present other challenges. by clinicians and the underreporting of symptoms by patients. According to results of a study by Grunberg and colleagues, more than 75% of physicians and nurses underestimated the incidence of delayed CINV following HEC and MEC, although they accurately predicted the incidence of acute CINV.4 The discrepancy between the perceived and actual incidence of CINV may be partly explained by the fact that patients are often at home when they experience delayed nausea and vomiting and may not report these symptoms. Underutilization of and noncompliance with practice guidelines are further barriers to optimal control of CINV.10 These guidelines are designed to help physicians deliver high-quality care; however, this goal can only be achieved through adherence to their recommendations.10 In particular, there is a marked need to implement more effective strategies for the management of delayed CINV. The prevention of CINV in patients receiving multiday chemotherapy also remains challenging, since these individuals are at risk for both acute and delayed CINV, based on the emetogenic risk and sequence of agents.1,11 Coverage decisions that limit the discretion of healthcare providers to prescribe specific formulations of antiemetics present other challenges.12 Studies have shown that, in general, oral antiemetic formulations are equivalent to intravenous (IV) formulations.1 With evidence to support the bioequivalence of one antiemetic formulation with another, the argument could be made that withholding the IV formulation until the patient has demonstrated failure on the oral formulation would appear to be costeffective and prudent. However, this strategy may result in unintended adverse consequences. For example, consistent adherence to oral antiemetic regimens may be challenging for patients who may already be taking several other medications. In addition, most private-practice and hospital-based providers do not dispense oral medications, and patients

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ing policy, cost, and reimbursement issues that may limit a patientâ&#x20AC;&#x2122;s access to optimal antiemetic therapies. Goals and strategies for effective CINV control Before deciding on an antiemetic strategy, clinicians must consider the type of CINV being targeted, individual patient risk factors, and the specific chemotherapeutic agents being administered. There are five classifications of CINV, as shown in Table 1.1 Addressing the specific variables and concerns related to each classification is essential for reducing morbidity and increasing the likelihood that patients will be able to complete chemotherapy. Several patient factors may influence the occurrence and severity of CINV.1,13,14 In general, patients who are female, younger than 50 years of age, and on HEC regimens are at greater risk for developing CINV, as are individuals who have previously experienced episodes of nausea and vomiting. Other risk factors include high tumor burden, history of motion sickness, opioid use for pain management, and alcohol use in patients who

Antiemetic treatment should be initiated before chemotherapy begins in order to provide maximum protection against symptoms.

are unaccustomed or sensitive to alcohol. Conversely, patients with a history of chronic alcoholism have a decreased risk of emesis.1,14 Clinicians must also consider potential nonchemotherapy-related causes of emesis, including bowel obstruction, vestibular dysfunction, electrolyte imbalance, brain metastasis, concomitant drugs, uremia, anxiety, or other factors.1

It is essential to know the emetogenic risk level of the chemotherapy agents being used.1 These levels are defined as: high risk (>90%), moderate risk (30%90%), low risk (10%-30%), and minimal risk (<10%) (Table 2). When selecting an antiemetic therapy, the emetogenicity of a chemotherapeutic agent or combination should be the dominant consideration.2 The toxicity of the antiemetic agents and potential drugâ&#x20AC;&#x201C;drug interactions should also be considered.2,15 Antiemetic treatment should be initiated before chemotherapy begins in order to provide maximum protection against symptoms and avoid CINV-related complications.1 Antiemetic agents exert their effects differently during the course of emesis and work synergistically with other antiemetics.1 Because these agents inhibit different pathways and a final common pathway has not yet been identified, no single antiemetic agent can be expected to provide complete protection throughout the different phases of emesis associated with chemotherapy.1 Antiemetic regimens should protect patients throughout the full period of anticipated CINV; the risk of CINV is at least 3 days for HEC and 2 days for MEC after the last dose of chemotherapy.1 For multidrug chemotherapy regimens, antiemetic therapy should be selected according to the agent with the highest emetogenic risk.1 The potential for anticipatory CINV in patients who have a poor initial experience with CINV increases the likelihood of symptoms with subsequent chemotherapy cycles. Thus, it is important to achieve optimal care with the first cycle of treatment.12 Optimizing control of CINV also requires that clinicians are aware of the most recent practice guidelines, and are willing to integrate these recommendations into everyday clinical practice. Adherence to the guidelines should be accompanied by accurate assessment of CINV symptoms through appropriate tools and better communication with patients after they leave the clinic. Advances in the treatment of CINV Over the past several decades, dramatic progress has been made in the supportive care of patients receiving chemotherapy. This is due largely to the introduction of more effective and better-tolerated antiemetic therapies. To date, serotonin subtype-3 receptor antagonists (5-HT3 RAs) and neurokinin-1 receptor antagonists (NK-1 RAs) appear to be among the most effective agents.2 Serotonin receptor antagonists The development of 5-HT3 RAs has marked a significant advancement in the treatment of CINV, and clinical data support the effectiveness of these agents.1 The 5-HT3 RAs that represent

Table 1 Classifications of CINV Acute CINV Occurs within minutes to several hours after drug administration. Usually resolves within the first 24 hours. Intensity generally peaks after 5 to 6 hours. Delayed CINV Develops in patients >24 hours after administration of chemotherapy. Occurs commonly after administration of cisplatin,a carboplatin, cyclophosphamide, and/or doxorubicin. Anticipatory CINV Occurs before patients receive their next chemotherapy treatment. Occurs after a negative past experience with chemotherapy. Nausea is generally more common than vomiting. Breakthrough CINV Occurs despite prophylactic treatment and/or requires rescue with antiemetic agents. Refractory CINV Occurs during subsequent treatment cycles in cases in which antiemetic prophylaxis and/or rescue failed in earlier cycles. a

Cisplatin-associated emesis reaches maximal intensity 48 to 72 hours after administration and may last 6 to 7 days. Source: Reference 1.

the cornerstone of prophylactic therapy for MEC and HEC include: dolasetron, granisetron, ondansetron, and palonosetron.2,16,17 These antiemetic agents have few adverse effects and no limiting toxicity at standard doses, with the most common side effects being headache, transient elevation of hepatic aminotransferase levels, and constipation.2 Dolasetron, granisetron, and on dansetron are effective in preventing acute emesis, but are relatively ineffective against delayed emesis, whereas palonosetron has been shown to prevent both.1 Based on a retrospective claims review of patients with lung cancer receiving cisplatin-based chemotherapy between 2005 and 2008, the group treated with palonosetron experienced a significantly lower risk for costly CINV than patients treated with any other 5-HT3 RA.18 Because of its efficacy in both acute and delayed CINV, palonosetron may also be effective in multiday chemotherapy and bone marrow transplantation settings. Further research will shed light on its potential in these areas.19 Neurokinin-1 receptor antagonists NK-1 RAs represent a relatively new Continued on page 12

December 2010 I VOL 3, NO 8

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CONTINUING EDUCATION Continued from page 11

Implications of Recent Guideline Updates on the Management of Chemotherapy-induced Nausea and Vomiting Investigational Agents and Novel Formulations for CINV

• An intranasal granisetron spray is being evaluated in phase 1 clinical trials.1

Table 2 Emetogenic Risk Levels of Intravenous Chemotherapeutic Agents Based on NCCN Guidelines Riska Level

Agents

High risk (>90%)

AC combination (doxorubicin or epirubicin with cyclophosphamide) Carmustine (>250 mg/m2) Cisplatin (≥50 mg/m2)

Cyclophosphamide (>1500 mg/m2) Dacarbazine Mechlorethamine Streptozocin

Moderate risk (30%-90%)

Aldesleukin (>12 million-15 million IU/m2) Altretamine Amifostine (>300 mg/m2) Arsenic trioxide Azacitidine Bendamustine Busulfan Carboplatin Carmustine (≤250 mg/m2)

Cisplatin (<50 mg/m2) Clofarabine Cyclophosphamide (≤1500 mg/m2) Cytarabine (>200 mg/m2) Dactinomycin Daunorubicin Doxorubicin Epirubicin Mechlorethamine Streptozocin

Idarubicin Ifosfamide Interferon alpha (≥10 million IU/m2) Irinotecan Melphalan Methotrexate (250 - >1000 mg/m2) Oxaliplatin Temozolomide

Low risk (10%-30%)

Amifostine (≤300 mg) Aldesleukin (≤12 million IU/m2) Cytarabine (low dose) (100-200 mg/m2) Docetaxel Doxorubicin (liposomal) Etoposide 5-Fluorouracil

Paclitaxel Paclitaxel, albumin-bound Pemetrex Pentostatin Romidepsin Topotecan

Minimal risk (<10%)

Alemtuzumab Asparaginase Bevacizumab Bleomycin Bortezomib Cetuximab Cladribine (2-chlorodeoxyadenosine) Cytarabine (<100 mg/m2) Decitabine

Floxuridine Gemcitabine Interferon alpha (>5 - <10 million IU/m2) Ixabepilone Methotrexate (>50 - <250 mg/m2) Mitomycin Mitoxantrone Denileukin diftitox Dexrazoxane Fludarabine Gemtuzumab ozogamicin Interferon alpha (≤5 million IU/m2) Methotrexate (≤50 mg/m2) Nelarabine Panitumumab

• An oral ondansetron spray is being investigated in Europe.2 • A transdermal gel containing lorazepam, diphenhydramine, and haloperidol (referred to as ABH gel) is being evaluated in small pilot studies as a rescue therapy for breakthrough CINV.3 • In July 2010, the US Food and Drug Administration approved an ondansetron orally dissolving film strip, which is indicated for the prevention of CINV associated with HEC and MEC.4 This formulation is intended for patients who have difficulty swallowing, as well as those who cannot retain tablets in the gastrointestinal system long enough for them to fully dissolve. • A new ginger capsule to treat CINV is currently being evaluated in phase 2/3 clinical trials.5 References 1. Almac Discovery announces commencement of phase I trials of granisetron nasal spray. Medical News Today. www.medicalnewstoday.com/articles/ 174130.php. 2. BioAlliance acquired European rights for ondansetron oral spray to complement its franchise in cancer supportive care from NovaDel Pharma Inc. Medical News Today. www.medicalnewstoday.com/ articles/108166.php. 3. Bleicher J, Bhaskara A, Huyck T, et al. Lorazepam, diphenhydramine, and haloperidol transdermal gel for rescue from chemotherapy-induced nausea/vomiting; results of two pilot trials. J Support Oncol. 2008;6(1):27-32. 4. FDA approves Strativa Pharmaceuticals’ Zuplenz® (ondansetron) Oral Soluble Film. Medical News Today. www.medicalnewstoday.com/articles/193766. php. 5. Aphios announces presentation of phaseI/III clinical trial data on Zindol® for cancer chemotherapy induced nausea. Medical News Today. www.medical newstoday.com/articles/151593.php.

class of antiemetic drugs. These agents have been shown to be effective in preventing acute and delayed CINV associated with MEC and HEC when combined with a 5-HT3 RA and dexamethasone.1,14,20 The NK-1 RAs aprepitant and fosaprepitant dimeglumine (an IV version of aprepitant) work by selectively inhibiting the binding of substance P at the NK-1 receptor, thereby providing a different mechanism of action than other antiemetic agents. In a phase 3 randomized, controlled trial, aprepitant demonstrated a benefit when added to antiemetic regimens for 3 platinum agents—cisplatin, carboplatin, and oxaliplatin—with a lesser magnitude of benefit for the oxaliplatin regimen.21 Another study showed that without aprepitant administration, 20% of patients receiv-

December 2010 I VOL 3, NO 8

Pegaspargase Rituximab Temsirolimus Trastuzumab Valrubicin Vinblastine Vincristine Vinorelbine

Risk = frequency of emesis in the absence of antiemetic prophylaxis. Source: Reference 1.

Table 3 Antiemetic Practice Guidelines: Web-based Resources Resource American Society of Clinical Oncology Multinational Association for Supportive Care in Cancer National Comprehensive Cancer Network

Website www.asco.org

Location in Website Practice & Guidelines (Supportive Care and Quality of Life)

www.mascc.org

Guidelines & Tools

www.nccn.org

Guidelines & Clinical Resources

Oncology Nursing Society

www.ons.org

Clinical Practice (Symptom Management)

ing carboplatin-containing regimens had moderate-to-severe delayed CINV.22 Furthermore, a retrospective cohort study of 3110 patients from 30 community-based oncology clinics showed that the type of chemotherapy regimen, younger age, and female gender were associated with a greater risk of CINV following HEC or MEC, whereas aprepitant use was associated with a decreased risk of CINV (16.2% for aprepitant users vs 21% for nonaprepitant users [P = .71]), suggesting that increased aprepitant use in HEC/ MEC may diminish CINV.23

Corticosteroids and other antiemetic agents First introduced more than 25 years ago, corticosteroids, including dexamethasone, continue to be used widely to prevent CINV.16 These drugs are effective as single agents in patients receiving chemotherapy with a low emetogenic risk.2 The addition of dexamethasone to antiemetic combinations containing 5HT3 RAs has also been shown to improve the efficacy of these regimens.1,2 Other antiemetic treatments that have been used for CINV include antihistamines, phenothiazines, substituted benza-

mides, butyrophenones, benzodiazepines, and cannabinoids.1 Olanzapine (an atypical antipsychotic agent) and gabapentin (GABA analogue/anticonvulsing agent) are currently being investigated for CINV.24,25 In a small phase 2 trial, olanzapine was shown to be effective for acute and delayed emesis in patients who received cyclophosphamide, doxorubicin, and/or cisplatin.1 Caution is recommended when using olanzapine in elderly patients, in accordance with the agent’s black box warning.1 Gabapentin is being studied in phase 3 studies to evaluate its efficacy in preventing CINV.26

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www.TheOncologyPharmacist.com Table 4 Updated Guidelines/Recommendations for CINV Emetogenicity NCCN (2010) High Acute Any 5-HT3 RA PLUS dexamethasone PLUS NK-1 RA

ASCO (2006)

MASCC (2010)

Any 5-HT3 RA PLUS dexamethasone PLUS NK-1 RA

Dexamethasone PLUS NK-1 RA

Any 5-HT3 RA PLUS dexamethasone PLUS NK-1 RA

Any 5-HT3 RA PLUS dexamethasone

Dexamethasone PLUS NK-1 RA

NK-1 RA

5-HT3 RA PLUS dexamethasone PLUS NK-1 RA NK-1 RA

Any 5-HT3 RA PLUS dexamethasone OPTIONAL NK-1 RA Dexamethasone OR first-generation 5-HT3 RA OR NK-1 RA ± dexamethasone

Any 5-HT3 RA PLUS dexamethasone

5-HT3 (palonosetron preferred) PLUS dexamethasone

Dexamethasone OR 5-HT3 RA

Dexamethasone

Dexamethasone OR metoclopramide OR prochlorperazine

Dexamethasone

Dexamethasone OR 5-HT3 RA OR dopamine antagonist

Delayed

None

Minimal Acute

No scheduled prophylaxis

Delayed

No scheduled prophylaxis

Delayed AC Regimens Acute Delayed Moderate Acute

Delayed

Low Acute

5-HT3 RA indicates serotonin subtype-3 receptor antagonist; AC, anthracycline plus cyclophosphamide; ASCO, American Society of Clinical Oncology; CINV, chemotherapy-induced nausea and vomiting; MASCC, Multinational Association for Supportive Care in Cancer; NCCN, National Comprehensive Cancer Network; NK-1 RA, neurokinin-1 receptor antagonist. Sources: References 1, 27, and 29.

