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VOL 3, NO 4
der a e L d The ews an in N eeting e M erag Cov
CANCER CENTER PROFILE
Conference News: HOPA The following articles are based on presentations at the 6th Annual Conference of the Hematology/Oncology Pharmacy Association held in New Orleans, Louisiana, March 24-27, 2010.
Changes Ahead with Healthcare Reform: What’s in Store for Oncology Pharmacy? By Caroline Helwick
In the healing garden. Back row left to right: Joy Dimagmaliw, RNC; Joann Signorino, RN-BC; Charlotte Bradley, RN, OCN; Robyn Rex, RN, OCN; Debora Velmer, RN, CCM; Patricia Molinelli, MS, RN, APN-C, AOCNS; Rita Messemer, RN; Janet Belmonte, RNC. Bottom row left to right: Amalia Apuzzio, RN-BC; Bozena Owsieniuk, RN; Erica Schermer; Kathy Wagle, PCT.
Steeplechase Cancer Center Provides Patient-centered Care in Community Setting By Karen Rosenberg
NEW ORLEANS—With the passage of the Patient Protection and Affordable Care Act, many changes are in store that will affect the field of oncology. Joseph S. Bailes, MD, chairman of the Government Relations Council and past-president of the American Society of Clinical Oncology, described what oncology pharmacists can expect in his keynote address. “Cancer is viewed in Washington as an area that needs much greater efficiency,” he said, predicting that essentialContinued on page 8
Joseph S. Bailes, MD
No, You Can’t Keep Your Health Plan Insurers and doctors are already consolidating their businesses in the wake of ObamaCare’s passage. By Scott Gottlieb, MD
teeplechase Cancer Center at Somerset Medical Center in Somerville, New Jersey, was established in 2007 in response to community needs for easily accessible high-quality cancer care. The center is named for the steeplechase horse race, held each October in the neighboring community of Far Hills, New Jersey. Proceeds from the race are donated to the center and go to support expanded facilities and services. The cancer center occupies a large, state-of-the-art facility and offers a full range of services. “It houses everything you need for diagnosis and treatment of cancer in one place,” notes Joan Perrone, RPh, one of four pharmacists who service the infusion center at Steeplechase. Somerset
Continued on page 6
resident Obama guaranteed Americans that after health reform became law they could keep their insurance plans and their doctors. It’s clear that this promise cannot be kept. Insurers and physicians are already reshaping their businesses as a result of Mr. Obama’s plan. The health-reform law caps how much insurers can spend on expenses and take for profits. Starting next year, health plans will have a regulated “floor” on their medical-loss ratios, which is the amount of revenue they spend on medical claims. Insurers can only spend 20% of their premiums on running their plans if they offer policies directly to consumers or to small employers. The spending cap is 15% for policies sold to large employers. This regulation is going to have its biggest impact on insurance sold directly to consumers—what’s referred to as the “individual market.” These policies cost more Continued on page 6
Y TAR EN LIM P M CO
Inside Conference News
Active Surveillance as a Management Strategy for Low-risk Prostate Cancer
EPO Ordering Form Improves Guidelines Compliance, Saves Practices Money Based on a presentation by Siu-Fun Wong, PharmD
National Safe Handling Initiative An interview with Timothy Tyler, PharmD, FCSHP
page 26 ©2010 Green Hill Healthcare Communications, LLC
Fostering a Dialogue to Improve Patient Care & Outcomes
Submit your cases online today at www.myelomacases.com
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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 guidelines3,4 and oncology safety standards5.
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. TOT0111/4-10 Totect and its logo mark are registered trademarks of TopoTarget A/S Image is copyright © Photo Researchers, Inc. Pharma Chemo Ad 4 23 10 indd 1
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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.
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 Symbion Science Park Fruebjergvej 3 DK-2100 Copenhagen Denmark
TOT0111/4-10 © 2010 TopoTarget USA
Pharma Chemo Ad 4 23 10 indd 2
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Editorial Board EDITOR-INCHIEF Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK
Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Center 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 Fausel, PharmD
Christopher J. Lowe, PharmD
John M. Valgus, PharmD, BCOP
Indiana University Simon Cancer Center Indianapolis, IN
Novant Health Winston-Salem, NC
University of North Carolina Hospitals and Clinics Chapel Hill, NC
David Baribeault, RPh, BCOP
Rebecca S. Finley, PharmD, MS
Emily Mackler, PharmD, BCOP
Boston Medical Center Boston, MA
Jefferson School of Pharmacy Philadelphia, PA
University of Michigan Health System & College of Pharmacy Ann Arbor, MI
Gary C. Yee, PharmD, FCCP, BCOP
Betty M. Chan, PharmD, BCOP
David C. Gammon, BS Pharm
Laura Boehnke Michaud, PharmD, BCOP, FASHP
John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
USC/Norris Cancer Hospital Los Angeles, CA
University of Massachusetts Memorial Hospital Worcester, MA
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. Dâ€™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
June 2010 I VOL 3, nO 4
Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
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he American Society of Clinical Oncology (ASCO) annual meeting ended this week but reports from the meeting are still appearing in the medical websites and daily newspapers and newscasts. New drugs and drug combinations are showing promise for many types of cancer. As these drugs become available for clinical practice, oncology pharPatrick Medina, macists will be called upon to conPharmD, BCOP fer with other members of the healthcare team and help determine which ones to use in our own practice and how best to use them. We will also have responsibility to educate patients and their caregivers about these new medications or combinations of agents not previously given, how to prevent or manage their possible adverse effects, and their potential for interactions with other drugs or supplements they may be taking. But our job does not end there. Many new therapies come with high costs, and pharmacists will increasingly have to be involved in the discussion of cost-effectiveness
PUBLISHING STAFF Publisher Philip Pawelko firstname.lastname@example.org Editorial Director Karen Rosenberg email@example.com Associate Editor Dawn Lagrosa firstname.lastname@example.org Director, Client Services John W. Hennessy email@example.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto firstname.lastname@example.org Executive Administrator Andrea Boylston Circulation Department email@example.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938
and comparative effectiveness and of practical issues, such as how to ensure reimbursement and minimize waste. Reports from the annual meeting of the Hematology/ Oncology Pharmacy Association provide examples of pharmacists’ approachs to these practical concerns. The Oncology Pharmacist attempts to filter news from ASCO and other major meetings through a pharmacist’s perspective, presenting not only results of large clinical trials but also of smaller studies that do not get as much attention, such as a study of a pharmacist/nurse model for supportive care or of use of computerized physician order entry to reduce prescribing errors. Finally, although many oncology pharmacists are involved in clinical trials and research, there are limited opportunities to publish their results. To help fill this gap, Green Hill Healthcare Communications will launch the Journal of Hematology Oncology Pharmacy later this year. We invite submissions of original research reports, reviews of disease state management and new drugs, case reports, and articles on practical issues in pharmacy management related to the treatment of patients with hematologic or oncologic malignancies. Please send inquiries about manuscript preparation to firstname.lastname@example.org and look for a call for papers in late summer or early fall. ●
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241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831 EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Email: email@example.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. ISSN #1944-9607. The Oncology Pharmacist is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2010 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare 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. ®
June 2010 • VOL 3, nO 4
FEATURE ARTICLES 9 Conference News: HOPA Palonosetron reduces readmissions for CINV in patients receiving IP cisplatin EPO ordering form improves guidelines compliance, saves practices money Oncology pharmacists can significantly reduce chemotherapy waste Standardized forms facilitate COG treatment
11 Breast Cancer Concurrent trastuzumab with chemotherapy beats sequential use for HER2-positive breast cancer Three new drugs on the horizon for HER2-positive breast cancer
14 Continuing Education Active surveillance as a management strategy for low-risk prostate cancer
22 Drug Therapy New treatments for chronic idiopathic thrombocytopenic purpura. Part 2. Eltrombopag
26 Safe Handling National safe handling initiative serves as reminder of need for precautions when handling hazardous drugs
DEPARTMENTS 16 News Notes 18 Oncology Drug Codes Lung cancer
28 International News 28 Financial Planning 29 Meetings
June 2010 I VOL 3, nO 4
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Taking a broader view — charting a unique course in cancer care
At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community. A commitment to patients — We created Genentech BioOncology™ Access Solutions™, a single source for all access and reimbursement issues, so healthcare providers can remain focused on patient care. Reducing barriers to treatment — We help make treatment possible for patients in financial need through our BioOncology Co-Pay Card Program and ongoing charitable donations to various independent nonprofit organizations in support of co-pay assistance. A commitment to care — Our first product was approved in 1985, and since then we have donated approximately $1.5 billion in medicine to uninsured patients through the Genentech® Access to Care Foundation and other donation programs. Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care.
© 2010 Genentech USA, Inc. All rights reserved. 10201400 Printed in USA.
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Cancer Center Profile Steeplechase Cancer Center...