Several novel delivery systems, including sprays, gels, and dissolving strips, as well as new compounds, are also in development in the United States and Europe (see sidebar). Implications of recent guideline updates for CINV Clinical practice guidelines, including those established by NCCN, ASCO, and MASCC, provide clinicians with valuable evidence-based resources for the management of CINV. The NCCN practice guidelines were updated in April 2010 by a panel of experts that included physicians, pharmacists, and nurses.1 These guidelines are revised as often as several times a year in order to incorporate the latest scientific data. New MASCC practice guidelines also became available earlier this year.27 The ASCO clinical practice guidelines, which were last updated in 2006, are in the process of being revised.28 In addition, the Oncology Nursing Society publishes a resource titled Putting Evidence Into Practice: Evidence-Based Interventions to Prevent, Manage, and Treat Chemotherapy-Induced Nausea and Vomiting.15 Practice guidelines, as well as other CINV-related resources, can be accessed via each of the society’s websites (Table 3). Key recommendations for the treatment of acute and delayed CINV, based on the latest NCCN, ASCO, and MASCC guidelines, are shown in Table 4.1,27,29 All three organizations stress that

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prevention is the overarching goal of antiemesis. Furthermore, they all concur that at biologically equivalent doses, the oral and IV antiemetic formulations have equivalent efficacy.

In its April 2010 guidelines update, NCCN changed the format of the emesis prevention algorithm for MEC by separating day 1 from days 2 and 3. For acute CINV in patients receiving both HEC and MEC, the combination of a 5-HT3 RA, dexamethasone, plus an NK-1 RA is recommended (aprepitant or fosaprepitant is specified in the MASCC and NCCN guidelines). To prevent delayed CINV in patients receiving HEC, the MASCC, NCCN, and ASCO guidelines all recommend dexamethasone plus aprepitant. To prevent delayed CINV in patients receiving a combination of anthracycline plus cyclophosphamide (AC regimen), the guidelines from all 3 societies recommend treatment with aprepitant. The 2010 version of the MASCC guidelines includes the following changes27,30: • For acute CINV in patients receiving non-AC regimens of MEC, palonosetron is specifically recom-

mended, with dexamethasone. The previous MASCC guidelines (2008 version) included a general 5-HT3 RA recommendation plus dexamethasone. • In patients with delayed CINV receiving an AC regimen, aprepitant alone is recommended. The 2008 guidelines recommended aprepitant or dexamethasone. • For acute CINV in patients receiving AC regimens, a 5-HT3 RA with dexamethasone and aprepitant or fosaprepitant is recommended. If aprepitant is not available, palonosetron plus dexamethasone is recommended. In addition, in its April 2010 guidelines update, NCCN changed the format of the emesis prevention algorithm for MEC by separating day 1 from days 2 and 3.1 Future directions and ongoing challenges The guidelines for preventing and treating CINV represent valuable clinical tools for implementing evidencebased practices. Application of these guidelines must be accompanied by accurate patient self-assessment of symptoms throughout the duration of CINV risk.5 It is important for clinicians to ask patients the appropriate questions and provide them with the most effective assessment tools. In addition, there is an ongoing need for better strategies to monitor patients more closely after

they leave the clinic. In the future, research will likely focus on topics such as CINV induced by high-dose chemotherapy; the prevention of cisplatin-induced delayed CINV; and better control of nausea—an important emetogenic challenge that is a different phenomenon than vomiting.30 Further studies are also needed to address current guideline limitations with respect to multiday chemotherapy regimens, combination chemotherapy, and patients who do not respond to initial antiemetic regimens. Nevertheless, based on the evidence, knowledge, and clinical judgment factored into these guidelines, adherence is a worthy attempt to deliver optimal patient care.10 Clinicians must continue to advocate for patients to ensure they receive the most effective antiemetic agents during the appropriate therapeutic window. They must also work with patients to address any cost or reimbursement issues that present barriers to treatment. Conclusion CINV is preventable in the majority of patients receiving chemotherapy.12 How ever, improved therapeutic interventions are needed, particularly for patients with delayed CINV. Ideally, an antiemetic therapy should provide adequate protection for the patient throughout the anticipated period of nausea and vomiting.5,14 Barriers to the optimal treatment of CINV are surmountable when Continued on page 14

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Implications of Recent Guideline Updates on the Management of Chemotherapy-induced Nausea and Vomiting the appropriate proactive steps are taken. Strategies for improving control of CINV include selecting the most effective therapy, integrating evidencebased guidelines into everyday practice, and using tools and resources to closely monitor patients concerning the intensity and duration of their symptoms. Moreover, it is important for clinicians to remain current on updates to the clinical practice guidelines. ● Loretta Fala assisted in the development of this article. References 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Antiemesis, V.2.2010. April 7, 2010. http://www.nccn.org/profession als/physician_gls/PDF/antiemesis.pdf. Accessed August 6, 2010. 2. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-2494. 3. Hawkins R, Grunberg S. Chemotherapy-induced nausea and vomiting: challenges and opportunities for improved patient outcomes. Clin J Oncol Nurs. 2009;13(1):54-64. 4. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer. 2004;100(10):2261-2268. 5. Wickham R. Best practice management of CINV in oncology patients: II. Antiemetic guidelines and ration-

ale for use. J Support Oncol. 2010;8(2 suppl 1):10-15. 6. Ballatori E, Roila F, Ruggeri B, et al. The impact of chemotherapy-induced nausea and vomiting on healthrelated quality of life. Support Care Cancer. 2007;15 (20):179-185. 7. Shih Y-CT, Xu Y, Elting LS. Costs of uncontrolled chemotherapy-induced nausea and vomiting among working-age cancer patients receiving highly or moderately emetogenic chemotherapy. Cancer. 2007;110 (3):678-685. 8. Burke TA, Wisniewski T, Ernst FR. Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting [published online ahead of print January 26, 2010]. Support Care Cancer. 9. Vanscoy GJ, Fortner B, Smith R, et al. Preventing chemotherapy-induced nausea and vomiting: the economic implications of choosing antiemetics. Community Oncol. 2005;2(2):127-132. 10. Grunberg SM. Obstacles to the implementation of antiemetic guidelines. J Natl Comp Cancer Network. 2009;7(5):601-605. 11. Ettinger DS. Nausea and vomiting with multi-day chemotherapy. From: Recent advances in the management of chemotherapy-induced nausea and vomiting: a case study compendium. Clinical Advances in Hematology & Oncology. 2010;8(5)(suppl 9):12-14. 12. Hesketh P. Penny wise, dollar foolish approach to antiemetic use may compromise patient care. American Society of Clinical Oncology. September 2009. http://jop. ascopubs.org/content/5/5/221.full.pdf. Accessed August 9, 2010. 13. Wiser W, Berger A. Practical management of chemotherapy-induced nausea and vomiting. Oncology. 2005; 19(5):637-645.

14. Georgy A, Neceskas J, Goodin S. Antiemetic treatment in patients with breast cancer: focus on drug interactions and safety concerns. Am J Health Syst Pharm. 2007;64(21):2227-2236. 15. Tipton JM, McDaniel RW, Barbour L, et al. Putting evidence into practice: evidence-based interventions to prevent, manage, and treat chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs. 2007;11(1):69-78. 16. Schwartzberg LS. Chemotherapy-induced nausea and vomiting: which antiemetic for which therapy? Oncology (Williston Park). 2007;21(8):946-953. 17. Michaud LB. Controlling chemotherapy-induced nausea and vomiting—a new antiemetic delivery system. HemOnc Today Website. Epub March 25, 2009. http:// www.hemonctoday.com/article.aspx?rid=38195. Accessed August 7, 2010. 18. Hatoum HT, Lin S, Buchner D, Cox D. Chemotherapy-induced nausea and vomiting-associated hospital and ER visits in real-world practice: palonosetron versus other 5-HT3-RA anti-emetic regimens. J Clin Oncol. 2010;28(15 suppl). Abstract 9127. 19. Navari RM. Palonosetron for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer. Future Oncol. 2010;6(7):1073-1084. 20. Emend® capsules [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2010. 21. Gralla RJ, Rapoport BL, Jordan K, et al. Assessing the magnitude of antiemetic benefit with the addition of the NK1 receptor antagonist (NK1) aprepitant for all platinum agents: analysis of 1,872 patients in prospective randomized clinical phase III trials (RCTs). J Clin Oncol. 2010;28(15 suppl). Abstract 9057. 22. Pflederer C, Goodgame BW, Morgensztern D, et al. A prospective study on the incidence of delayed nausea and vomiting following administration of carboplatincontaining regimens for treatment of cancer without

prophylactic aprepitant. J Clin Oncol. 2010;28(15 suppl). Abstract e19552. 23. Gilmore JW, Feinberg BA, Wisniewski T, et al. Risk factors for nausea and vomiting (NV) following highly or moderately emetogenic chemotherapy (HEC or MEC) in U.S. community oncology practice. J Clin Oncol. 2010;28(15 suppl). Abstract e19531. 24. Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology Group study. Support Care Cancer. 2005;13(7):529-534. 25. Lohr L. Chemotherapy-induced nausea and vomiting. Cancer J. 2008;14(2):85-93. 26. National Institutes of Health. CINV clinical studies—gabapentin. ClinicalTrials.gov. http://clinicaltrials. gov/ct2/show/NCT00880191?term=gabapentin+ANd+ CINV&rank=1. Accessed August 10, 2010. 27. Multinational Association of Supportive Care in Cancer. Antiemetic Guidelines (English). Updated April 2010. www.mascc.org/mc/page.do?sitePageId=88041. Accessed August 10, 2010. 28. American Society of Clinical Oncology (ASCO). Original guidelines and guideline updates in progress. Updated October 6, 2009. www.asco.org/ASCO/Down loads/Cancer%20Policy%20and%20Clinical%20Affairs /Clinical%20Affairs%20%28derivative%20prod ucts%29/Guidelines%20in%20Progress%2010.6.09.pdf. Accessed August 11, 2010. 29. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: update 2006. J Clin Oncol. 2006;24:2932-2947. 30. Roila F, Herrstedt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232-v243.

COMMENTARY

Improving Outcomes for Chemotherapyinduced Nausea and Vomiting: A Pharmacist’s Perspective By Sally Barbour, PharmD, BCOP, CPP Duke Comprehensive Cancer Center, Durham, North Carolina

hemotherapy-induced nausea and vomiting (CINV) is still one of the most dreaded side effects of systemic cancer treatment and is a cause of great distress for numerous patients.1 Nausea, specifically, remains a symptom that is often ranked high on the list of patient concerns related to their treatment. In a recent survey of women receiving cisplatin-based chemotherapy for gynecologic malignancies, the potential of uncontrolled CINV ranked just above death.2 Although we have witnessed significant advances in the prevention and management of CINV over the past 10 years, some patients still experience symptoms. Etiology/pathophysiology of CINV Recent insights into the causes of nausea and vomiting have led to the development of novel antiemetic agents and a more comprehensive approach to prevention and treatment. The etiology of CINV is multifactorial, and is the end result of a complex network of pathways,

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neurotransmitters, and receptors. It follows that the most effective approach to the management of CINV is to utilize agents with different mechanisms of action that can target these various areas. There are three main components to the emetic reflex: the emetic or vomit-

Recent insights into the causes of nausea and vomiting have led to the development of novel antiemetic agents.

ing center; the chemoreceptor trigger zone (CTZ); and visceral afferent nerve fibers of the small intestine. The vomiting center is not an anatomically distinct area, but rather several regions in the brainstem that coordinate input from multiple sources, such as the gas-

trointestinal tract, the cortical system, and the CTZ (Figure). Upon receiving this input, the vomiting center activates the salivary receptors, respiratory center, and vasomotor centers, as well as the cranial nerves. These areas provide the final efferent output to the abdominal muscles, stomach, diaphragm, and esophagus, resulting in emesis. The second component of the emetic reflex, the CTZ, is located in the area postrema in the floor of the fourth ventricle. Located outside of the blood– brain barrier, the CTZ can detect toxins in the blood, such as chemotherapeutic agents. The third component, visceral afferent nerve fibers, originate from the small intestine. These appear to have the greatest role in CINV, and a variety of receptors, including serotonin subtype-3 (5-HT3) and neurokinin-1 (NK1) receptors, are located on their terminal ends.3-5 Serotonin receptors, which are located both centrally and peripherally, have been shown to play a key role in the

modulation of acute CINV. NK-1 receptors, which are widely distributed throughout the central nervous system, as well as in peripheral sites such as the gastrointestinal tract, also play a significant role, especially in the delayed phase of CINV.4,6 Therefore, some of the most effective agents currently being used in the prevention and treatment of CINV target these receptors. The evolving role of 5-HT3 receptor antagonists The development of 5-HT3 receptor antagonists (RAs) has had a significant impact on the management of CINV, and the utility of these agents has been demonstrated in patients receiving numerous types of chemotherapy regimens.7-10 Currently, there are four 5-HT3 RAs available for use in the United States: the first-generation agents, dolasetron, ondansetron, and granisetron, and the second-generation agent, palonosetron. These drugs have minimal toxicities when used at recom-

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www.TheOncologyPharmacist.com mended doses, with the most commonly observed adverse events being headache and constipation.8-10 Transient elevations in hepatic enzymes and potential QTc prolongation have also been reported in some patients.8-10 All of these 5-HT3 RAs are recommended for the prevention of acute CINV, with palonosetron also having data to support its use in the management of delayed CINV.8-10 Dolasetron is available as both an intravenous (IV) and oral formulation. Ondansetron is approved in a variety of oral formulations as well as an injectable formulation. Granisetron can be administered as either an oral or injectable formulation, and was also recently approved as a transdermal patch, indicated for 5 consecutive days of therapy. Both oral and IV formulations of palonosetron have been approved by the US Food and Drug Administration; however, only the injectable formulation is currently available in the United States. Single-dose schedules of 5-HT3 RAs are as effective as multidose schedules, and the oral formulations are therapeutically equivalent to the IV formulations.4,8-10 Although the advent of dolasetron, ondansetron, and granisetron represents a significant advance in the prevention and treatment of acute CINV, the efficacy of these agents in the delayed CINV setting is minimal with highly emetogenic chemotherapy (HEC) and modest, at best, with moderately emetogenic chemotherapy (MEC).11 Therefore, these drugs are not recommended for delayed CINV associated with HEC in the most recent CINV guidelines; however, they do remain an option for delayed emesis in patients receiving MEC. Palonosetron differs from first-generation agents in that it has a 100-fold higher binding affinity for the 5-HT3 receptor and a longer half-life (40 hours).10 Several trials have compared palonosetron with other 5-HT3 RAs. Aapro and colleagues compared palonosetron (0.25 mg or 0.75 mg) with ondansetron (32 mg) in patients receiving HEC.12 In this trial, dexamethasone was also administered at investigator discretion. Overall, there was no significant difference between palonosetron and ondansetron in the control of acute or delayed emesis. However, a post-hoc secondary subgroup analysis of the patients who received dexamethasone showed better control of acute and delayed emesis with palonosetron.12 In another phase 3 trial, Saito and colleagues compared palonosetron 0.75 mg with granisetron 40 µg/kg prior to chemotherapy on day 1.13 All patients in this trial received dexamethasone 16 mg on day 1, followed by additional doses on days 2 and 3. The complete response rate in the acute CINV phase was similar for palonosetron and granisetron (75% and 73%, respectively).13 However, in the de -

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layed CINV phase, the complete response rate was 57% for palonosetron and 45% for granisetron (P <.0001). Until recently, consensus guidelines for CINV have listed all of the 5-HT3 RAs as equivalent, with no preferences for use. However, the Multinational Association for Supportive Care in Cancer (MASCC) has now updated its guidelines to recommend palonosetron as the 5-HT3 RA of choice for MEC.9 Ongoing challenges in CINV control Several resources, including guidelines published by MASCC, the National Comprehensive Cancer Network (NCCN), and the American Society of Clinical Oncology (ASCO), are available to help guide clinicians in the management of CINV.8-10 All of these recommendations are developed by multidisciplinary teams of pharmacy, nursing, and physician practitioners and, in general, many similarities exist among these guidelines. Despite the availability of these and other resources, challenges related to the treatment of CINV still exist, including the management of delayed, breakthrough, and refractory symptoms, and appropriate strategies for patients receiving multiday chemotherapy.

Delayed CINV continues to be an issue, even when consensus guidelines are followed.

Delayed, breakthrough, and refractory CINV Delayed CINV continues to be an issue, even when consensus guidelines are followed. Novel agents such as palonosetron and the NK-1 RA, aprepitant, have shown efficacy in reducing the incidence of delayed CINV and are indicated for use in this setting; however, some patients still experience symptoms. MASCC, NCCN, and ASCO guidelines recommend scheduled prophylaxis for delayed CINV associated with highly and moderately emetogenic single-day regimens. For patients who experience delayed CINV despite optimal antiemetics, however, there are no clear recommendations. Therefore, utilization of agents with a different mechanism of action should be considered and, if effective, should be incorporated into a patient’s subsequent cycles of therapy. Likewise, the guidelines cite no preferred agents for breakthrough or refractory CINV. Therefore, treatment with agents from drug classes not currently being utilized in the patient’s existing antiemetic regimen may be a viable option.

Chemoreceptor Trigger Zone Cerebral Cortex

Visceral Afferents Vomiting Center

Salivary Receptors

Cranial Nerves

Abdominal Muscles

Respiratory Center

Source: Reference 3.

Figure. Pathway to Emesis

Multiday chemotherapy Many patients with cancer receive multiday chemotherapy, which presents additional CINV management challenges. These regimens are complicated by the overlap of acute and delayed emesis in addition to varying levels of emetogenicity which may occur throughout the course of treatment. Basic CINV treatment principles apply to these situations, such as ensuring that the daily level of emetogenicity (acute or delayed) is matched with the appropriate antiemetic; continued assessment of efficacy; and individualization of antiemetic regimens. However, it has yet to be determined how to best utilize newer agents, such as aprepitant and palonosetron, in these multiday regimens. For 5-day cisplatin regimens, for example, there is data to show that palonosetron dosing on days 1, 3, and 5 is effective.14 However, for non–cisplatin-based combinations or other multiday regimens, the dosing strategy is not as clear. Incorporating agents such as aprepitant also poses a challenge since it is not clear how NK-1 RAs should be scheduled with multiday chemotherapy. Current guidelines recommend starting aprepitant on day 1 of the multiday regimen; however, there is not sufficient data to verify that this or any other dosing strategy is preferable. In addition, there is some evidence suggesting that dosing beyond 3 days is safe, but improvement in efficacy has not yet been demonstrated with this approach.10,15 Conclusion Much has been learned about the etiology of CINV over the past several years, which has led to great strides in the prevention and management of symptoms. New agents have increased our armamentarium, but there is still room for improvement, especially in the areas of delayed, breakthrough, and refractory symptoms, and the treatment of patients who receive multiday chemotherapy. A multidisciplinary approach to

the assessment and management of CINV will help patients receive the optimal benefits of therapy. ● References 1. de Boer-Dennert M, de Wit R, Schmitz PI, et al. Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. Br J Cancer. 1997; 76:1055-1061. 2. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer. 2005;13(4):219-227. 3. Hesketh PJ. Understanding the pathobiology of chemotherapy-induced nausea and vomiting. Providing a basis for therapeutic progress. Oncology. 2004;18(10 suppl 6):9-14. 4. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-2494. 5. Hornby PJ. Central neurocircuitry associated with emesis. Am J Med. 2001;111(8 suppl 1):106S-112S. 6. Frame DG. Best practice management of CINV in oncology patients: I. Physiology and treatment of CINV. J Support Oncol. 2010;8(2 suppl 1):5-9. 7. del Giglio A, Soares HP, Caparroz C, et al. Granisetron is equivalent to ondansetron for prophylaxis of chemotherapy induced nausea and vomiting: results of a meta-analyses of randomized controlled trials. Cancer. 2000;89(11):2301-2308. 8. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: update 2006. J Clin Oncol. 2006;24:2932-2947. 9. Multinational Association for Supportive Care in Cancer. MASCC/ESMO Antiemetic Guidelines 2010. www.mascc.org. Accessed August 30, 2010. 10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™. Antiemesis, V.2.2010. April 7, 2010. http://www.nccn.org/profession als/physician_gls/PDF/antiemesis.pdf. 11. Geling O, Eichler H-G. Should 5-hydroxytryptamine-3 receptor antagonists be administered beyond 24 hours after chemotherapy to prevent delayed emesis? Systematic re-evaluation of clinical evidence and drug cost implications. J Clin Oncol. 2005;23(6):1289-1294. 12. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapyinduced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17(9):1441-1449. 13. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versus granisetron plus dexamethasone for prevention of nausea and vomiting during chemotherapy: a double-blind, double-dummy randomized, comparative phase III trial. Lancet Oncol. 2009;10 (2):115-124. 14. Einhorn LH, Branes MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer. 2007;15(11):1293-1300. 15. de Wit R, Herrstedt J, Rapoport B, et al. The oral NK(1) antagonist, aprepitant, given with standard antiemetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy: a combined analysis of two randomised, placebocontrolled phase III clinical trials. Eur J Cancer. 2004; 40(3):403-410.

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CONTINUING EDUCATION COMMENTARY

Clinical Management of Chemotherapyinduced Nausea and Vomiting: A Nurse’s Perspective By Carrie Tompkins Stricker, PhD, RN Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania

cornerstone of oncology nursing practice is symptom management, and perhaps nowhere is this expertise more critical than for patients who are at risk for chemotherapy-induced nausea and vomiting (CINV), one of the most feared symptoms of cancer treatment. Despite the past decade’s major advances in available medications for the prevention and control of CINV, many patients still needlessly suffer from uncontrolled nausea and vomiting, especially delayed CINV, due to a myriad of provider and patient factors. Provider factors include underestimation of prevalence, lack of routine assessment, and poor knowledge of and adherence to clinical guidelines.1-3 Patient factors include underreporting of symptoms, issues with adherence to prescribed antiemetic medications, and economic and insurance issues that limit access to appropriate antiemetics.1,3,4 Armed with the most up-to-date information, including recently updated antiemetic guidelines, oncology nurses can use their expert clinical assessment, management skills, and patient education and advocacy efforts to help overcome these challenges.

CINV tends to increase over time.3 Baseline assessments should be aimed at identifying individual risk factors for CINV (Table). Individuals with one or more risk factors may require more aggressive up-front strategies aimed at CINV control, especially with moderately emetogenic chemotherapy (MEC), for which guidelines leave substantial room for individualization of antiemetic therapy. One clinical pearl is to ask patients what their perceived risk for developing CINV is, as this has predicted actual symptoms in clinical studies.5,6 In addition to risk factors, nurses should assess factors that may influence choice of antiemetics. These include issues of access to prescribed antiemetics (eg, insurance coverage, copayment amount, and variation depending on route of

Assessment of CINV Oncology nurses typically have the most frequent direct contact with patients receiving chemotherapy, and are in the best position to assess CINV on an ongoing basis. Assessment should include both a baseline/pretreatment assessment of factors influencing risk and therapeutic strategies for CINV, as well as ongoing, iterative assessment of symptoms once therapy has begun (Figure 1). Assessment should not be abandoned until the patient’s treatment course is completely over, since

administration [intravenous (IV) vs by mouth (PO)], prior experience with antiemetics if the patient is not chemotherapy-naïve, likelihood of adhering to oral antiemetic therapy, and symptoms or comorbidities that may affect antiemetic choice (eg, limiting use of certain serotonin subtype-3 receptor antagonists [5-HT3 RAs] in individuals with chronic constipation). Ongoing assessments are essential, since individuals tend to underreport their symptoms without direct inquiry from providers,7 leading to suboptimal management of CINV. This is especially true for delayed CINV, given that delayed symptoms are not only more difficult to control, but typically occur when the healthcare team is no longer in direct contact with the patient. Since delayed CINV is often worse on days 2 through 4 after single-day chemotherapy,6,8,9 nurses should consider assessment phone calls to patients during this time period. Another strategy that oncology nurses can use to overcome these challenges is to involve the patient and/or family in

Figure 1. The Cycle of CINV

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Assessment should not be abandoned until the patient’s treatment course is completely over, since CINV tends to increase over time.

Individual Patient Risk Factors for CINV •Younger age (<50 years) •Female gender • No/Low alcohol consumption (<1 drink/day) •History of nausea with stress •History of motion sickness or hyperemesis of pregnancy •Patient’s initial expectations about developing CINV •Pretreatment or infusion-related anxiety •Currently taking anxiolytics or antidepressants Table

Source: Reference 3.

tracking both symptoms and the effectiveness of prescribed and self-care strategies for managing CINV. In addition to patient diaries, nurses may also utilize publicly available tools, such as the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool (MAT) (Figure 2).10 The MAT allows the patients to record nausea and vomiting as distinct symptoms during each chemotherapy cycle, and can help nurses modify the antiemetic treatment regimen based on the time course of symptoms, as well as which strategies have been most and least effective. The MAT is also reliable and valid when given to patients to recall their recent experiences with CINV when they return to the office for the next chemotherapy cycle.10 This tool can be accessed at www.MASCC.org. Management strategies Unlike other symptoms, such as pain, where individualized treatment cannot typically be determined until the symptom presents, prevention is the key to successful treatment of CINV. Fortunately, guidelines are available to optimize both prevention and management of CINV. When designing management strategies, nurses should keep these “C’s” in mind: Chemotherapy regimen, Class of antiemetic agents, Cost of therapy, and Comorbidities and Concomitant medications. Chemotherapy and class of agents The principal factor that should guide selection of antiemetic therapy is the

chemotherapy regimen, which will influence which classes of antiemetic agents are used. For highly emetogenic chemotherapy (HEC), the choice of antiemetic therapy is straightforward. What is commonly called triple therapy is indicated; dexamethasone, a 5-HT3 RA, and a neurokinin-1 (NK-1) RA (ie, aprepitant or fosaprepitant) should be used. For MEC, at a minimum patients should receive a 5-HT3 RA and dexamethasone (double therapy), with aprepitant being added on days 1 through 3 in patients receiving anthracycline plus cyclophosphamide chemotherapy, those who have had inadequate control with double therapy, and those receiving other MEC regimens and who are at higher risk for CINV based on individual risk factors. According to recent updated guidelines from MASCC, palonosetron is the 5-HT3 RA of choice when aprepitant is not utilized for MEC. The choice of agents for prevention of delayed CINV can be somewhat confusing for MEC regimens, since guidelines give a myriad of options. When aprepitant is indicated, it can be used either alone—or for greater effectiveness—in combination with dexamethasone, on days 2 and 3. When aprepitant is not used, most guidelines give preference to using dexamethasone alone on days 2 and 3, as it is highly effective for delayed CINV and is very affordable. For chemotherapies of low to minimal emetic risk, minimal to no preventive therapy is needed. Clinicians typically overtreat for CINV with these therapies, commonly using 5-HT3 RAs,2 which are usually not necessary and are costlier than other recommended therapies such as dexamethasone. With respect to antiemetic class, a common mistake is to duplicate the use of agents from the same class by giving them concurrently. This does not improve efficacy and only increases side effects and cost.2 In practice, this occurs most commonly with the prescription of agents for use as rescue therapy (ie, medications prescribed to treat breakthrough nausea and vomiting that occurs despite the use of scheduled prophylactic antiemetics). An example would be giving palonosetron on day 1 or applying a granisetron patch the day before chemotherapy, and then prescribing another serotonin-RA (ie, dolasetron, grani-

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www.TheOncologyPharmacist.com setron, or ondansetron) for as needed (prn) use on days 2 and 3. Palonosetron has a half-life of 40 hours, and the granisetron patch is designed to stay in place for 5 days; thus, a second serotonin antagonist would be an ineffective rescue agent during these corresponding time periods. An evidence-based alternative would be to prescribe a prn agent from a different class, such as dexamethasone (if not already scheduled for use), or a dopamine RA (eg, metoclopramide) or phenothiazine (eg, prochlorperazine). A reference list of classes of antiemetics and corresponding agents is available in the National Comprehensive Cancer Network Antiemesis guidelines at www.nccn.org. Cost of therapy Cost is also an important consideration in making decisions about antiemetic therapies. For oral medications, individual pharmaceutical companies offer financial assistance for those in the greatest financial need, including the uninsured as well as underinsured individuals with high copayments and low income levels. These can be accessed via company websites. Organizations such as the American Cancer Society, the Leukemia and Lymphoma Society, the Patient Assistance Foundation, and the Patient Advocacy Network offer copayment assistance that is not strictly need-based. For individuals with high copayments for oral medications, using available IV formulations (eg, fosaprepitant IV on day 1 instead of aprepitant PO) may be one alternative to help diminish out-of-pocket expenses, as facility-administered medications are often better covered.