Continued from cover
Left to right: radiation oncologist Joel Braver, MD; urologist Joel Fischer, MD, chair of the Prostate Cancer Institute; Kathleen Toomey, MD, medical director of the Steeplechase Cancer Center; and Katrina Losa, RN, director of the Steeplechase Cancer Center.
Medical Center is the only full-service counseling, a cancer registry, clinical trihospital in the county, and “it’s an inte- als, rehabilitation medicine, palliative gral part of the community,” she says. care and pain management, and nutri“We do community fundraisers and are tion counseling. “Besides the clinical triwell supported by the community.” als that are available to patients, there Kathleen Toomey, MD, are four multidisciplinary medical director of the cancer groups [breast, prostate, cocenter, notes that patients are lorectal, and lung] that come not only able to get their care together and discuss cases. In close to home but are able to the case of breast and colon continue to see their own doccancer, all new cases are distors. “The doctors who know cussed in a multidisciplinary the patients best are here and forum,” Toomey says. The can help coordinate their care Tobacco Quitcenter is availwith the many specialists.” Joan Perrone, RPh able to help patients stop In addition to medical, radismoking. ation, and surgical oncology, Somerset Medical Center Steeplechase’s services include plastic is a clinical research affiliate of The surgery, a breast care center, genetic Cancer Institute of New Jersey, allowing
patients access to clinical trierators, flat-screen televisions, als. Currently, patients are and DVD/VHS players. enrolled in treatment trials Patricia Molinelli, MS, RN, for breast, prostate, renal, APN-C, AOCNS, is nurse bladder, and colorectal canmanager of the inpatient and cers as well as chemotherapyoutpatient oncology units. She induced peripheral neuropacame to the center from large thy. There are also industry academic medical centers in registry trials in multiple New York and values the intiPatricia Molinelli, myeloma and chronic lymmacy afforded by working in a MS, RN, APN-C, phocytic leukemia and a large smaller setting. “I try to know AOCNS annual screening trial for one thing that is important to prostate cancer. “We accrued every patient,” she says. Care 92 patients to trials last year, 23 on treat- at the center is patient-centered. As ment trials and 69 on the screening trial,” Molinelli describes it, “I am the gateToomey notes. keeper, the coordinator of all these orbits. A complementary medicine suite pro- The patient is the sun.” She views family vides a variety of services including members and other caregivers as “an yoga, meditation, and massage. Other extension of the patient” and takes care resources include a patient library, an to provide for their comfort with a wellonsite wellness boutique, a survivorship stocked pantry, games, and DVDs for visprogram, a healing garden, and educa- itor use. “We try to take a lot of the burtional and support groups for patients den off the family,” she explains. She also and their families. points to the latest technology in eviThe Steeplechase Cancer Center dence throughout the center. “We rush to earned its 3-year Community Com- get whatever is available to reduce medprehensive Cancer Program accredita- ical errors and increase patient safety.” tion from the American College of Her current goal is to incorporate genetSurgeons in 2008, and it ranks in the ics into the cancer program. 99th percentile for patient-satisfaction Other future plans include a new scores in New Jersey. interdisciplinary group for lymphoma, Inpatient services are provided at the myeloma, and leukemias, and a head 35-bed Paul R. Nardoni Oncology and neck group as well as gynecologyPavilion. Patient rooms have sofa beds oncology and palliative care programs, for visitors wishing to stay overnight in and a men’s cancer support group. A addition to amenities such as blanket Day of Hope is planned for cancer surwarmers, lounge chairs, showers, refrig- vivor month. ●
No, You Can’t Keep Your Health Plan Continued from cover to market. They also have higher medical costs, owing partly to selection by less healthy consumers. Finally, individual policies have high start-up costs. If insurers cannot spend more of their revenue getting plans on track, fewer new policies will be offered. This will hit WellPoint, one of the biggest players in the individual market, particularly hard. The insurance company already has a strained relationship with the White House: Earlier this month Mr. Obama accused WellPoint of systemically denying coverage to breast cancer patients, though the facts don’t bear that out. Restrictions on how insurers can spend money are compounded by simultaneous constraints on how they can manage their costs. Beginning in 2014, a new federal agency will standardize insurance benefits, placing minimum actuarial values on medical policies. There are also mandates forcing insurers to cover a lot of expensive primary-care services in full. At the same time, insurers are being blocked from raising premiums—for now
June 2010 I VOL 3, nO 4
by political jawboning, but the threat of legislative restrictions looms. One of the few remaining ways to manage expenses is to reduce the actual cost of the products. In health care, this means pushing providers to accept lower fees and reduce their use of costly services like radiology or other diagnostic testing. To implement this strategy, companies need to be able to exert more control over doctors. So insurers are trying to buy up medical clinics and doctor practices. Where they can’t own providers outright, they’ll maintain smaller “networks” of physicians that they will contract with so they can manage doctors more closely. That means even fewer choices for beneficiaries. Insurers hope that owning providers will enable health policies to offset the cost of the new regulations. Doctors, meanwhile, are selling their practices to local hospitals. In 2005, doctors owned more than two-thirds of all medical practices. By next year, more than 60% of physicians will be salaried
employees. About a third of those will be working for hospitals, according to the American Medical Association. A review of the open job searches held by one of the country’s largest physicianrecruiting firms shows that nearly 50% are for jobs in hospitals, up from about 25% five years ago. Last month, a hospital I’m affiliated with outside of Manhattan sent a note to its physicians announcing a new subsidiary it’s forming to buy up local medical practices. Nearby physicians are lining up to sell—and not just primary-care doctors, but highly paid specialists like orthopedic surgeons and neurologists. Similar developments are unfolding nationwide. Consolidated practices and salaried doctors will leave fewer options for patients and longer waiting times for routine appointments. Like the insurers, physicians are responding to the economic burdens of the President’s plan in one of the few ways they’re permitted to. For physicians, the strains include higher operating costs. The Obama health plan puts expensive new mandates
on doctors, such as a requirement to purchase IT systems and keep more records. Overhead costs already consume more than 60% of the revenue generated by an average medical practice, according to a 2007 survey by the Medical Group Management Association. At the same time, reimbursement under Medicare is falling. Some specialists, such as radiologists and cardiologists, will see their Medicare payments fall by more than 10% next year. Then there’s the fact that medical malpractice premiums have risen by 10%-20% annually for specialists like surgeons, particularly in states that haven’t passed liability reform. The bottom line: Defensive business arrangements designed to blunt ObamaCare’s economic impacts will mean less patient choice. ● Dr. Gottlieb, a former official at the Centers for Medicare & Medicaid Services, is a fellow at the American Enterprise Institute and a practicing internist. He’s partner to a firm that invests in health-care companies. Reprinted with permission. © Scott Gottlieb. Originally printed in Opinion Journal. The Wall Street Journal. May 18, 2010.
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ALOXI provides powerful CINV prevention that can’t be ignored. ®
ALOXI is the only IV 5-HT3 antiemetic specifically approved for the prevention of both acute and delayed CINV. • Powerful chemotherapy-induced nausea and vomiting (CINV) prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy1,2 • Powerful acute CINV prevention following highly emetogenic chemotherapy3
Eisai offers: • Contracting opportunities • Reimbursement resources Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy. Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of Full Prescribing Information. References: 1. Gralla R, et al. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, et al. Cancer. 2003;98:2473-2482. 3. Aapro MS, et al. Ann Oncol. 2006;17:1441-1449.
STARTS STRONG. LASTS LONG.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO00035-A 05/10
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Conference News HOPA
Changes Ahead with Healthcare Reform... Continued from cover ly all aspects of oncology will be affected by healthcare reform. “This horse has left the barn, and they tied an awful lot to it,” he said of the act. “We will all be engaged in this, whether we like it or not.” ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy. Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates reported in practice. In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1). Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study. In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear. Dermatological: < 1%: allergic dermatitis, rash. Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia. Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.
But this “engagement” does not have to be negative, he indicated. The healthcare reform act illustrates “the critical role that oncology pharmacy plays” in areas that include drug development and General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome. Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy. Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia. Musculoskeletal: < 1%: arthralgia. Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia. Psychiatric: 1%: anxiety, < 1%: euphoric mood. Urinary System: < 1%: urinary retention. Vascular: < 1%: vein discoloration, vein distention. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting. DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low. Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone. In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase). A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction. In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents. Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed. Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown. Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
usage, literature evaluation, development of pathways and guidelines, and comparative effectiveness research (CER), he told attendees. It is estimated that at least half the Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established. Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients. Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated. Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment. Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment. Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized. OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed. Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information]. • Patients should be instructed to read the patient insert. Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449-A 08/09
compounds now in clinical development are oncolytics, and many are oral agents that will require strict monitoring. “You are critical to this area,” he said. Pharmacists will also be central players in the merging of major medical and pharmacy benefits. This has many implications; for example, it could affect how institutions will issue formularies, he said. Risk evaluation and mitigation strategies, which the US Food and Drug Administration is increasingly putting in place for drug safety and monitoring, will fall under the auspices of pharmacy. Finally, “step therapy,” which is commonly used in other diseases, may enter oncology, although Bailes said he does not see this “fitting in with how oncologists practice.” Evaluation of the medical literature is becoming important in the development of compendia and in justifying or denying the off-label use of drugs. “You will see the Centers for Medicare & Medicaid Services doing a more critical read of the clinical trial literature, especially with regard to the study populations. You will see this evolving fairly rapidly as a way for Medicare to deal with compendia problems,” he predicted. Pathways and guidelines are being increasingly promoted by payers, institutions, and practices. It is unclear what this means for choice of treatments, but evidence-based development is critical, as is monitoring of compliance. “You, the oncology pharmacists, will be at the center of these discussions in your institutions because your work revolves around pharmaceuticals,” he said. CER will change practice CER aims to assess how various drugs, devices, therapies, or procedures compare in treating a disorder. It is a major focus of the movement to obtain valuebased cancer care. In oncology, the major focus is on drugs and their cost implications. The Institute of Medicine has articulated 100 priority topics for CER. How this research is conducted will be very important, and there is a need for methodology to compare studies. In 2009-2010, CER received significant short-term funding ($1.1 billion) from the American Recovery and Reinvestment Act. Current healthcare reform proposals would restructure this initiative and enhance long-term funding. “This has become very politicized,” Bailes noted. “In restructuring, more stakeholders have been brought in and they have an enormous say.” The Congressional Budget Office has estimated “trillions of dollars” in savings Continued on page 9
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Palonosetron Reduces Readmissions for CINV in Patients Receiving IP Cisplatin NEW ORLEANS—A retrospective analysis of healthcare resource utilization for patients with ovarian cancer receiving intraperitoneal (IP) cisplatin chemotherapy identified a trend toward more hospital readmissions for chemotherapy-induced nausea and vomiting (CINV) among patients receiving ondansetron prophylaxis, as compared with palonosetron. The study from Brigham and Women’s Hospital (BWH) in Boston was presented by Ann McDonnell, PharmD, BCOP. Palonosetron was identified as a highexpenditure drug by the Partners HealthCare System Center for Drug Policy, a center established by BWH’s integrated healthcare system to study the effectiveness of new drugs before or as they are being introduced to the market. An evaluation of prior medication use identified the gynecologic oncology group as the predominant prescriber of palonosetron at BWH, frequently for patients receiving IP cisplatin. Palonosetron and ondansetron are the two 5-hydroxytryptamine-3 (5HT3) receptor antagonists included on the BWH formulary. A literature review concluded that these agents can be considered clinically interchangeable (Yeh YV, et al. J Oncol Pharm Pract. May 7, 2010. Epub ahead of print), but the cost of generic ondansetron is severalfold lower than that of palonosetron, McDonnell pointed out. In March 2008, BWH instituted protocol guidelines that consisted of ondansetron for first-line use and palonosetron for second-line use (Table). “When ondansetron became generic, the differences in cost became substantial. We changed practice to use ondansetron first-line, but anecdotal reports from our healthcare providers suggested that patients who receive ondansetron were more likely to have additional healthcare resource use due to CINV,” she said. The study aimed, therefore, to describe the use of these agents in patients receiving IP cisplatin and to compare the two agents with regard to resource utilization. The investigators reviewed medical records during three time periods: two periods prior to BWH guidelines (January through June 2006 for ondansetron and October 2007 through June 2008 for palonosetron) and one period after guideline implementation for ondansetron (March through June 2008). The occurrence of CINV-related hospital readmissions, emergency depart-
Table. Dosing Regimens Used at Brigham and Women’s Hospital Ondansetron Group
Aprepitant 125 mg, oral Dexamethasone 12 mg, IV Ondansetron 24 mg, oral or IV
Aprepitant 125 mg, oral Dexamethasone 12 mg, IV Palonosetron 0.24 mg, IV
Aprepitant 80 mg, oral Dexamethasone 12 mg, IV Ondansetron 24 mg, oral or IV
Aprepitant 80 mg, oral Dexamethasone 12 mg, IV
Aprepitant 80 mg, oral Dexamethasone 12 mg, oral
Aprepitant 80 mg, oral Dexamethasone 12 mg, oral
ment visits, and outpatient encounters (ie, clinic visits, telephone calls) within 7 days after cisplatin administration was compared. Reasons for healthcare resource use were determined by reviewing medical charts. CINV-related resource use was defined as events associated with dehydration due to nausea and vomiting, hypovolemia, hypokalemia, constipation, shortness of breath, or syncope/collapse. Trend toward increased readmissions with ondansetron Hospital readmissions tended to be greater with ondansetron: 2/39 (5.1%) patients, both CINV related, compared with 2/89 (2.3%), neither of which was CINV related (P = .09 for CINV-related admissions). One of the readmitted patients had documented electrolyte imbalance, nausea and vomiting, and dehydration on day 7 of the chemotherapy cycle. This patient received oral ondansetron only on the day of IP cisplatin during her hospital stay. The other readmitted patient received intravenous ondansetron for 2 days and reported dehydration 4 days after IP cisplatin. There were no CINV-related emergency department visits. CINV-related outpatient visits were documented in four (10.3%) patients receiving ondansetron and seven (7.9%) patients receiving palonosetron (P = .657). Twice as many of the ondansetron group patients (5.1% vs 2.3%) switched to the alternate 5-HT3 receptor antagonist. “To our knowledge this is the first realworld comparison of healthcare resource use between patients given ondansetron or palonosetron for prophylaxis of CINV,” McDonnell said. “Our analysis found a trend toward a higher incidence of CINV-related hospital readmissions with ondansetron, though not statistically significant, which is consistent with clinicians’ anecdotal reports.” These findings need to be confirmed in prospective, randomized trials that
Palonosetron uniquely inhibits neurokinin-1 agonist responses in vitro and in vivo. compare outcomes with single-dose palonosetron versus multiday ondansetron therapies in the IP cisplatin population, she said. She noted that the dosing of ondansetron might have been suboptimal in some cases; 27% of patients in this study received only 1 day of ondansetron during their hospital stay. During the discussion, it was noted that the dose of cisplatin that many patients were given (100 mg/m2) is now viewed as unacceptably high. Regardless, McDonnell emphasized that oncologists at BWH were unhappy with ondansetron. “It is a challenge to get our physicians to accept ondansetron for patients receiving IP cisplatin,” she said. Palonosetron inhibits NK1 agonist responses In a second presentation, Barbara Slusher, PhD, chief scientific officer for the Johns Hopkins Brain Science Institute NeuroTranslational Program,
Baltimore, reported results of translational work showing that palonosetron uniquely inhibits neurokinin-1 (NK1) agonist responses in vitro and in vivo. The same was not found for ondansetron or granisetron. Previous work has shown that palonosetron exhibits allosteric binding and positive cooperativity (Rojas C, et al. Anesth Analg. 2008;107:469-478) and triggers receptor internalization and prolonged inhibition of receptor function (Rojas C, et al. Eur J Pharmacol. 2010; 626:193-199). NK1 receptor antagonists are used to prevent delayed emesis. Palonosetron helps prevent delayed emesis as well. Slusher and her colleagues investigated whether palonosetron indirectly antagonizes the NK1 pathway. “Our results provide a rationale for the efficacy observed with palonosetron in delayed emesis in the clinic,” Slusher said. ● —CH
Changes Ahead with Healthcare Reform... Continued from page 8 if CER findings are tied to provider incentives, he added. The fiscal year 2011 budget is likely to include additional funding for CER. The Agency for Healthcare Research and Quality will be budgeted approximately $286 million, which is an increase of $261 million over fiscal year 2010. The Senate Finance Committee proposal recommends that CER be governed by a nonprofit entity with a public/private board. It proposes long-term funding from private insurers and a Medicare trust fund on a per-member basis.