Source: Reference 10.

Figure 2. Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool

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Comorbidities and concomitant medications Comorbidities and concomitant medications are of special concern in older patients receiving chemotherapy, as the elderly have a high incidence of comorbid disease and are more likely to be using other medications.11 Approximately 40% of individuals 65 years and older take 5 or more prescription medications; thus, drug–drug interactions and polypharmacy warrant careful attention. Jakobsen and Herrstedt discuss these concerns in detail in their excellent review of CINV in the elderly cancer patient, and a few examples warrant mention.11 Caution is advised when using extended dexamethasone in individuals taking chronic nonsteroidal anti-inflammatory drugs, given the elevated risk of gastric bleeding. At a minimum, gastrointestinal prophylaxis with proton pump inhibitors should be considered. Diabetics should monitor their blood sugars more closely given corticosteroids’ effects on raising plasma glucose levels. For individuals with seizure disorders, metoclopramide and prochlorperazine should be used with caution, given the increased risk for con-

vulsions. Interestingly, the risk for extrapyramidal side effects with metoclopramide is greater in younger as compared to older individuals. Aprepitant has a number of drug–drug interactions listed in its package insert.12 International normalized ratio levels should be monitored closely when aprepitant and warfarin are concomitantly used, given the slight lowering of warfarin plasma levels. Antiemetic guidelines already take into consideration the drug–drug interaction between corticosteroids and aprepitant with their recommendations for dexamethasone dosing, given the approximate 50% increase in corticosteroid levels when aprepitant is used. Conclusion Oncology nurses play a critical role in optimizing the prevention and management of CINV. Careful, proactive, and iterative assessment, ongoing and interactive communication with patients and families, and up-to-date knowledge of available therapeutic agents and considerations with respect to cost, comorbidities, and concomitant medications are all essential to ensuring the best possible outcomes for patients receiving chemotherapy. Fortunately, numerous resources are available to the practicing nurse, including web-based guidelines. Nurses can play a key role in overcoming barriers to optimal CINV prevention and management by helping to standardize care through the adaptation and implementation of evidence-based recommendations in their practice setting. ● References 1. Bender CM, McDaniel RW, Murphy-Ende K, et al. Chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs. 2002;6(2):94-102. 2. Grunberg SM. Obstacles to the implementation of antiemetic guidelines. J Natl Compr Canc Netw. 2009; 7(5):601-605. 3. Stricker CT, Eaby B. Chemotherapy-Induced Nausea and Vomiting. A Guide to Oncology Symptom Mana gement. Pittsburgh, PA: Oncology Nursing Society Press; 2009:91-122. 4. Hawkins R, Grunberg S. Chemotherapy-induced nausea and vomiting: challenges and opportunities for improved patient outcomes. Clin J Oncol Nurs. 2009;131:54-64. 5. Roscoe JA, Bushunow P, Morrow GR, et al. Patient expectation is a strong predictor of severe nausea after chemotherapy: a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma. Cancer. 2004;101(11):2701-2708. 6. Stricker CT, Velders L. Predictors of chemotherapyinduced nausea and vomiting in women with early stage breast cancer [abstract]. Support Care Cancer. 2005; 13(6):422. 7. Johnson GD, Moore K, Fortner B. Baseline evaluation of the AIM Higher Initiative: establishing the mark from which to measure. Oncol Nurs Forum. 2007;34(3):729-734. 8. Dibble SL, Casey K, Nussey B, et al. Chemotherapyinduced vomiting in women treated for breast cancer. Oncol Nurs Forum Online. 2004;31(1):E1-E8. 9. Dibble SL, Isreal J, Nussey B, et al. Delayed chemotherapy-induced nausea in women treated for breast cancer. Oncol Nurs Forum Online. 2003;30(2):E40-E47. 10. Molassiotis A, Coventry PA, Stricker CT, et al. Validation and psychometric assessment of a short clinical scale to measure chemotherapy-induced nausea and vomiting: the MASCC Antiemesis Tool (MAT). J Pain Symptom Manage. 2007;34(2):148-159. 11. Jakobsen JN, Herrstedt J. Prevention of chemotherapy-induced nausea and vomiting in elderly cancer patients. Crit Rev Oncol Hematol. 2009;71(3):214-221. 12. Emend capsules [package insert]. Whitehouse Station, NJ: Merck & Co., Inc. 2010.

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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems

Medications Used for the Treatment of Hematologic Cancers The following sections will assist healthcare professionals and payers by providing appropriate coding, billing, and reimbursement information associated with the management of multiple myeloma or myelodysplastic syndromes.

Multiple Myeloma Multiple myeloma is a type of cancer that begins in plasma cells (white blood cells that produce antibodies).

The following sections include: • Associated ICD-9-CM codes used for the classification of multiple myeloma or myelodysplastic syndromes • Drugs that have been FDA-approved in the treatment of multiple myeloma or myelodysplastic syndromes • Drugs that are Compendia listed for off-label use for breast cancer based on clinical studies that suggest beneficial use in some cases. Please note: if a check mark appears in the FDA column it will NOT appear in the compendia off-label use column • Corresponding HCPCS/CPT® codes and code descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable), if applicable • Possible CPT® Administration Codes for each medication

generic (Brand) name

HCPCS code: code description

J9017: injection, arsenic trioxide, 1 mg J8499b: prescription drug, oral, non-chemotherapeutic, not otherwise specified betamethasone J0702: injection, acetate and betamethasone acetate betamethasone 3 mg, and sodium phosphate betamethasone sodium (Celestone Soluspan) phosphate 3 mg bortezomib J9041: injection, (Velcade) bortezomib, 0.1 mg carmustine J9050: injection, (BiCNU) carmustine, 100 mg cisplatin J9060: cisplatin, powder (Platinol AQ) or solution, per 10 mg cisplatin J9062: cisplatin, (Platinol AQ) 50 mg cortisone acetate J8499b: prescription drug, (Cortone) oral, non-chemotherapeutic, not otherwise specified cyclophosphamide J8530: cyclophosphamide, (Cytoxan) oral, 25 mg cyclophosphamide J9070: cyclophosphamide, (Cytoxan) 100 mg (all 100-mg NDCs inactive; 500-mg NDCs used to calculate code price)

Associated ICD-9-CM Codes Used for Multiple Myeloma 203 Multiple myeloma and immunoproliferative neoplasms The following fifth-digit subclassification is for use with category 203: 0 without mention of having achieved remission >Failed remission< 1 in remission 2 in relapse 203.0 Multiple myeloma Kahler’s disease Myelomatosis excludes: solitary myeloma (238.6) 203.1 Plasma cell leukemia Plasmacytic leukemia 203.8 Other immunoproliferative neoplasms

FDAapproved for multiple myeloma

arsenic trioxide (Trisenox) betamethasone (Celestone)

December 2010 I VOL 3, NO 8

Compendia listed off-label use for multiple myelomaa

Current code price (AWP-based pricing), effective 11/1/10

Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10

CPT ® administration codes

✓

$47.51

$37.25

✓

NDC level pricing $8.00

NDC level pricing $6.24

✓

$46.66

$39.29

✓

$205.69

$175.88

✓

$4.33

$1.50

96409, 96413, 96415

✓

$21.66

$7.49

96409, 96413, 96415

✓

NDC level pricing $2.09

NDC level pricing $0.83

✓

$10.57

$5.96

✓

96413, 96415 N/A

11900, 11901, 20600, 20605, 20610, 96372

96409 96413, 96415

N/A

N/A 96409, 96413, 96415

www.TheOncologyPharmacist.com

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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems

FDAapproved for multiple myeloma

generic (Brand) name cyclophosphamide (Cytoxan)

HCPCS code: code description ✓ J9080: cyclophosphamide, 200 mg (all 100-mg NDCs inactive; 500-mg NDCs used to calculate code price) ✓ cyclophosphamide J9090: cyclophosphamide, (Cytoxan) 500 mg ✓ cyclophosphamide J9091: cyclophosphamide, (Cytoxan) 1 gram ✓ cyclophosphamide J9092: cyclophosphamide, (Cytoxan) 2 grams daunorubicin J9151: injection, (DaunoXome) daunorubicin citrate, liposomal formulation, 10 mg dexamethasone J8540: dexamethasone, (Decadron) oral, 0.25 mg dexamethasone J1100: injection, (Decadron) dexamethasone sodium phosphate, 1 mg doxorubicin J9000: injection, (Adriamycin) doxorubicin hydrochloride, 10 mg ✓ doxorubicin liposomal J9001: injection, (Doxil) doxorubicin hydrochloride, all lipid formulations, 10 mg epirubicin J9178: injection, (Ellence) epirubicin HCl, 2 mg etoposide J8560: etoposide, oral, (Vepesid) 50 mg etoposide J9181: injection, (Etopophos, Toposar) etoposide, 10 mg hydrocortisone J8499b: prescription drug, (Cortef) oral, non-chemotherapeutic, not otherwise specified hydrocortisone J1720: injection, (Solu-Cortef) hydrocortisone sodium succinate, up to 100 mg ifosfamide J9208: injection, (Ifex) ifosfamide, 1 gram interferon alfa-2b J9214: injection, interferon, (Intron-A) alfa-2b, recombinant, 1 million units interferon alfa-n3 J9215: injection, interferon, (Alferon-N) alfa-n3, (human leukocyte derived), 250,000 international units lomustine J8999b: prescription drug, (CeeNU) oral, chemotherapeutic, not otherwise specified lomustine S0178: lomustine, (CeeNU) oral, 10 mg

melphalan (Alkeran) melphalan (Alkeran)

J8600: melphalan, oral, 2 mg J9245: injection, melphalan hydrochloride, 50 mg

Compendia listed off-label use for multiple myelomaa

Current code price (AWP-based pricing), effective 11/1/10 $21.15

Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10 $11.92

CPT ® administration codes 96409, 96413, 96415

$52.87

$29.79

96409, 96413, 96415

$95.21

$59.59

96409, 96413, 96415

$171.35

$119.18

96409, 96413, 96415

✓

$68.00

$57.66

96413

✓

$0.09

$0.37

N/A

✓

$0.15

$0.09

✓

$13.20

$3.04

$613.03

$486.80

✓

$5.38

$1.80

✓

$57.33

$28.48

✓

$0.53

$0.55

✓

NDC level pricing $2.33

NDC level pricing $3.42

✓

$42.00

$34.15

96413, 96415

✓

$21.90

$16.06

96372, 96401

✓

$25.09

None reported

11900, 11901

✓

NDC level pricing $10.59

NDC level pricing S0178 not payable by Medicare $4.80

✓

$5.68

✓

$1,922.50

$1,401.83

11900, 11901, 20600, 20605, 20610, 96372, 96374 96409 96413

96409, 96413 N/A 96413, 96415 N/A

96365, 96366, 96372, 96374

N/A

N/A 96409, 96413 Continued on page 20

www.TheOncologyPharmacist.com

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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Continued from page 19

generic (Brand) name

HCPCS code: code description

methylprednisolone (Depo-Medrol)

J1020: injection, methylprednisolone acetate, 20 mg J1030: injection, methylprednisolone acetate, 40 mg J1040: injection, methylprednisolone acetate, 80 mg J2920: injection, methylprednisolone sodium succinate, up to 40 mg J2930: injection, methylprednisolone sodium succinate, up to 125 mg J9265: injection, paclitaxel, 30 mg J3590b: unclassified biologics

methylprednisolone (Depo-Medrol) methylprednisolone (Depo-Medrol) methylprednisolone (Solu-Medrol) methylprednisolone (Solu-Medrol) paclitaxel (Onxol, Taxol) peginterferon alfa-2b (Peg-Intron)

FDAapproved for multiple myeloma

Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10

CPT ® administration codes

✓

$3.78

$2.48

11900, 11901, 20600, 20605, 20610, 96372

✓

$5.22

$4.72

11900, 11901, 20600, 20605, 20610, 96372

✓

$9.52

$8.59

11900, 11901, 20600, 20605, 20610, 96372

✓

$2.36

$1.81

96365, 96366, 96372, 96374

✓

$4.15

$2.54

96365, 96366, 96372, 96374

✓

$15.54

$7.45

96413, 96415

✓

S0148: injection, pegylated interferon alfa-2b, 10 micrograms prednisolone J7510: prednisolone, (Prelone, Millipred) oral, per 5 mg prednisone J7506: prednisone, (Orasone, Deltasone) oral, per 5 mg procarbazine J8999b: prescription drug, (Matulane) oral, chemotherapeutic, not otherwise specified procarbazine S0182: procarbazine HCl, (Matulane) oral, 50 mg

✓

NDC level pricing $116.77

✓

$0.59

NDC level pricing S0148 not payable by Medicare $0.02

✓

$0.04

N/A

✓

teniposide (Vumon) thalidomide (Thalomid)