Language was added to ensure that CER not be used as the sole basis for Medicare coverage decisions. Coverage determinations must give weight to all relevant studies and evidence, and to evidence suggestive of benefits to specific subpopulations, “even if, on average, no such benefit is seen,” he said. “I think this will change over time, however, as experience widens with CER and more become involved,” he predicted. “Our view is that oncology needs to be part of the decision-making process in CER.” ●
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EPO Ordering Form Improves Guidelines Compliance, Saves Practices Money NEW ORLEANS—Implementation College of Pharmacy in Pomona, of an explicit order form for darbepoet- California. in alfa significantly improved compli“We wanted to detect prescribing ance with current guidelines and led to errors in the daily encounters with large cost savings, California pharma- patients,” Wong said. To this end, the cists report. investigators retrospectively In July 2007, the Centers reviewed cases in which for Medicare & Medicaid Serpatients received darbepoetin vices (CMS) implemented alfa between May 2008 and stricter guidelines for treating February 2009. They discovchemotherapy-induced aneered that in 50% of cases, the mia with erythropoiesis-stimudrugs were not given in lating agents. “This changed accordance with the updated the prescribing requirements CMS guidelines. and created some confusion,” “There was a fairly high Siu-Fun Wong, said Siu-Fun Wong, PharmD, noncompliance rate, and PharmD of the Hematology-Oncology this also was associated with Medical Group of Orange loss of revenue,” Wong said. County, Orange, California, who preIn an effort to correct the high nonsented the study at the meeting. compliance event rate, they developed a The lead author was her student, Darbepoetin alfa (Aranesp) AdminStacy L. Yang, a PharmD candidate at istration Order Form (AAOF), then Western University of Health Sciences assessed compliance once it was institut-
ed. The form is quite explicit, although it is designed to be self-directed. Staff attended in-service training on its use. The study evaluated guideline compliance before use of the AAOF, involving 38 patients receiving 231 interventions. After implementation, 53 patients received 143 interventions. Implementation of the AAOF significantly reduced noncompliance events pertaining to initial dosing and maintenance dose frequency, the review found. Prior to the AAOF, 27 (71.1%) of 38 patients received an inappropriate initial weight-based dose but this practice occurred only in two (3.8%) of 53 patients when the form was used (P <.001). Inappropriate dose frequency occurred at baseline in 41 (17.7%) of 231 interventions, but with the AAOF, no cases occurred at all (P <.0001). There were no significant changes in inappropriate dosing, dose
reduction, or dose escalation. In total, there were 19 inappropriate documentations after the intervention, and in eight (15.1%) of 53 patients providers did not use the AAOF. Failure to document doses given or laboratory values occurred in <5% of interventions, she added. “Most important, better compliance impacted reimbursement,” Wong said. The projected cost-avoidance analysis showed that $72,611 per year was captured by implementation of the form. The projected number of noncompliance events per year was 132 before AAOF and just 18 after AAOF, representing projected reimbursement losses of $84,076 versus $11,465. “Even with the declining use of darbepoetin alfa, we saved the practice over $70,000,” she noted. ● —CH
Oncology Pharmacists Can Significantly Reduce Chemotherapy Waste NEW ORLEANS—Oncology pharmacists can save their institutions thousands of dollars annually by reducing chemotherapy waste, according to the experience of the Veterans Affairs’ North Texas Health Care System in Dallas. Sarah Gressett Ussery, PharmD, described her institution’s chemotherapy monitoring and management. “Our findings speak to the role of the hematology/oncology pharmacist in reviewing orders for their appropriateness, and knowing which drugs are expensive,” Ussery told The Oncology Pharmacist. “Having an oncology pharmacist in charge significantly reduced waste. Before this, we were not even aware of how much was wasted.” Ussery and colleagues documented chemotherapy waste over a 2-month period in 2005 and found that 143 chemotherapy doses were wasted, most frequently bevacizumab, docetaxel, gemcitabine, oxaliplatin, and rituximab. The total cost of waste was $90,400, which extrapolated to more than $500,000 annually. Documenting waste again, this time in a 2-month period in 2007, they identified 61 wasted doses costing $42,000, extrapolating to $250,000 annually. The reasons for drug waste were disease progression (23%), symptomatic toxicity (18%), patient no-show (15%), wrong order or ordered too early (13%), treatment delay per
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patient preference (12%), dose adjustment (8%), laboratory abnormality (8%), and other reason (3%). Concerns over this waste precipitated the hiring of a hematology/oncology pharmacist who implemented a chemo-
therapy management program and provided oversight. The key to this program was to delay the preparation of expensive chemotherapies. Waste was then calculated with this program in place. Under the
chemotherapy management program, waste over a 2-month period was only $15, extrapolating to $90 annually, Ussery reported. ● —CH
Standardized Forms Facilitate COG Treatment NEW ORLEANS—The use of standardized pediatric chemotherapy forms can improve safety by creating a consistent and streamlined method of ordering Children’s Oncology Group (COG) trial protocols and regimens, according to investigators from Memorial Regional Hospital and Joe DiMaggio Children’s Hospital in Hollywood, Florida. Wayne R. Shipman, RPh, and Maribeth Arzola, PharmD, showcased the order set they developed for this purpose. It consists of a preprinted chemotherapy ordering form, preprinted medication administration record, and preprinted pharmacy dispensing record that correspond to the 14 COG treatment protocols they use. The forms reflect the protocol for a complete plan of care, they noted. “Prior to the introduction of our standardized pediatric order sets, we encountered many mistakes in pediatric chemotherapy orders, and these required
multiple pharmacy interventions. After the introduction of the preprinted forms, there was a 93% reduction in chemotherapy transcribing and calculations errors,” Arzola said. These errors were mostly illegible or confusing orders; wrong dosing; and crossed out, altered, or incomplete orders, she explained. “We decided to revamp the process,” she said. “We redid how we order chemotherapy, dispense chemotherapy, and check chemotherapy on the medication administration record.” A multidisciplinary team (Chemotherapy Safe Practice Committee) and the oncology pharmacy team created the templates. The standardized order set consists of a COG protocol template (per tumor site) for chemotherapy orders with a medication dose calculator, which requires two physician signatures; a medication administration record per
COG protocol; and a pharmacy triplecheck form, which reflects the COG protocol template and enables the pharmacist to interpret and verify the patient’s plan of care. The system is not perfect, they acknowledged. Second signatures are sometimes missing, heights and weights may be inconsistent between the order forms, incomplete forms are still sent to the pharmacy, reasons for dose modifications are sometimes lacking, and “crossing out” doses is still an issue. But the order set has greatly improved accuracy in writing, checking, interpreting, and entering chemotherapy orders; has decreased pharmacy chemotherapy preparation turnaround times; has increased nursing chemotherapy administration efficiency; and has shortened length of stay and throughput times for pediatric patients and their families. ● —CH
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Concurrent Trastuzumab with Chemotherapy Beats Sequential Use for HER2-positive Breast Cancer By Daniel M. Keller, PhD SAN ANTONIO—Interim analysis of a large trial of women treated with trastuzumab for human epidermal growth factor receptor type 2 (HER2)-positive breast cancer before or after surgery indicates that concurrent use with a taxane may improve overall survival (OS) and disease-free survival (DFS) compared with sequential administration. Previous trials have shown a large benefit of trastuzumab but left open the question of the optimal timing of its use. (See, eg, the HERA trial: Piccart-Gebhart MJ. N Engl J Med. 2005;353:1659-1672.)
trial randomized women to one of three treatment arms: doxorubicin/cyclophosphamide then paclitaxel (control), doxorubicin/cyclophosphamide, then paclitaxel, then trastuzumab for 52 weeks (sequential therapy), or doxorubicin/ cyclophosphamide, then paclitaxel plus trastuzumab for 12 weeks followed by trastuzumab for 40 weeks (concurrent therapy). Compared with the control regimen (n = 1097), sequential therapy (n = 1087) was associated with a 30% benefit in DFS at a median of 5.5 years of follow-
Concurrent use with a taxane may improve overall survival and disease-free survival compared with sequential administration. At the San Antonio Breast Cancer Symposium in December 2009, Edith Perez, MD, director of the breast program at Mayo Clinic in Jacksonville, Florida, reported results of the N9831 trial that tested concurrent or sequential trastuzumab (San Antonio Breast Cancer Symposium; 2009. Abstract 80). The
up (estimated hazard ratio [HR], 0.70; log rank P = .0005). An additional 23% benefit in DFS occurred in the concurrent therapy group (n = 949) when compared with the sequential arm at a median follow-up of 5.3 years (estimated HR, 0.77; log rank P = .019). Based on the specific statistical methods designed for
interim analysis, however, this last differ- involved less than one half of the ence was not deemed to be significant. planned events for which the study was Perez presented results comparing powered to show a difference. She concontrol and concurrent theracluded that the results were py for a median follow-up of still strong enough to recomapproximately 3 years. Commend overlapping trastuzupared with the control arm, mab with a taxane. concurrent therapy was assoMark Pegram, MD, direcciated with a 52% benefit in tor of clinical research at DFS (adjusted HR, 0.48; P < the Sylvester Comprehen.00001) and a 35% benefit in sive Cancer Center of the OS (unadjusted HR, 0.65; P University of Miami Miller = .0007). School of Medicine in Edith Perez, MD Speaking with The OnFlorida, said, “While maybe cology Pharmacist before her not completely technically presentation, Perez said she thought the statistically significant…[the study is] N9831 trial results would change prac- so consistent with what was expected, tice patterns worldwide, especially in based on all of the science, that I think countries where the usual practice is it will be embraced fairly widely and sequential therapy. Most observers felt fairly quickly.” that the N9831 results made a good But Aman Buzdar, MD, of the M. D. case for using concurrent trastuzumab Anderson Cancer Center in Houston, with the taxane, although most said Texas, cautioned that physicians need using sequential therapy would not be to be familiar with using the drugs bad practice. together and have to follow patients Julie Gralow, MD, professor of med- closely. “Some of the toxicities are also ical oncology at the University of synergistic when you combine chemoWashington in Seattle, a coauthor of therapeutic agents with antibody treatN9831, noted that the interim results ment,” he warned. ●
Three New Drugs on the Horizon for HER2-positive Breast Cancer
hree new drugs are in the pipeline to treat human epidermal growth factor receptor (HER) type 2-positive metastatic breast cancer (MBC). Two appear to have the potential to provide incremental gains, and one looks like a game changer.
T-DM1 The one getting the most attention at recent oncology conferences is T-DM1, a first-in-class conjugate of the monoclonal antibody trastuzumab and DM1, a derivative of maytansine. Maytansine is an antimicrotubule agent that proved too toxic to use alone a couple of decades ago. The key to taming it for use today is a linker that attaches DM1 to trastuzumab and is cleaved once the drug has been internalized in cells overexpressing HER2, releasing the DM1 inside. The drug is almost undetectable in the circulation (LoRusso P, et al. San Antonio Breast Cancer Symposium; 2009. Abstract 5099). Ian Krop, MD, PhD, and coworkers reported on a phase 2 study of 110
patients with HER2-positive MBC previously treated with an anthracycline, a taxane, capecitabine, lapatinib, and trastuzumab. Patients received singleagent T-DM1 at a dose of 3.6 mg/kg intravenously every 3 weeks. Even in this population of heavily pretreated patients with more than 2 years of HER2-directed therapy, the overall response rate (ORR) was 30%, more than 46% had stable disease, and the clinical benefit rate (CBR) was 40% to 45%. The median time to progression was 7.3 months (San Antonio Breast Cancer Sym posium; 2009. Abstract 5090). In another phase 2 study of 112 heavily pretreated patients with MBC, T-DM1 showed good efficacy and tolerability. The ORR was 26.7% by independent review and 38.9% by investigator assessment, with a median progression-free survival of 4.6 months (Vogel CL, et al. J Clin Oncol. 2009; 27[15S]:Abstract 1017). In the 66 patients in that trial who were previously treated with lapatinib and trastuzumab, T-DM1 produced very
similar response rates (24.2% and 34.8%, respectively). The main adverse effects, as exemplified in the Krop study, were fatigue, nausea, and brief, transient thrombocytopenia. Most have been grade 1 or 2. Phase 3 trials are ongoing, comparing TDM1 to other combined therapies. Carlos Arteaga, MD, professor of medicine at Vanderbilt University in Nashville, Tennessee, is very positive about T-DM1, especially for heavily pretreated patients. “The conjugate has shown remarkable activity as a third line in HER2-positive metastatic breast cancer,” he said. Harold Burstein, MD, PhD, of DanaFarber Cancer Institute in Boston, noted that T-DM1 may have efficacy as a single agent “because it is, in essence, chemotherapy plus trastuzumab.” And, he added, “It does not seem to cause significant alopecia, which is very exciting for patients.” Although some patients have done well on trial for more than 1 year, and in some cases 2 years, Eric Winer, MD,
director of breast oncology at DanaFarber, cautioned that “We have not treated a sufficient number of patients for years to know for certain that there isn’t a low level of cumulative toxicity.” Adam Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh, remains very optimistic about T-DM1. “It will have a major role in clinical practice...at least be equivalent to capecitabine/lapatinib with probably fewer side effects,” he said. In a more general sense, the linker technology used to join DM1 with trastuzumab may be applicable to use with other monoclonal antibodies against other tumor types, “the so-called targeted chemotherapy concept that has been the Holy Grail for everybody for so many years,” according to Luca Gianni, MD, director of medical oncology and clinical pharmacology at Italy’s National Tumor Institute in Milan. Neratinib Another drug in development is neraContinued on page 13
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OncoMed provided funding and editorial support for this article www.OncoMed.net
2 OF A SERIES PART
Oncology Practice Management
New Jersey Hematology and Oncology Center Partners with OncoMed Bayonne, New Jersey—As ications. If they followed the source the pharmacy funcspecialty pharmacies that demand for their services traditional practice of hema- tion to a pharmacy that was concentrate on more than grew and it became increastology and oncology pro- highly specialized in oncoloone class of pharmaceuticals ingly clear that their pracviders, they would “buy and gy medications. This pharis the OncoMed care mantice was becoming a regionbill” the medications, mean- macy would prepare the agement support team’s abilal center for patients battling ing they would have the drugs under the highest clinity to work with insurers to cancer, the medical staff at responsibility of sourcing and ical standards, deliver them get the authorizations that Colanta Hematology & purchasing the medications, just in time for treatment the Colanta Hematology & Oncology Center made the storing them, preparing and day (thereby eliminating Oncology Center’s patients decision to build and open sometimes compounding them waste), handle all the hassles need. OncoMed’s team inan outpatient infusion cen- Kevin Askari, RPh for patients, managing the of insurance prior authoriza- Burt Zweigenhaft cludes patient care navigater that could adequately President and Chief inventory on an ongoing basis, tion and reimbursement, CEO, OncoMed tors and patient reimburseand comfortably serve their Clinical Pharmacist and dealing with a bevy of and free the center from the ment specialists who have OncoMed patients. insurance prior authorization challenges of safely storing and dispens- extensive experience working with inThe result was a state-ofand reimbursement procedures ing the drugs and the huge, capital- surers, oncology drug manufacturers, and the-art infusion center with 20 recliners and requirements in order to get paid. intensive “carry costs” that maintaining medical foundations. These specialists in a patient-focused environment that is Although buy and bill traditionally such an inventory requires. always know where to go to search for open to serve patients 7 days a week. The had its benefits, including a substantial Dr Colanta and his colleagues needed funding for patients who are medical staff of three physicians and four margin paid by Medicare and other com- researched their options and chose banking on that expertise for their nurses, led by practice administrator recovery. Romel Colanta, MD, now delivers a OncoMed has become a pivotal part“The partnership with OncoMed has enabled broad array of outpatient oncology servicner to the Colanta Hematology & Onus to make better use of our capital.” es, including chemotherapy, albumin, cology Center by owning the pharmaantiemetic, and iron therapy infusions. ceutical worry and letting the physicians Additionally, the infusion center staff —Romel Colanta, MD focus solely on guiding their patients to provides supportive cancer care services, Practice Administrator remission. including therapeutic phlebotomy, antiWe sat down with Dr Colanta and Colanta Hematology & Oncology Center biotic infusion, and electrolyte replaceasked him about the new center and its ment. They also provide multidisciplipartnership with OncoMed. nary infusion services for patients referred to the center by gastroenteroloWhy did your infusion center choose gists, neurologists, and infectious disease mercial payers, changes that resulted OncoMed—The Oncology Pharmacy. to partner with OncoMed? specialists. from the Medicare Modernization Act OncoMed is an oncology pharmacy, The buy-and-bill model that oncoloWith the high volume of oncology lowered a margin that sometimes paid meaning that its sole business is oncolo- gists have always worked under is no drugs required to treat their patient physicians 40% over the cost of the drug gy medications. Its specially trained and longer viable. Physicians can’t make an panel, the medical staff at Colanta had to to just 6%. certified oncology pharmacists work in a office run on a 6% margin. Under buy make the decision as to how they would The Colanta team decided there was a technologically advanced pharmacy built and bill, the average sales price (ASP) + supply their patients with oncology med- better way. They knew they could out- exclusively for oncology pharmaceutical 6% methodology can very quickly go to prescription processing and dispensing, ASP + 4%, +2%, or -2% if we run into including a USP <797>-compliant class any obstacles in getting reimbursed. And 5 clean room. To protect the supply with expensive drugs like chemotherapy, chain and ensure a complete and full we cannot take that risk. Plus, OncoMed drug pedigree, all inventories are pur- helps patients get funding for medication chased directly from pharmaceutical even after the patient’s insurer has manufacturers. The company’s “just-in- denied coverage. time treatment-day” service means that oncologists and hematologists in any In addition to this new center, you state in the nation are guaranteed deliv- now have two additional sites in New ery of medications and all therapy- Jersey. How has the partnership with specific administration supplies within OncoMed enabled you to successfully 24 hours of placing the order. Given the launch and grow the center? Colanta Hematology & Oncology When we opened, 90% of what we Center’s close proximity to one of infused in the clinic was oncolytics. As we OncoMed’s regional oncology pharmacy have grown, we infuse a far broader array sites, they were eligible to get same day of medications. The backbone of our pracand even emergency stat dose delivery tice is still chemotherapy, but we have increased our nononcolytic infusions. For The outpatient infusion center at Colanta Hematology & Oncology Center comfortably serves when needed. But what also set OncoMed apart from patients. Continued on page 13
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EVOLUTION IN ONCOLOGY PRACTICE MANAGEMENT™ Continued from page 12
patients referred by gastroa patient comes in and his or intestinal practitioners, we inher benefits are precertified, fuse infliximab, and for those we send the person’s case referred by infectious disease information to OncoMed, physicians, we provide antibiand the drugs are sent to us otic infusions. Some of those directly, along with all the drugs are still viable [under administration supplies. We buy and bill], but not all. We get them on a next-day have been able to devote basis, or sooner if needed, money that has traditionally and everything is clearly gone to purchasing medica- Ellen Scharaga, RPh labeled with patient-specific tion and instead expand our Senior Vice President information. That makes a services. The partnership with OncoMed huge difference to us when OncoMed has enabled us to dealing with OncoMed vermake better use of our capital. sus some specialty pharmacies that some insurers have imposed upon us to use, How does the medication ordering which get the drugs wrong, ship them and fulfillment process work with late, and have no idea of the correct OncoMed? administration supplies. Having an efficient and focused process in place is very important. We How does the relationship with have been able to institute a process OncoMed allow you and your team to where we have someone devoted to focus on what is important? being our liaison with OncoMed. When I will give you a “before-and-after”
example. Before we worked with OncoMed, 50% or more of our time was spent on managing drug costs and reimbursement. We had five people managing pharmacy at the three locations; we have been able to reduce that number of employees to one. Before, we had to continually make sure that we were not underwater on drugs, as reim- Pharmacists filling orders at the OncoMed facility. bursement rates and times fluctuated. such a move? OncoMed has made it possible to not It is definitely a relationship that every devote time and effort on that. infusion center or oncologist has to explore. When dealing with narrowing Based on your experience, what reimbursement margins and delayed would you say about OncoMed to he- reimbursement, ultimately it will be benmatologists and oncologists considering eficial to switch to OncoMed.