✓

$376.55

NDC level pricing S0182 not payable by Medicare $323.66

N/A

✓

NDC level pricing $55.68

✓

NDC level pricing $1,348.55

NDC level pricing $1,090.84

96413

✓

$5.83

$3.98

96409

✓

$11.66

$7.96

96409

✓

$29.15

$19.90

96409

$263.39

$223.10

peginterferon alfa-2b (Peg-Intron)

topotecan (Hycamtin) vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS) zoledronic acid (Zometa)

Compendia listed off-label use for multiple myelomaa

Current code price (AWP-based pricing), effective 11/1/10

Q2017: injection, teniposide, 50 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J9350: injection, topotecan, 4 mg J9370: vincristine sulfate, 1 mg J9375: vincristine sulfate, 2 mg J9380: vincristine sulfate, 5 mg J3487: injection, zoledronic acid (Zometa), 1 mg

December 2010 I VOL 3, NO 8

✓

96372

N/A

96413, 96415 N/A

96365, 96374

www.TheOncologyPharmacist.com

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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Associated ICD-9-CM Codes Used for Myelodysplastic Syndromes

Myelodysplastic Syndromes Myelodysplastic syndromes are a group of diseases in which the bone marrow does not make enough healthy blood cells.

generic (Brand) name

HCPCS code: code description

amifostine (Ethyol) arsenic trioxide (Trisenox) azacitidine (Vidaza) clofarabine (Clolar) cytarabine (Cytosar-U) cytarabine (Cytosar-U) darbepoetin alfa (Aranesp)

J0207: injection, amifostine, 500 mg J9017: injection, arsenic trioxide, 1 mg J9025: injection, azacitidine, 1 mg J9027: injection, clofarabine, 1 mg J9100: injection, cytarabine, 100 mg J9110: injection, cytarabine, 500 mg J0881: injection, darbepoetin alfa, 1 microgram (non-ESRD use) J0882: injection, darbepoetin alfa, 1 microgram (for ESRD on dialysis) J0894: injection, decitabine, 1 mg J0885: injection, epoetin alfa (for non-ESRD use), 1000 units J0886: injection, epoetin alfa 1000 units (for ESRD on dialysis; renal dialysis facilities and hospitals must use code Q4081, effective 1/1/07) Q4081: injection, epoetin alfa, 100 units (for ESRD on dialysis; for renal dialysis facilities and hospital use)

darbepoetin alfa (Aranesp) decitabine (Dacogen) epoetin alfa (Procrit, Epogen) epoetin alfa (Procrit, Epogen)

epoetin alfa (Procrit, Epogen)

238 Neoplasm of uncertain behavior of other and unspecified sites and tissues 238.7 Other lymphatic and hematopoietic tissues excludes: acute myelogenous leukemia (205.0) chronic myelomonocytic leukemia (205.1) myelosclerosis, not otherwise specified (289.89) myelosis: not otherwise specified (205.9) megakaryocytic (207.2) 238.72 Low-grade myelodysplastic syndrome lesions Refractory anemia (RA) Refractory anemia with ringed sideroblasts (RARS) Refractory cytopenia with multilineage dysplasia (RCMD) Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) 238.73 High-grade myelodysplastic syndrome lesions Refractory anemia with excess blasts-1 (RAEB-1) Refractory anemia with excess blasts-2 (RAEB-2) 238.74 Myelodysplastic syndrome with 5q deletion 5q minus syndrome, not otherwise specified excludes: constitutional 5q deletion (758.39) high-grade myelodysplastic syndrome with 5q deletion (238.73) 238.75 Myelodysplastic syndrome, unspecified

FDAapproved for myelodysplastic syndromes

Compendia listed off-label use for myelodysplastic syndromesa

Current code price (AWP-based pricing), effective 11/1/10

Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10

CPT ® administration codes

✓

$564.95

$318.66

✓

$47.51

$37.25

$6.03

$5.13

✓

$135.00

$115.41

✓

$1.25

$1.98

✓

$10.20

$3.67

✓

$6.44

$2.90

96409, 96413, 96415, 96450 96409, 96413, 96415, 96450 96372, 96374

✓

$6.44

$2.90

96372, 96374

$35.50

$30.74

96413, 96415

✓

$15.34

$9.68

96372, 96374

✓

$15.34

$9.68

96372, 96374

✓

$1.53

$0.97

96372, 96374

✓

96374 96413, 96415 96401, 96409, 96413 96413, 96415

Continued on page 22 www.TheOncologyPharmacist.com

December 2010 I VOL 3, NO 8

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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Continued from page 21

generic (Brand) name

HCPCS code: code description

etoposide (Vepesid) etoposide (Toposar, Etopophos) filgrastim (Neupogen) filgrastim (Neupogen) fludarabine (Fludara) imatinib (Gleevec)

J8560: etoposide, oral, 50 mg J9181: injection, etoposide, 10 mg J1440: injection, filgrastim (G-CSF), 300 micrograms J1441: injection, filgrastim (G-CSF), 480 micrograms J9185: injection, fludarabine phosphate, 50 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0088: imatinib, 100 mg

imatinib (Gleevec) lenalidomide (Revlimid) lymphocyte immune globulin (Atagam) lymphocyte immune globulin (Thymoglobulin) sargramostim (Leukine) thalidomide (Thalomid) topotecan (Hycamtin)

FDAapproved for myelodysplastic syndromes

J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J7504: lymphocyte immune globulin, antithymocyte globulin, equine, parenteral, 250 mg J7511: lymphocyte immune globulin, antithymocyte globulin, rabbit, parenteral, 25 mg J2820: injection, sargramostim (GM-CSF), 50 micrograms J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J9350: injection, topotecan, 4 mg

Compendia listed off-label use for myelodysplastic syndromesa

Current code price (AWP-based pricing), effective 11/1/10

Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10

✓

$57.33

$28.48

✓

$0.53

$0.55

✓

$283.02

$233.43

✓

$450.66

$366.81

✓

$285.16

$139.57

NDC level pricing $48.56

CPT ® administration codes N/A 96413, 96415 96365, 96366, 96369, 96370, 96372, 96374 96365, 96366, 96369, 96370, 96372, 96374 96413

✓

NDC level pricing $643.21

NDC level pricing S0088: not payable by Medicare NDC level pricing $496.95

96365, 96366

✓

$636.48

$417.51

96365, 96366

✓

$44.64

$23.88

✓

NDC level pricing $1,348.55

NDC level pricing $1,090.84

✓

N/A

96365, 96366, 96372 N/A

96413

Compendia references available upon request. When billing a non-classified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J8999 for CeeNU) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 to ensure appropriate reimbursement.

References HCPCS Level II Expert, 2010 • Current Procedural Terminology (CPT®), 2010 (CPT® copyright © 2010 American Medical Association. All rights reserved. CPT® is a registered trademark of the American Medical Association) • ICD-9-CM for Professionals Volumes 1 & 2, 2010 • The Drug Reimbursement Coding and Pricing Guide by RJ Health Systems International, LLC, Volume 7, Number 4, 4th Quarter 2010 • FDA-approved indication (from product’s prescribing information) • National Cancer Institute® • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMS (Centers for Medicare & Medicaid Services), Medicare Allowable 4th Quarter 2010 (effective dates: 10/1/10-12/31/10). Prices listed herein are effective as of November 1, 2010. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; ESRD, end-stage renal disease; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HCPCS, Healthcare Common Procedure Coding System; NDC, National Drug Code.

This information was supplied by:

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

December 2010 I VOL 3, NO 8

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Cancer Center Profile Geisinger Medical Center’s Cancer Institute Joins the NCCCP... Continued from cover

Thanjavur Ravikumar, MD, FACS, performs surgery in Geisinger’s Center for Surgical Innovation.

Geisinger’s Cancer Institute, believes that serving this mix of patients marries well with the NCCCP’s mission of reducing cancer healthcare disparities. NCCCP cancer centers are directed to increase programs to reach the underserved in their communities more effectively, thus improving access to cancer screening, treatment, and research. Community outreach The centerpiece at Geisinger is value-based healthcare delivery, a philosophy evident in its advanced patientcentered medical home program, known as ProvenHealth Navigator. At Geisinger, medical homes are caregivers, such as primary care physicians or nurse case managers, who provide service excellence beyond just seeing patients in an acute-care setting. Their proactive approach to chronic diseases is recognized by the National Committee for Quality Assurance—all 40 facilities distributed throughout Geisinger’s community have been recognized as Level 3, the highest level awarded for the medical home model. This philosophy of managing patients through a disease continuum that is continued into wellness programs—a philosophy that is also practiced by Geisinger’s cancer specialists—parallels the NCCCP’s vision of cancer as a disease continuum, according to Ravikumar. NCCCP cancer centers are tasked with improving the quality of care at community hospitals by promoting datadriven, evidence-based, and coordinated cancer care. In addition, NCCCP cancer centers are working to enhance their cancer survivorship and palliative care services. With a $1.7-million award from the NCCCP, Geisinger hopes to reach these goals. To do so, Geisinger will use its

December 2010 I VOL 3, NO 8

medical home model to reach patients and physicians who are not members of the Geisinger system. “We need to provide the same services to both Geisinger patients and non-Geisinger patients in the 11 counties that surround us,” said Ravikumar in an interview with The Oncology Pharmacist. “Our plan through the NCCCP, our obligation, is to all patients in the counties that we serve.”

The centerpiece at Geisinger is value-based healthcare delivery, a philosophy evident in its advanced patientcentered medical home program. According to Ravikumar, Geisinger plans to reach out to area physicians who are not participants in the Geisinger system through the Keystone Health Information Exchange (KeyHIE) initiative. This initiative aims to provide healthcare professionals with the timely information they need to provide the best care possible for their patients. Through the initiative’s master patient list, patients’ charts and all medical information that reside at any participating hospital can be accessed through a secure web-based browser. Information technology GMC’s Cancer Institute also has “significant strength in information technology,” noted Ravikumar. This is another area that marries well with the NCCCP’s mission. NCCCP cancer centers are charged with exploring what is needed to adapt or adopt the tools of the National Cancer Institute’s (NCI)

cancer Bioinformatics Grid (caBIG) as well as to enhance their electronic health record (EHR) networks to support and link cancer patients and researchers nationwide. “What the NCCCP wants to do is connect all the cancer centers in the country through a grid called caBIG. They are trying to bring everyone up to speed. We are already advanced in that area, so perhaps the NCCCP thought that it would be a good thing for centers like ours to lead the way,” said Ravikumar. For the past 8 years, Geisinger has been recognized as one of the nation’s “100 Most Wired Hospitals and Health Systems” by Hospitals & Health Networks (H&HN), the journal of the American Hospital Association. As one of the most digitally advanced healthcare providers in the nation, Geisinger uses information technology to address safety and quality, customer service, business processes, workforce, and public health. Research In addition, Geisinger already has a very robust biospecimen initiative through MyCode. Currently, MyCode has 20,000 DNA samples from patients throughout Geisinger. Patients at all levels of health are asked to participate, provide a blood sample, and give consent for its use in research. “If any studies need to be done across the cancer research at the community level, we are well positioned to carry out the mission of the NCCCP,” explained Ravikumar. To help the NCCCP reach its goal of applying NCI Best Practices for Biospecimen Resources to enable all community cancer centers to contribute to the national biobank, Geisinger is expanding its specimen collection beyond Geisinger-affiliated cancer centers by “helping them retrieve the specimen when they operate on cancer patients,” Ravikumar said. As a member of the Community Clinical Oncology Program (CCOP), Geisinger already has 11 of the 15 NCCCP clinical trials open at its cancer centers. According to Ravikumar, Geisinger plans to expand those 11 trials and open the additional four trials to patients in its community. Because of its rural patient base, Geisinger will offer trials at multiple sites so, as Ravikumar explains, the patients “do not have to come to us in our main center.” In addition, Geisinger accrues to trials through other oncology groups including the Eastern Cooperative Oncology Group and the North Central Cancer Treatment Group. “Using the NCCCP mechanism, we are going to make these trials available to people in the community through outreach and navigators and transportation service,” explained

Ravikumar. “In addition, for clinical trials, we are going to enlist oncologists, radiation doctors, surgeons, and primary care physicians who are not Geisinger physicians and make sure that they have access to NCCCP clinical trials.” Quality care All of this, of course, is about the quality of care delivered. “We have some ideas of how we will use our EHR and our model of ProvenHealth to improve the quality of patient care, so every patient gets the same level of care,” said Ravikumar, a surgeon by profession. This care will continue through the disease continuum and include survivorship and palliative care. This past year, Geisinger has launched the Geisinger accelerated performance program (GAPP) initiative. “One of the central focuses of the GAPP initiative is palliative care, making sure that the patients that we cannot cure we offer palliation as a focus and that we keep their quality of life central to our mission.” GMC’s Cancer Institute will not be resting on its laurels. By becoming an NCCCP cancer center, Geisinger hopes to improve on its delivery of innovation and discovery and to enhance its diffusion of research and technology to positively influence cancer care today and tomorrow. Ravikumar looks forward to working with the other physician directors at the other sites. “We belong to the club. We may have one model. Others may other models. We will basically learn from each other,” Ravikumar said. ●

Recent FDA Approval Dasatinib for Ph+ CP-CML The US Food and Drug Administration (FDA) has approved a new indication for dasatinib (Sprycel, Bristol-Myers Squibb)—treatment of Philadelphia chromosome–positive chronic phase chronic myeloid leukemia (Ph+ CP-CML). This indication expands on the drug’s original approval in 2006 to treat adults with CP-CML with resistant disease or who were intolerant of prior therapies. An oral kinase inhibitor, dasatinib’s side effects could include decreased bone marrow activity, fluid retention, diarrhea, headache, muscle and bone pain, and rash. Approved under the FDA’s accelerated approval program, the manufacturer is required to collect additional long-term efficacy and safety data.