To learn more about OncoMed or to request a presentation, contact OncoMed at 1-877-662-6633, extension 1298 or firstname.lastname@example.org, or go to www.oncomed.net.
Breast Cancer Three New Drugs on the Horizon... Continued from page 11 tinib, an oral small molecule, pan-ERBB irreversible tyrosine kinase (TK) inhibitor, meaning it inhibits the TKs associated with the HER1, HER2, and HER4 cell surface receptors. The consensus among oncologists is that neratinib shows good activity as a single agent as well as in combination with trastuzumab after progression on trastuzumab. “There is activity of neratinib in both trastuzumaband lapatinib-pretreated [patients],” said Debu Tripathy, MD, director of the Women’s Cancer Program at the University of Southern California in Los Angeles.
mg/day of neratinib, Awada and coworkers found a 100% incidence of diarrhea among patients with MBC who were previously treated with lapatinib and a 93% incidence if no prior lapatinib exposure. ORRs were 43% if no prior lapatinib and 25% with prior exposure. CBRs were 57% and 50%, respectively (San Antonio Breast Cancer Symposium; 2009. Abstract 5095). Burstein and coworkers found the same incidence of early-onset diarrhea using 240 mg/day of neratinib and reported that it could be controlled with antidiarrheal medications and
The consensus among oncologists is that neratinib shows good activity as a single agent as well as in combination with trastuzumab after progression on trastuzumab.
In the past, the most prevalent concern about neratinib was the high incidence of diarrhea; however, at the San Antonio Breast Cancer Symposium in December 2009, researchers said that the diarrhea is manageable with medication and appears to diminish in frequency and severity over several weeks of treatment. In a small phase 1/2 study using 240
dose reductions. Vomiting occurred in 29% of patients. The drug appeared to have acceptable cardiovascular safety, with no grade 3/4 toxicity that was considered related to neratinib. In a cohort of 67 patients, only 3% had a left ventricular ejection fraction <50% (San Antonio Breast Cancer Symposium; 2009. Abstract 5096).
Both Burstein and Gabriel Hortobagyi, MD, of The University of Texas M. D. Anderson Cancer Center in Houston, commented that studies indicate that the response rate to neratinib is probably higher than to lapatinib in similar groups of patients. “We are much more excited about neratinib now than we are about lapatinib,” said Hortobagyi. Thinking ahead, Sandra Swain, MD, medical director of the Washington Cancer Institute at Washington Hospital Center in Washington, DC, said diarrhea is manageable with neratinib in the metastatic setting, but it may be “a significant problem if you’re going to take it in the adjuvant setting.” Pertuzumab Pertuzumab is a recombinant monoclonal antibody that inhibits dimerization of HER2 with itself (homodimers) and with other HER receptors (heterodimers), thereby preventing the activation of HER signaling pathways. It has limited potency alone but appears to synergize with trastuzumab. A group led by Jose Baselga, MD, director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, enrolled patients with HER2positive MBC whose disease had progressed on trastuzumab in a phase 2
trial. Patients received pertuzumab alone (840 mg loading dose then 420 mg every 3 weeks) and, if their disease progressed, trastuzumab was added. In the pertuzumab-only group (n = 29), the ORR was 3% and the CBR was 10%. For the combined therapy group (n = 16), ORR was 21%, and CBR was 43% (San Antonio Breast Cancer Symposium; 2009. Abstract 5114). Baselga stressed the need for “total HER2 blockade,” involving both the homodimer and heterodimer signaling pathways. He speculated that either trastuzumab or lapatinib would block the homodimer pathway but not the heterodimer one. “Half the problem is equal to the whole problem,” he said. Arteaga commented that as the proportion of HER2/HER3 heterodimers increases, the tumor becomes more sensitive to pertuzumab, which blocks heterodimerization. In addition, HER3 has powerful phosphorylating activity for HER2, driving HER2 activity. Brufsky believes dimers involving HER3 are “an extremely important target” not only in breast cancer but also in lung (HER1/HER3), ovarian (HER3/ HER4), and other tumors, and, thus, pertuzumab may have activity in those tumors as well. ● —DMK
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CONTINUING EDUCATION EDITORIAL BOARD
PROGRAM TOP3 • RELEASE DATE: JUNE 15, 2010 • EXPIRATION DATE: JUNE 15, 2011
Scott E. Eggener, MD
ESTIMATED TIME TO COMPLETE: 1.0 HOUR
Assistant Professor of Surgery/Urology University of Chicago Medical Center 5841 South Maryland Ave, MC6038 Chicago, IL 60637
Active Surveillance as a Management Strategy for Low-risk Prostate Cancer
David Frame, PharmD Clinical Hematology/ Oncology/BMT Specialist Assistant Professor of Pharmacy University of Michigan 428 Church Street Ann Arbor, MI 48109
By Scott E. Eggener, MD Assistant Professor of Surgery/Urology, University of Chicago Medical Center, Chicago, Illinois STATEMENT OF NEED
With the introduction and widespread use of prostatespecific antigen screening, the number of men being diagnosed with prostate cancer has increased. Almost 50% of these cancers, however, have biological characteristics associated with a low risk of cancer progression. As a result, clinicians are interested in management strategies that offer the possibility of delaying, obviating, or minimizing the impact of treatment to avoid having patients undergo unnecessary treatment. Oncology nurses and pharmacists should be aware of the most recent data regarding one such strategy, active surveillance with selective delayed intervention, so that they may discuss it with patients diagnosed with various types of prostate cancer.
PLANNING COMMITTEE Gloria Mui Medical Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604 Julie Ann Tagliareni CME Director Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604
Registered pharmacists and other interested healthcare professionals, especially those caring for cancer patients
Anne L. Finger President Veritas Institute for Medical Education, Inc. 611 Route 46 West Hasbrouck Heights, NJ 07604
After completing this activity, the reader should be better able to: • Discuss active surveillance with selective delayed intervention with patients diagnosed with prostate cancer
Dawn Lagrosa Associate Editor Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Karen Rosenberg Editorial Director Green Hill Healthcare Communications, LLC 241 Forsgate Drive Monroe Twp, NJ 08831 Eileen Koutnik-Fotopoulos 77A Beers Street Keyport, NJ 07735
• Appropriately select candidates for active surveillance based on disease characteristics at diagnosis • Evaluate patient progress to determine if, and, when treatment may be warranted
he number of American men dying of prostate cancer has decreased 30% over the past 25 years, but it remains the second leading cause of cancer death. In 2009, an estimated 192,280 new cases of prostate cancer were diagnosed and 27,360 men died of the disease.1 There is no universally accepted strategy for screening, diagnosis, and treatment of prostate cancer.2 The introduction and widespread use of prostate-
specific antigen (PSA) screening, however, has led to an increasing number of men being diagnosed with prostate cancer each year. Almost 50% of these cancers have biological characteristics associated with a low risk of cancer progression.3 The challenge facing patients and physicians is accurately determining which men have cancers with a significant risk of progression or metastases whom would benefit from treatment, compared with those unlikely to be impacted by the cancer during their natural lifespan. Although radical prostatectomy (RP) and radiation therapy are effective treatments, they can result in serious long-term side effects such as urinary problems and erectile dysfunction. As a result, clinicians are interested in management strategies that offer the possibility of delaying, obviating, or minimizing the impact of treatment to avoid having patients undergo unnecessary treatment.3 One strategy is active surveillance (AS) with selective delayed intervention.3 AS involves characterizing the cancer using all available tools, determining whether the patient is a good candidate for AS, and frequently evaluating the cancer and overall health of the patient to determine if, and, when treatment may be warranted.2 Current clinical practice guidelines Because many prostate cancers detected through PSA screening may not require immediate treatment, the American Urological Association and National Comprehensive Cancer Network (NCCN) recommend that during discussion of treatment approaches for cancer clinicians include AS as an option for men with low-risk prostate cancer who have a life expectancy of less than 10 years.4,5 In addition, a new “very low risk” category has been added to the
CONTINUING PHARMACY EDUCATION ACCREDITATION AND CONTACT HOURS STATEMENT
Veritas Institute for Medical Education, Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This program (UPN 0394-0000-10-004-H01-P) is acceptable for 1.0 Contact Hours. Initial release date: June 15, 2010. A statement of credit will be available online to participants who successfully complete the program, learning assessment (>70%), and program evaluation form. There is no registration or processing fees. METHOD OF PARTICIPATION
1. Read the article in its entirety 2. Log on to www.TheOncologyPharmacist.com 3. Click on “CE Credits” 4. Click on “Click here to complete the posttest and obtain a CE certificate online” 5. Register to participate 6. Enter program number TOP3 7. Complete and submit the CE posttest and CE Activity Evaluation and Request for Credit Form online 8. Print your Statement of Completion This activity is provided free of charge to participants.