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CONTINUING EDUCATION CREDITS

Current activities at www.COEXM.com include:

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Hematologic Cancers

Lymphoma Expert Outlines Recent Refinements in Diagnosis and Treatment By Walter Alexander

hat important changes in recent years do those treating patients with lymphoma need to keep in focus? Those treating newly diagnosed T-cell lymphomas, according to Owen A. O’Connor, MD, PhD, professor of medicine and pharmacology and chief of the division of hematologic malignancies and medical oncology at the New York University Langone Medical Center Cancer Institute in New York City, need to enroll their patients in clinical trials of combinations of newer agents, and those treating mantle cell lymphomas can consider upfront autologous stem cell transplant (SCT). The emphasis on clinical trials comes as a result of an “explosion” in the number of new drugs with independent activity in T-cell lymphoma that are being evaluated in chemotherapy regimens not based exclusively on conventional cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) combinations. Why not wait until phase 3 trials are complete and conclusions on the new agents’ efficacy are well grounded? Exploration of new agent combinations is important, O’Connor told The Oncology Pharmacist, given that T-cell lymphomas represent the most challenging subtype of non-Hodgkin lymphoma, with an unfavorable prognosis and few patients surviving beyond 1 or 2 years. “Many of the therapies that we have developed for B-cell lymphomas have been applied to patients with T-cell lymphomas, but it’s clear that strategy hasn’t been very successful—simply because Tcell lymphomas, in general, don’t respond to the same types of therapies that B-cell lymphomas respond to.”

New drugs for T-cell lymphomas Among candidates for T-cell lymphoma treatment, O’Connor listed the histone deacetylase inhibitors vorinostat, romidepsin, and belinostat as having single-agent activity. The new antifolate, pralatrexate, the first drug approved by the US Food and Drug Administration for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma, has significant single-agent activity in patients with drug-resistant disease. Furthermore, among the proteasome inhibitors, bortezomib has singleagent activity in T-cell lymphomas. “So, you can begin to envision how we might begin to look at combinations of these drugs to concoct a new platform that will be truly T-cell dedicated in its focus, and hopefully in its effects,” O’Connor said.

December 2010 I VOL 3, NO 8

Patients with newly diagnosed T-cell lymphomas who do not enroll in clinical trials of newer regimens will get conventional therapies unlikely to generate the response rates possible with newer regimens being tested in clinical trials, O’Connor said. National Comprehensive Cancer Network guidelines for treatment of peripheral T-cell lymphoma, both at diagnosis and in the relapsed/ refractory setting, recommend enrollment in a clinical trial as the best treatment option. “That’s a testament to the fact that there is no consensus regarding the optimal therapy. And it supports the fact that we do need to identify new treatment paradigms for the treatment of the disease.” Unfortunately, only 3% to 5% of patients in the United States are being enrolled in clinical trials. The pattern of insurance company refusal to reimburse expenses of patients enrolled in clinical trials in the United States is a well-recognized barrier. Although drug manufacturers do routinely underwrite drug costs, expenses for other therapies, blood tests, routine visits, and imaging can be substantial and are not covered. That refusal, O’Connor suggested, is shortsighted in that patients not enrolling in clinical trials will be undergoing reimbursable treatment elsewhere. Costs above the standard of care in clinical trials are generally covered by the sponsoring pharmaceutical company, and in 2014, a provision of the Affordable Care Act providing coverage for patients in

T-cell lymphomas represent the most challenging subtype of non-Hodgkin lymphoma, with an unfavorable prognosis and few patients surviving beyond 1 or 2 years.

clinical trials will go into effect. In Europe, where barriers to enrollment are few, large numbers of patients are being enrolled in phase 3 trials. “I have always argued that if you look at the response rates with newer regimens in our clinical trials in lymphoma, you see they are in the range of 20% to 30%, which rivals any conventional

“I believe that integrating autologous SCT into the upfront treatment of patients with mantle cell lymphoma is going to have a very, very favorable impact on long-term survival.” —Owen A. O’Connor, MD, PhD therapy for the average multiplerelapsed or refractory lymphoma. But our experience is that many of the newer regimens in clinical trials are without the hematologic toxicities of conventional therapy, and probably have better overall response rates,” O’Connor said. New approaches to mantle cell lymphoma Perhaps the most striking recent change in lymphoma treatment strategy is in the treatment of mantle cell lymphoma. The change emerges from recognition that autologous SCTs probably have much less efficacy and should have a much smaller role for patients with relapsed disease than they do for patients with a first remission that is near-complete or complete. Substantial evidence is beginning to emerge supporting combination chemotherapy regimens that integrate high-dose Ara-C with other induction regimens, such as the Nordic Lymphoma Group’s maxiCHOP regimen or the hyper-CVAD (cyclo phosphamide/vincristine/doxorubicin/dex a methasone) regimen, which is modeled on The M. D. Anderson regimen, followed by consolidation with an autologous SCT. The addition of rituximab remains a debatable issue, O’Connor told The Oncology Pharmacist. He noted, “When I started out in the field, we used to often quote a median overall survival in the order of 3 months, with a median duration of benefit of about 18 months. Nowadays, we recognize that the median progression-free survival following hyperCVAD and autologous SCT may be in the order of 6 to 7 years—and some of the Nordic data suggest even longer.” The possible median survival or progression-free survival rates with many of the new regimens remain undetermined. “I believe that integrating autologous SCT into the upfront treatment of patients with mantle cell lymphoma is going to have a very, very favorable impact on long-term survival,” O’Connor said.

Differentiating subtypes of lymphoma In mantle cell lymphoma and other lymphomas, another evolutionary advance in the past several years is evident in the ability to divide what was historically thought to be one disease into a multiplicity of diseases through the use of gene expression array and other sophisticated technologies. For example, with diffuse large B-cell lymphoma (DLBCL), based on gene expression profiling, oncologists can identify subtypes based on cell of origin: germinal center or postgerminal center. Patients with postgerminal center DLBCL tend to have an inferior prognosis compared with patients with the germinal center DLBCL. With DLBCL, as with mantle cell lymphoma, it has become evident that the most important prognostic factor may be the proliferation rate. Mantle cell lymphoma that is growing very rapidly and very aggressively, with a Ki-67 index of more than 30% or 40%, represents highly aggressive disease that needs to be treated in a very aggressive fashion, O’Connor said. Furthermore, subtypes of mantle cell lymphoma have been identified where the proliferation rate is very, very low. These are more like the indolent lymphomas, follicular and small lymphocytic lymphoma, and patients with these lymphomas actually have a very favorable long-term prognosis. Personalized treatment a possibility This ability to fractionate disease subtypes based on underlying molecular pathogenesis opens the door for personalizing treatment opportunities. “So the idea that we can now begin to tailor therapies, that we can personalize the treatment for some of the underlying biologies, is becoming a reality,” O’Connor said. He continued, “You might imagine that in the future, we will treat patients who have aggressive mantle cell lymphoma with very aggressive induction chemotherapy regimens followed by transplant, versus those patients with Continued on page 29

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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

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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.

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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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Personal Finance

The Golden Years: Are You Financially Prepared? By Eileen Koutnik-Fotopoulos

ost people understand the importance of saving for retirement and want to save more, but do not know where to begin.

December 2010 I VOL 3, NO 8

Furthermore, the economic downturn has resulted in fewer people putting away money for retirement. The lack of retirement knowledge

and individuals not doing a good job of saving and planning for retirement is reflected in two October 2010 surveys. Major findings from an online survey of 2000 adults (aged 21-65) released by the Teachers Insurance and Annuity Association-College Retirement Equities Fund (TIAACREF), a national financial services organization, finds: • 93% of participants know that saving is essential for financial security, but 82% admit that they do not know how much they should be saving • 39% of participants are not saving at all for retirement • 77% of participants report that they plan to save more for retirement next year • 65% of participants say they will be unable to retire in the manner they hoped. The 2010 Retirement Confidence Survey from the nonprofit research organization Employee Benefit Research Institute (EBRI) estimates that the nation’s aggregate retirement savings shortfall is $4.55 trillion. This translates to an overall average of $47,732 per individual aged 36 to 62 years. The survey included 1153 adults aged 25 years and older. Among the survey’s key findings: • Only 16% of respondents report being very confident about having enough money to retire comfortably • 69% of respondents report that they and/or their spouse have saved for retirement and 60% are currently saving for retirement • 54% of respondents say that the total value of their household’s savings and investments, excluding the value of their primary home and any defined benefit plans, is less than $25,000 • 46% of respondents report that they and/or their spouse have tried to calculate how much money they will need for a comfortable savings • 24% of respondents report that they have postponed their planned retirement age in the past year. The TIAA-CREF and EBRI surveys demonstrate that a majority of individuals need to put more thought and effort into their retirement savings. Determining how much to save depends on your situation and needs. Here are suggestions to help you plan more effectively for your golden years: • Determine the age you want to retire and how much you will need in retirement. If you plan to retire before age 65, you may need a more

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Personal Finance aggressive savings plan. Think about the lifestyle you want during retirement. Do you plan to travel more or indulge in expensive hobbies? Will you continue to work part-time for an employer or on your own? • Calculate the cost of retirement once you determine the lifestyle you want. Consider the additional healthcare costs that often accom-

pany aging and determine the income you will need for these expenses. • Identify your sources of retirement income, including your personal savings and investments, your IRA, 401(k), or other employee-sponsored plans, and Social Security. How much income will these

sources provide? Determine the amount and frequency of withdrawals you will need from these vehicles without depleting them. • Review your portfolio and adjust your savings and investment strategies if you do not think you will have enough to meet your retirement needs.

• Monitor your progress. Once strategies are in place, you will need to follow your progress to make sure you are on track to reach your retirement savings goals. Keep in mind that you will probably need to make adjustments in your planning to reflect market changes and family needs. ●

A Friday Satellite Symposium preceding the 52nd ASH Annual Meeting HEMATOLOGIC CANCERS

Lymphoma Expert Outlines Recent Refinements... Continued from page 26

more favorable prognostic disease that can be ‘watched and waited’ or given single-agent rituximab.” Shift in treatment goals At the same time that progress in treatment efficacy has been occurring, a change with respect to general attitudes about side effects has led to a shift in treatment goals. The operant question, O’Connor said, has become, “Are we treating that patient with curative intent or as someone with a chronic disease? I think we’re getting much more sophisticated and less addicted to the idea that everybody needs to be cured.” Follicular lymphoma, he continued, is a great example, because it is a disease of people who are older than 60 years. With simple, well-tolerated therapies like rituximab, patients can be kept alive for 15 to 20 years or more, and will likely die of something other than the cancer. If the treatment goal is to cure the patient, for example, someone with Hodgkin lymphoma or with DLBCL, then asking them to tolerate a little bit more toxicity and risk for the bigger gain is justified. But with indolent disease, excessive treatment or overuse of chemotherapy will, with time, only make the lymphoma more drug resistant and the natural host cells more sensitive to future therapy. “There, I believe, we are getting a lot wiser and smarter about titrating therapies for the aggressiveness of the disease. We’re really trying to manage the patients as if they have a chronic disease, much the way cardiologists manage heart disease or an endocrinologist manages diabetes. The idea is that we don’t need to cure everybody, and, in many cases, we now have the pharmacologic tools to manage them.” ●

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Challenging Cases in Multiple Myeloma A Dialogue Between Community and Academic Clinicians to Improve Patient Care and Outcomes December 3, 2010 Rosen Centre Hotel Ballrooms A & B, Orlando, Florida Register online today at www.myelomacases.com/register PROGRAM DESCRIPTION

PROGRAM AGENDA

This continuing medical education symposium will serve as a forum for discussion of current questions and concerns regarding the treatment and management of patients through the multiple myeloma (MM) life cycle. A panel of domestic and international myeloma experts will be joined by representatives from community cancer care facilities and private oncology practices. By thoroughly engaging participants with interactive cases and physician point-counterpoint-style discussions, this symposium will provide evidence-based treatment and management recommendations and address new treatment regimens and management strategies based on recent clinical trials and emerging data. In addition to considering differences in domestic and international care, barriers and/or limitations faced by community cancer centers and private-practice oncologists will be debated.

12:30 -

1:00 PM

Registration and Lunch Service

1:00 -

1:10 PM

Welcome and Introduction Sundar Jagannath, MD - Chair

CASE PRESENTATIONS Each case will be presented by an expert faculty member and discussed by the international and community panel. 1:10 – 1:40 PM

Case 1: Difficult diagnosis G. David Roodman, MD, PhD

1:40 – 2:10 PM

Case 2: Newly diagnosed, stem cell transplant eligible patient Sundar Jagannath, MD

2:10 – 2:40 PM

Case 3: First-line therapy in a non-SCT eligible patient Stefan Knop, MD

2:40 – 3:10 PM

Case 4: Multiple risk factors Jonathan L. Kaufman, MD

3:10 – 3:40 PM

Case 5: Treatment of MM across the life cycle Noopur Raje, MD

3:40 -

3:50 PM

Question & Answer Session

3:50 -

4:00 PM

Closing Remarks Sundar Jagannath, MD

LEARNING OBJECTIVES At the end of this activity participants will be able to: • Apply early management strategies that consider new diagnostic and staging criteria for SMM, MGUS, and MM and new imaging studies in order to improve prognosis for your patients. • Evaluate novel therapeutic regimens as induction therapy for your patients considering an SCT in order to provide the most rapid response and allow the largest amount of stem cell collection, while maintaining safety and tolerance. • Integrate novel agent-based regimens that provide optimal outcomes and a survival benefit into your management strategy for patients ineligible for SCT after appraising emerging data from clinical trials. • Identify patient- and disease-associated factors that impact choice of therapeutic agent and formulate management strategies using a risk-adapted approach to treatment of MM. • Construct optimal treatment regimens based on novel combinations and make informed treatment decisions in order to improve the long-term outlook for myeloma patients across the life cycle of the disease.

TARGET AUDIENCE This activity has been developed for hematologists and medical oncologists, as well as nurses, pharmacists, and other allied health professionals who are interested in meeting the challenges faced when treating patients with multiple myeloma in academic and community settings.

ACCREDITATION INFORMATION Physician Accreditation The University of Cincinnati designates this activity for a maximum of 3 AMA PRA Category 1 Credits ™. The University of Cincinnati is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity. Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 3.0 contact hours. Registered Pharmacy Designation Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 3.0 contact hours (0.3 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-10-058-L01-P.

FACULTY CHAIR: Sundar Jagannath, MD Professor, Hematology and Medical Oncology Mount Sinai School of Medicine’s Tisch Cancer Institute Director of the Multiple Myeloma Program, The Mount Sinai Medical Center New York, NY Leon Dragon, MD, FACP Medical Director Kellogg Cancer Center Northshore University HealthSystem Highland Park, IL

Stefan Knop, MD University Hospital Würzburg Würzburg, Germany

Charles M. Farber, MD, PhD Section Chief of Hematology and Oncology Department of Medicine Carol G. Simon Cancer Center, Morristown, NJ Shoba Kankipati, MD Associate Physician EPIC Care East Bay Partners in Cancer Care San Francisco Bay Area, CA Jonathan L. Kaufman, MD Assistant Professor Blood and Marrow Transplantation Department of Hematology and Medical Oncology Emory University School of Medicine Member, Winship Cancer Institute Emory University, Atlanta, GA

Noopur Raje, MD Associate Professor of Medicine Harvard Medical School Director, Center for Multiple Myeloma Massachusetts General Hospital Boston, MA G. David Roodman, MD, PhD Professor of Medicine Vice Chair for Research Department of Medicine Director, Myeloma Program Director, Bone Biology Center University of Pittsburgh Medical Center Pittsburgh, PA Ari Umutyan, MD Redwood Regional Medical Group Hematology and Medical Oncology Napa, CA

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

This activity is jointly sponsored by the University of Cincinnati, Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC.

December 2010 I VOL 3, NO 8

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Conference News ONCOLOGY CONGRESS

PARP Inhibitors Show Promise in Trials By Laird Harrison

SAN FRANCISCO—Poly(ADP-rib - maintained for a long period of time, ose) polymerase (PARP) inhibitors are getting close to 1 year in the average showing impressive potency against patient,” said Armstrong. ovarian cancer in early clinical trials, The drug appears to work by interferaccording to Deborah Armstrong, MD, ing with the process by which tumor an associate professor of oncology, gyne- cells repair themselves. cology, and obstetrics at Johns Hopkins DNA damage can happen for many University, Baltimore, Maryland. reasons, including platinum therapy. At least eight companies are testing Cells repair single-strand DNA damage PARP inhibitors and one through a process called agent, iniparib (BSI-201, base excision repair. They BiPar Sciences), is in phase 3 repair double-strand damclinical trials with applicaage through homologous tions to the US Food and recombination (otherwise Drug Administration (FDA) known as nonhomologous clearly on the horizon, she end-joining). said at the sixth annual Base excision repair deOncology Congress. “One pends on PARP, which of these drugs will see the binds to single-strand breaks light of day fairly soon and and recruits DNA repair Deborah Armstrong, MD will be going to the FDA enzymes. Without PARP, pretty quickly,” Armstrong single-strand breaks are not predicted. repaired; instead they become doublePARP inhibitors appear especially strand breaks. effective when combined with platinum This is germane to cells with BRCA drugs, but even on their own they can mutations, because the BRCA1 and improve ovarian cancers in some BRCA2 genes supply proteins critical patients, she said. And the drugs have for the repair of a double-strand break. shown some promise against breast can- Without these proteins, a doublecer as well. strand break results in a collapsed fork In ovarian cancer, PARP inhibitors and cell death. appear most effective in patients with People with BRCA gene mutations mutation in the BRCA1 or BRCA2 gene. have one normal and one mutated copy In one recent trial in patients with a of these genes. Cancers occur when the BRCA1 or BRCA2 mutation and recur- normal gene is damaged by an event rent ovarian cancer (Audeh MW, et al. such as exposure to ionizing radiation. Lancet. 2010;376:245-251), 11 of 33 However, only the tumor cells have two patients responded to 400-mg twice- damaged copies; the body’s other cells daily olaparib. “These responses were maintain a normal copy of the gene.

If PARP is inhibited, single-strand breaks become double-strand breaks in both the tumor cells and the healthy cells. The tumor cells cannot repair this damage so they die. But the healthy cells are able to repair their DNA using homologous recombination with proteins provided by their normal BRCA1 or BRCA2 genes. “So the tumor cells are much more sensitive to low-level PARP inhibition,” said Armstrong. “And this gives us a very nice clinical window to use.” Because some patients without BRCA defects also respond to PARP inhibition, researchers are wondering if there could be other types of defects related to the homologous recombination pathway that repairs double-strand breaks. Besides BRCA mutations, a somatic deletion of both BRCA genes or promoter methylation could also interrupt the pathway. Some investigators have proposed defects in other genes involved in homologous recombination, such as RAD51. Others have suggested somatic mutations affecting the pathway. “High-grade serous ovarian cancers may be defined by the defects in this pathway,” said Armstrong. “There have been estimates this could be in as many as 5% to 31% of ovarian cancers.” She cited a survey reported by Doug Levine, MD, a gynecologic oncologist at Memorial Sloan-Kettering Cancer Center, New York, which found that 49% of the ovarian cancers they studied had defects in the homologous recombination pathway.

“So I think that leads us to the concept that maybe this is a good target for at least a significant minority of hybrid ovarian cancers, and potentially even the majority of high-grade serous cancers,” Armstrong said. The latest research also supports therapies in which a PARP inhibitor is paired with platinum therapy. In a study presented last year by O’Shaughnessy and colleagues, the PARP inhibitor BSI-201 was combined with gemcitabine/carboplatin in patients with triple-negative metastatic breast cancer (J Clin Oncol. 2009;27:18[suppl]:Abstract 3). Of the 44 patients receiving only the chemotherapy, seven (16%) achieved an objective response. Of the 42 patients receiving the BSI-201 in addition to the chemotherapy, 20 (48%) responded, a statistically significant difference (P = .002). “This is the really astounding data,” said Armstrong. “You essentially saw a tripling of the response rate.” She added that in the O’Shaughnessy study there was essentially no additional toxicity when BSI-201 was added to the chemotherapy. However, she warned that there are still very little data on toxicity because PARP inhibitors have rarely been matched against placebo in clinical trials. “We have DNA repair processes for a reason,” she said. “Will we be seeing a higher rate of secondary malignancies if we are inhibiting DNA repair processes?” She’s looking forward to that answer from the next round of research, now under way. ●

Prevention (CDC) invited 15 experts to serve on the Advisory Committee on Breast Cancer in Young Women. This committee is tasked with helping the agency develop evidence-based approaches to its mission. The experts, ranging from researchers to clinicians to breast cancer survivors, will work on approaches to prevention research, public awareness campaigns, and education efforts.

Americans worry about. For example: • 80% of respondents did not know that lung cancer is the number one killer • 83% of female respondents and 75% of male respondents did not know that lung cancer takes more lives than breast and prostate cancer, respectively • Only 12% of respondents knew the symptoms of lung cancer, as well as that radon is the second leading cause of lung cancer • Only 6% of respondents had spoken to their doctor about their risk for lung cancer • 32% of respondents knew that half of lung cancer occurred in patients who had previously quit smoking • 98% of respondents recognized that lung cancer does not just affect people who smoke. ●

News Notes Position Statement for AYA Patients with Cancer The LIVESTRONG Young Adult Alliance has released a position statement on quality cancer care for adolescents and young adults (AYAs). The statement notes four critical elements of care: (1) timely detection; (2) efficient processes for diagnosis, initiation of treatment, and promotion of adherence; (3) access to healthcare professionals who possess knowledge specific to the biomedical and psychosocial needs of this population; and (4) research that will ultimately derive objective criteria for the development of AYA oncology care guidelines. The statement details specific critical elements, sample strategies, and outcome measures for improving survival, quality of life, and quality of care throughout the cancer care continuum.

December 2010 I VOL 3, NO 8

The LIVESTRONG Young Adult Alliance intends for this statement to be a first step toward raising awareness of the need for guidelines for AYA patients with cancer and recognizes the need to test and validate the extent to which its recommendations result in improved survival and quality of life. The position statement was the outcome of a meeting of clinicians, re searchers, and advocates convened in June 2009.

CDC Advisory Committee on Breast Cancer in Young Women As part of its efforts to develop initiatives to improve knowledge of breast health and breast cancer, particularly in women younger than 40 years of age and those at elevated risk, the US Centers for Disease Control and

Americans Need Lung Cancer Education Americans lack knowledge about lung cancer—its causes, its symptoms, its death rates—according to a survey released by the National Lung Cancer Partnership. The survey of 1000 adult men and women found that even though lung cancer is the number one cancer killer, it is not a disease that

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Presents the Third Annual Curriculum for

CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, are pleased to offer your multidisciplinary cancer team this series of newsletters focusing on the challenges of treating patients with multiple myeloma.

SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University School of Medicine

★ Earn Continuing Education Credits ★ 8-part newsletter series

CASE STUDY DISCUSSIONS: • Front-line Therapy

• Non-Transplant Patients

• Maintenance Settings

• Cytogenetics

• Transplant Settings

• Side Effect Management

• Retreatment Settings

• Bone Health

Each newsletter will feature: • Contributions from thought-leading physicians, nurses, and pharmacists

• Continuing Education credits available to physicians, nurses, and pharmacists

PARTICIPATE TODAY at www.COEXM.com For complete learning objectives and accreditation information, please refer to each activity.

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

These activities are jointly sponsored by

These activities are supported by an educational grant from Millennium Pharmaceuticals, Inc.

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Conference News ESMO

The following articles are based on presentations at the 35th European Society for Medical Oncology Congress held in Milan, Italy, October 8-12, 2010.

For Breakthrough Cancer Pain, Fentanyl Nasal Spray Easily Titratable and Effective By Caroline Helwick

MILAN—Breakthrough pain in cancer patients can be managed easily and effectively with fentanyl pectin nasal spray (FPNS), according to new data. FPNS can be easily titrated to an effective dose and there is little need for rescue medication, according to David Brooks, MD, of Chesterfield and North Derbyshire Royal Hospital NHS Trust in Chesterfield, United Kingdom. “This study shows that if you put in the effort, you can titrate this drug to the right dose in the majority of patients, and they will stick with the treatment and achieve successful pain control,” Brooks said. The study’s first author was Luis Torres, MD, of the Servicio de Anestesia-Reanimacion y Tratamiento del Dolor, Hospital Puerta del Mar in Cadiz, Spain. Typically, breakthrough pain has a

rapid onset and is severe to excruciating in intensity, although the pain’s duration is relatively short, he said. Currently, immediate-release morphine is still the mainstay of treatment but takes at least 30 minutes for maximum effect. “Its onset is too slow for the appropriate management of breakthrough pain,” Brooks noted. Intranasal drug delivery is a simple and acceptable means of administering strong analgesics, and has rapid absorption, he said. Brooks reported on an analysis of the open-label dose-titration outcomes in the FPNS phase 3 clinical trial program involving 500 cancer patients with breakthrough pain. The program consisted of three studies, which found that there was rapid onset of efficacy and significant pain relief for FPNS versus placebo. The current analysis of

the program evaluated FPNS’s ease of titration, speed of relief, and reliability. Of the 500 patients, 401 (80.2%) were successfully titrated and continued through their treatments. Overall, they were successfully titrated to the following dosages: 100 µg (17.7%), 200 µg (12.8%), 400 µg (32.0%), and 800 µg (28.5%). FPNS required an average of only 2.7 steps for titration across the three studies, Brooks reported. Successful dose titration did not vary by age or weight. Success rates were consistent across the three multinational trials that involved 13 countries, the authors reported. Only 8% of patients could not be successfully titrated because of an FPNSrelated reason, most commonly an adverse event or inadequate efficacy at the highest dose. Treatment-related adverse events included headache, nau-

sea, and vomiting, which were consistent with the pharmacologic effects of fentanyl. Only 6% of FPNS-treated episodes required additional rescue medication within 60 minutes, and only 10% required an increase in dose for FPNS to maintain its efficacy. Of the 205 patients who completed the open-label treatment phase, 71% elected to continue treatment with FPNS in the ensuing extension period, Brooks noted. “I see this agent used not just for breakthrough pain but to preempt pain before it occurs, such as when patients get out of bed to go to the toilet,” he added. “As a preemptive analgesic it might allow for more activity.” This study was sponsored by Archimedes Pharma, which manufactures PecFent. ●

Sex and the Cancer Patient: Still a Problem with Targeted Agents MILAN—Sexual issues related to cancer and its treatment are substantial—and do not seem to be resolving with the use of new molecular targeted agents instead of endocrine therapy and chemotherapy. This conclusion can be drawn from two studies presented by investigators from Argentina and France. Argentine investigators questioned 29 female and 21 male cancer patients on issues of sexuality. Half were married and all had good performance status. Most of the women had gynecologic cancers (48% of the total population). Gastrointestinal cancers were seen in 30% overall and urologic cancers in 12%; the remainder were respiratory, head and neck, and skin cancers. “We found the three phases of human sexual response to be affected, all reaching statistical significance. Most impact was seen in females,” said Bonicatto Silvia, MD, of the Hospital San Roque de Gonnet in Buenos Aires. “When the descriptors of ‘a little’ versus ‘not at all’ were compared, the most affected areas were arousal and orgasm.” Although 84% of all patients reported “some” sexual arousal before treat-

December 2010 I VOL 3, NO 8

ment, this fell to 53% after treatment. Conversely, before treatment 16% reported “no arousal,” and this rose to 47% after treatment, Silvia reported. For orgasm, “some” orgasmic function was reported by 84% before treatment, declining to 53% after treatment, whereas “no” orgasms were reported by 16% and 47%, respectively. Desire was somewhat less affected, with 86% reporting desire at baseline and 69% posttreatment. Pre- and posttreatment means are shown in the Table. Women were particularly affected by a lack of lubrication. Before treatment, 64% reported lubrication or “vaginal wetness during sex,” but this dropped to 36% after treatment. For men, erectile dysfunction was less affected, with 52% reporting sexual function before treatment and 43% after treatment. Not surprisingly, sexual activity declined. Before their cancer treatments, 100% of men and 82% of women reported some degree of sexual activity. After treatment, 82% of men were still sexual but only 39% of women were.