June 2010 I VOL 3, nO 4
updated NCCN guidelines using a modification of the Epstein criteria for clinically insignificant prostate cancer (Table). AS is offered and recommended for men in this category when life expectancy is less than 20 years.5 Multicenter study examines active surveillance Studies have assessed the safety and efficacy of AS for low-risk localized prostate cancer.2,3,6 One multicenter, retrospective study evaluated the actuarial rates and predictors of remaining on AS, the incidence of disease progression, and the pathologic findings of delayed RP.3 Patient criteria Each man in a cohort of 262 men from four institutions was offered multiple options but ultimately chose AS. All patients met the following criteria for eligibility3: • 75 years of age or younger • PSA 10 ng/mL or less • Clinical stage T1 to T2a • Biopsy Gleason sum 6 or less • Three or fewer positive cores at diagnostic biopsy • No single core with >50% cancer • Repeat biopsy before AS (restaging) • No treatment for 6 months following the repeat biopsy. Patient assessment AS was defined as starting on the date of the second biopsy. Evaluation of patient progress included office visits, review of general health and urinary symptoms, digital rectal examinations, and PSA screenings every 6 to 12 months. Biopsies were routinely recommended within 18 months of starting AS and subsequently every 1 to 3
Veritas Institute for Medical Education, Inc. is required to disclose to the activity audience the relevant financial relationships of the planners and faculty involved in the development of CE content. An individual has a relevant financial relationship if he or she has a financial relationship in any amount occurring in the last 12 months with a commercial interest whose products or services are discussed in the CE activity content over which the individual has control. In addition, all faculty are expected to openly disclose any unlabeled/unapproved/investigational uses of drugs or devices discussed in this activity. Disclosures are as follows: • Scott E. Eggener, MD, has nothing to disclose. • David Frame, PharmD, has nothing to disclose. The staffs of Veritas Institute for Medical Education, Inc. and Green Hill Healthcare Communications, LLC have nothing to disclose. DISCLAIMER
The opinions expressed in this activity are those of the presenters and do not necessarily reflect the opinions or recommendation of Veritas Institute for Medical Education, Inc. Copyright © 2010 Veritas Institute for Medical Education, Inc. All rights reserved.
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www.TheOncologyPharmacist.com years or prompted by a change in clinical status, a sign of possible disease progression. Magnetic resonance imaging (MRI) of the prostate was selectively used at diagnosis and every 1 to 3 years after starting AS. In isolated cases, MRI findings warranted biopsy earlier than was scheduled. Study results Forty-three (16%) patients elected
active treatment, with a median followup of 29 months. The 2- and 5-year probabilities of remaining on AS were 91% and 75%, respectively. Of the 43 patients undergoing delayed treatment, 41 (95%) were without disease progression at a median of 23 months following treatment. The most commonly reported reasons for stopping AS included upgrading (35%) or higher volume of cancer (16%) on surveillance biopsy or a change in
patient preference (14%). The active treatment choices among the cohort were RP for 26 (61%) patients, radiation therapy for 13 (30%), cryotherapy for one (2%), and androgen deprivation for three (7%). Patients with cancer on the second biopsy (hazard ratio [HR], 2.23; 95% confidence interval [CI], 1.23-4.06, P = .007) and a greater number of cancerous cores from the two biopsies combined (P =
.002) were more likely to undergo treatment. Bone metastases developed in one patient 38 months after starting AS. Age, PSA, clinical stage, prostate volume, and the number of total biopsy cores were not predictive of outcome. Clinical implications of AS This study demonstrates that for select patients with low-risk prostate Continued on page 16
Active Surveillance as a Management Strategy for Low-risk Prostate Cancer: A Pharmacist’s Perspective David Frame, PharmD Clinical Hematology/Oncology/BMT Specialist and Assistant Professor of Pharmacy, University of Michigan, Ann Arbor
ggener discussed the role of active surveillance (AS) in the treatment of prostate cancer, addressing an important option that is often overlooked. We must remember that the Hippocratic oath is to do no harm. The potential of causing harm by performing a radical prostatectomy is very real and can even result in mortality. A Canadian study exploring complications occurring within 30 days after radical prostatectomy among 11,010 men who underwent this surgery between 1990 and 1999 showed a low, but clinically significant, 0.5% mortality rate with another 20.4% having one or more complications within these 30 days.1 Other risks associated with this procedure are deep vein thrombosis and herniation, and the most common side effects are impotence and incontinence, which may be long-term and significantly affect quality of life. Because of these risks of radical prostatectomy, it is essential to consider AS if these side effects could be spared without increasing the risk of mortality from the cancer in individuals diagnosed with low- or very-low-risk prostate cancer. Prostate cancer is the second leading cause of cancer death in men, effecting 192,280 men and accounting for approximately 25% of all new cancer diagnoses in men in 2009. Given these numbers, even low percentages of unnecessary procedures could result in a significant increase in the percentage of unnecessary complications. To this end, the American Cancer Society (ACS) revised its recommendations on prostate cancer screening in March of this year.2 The revised recommendations are partially based on two large trials that sought to determine whether prostate cancer screening with prostate-specific
antigen (PSA) levels and digital rectal examination (DRE) saves lives.3,4 In the American study, more than 76,000 men were randomized to receive “usual care” or to have annual PSA tests for 6 years, and DREs every year for 4 years. Overall, no significant difference in prostate cancer death rates was demonstrated between the two groups after 7 to 10 years of follow-up.3 In the European trial, 182,000 men were stratified to either a control group or a screening group.4 Men in the screening group had PSA tests every 4 years and, on average, two DREs during that period. Interestingly, after approximately a 9-year follow-up, the researchers found that screening did reduce the rate of prostate cancer death by 20% but also was associated with a high risk of overdiagnoses. It is important to realize that much longer maturity is required before these studies can be fully analyzed. The reason for these studies, as pointed out by Eggener, is to help further determine whether finding prostate cancer early truly leads to decreased mortality. Some prostate cancers grow slowly and may never cause any problems, whereas others are more aggressive. This distinction, however, cannot necessarily be determined by the standard PSA and DRE screening tools. Based on all of the current information, the ACS recommends that men without high risk who have no symptoms at 50 years of age and are in relatively good health with a life expectancy of 10 years or more, use decisionmaking tools to help them make an informed choice about testing. Men with no symptoms who are not expected to live more than 10 years (because of age or poor health) should not be offered prostate cancer screening at
all.2 So for those readers unsure of the appropriateness of the revised American Urological Association and National Comprehensive Cancer Network (NCCN) recommendations to include AS in discussions of treatment approaches for men with low-risk prostate cancer who have a life expectancy of less than 10 years or 20 years in the very-low-risk category, they seem to pale in comparison with the new ACS screening guidelines. It should also be noted that in the revised NCCN guidelines the recommendation for AS for the very-low-risk group with less than 20 years expected survival is a category 2B recommendation, which means the recommendation is based on lower level evidence and there is not a uniform consensus among committee members.5 I believe that a significant question that needs to be further explored is the potential risk of AS, that is, the risk of developing advanced cancer due to inadequate diagnosis, classification, or follow-up of these patients. A Scandinavian trial comparing AS with radical prostatectomy in localized prostate cancer demonstrated a relative risk of 0.65 for both 12-year disease-specific mortality (P = .03) and distant metastasis (P = .006).6 The Epstein criteria for predicting pathologically insignificant prostate cancer have been shown to misdiagnose in as many as 8% of cases of nonorgan-confined disease upon postsurgical findings.7 Finally, it is very important that if patients agree to AS, they must commit to regularly scheduled examinations, including repeat biopsies. Cancer progression is suggested when more core biopsies are positive, when no single core has less than 50% can-
cer by volume, when the Gleason score increases to 4 or 5, or when PSA doubling time is less than 3 years. Although “trigger” points for intervention are suggested, these have also not been validated with good clinical trials. Because it is likely that many patients will be on AS, pharmacists must fully understand the potential benefits as well as the unanswered questions with this approach. In the near future, AS will likely be revisited, because many ongoing studies are evaluating genetic components as they relate to disease-risk classification. References 1. Alibhai SM, Leach M, Tomlinson G, et al. 30day mortality and major complications after radical prostatectomy: influence of age and comorbidity. Natl Cancer Inst. 2005;97:15251532. 2. American Cancer Society. Prostate cancer: early detection. 2010. www.cancer.org/doc root/CRI/content/CRI_2_6x_Prostate_Can cer_Early_Detection.asp?sitearea=&level=. Accessed April 15, 2010. 3. Andriole GL, Grubb RL, Buys SS, et al; for the PLCO Project Team. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-1319. 4. Schroder FH, Hugosson J, Roobol MJ, et al; for the ERSPC Investigators. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:13201328. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Prostate Cancer. V.1.2010. www.nccn.org/profession als/physician_gls/PDF/prostate.pdf. Accessed April 15, 2010. 6. Bill-Axelson A, Holmberg L, Filen F, et al; for the Scandinavian Prostate Cancer Group Study Number 4. Radical prostatectomy versus watchful waiting in localized prostate cancer: The Scandinavian Prostate Cancer Group-4 randomized trial. J Natl Cancer Inst. 2008; 100:1144-1154. 7. Jeldes C, Suardi N, Waltz J, et al. Validation of the contemporary Epstein criteria for insignificant prostate cancer in European men. Eur Urol. 2008;54:1306-1313.