Table

Desire Arousal Orgasm

Effect of Cancer Treatment on Key Sexual Areas (Scale 0-4) Before treatment (mean) 2.92 3.45 3.39

After treatment (mean) 2.47 2.31 2.61

Targeted agents affect sex life too Also at the meeting, French researchers reported on one of the few studies to investigate the impact of newer cancer treatments on sexual functioning, finding significantly decreased levels of sexual function and satisfaction in patients taking targeted therapies. Yohann Loriot, MD, and Thomas Bessede, MD, from the Institut Gustave Roussy in Villejuif, France, surveyed 51 patients (40 men, 11 women), median age 58, who had been treated with a targeted therapy for more than 3 months. The drugs involved were sunitinib, sorafenib, temsirolimus, everolimus, bevacizumab, erlotinib, and cetuximab. Men completed the International

Index of Erectile Function (IIEF) questionnaire and women completed the Female Sexual Function Index (FSFI) questionnaire. The median overall IIEF score for men was 40, which was just 53% of the maximum score (range, 5-75). Specifically, the mean scores (out of the maximum) were 14/30 for erectile function, 6/15 for intercourse satisfaction, 6/10 for orgasmic function, 6/10 for sexual desire, and 5/10 for overall satisfaction. Women scored even lower. Median FSFI was 8.4, which was just 24% of the maximum (range, 2-29.6). Mean scores were 2.2/6 for desire, 1.86/6 for arousal, 1.5/6 for lubrication, 1.7/6 for orgasm, 2.6/6 for satisfaction, and 2/6 for pain. “The sex lives of the patients in our study had reduced quality and intensity,” Loriot said. “We also found that more than half the patients expressed a wish for a satisfying sexual life, but many found it difficult to initiate a discussion on the topic with their doctors.” ● —CH Conference News continued on page 34

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value-focused www.ValueBasedCancer.com www.ValueBasedCancer.com

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Value-Based Value-BasedCancer CancerCare Care will willbebeatatthe theASCO ASCOAnnual Annual Meeting, June 4-8, in Chicago. Meeting, June 4-8, in Chicago.

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Breast Cancer Conference (EBCC7). Breast Cancer Conference (EBCC7). This improvement, the researchers By Rosemary Frei, MSc This improvement, the researchers By Rosemary Frei, MSc Barcelonaâ&#x20AC;&#x201D;Survival for patients with suggest, is due to increased use of The 2010 Genitourinary Cancers Barcelonaâ&#x20AC;&#x201D;Survival for patients with suggest, is due to rise increased use of San Francisco, CAâ&#x20AC;&#x201D;The popularity of The 2010 Progress Genitourinary Cancers metastatic breast cancer has improved anthracyclines and the of targeted Symposium: in Multi San Francisco, CAâ&#x20AC;&#x201D;The metastatic breast cancer has improved anthracyclines and the rise of targeted minimally Symposium: Progresswas in held Multidramatically in the last 20 years, espe- therapies. Management invasive radical popularity prostatec- of disciplinary minimally radical prostatec- March dramatically in the last 20 years,with espe- â&#x20AC;&#x153;There therapies. disciplinary Management cially in the subgroup of patients is no doubt that trastuzu- tomy 5-7 in San Francisco. Allwas ses-held (MIRP),invasive intensity-modulated tomy (MIRP), cially in the subgroup patients with is no which doubt that trastuzu March 5-7 in San Francisco. All sesHER2-positive tumors, of according to mab â&#x20AC;&#x153;There (Herceptin), targets the - radiation sions emphasized a multidisciplinary therapy intensity-modulated (IMRT), and of radiation therapy (IMRT), and of approach HER2-positive mab gene, (Herceptin), which important targets the brachytherapy sions emphasized a multidisciplinary research presentedtumors, at the 7thaccording European to HER2 is the most to care; a number of them combined with IMRT research presented at the 7th European HER2 gene, is the most important forbrachytherapy approach to cost care;and a number of them brought out the value issues prostate cancercombined started towith take IMRT off Continued on page 27 for 2002, prostate cancer started analysis to take off associated broughtwith out the cost for andgenitourivalue issues Continued on page 27 after caring a new database 2002, a new database analysis nary associated cancers. with caring for genitourihasafter confirmed. hasthe confirmed. nary cancers. At American Society of Clinical At the American Society of Can Clinical Oncologyâ&#x20AC;&#x2122;s 2010 Genitourinary - and Womenâ&#x20AC;&#x2122;s Hospital, Harvard Oncologyâ&#x20AC;&#x2122;s 2010Paul Genitourinary Can- Medical and Womenâ&#x20AC;&#x2122;s Hospital, Harvard cers Symposium, L. Nguyen, School, Boston, and his cocerspresented Symposium, Nguyen, Medical School, his cofoundBoston, MIRP and jumped MD, the Paul resultsL. of his investigators MD, analysis presentedof the investigators found MIRP jumped teamâ&#x20AC;&#x2122;s dataresults from of thehis from 1.5% of radical prostatectomies teamâ&#x20AC;&#x2122;s analysis of dataand from from of 28.7% radicalinprostatectomies Surveillance, Epidemiology Endthe (RPs) in 1.5% 2002 to 2005. They Surveillance, Epidemiology and End also(RPs) in 2002 28.7% in 2005. They Results (SEER)-Medicare database. found that to IMRT soared from also found that IMRT treatments soared from Results (SEER)-Medicare Dr Nguyen, director of database. Prostate 8.7% of external radiation Dr Nguyen, director of Prostate 8.7% of external radiation treatments addiBrachytherapy, Dana-Farber/Brigham for prostate cancer to 81.7%. In Brachytherapy, Dana-Farber/Brigham for prostate cancer to 81.7%. In 24 addiContinued on page

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Conference News ESMO

Prolonging Chemotherapy in Metastatic Breast Cancer Improves Survival MILAN—Prolonging chemotherapy until disease progression improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic breast cancer (MBC), according to a systematic analysis conducted in Italy. The findings address an important debate in oncology, said Alessandra Gennari, MD, of Ospedali Galliera in Genova. “In metastatic breast cancer there is substantial controversy over how long chemotherapy should be continued in the absence of significant toxicity, after the achievement of disease control,” said Gennari. Typically, the number of cycles tends to be based on the response to treatment, symptomatic improvement, patient tolerability and, “most importantly,” physician preference, she said. “We asked whether prolonging chemotherapy after patients respond or stabilize would be associated with longer survival and time to progression.” The investigators searched for randomized trials in the first-line MBC setting comparing longer and shorter durations of chemotherapy. Data were

obtained from literature databases and meeting abstracts and through contact with individual authors of studies. Trials comparing different types of chemotherapy or including high-dose chemotherapy were excluded.

“These results provide support to the clinical approach of prolonging first-line chemotherapy in the absence of significant toxicity and disease progression.” —Alessandra Gennari, MD

Subgroup analyses were performed according to time of randomization, type of maintenance chemotherapy, number of cycles in the shorter arm, and whether patients received concomitant endocrine treatment.

The investigators found 11 studies involving 2269 patients to be eligible for analysis. Longer chemotherapy was better Patients receiving chemotherapy of longer duration had a 36% reduction in the risk of progression and a 9% reduction in the risk of death. “These results are more than clinically meaningful— they are statistically significant,” Gennari said at a press briefing. “The results justify why we must tell patients that they should continue chemotherapy.” Assuming that the median OS in MBC after first-line chemotherapy is 24 months, longer chemotherapy was associated with absolute improvements of about 3 months in PFS and 2 months in OS. In the regression analysis, the magnitude of this effect was remarkably similar across groups of trials, and the effect of longer chemotherapy was independent of any of the factors in the subgroup analysis. “These results provide support to the clinical approach of prolonging first-

line chemotherapy in the absence of significant toxicity and disease progression,” she commented. Questions remain as to the optimal maintenance chemotherapy, such as: Should the same drug or a different one be used? Should sequences be planned? What is the role of low-dose maintenance therapies? Would targeted agents be optimal? “Do more prolonged side effects justify a gain of 3 months in PFS and 2 months of OS?” asked Miguel Martin, MD, of the Hospital Universitario Gregorio Marañón in Madrid, who discussed the paper at the meeting. “I guess that most patients would accept that deal.” He said there were many caveats to the analysis, including potential literature bias. Many negative trials are never published, he noted. “Even considering the caveats of the analysis,” he concluded, “this Italian study provides support for the administration of chemotherapy until disease progression.” ● —CH

INTERNATIONAL NEWS

Reports from the European Association for the Study of Diabetes and the International Thyroid Congress By Jill Stein

Increased Cancer Risk in Insulin Users Decreases Over Time STOCKHOLM—New data undermine the widely held notion that the greater likelihood of cancer seen in diabetic patients on insulin therapy increases with longer insulin use. In fact, the findings, reported at the 46th European Association for the Study of Diabetes meeting, show that the increased cancer risk in diabetes drops substantially with long-term insulin use. Daniel Witte, MD, PhD, research group leader at the Steno Diabetes Center in Gentofte, Denmark, and colleagues tracked the entire Danish population of 5.5 million people over 13 years to assess the association between length of insulin use and cancer incidence. The Steno Diabetes Center is owned by Novo Nordisk. Over the past several decades, numerous studies have found elevated rates of cancer of the liver, kidney, female breast, and corpus uteri in diabetic patients. The new study confirmed that there is an excess cancer risk in patients with diabetes and also that insulin-using dia-

December 2010 I VOL 3, NO 8

betics have a higher cancer risk than diabetics not using insulin. For example, 20.9% of nondiabetic Danish men 65 years of age and older are likely to develop cancer over the next 10 years compared with 22.3% of diabetic men not using insulin and 23.7% of diabetic men using insulin. The corresponding figures for women are 15.4%, 16.1%, and 19.5%. For all cancer types combined, the effect of insulin use was highest immediately after the start of treatment and decreased to a stable level 3 to 4 years after the first insulin prescription. This pattern was also seen for the duration of diabetes, with the risk being highest in the period just after diagnosis and decreasing to a point where the patient had no excess risk after 3 years. The investigators say that theirs is the largest registry linkage study to date to focus on diabetes. The investigators noted that their results suggest that it may not be duration or insulin that carries the risk. Instead the risk may be partly due to causes common to cancer and diabetes/insulin treatment, such as obesity.

Thyroid Cancer Patients Embrace Unconventional Treatments PARIS—Most patients with thyroid cancer report that they used some form of complementary and alternative medicine (CAM) over the past 12 months, researchers reported at the 14th International Thyroid Congress. Jennifer E. Rosen, MD, assistant professor of surgery at Boston University School of Medicine, Massachusetts, and colleagues analyzed responses to an online questionnaire on CAM use that was completed by 1324 patients who belonged to a thyroid cancer survivors’ organization. The survey found that 80% of patients said they had used some form of CAM therapy during the past 12 months and that only 6.6% of respondents said that they did not use any form of CAM. The two most commonly used CAM therapies were prayer (35.3%) and multivitamins (41.8%). When prayer and multivitamins were excluded from the analysis, 67.5% of patients used some form of CAM therapy during the past 12 months.

After prayer and multivitamins, the five most commonly used CAM practice therapies were massage therapy, chiropractic therapy, yoga, meditation, and acupuncture. The five most commonly used CAM biologic therapies were herbal tea, special diets, herbal supplements, homeopathy, and ginger. CAM therapies were most often used for the treatment of symptoms (69.1%), but a high percentage of patients used CAM as part of their thyroid cancer treatment (30.9%). More than half of patients (54.2%) said that they had used CAM more than 10 times in the past 12 months. About two thirds of patients believed that CAM treatments were helpful, and about one third believed that they had no effect. Nearly 20% of respondents reported that their physician did not know that they were using CAM therapies and had not inquired about CAM use. Overall, the results demonstrate that the rate of CAM use in thyroid cancer patients is twice that reported from national surveys of the general US population. ●

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Chronic Lymphocytic Leukemia The Essentials of Patient Care LOG ON TODAY TO PARTICIPATE www.coexm.com/ace02.asp Release Date: April 29, 2010 Expiration Date: April 28, 2011

TARGET AUDIENCE This activity is intended for hematologists, oncologists and others who are involved with the care of patients with Chronic Lymphocytic Leukemia (CLL).

STATEMENT OF NEED CLL is the most common type of leukemia in the United States, with over 15,000 new cases per year, characterized by the accumulation of monoclonal B cells in the bone marrow, peripheral blood, and lymphoid tissue. Primarily a disease of the elderly, the median survival for CLL varies substantially: many patients survive more than 10 years after diagnosis, but a subset of symptomatic patients have shorter life expectancies—in the range of 1.5 to 6 years. The clinical/research body of knowledge in CLL is rapidly changing and represents a challenge for the whole treatment team.

FACULTY Neil E. Kay, MD Professor Department of Medicine Mayo Clinic Rochester, Minnesota

Michael Keating, MD Course Chair Professor of Medicine Deputy Department Chairman Department of Leukemia M.D. Anderson Cancer Center Houston, Texas

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: • List the essential steps in diagnosis and treatment planning of the CLL patient • Select CLL treatment regimens based on patient characteristics • Define data supporting the benefit/risk ratio of upfront, relapsed, and refractory CLL setting • Define strategies to manage fludarabine-resistant CLL • Describe emerging therapies in CLL

This activity is supported by an educational grant from Genentech BioOncology and Biogen Idec.

This activity has been approved for 1.5 AMA PRA Category 1 Credits™. For further information and to participate, please go to: www.coexm.com/ace02.asp

In collaboration with

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9-13 HOLLYWOOD, FL National Comprehensive Cancer Network Annual Congress www.nccn.org

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

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

December 2010 I VOL 3, NO 8

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NOW IN THE TREATMENT OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

DRIVING BETTER OUTCOMES RITUXAN+FC improved median PFS in first-line and previously treated CLL1,2 In relapsed/refractory* CLL 2.1-year follow-up

In first-line CLL 1.7-year follow-up

39.8 months R-FC

26.7 months

31.5 months

R-FC

21.7 months FC

8.3

5.0

month

improvement in median

PFS

CLL8 TRIAL (N=817)

REACH TRIAL (N=552) RITUXAN-NAIVE PATIENTS

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

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

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

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

BOXED WARNINGS RITUXAN administration can result in serious, including fatal, adverse reactions. These include infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, and progressive multifocal leukoencephalopathy (PML)

Warnings and Precautions RITUXAN can also result in serious, including fatal, adverse reactions. These include hepatitis B reactivation with fulminant hepatitis and hepatic failure resulting in death; other infections, including bacterial, fungal, new or reactivated viral infections; cardiovascular events; severe, including fatal, renal toxicity; and abdominal pain, bowel obstruction and perforation, in some cases leading to death

Additional Important Safety Information The most common adverse reactions of RITUXAN (incidence ≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia. Most patients treated with R-FC experienced at least one Grade 3 or 4 adverse reaction. The most frequently reported Grade 3 or 4 adverse reaction was neutropenia In clinical trials, CLL patients 70 years of age or older who received R-FC had more Grade 3 and 4 adverse reactions compared with younger CLL patients who received the same treatment

For additional safety information, please see following page for brief summary of full prescribing information, including BOXED WARNINGS. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. References: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2010. 2. Data on file, Genentech, Inc. ©2010 Genentech USA, Inc., and Biogen Idec Inc. All rights reserved.

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