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CONTINUING EDUCATION Active Surveillance as a Management Strategy... Continued from page 15 CASE STUDY
66-year-old man who had been undergoing annual prostate-specific antigen (PSA)-based prostate cancer screening had a normal digital rectal examination (DRE) but a PSA level of 6.4 ng/mL. PSA testing was repeated 1 month later and found to be 6.2 ng/mL. Prostate biopsy revealed two of 12 cores with Gleason 6 prostate cancer, encompassing 20% of each core. He had excellent sexual and urinary function. His medical history showed moderate obesity and medication-controlled hypertension. After meeting with multiple specialists and considering his options, he elected to proceed with active surveillance (AS) and, therefore, underwent a restaging 12-core biopsy. No cancer was identified and he formally entered AS. For 6 years, he underwent evaluations every 6 months without a significant change in health status, DRE, or PSA (range, 4.3 ng/mL-7.1 ng/mL). Surveillance biopsies performed every 12 to 18 months did not show a higher-grade or higher-volume cancer and ranged from zero to two cores with cancer. Seven years following the initiation of AS, the patient experienced a myocardial infarction, underwent the placement of two coronary stents, and was started on clopidogrel and aspirin. He continues routine surveillance of his prostate cancer with annual evaluations.
Table. Modified Epstein Criteria for Clinically Insignificant Prostate Cancer • Clinical stage T1c • Biopsy Gleason score ≤6 • Presence of disease in fewer than three biopsy cores • ≤50% prostate cancer involvement in any core • Prostate-specific antigen density <0.15 ng/mL/g Source: Reference 5.
cancer, AS with judicious monitoring appears to be safe, durable, and associated with a low risk of systemic progression within the first 5 years. My colleagues and I strongly recommend a second biopsy before considering AS, because cancer detected at restaging biopsy and a higher number of cores with cancer are linked with a lower likelihood of remaining on AS.3 The success of any AS program relies on accurate disease characterization at diagnosis. Because this study specified strict clinical and pathologic inclusion criteria and required a second biopsy before starting AS, we were able to identify a cohort of men with a low risk of
cancer progression. The rate of discontinuing AS was about 5% per year, lower than that of similar studies, largely due to the strict inclusion criteria. Furthermore, it is crucial that all men participating in an AS program be counseled on the low but real risk of potentially life-threatening cancer progression.3 Early to intermediate-term data for appropriately selected AS patients suggest metastasis rates are consistently less than 1%, with follow-ups ranging from 2 to 8 years.2 To minimize the risk, we strongly recommend a restaging biopsy. This proactive approach excludes up to 30% of patients considered for AS based on the initial diagnostic biopsy, mini-
mizes the risk of Gleason grade sampling error, and predicts the likelihood of continuing on AS.3 Studies indicate that AS is used as a treatment strategy in only 10% of patients with newly diagnosed prostate cancer.2,3 Our findings as well as those from other researchers show that AS should be discussed and considered for appropriately selected patients.2,3,6 Multiple limitations of this study, however, warrant consideration. Based on the short-term follow-up of this study (median, 29 months) and of other studies (median, 22-64 months), caution should be exercised in extrapolating these findings to justify AS as a long-term management strategy. Extended followup is mandatory to address this concern.3 The data in this study provide an observational experience, which will continue to provide insights into the natural history of low-risk prostate cancer, generalized rates of delayed treatment given the variable practice patterns, overall cancer-specific success rates, and causes of death.3 Whereas a strength of this study is the multi-institutional cohort, this has also led to variations in the intensity of follow-up, diagnostic and restaging strat-
egies, occurrence of surveillance biopsies, pathologic assessment, and indications for treatment.3 Therefore, generalizing of the findings to include other populations should be done with caution. The most common reason for stopping AS in this study was the outcome of a surveillance biopsy; in other AS studies it was patient preference or increasing PSA alone, underscoring the variable nature of currently available series and need for prespecified study methodology.3 My view on AS is to appropriately select patients, discuss initial observation as an option, monitor frequently (based on serial prostate biopsies), and, if necessary, implement active therapy while the disease is still at a highly curable stage. Most men will not require an intervention, and those who do can benefit from a period when quality of life and cancer-related outcomes do not appear to be compromised. ● References 1. American Cancer Society. What are the key statistics about prostate cancer? March 3, 2010. www.cancer.org/docroot/CRI/content/CRI_2_4_1 X_What_are_the_key_statistics_for_prostate_can cer_36.asp?sitearea=. Accessed March 12, 2010. 2. Large MC, Eggener SE. Active surveillance for low-risk localized prostate cancer. Oncology (Williston Park). 2009;23:974-979. 3. Eggener SE, Mueller A, Berglund RK, et al. A multi-institutional evaluation of active surveillance for low risk prostate cancer. J Urol. 2009;181:1635-1641. 4. American Urological Association. ProstateSpecific Antigen: Best Practice Statement: 2009 Update. Linthicum, MD: American Urological Association Education and Research Inc; 2009. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Prostate Cancer. V.1.2010. www.nccn.org/professionals/ physician_gls/PDF/prostate.pdf. Accessed March 12, 2010. 6. Klotz L, Zhang L, Lam A, et al. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol. 2010;28:126-131. Eileen Koutnik-Fotopoulos contributed to the preparation of this manuscript.
News Notes Americans’ Behaviors Regarding Skin Cancer Most people express concern about skin cancer and believe it is important to protect their skin; however, their attitudes and behaviors do not necessarily reflect these concerns, according to a new survey by the American Academy of Dermatology. A survey of more than 7000 Americans between January 12 and January 31, 2010, found encouraging news as well as areas for patient education. Although 75% said they would do anything to prevent skin cancer; 28% said they never check moles and skin blemishes for changes, 59% have never been checked for skin cancer by a healthcare professional, and 70% do not
June 2010 I VOL 3, nO 4
apply sunblock on the average day. In addition, 72% said that a tan makes people look more attractive, 66% said a tan makes people look healthier, and 60% agreed that sun exposure is good for you.
Breast MRI Accreditation Program In May 2010, the American College of Radiology Committee on Breast Magnetic Resonance Imaging (MRI) Accreditation launched its Breast MRI Accreditation Program (BMRAP). This program enables facilities to improve and maintain the quality of their breast MRI services through a peer-review assessment of their processes, equipment, and the quality of their images. BMRAP sets
quality standards for providers and will help them continuously improve their patient care by evaluating the qualifications of personnel, equipment performance, effectiveness of quality control measures, and image quality. For facilities that solely offer breast MRI services, BMRAP fulfills the accreditation requirements under the Medicare Improvements for Patients and Providers Act
Medicaid Rolls Likely to Expand The Patient Protection and Affordable Care Act will add an estimated 15.9 million Americans to the Medicaid rolls by 2019, according to a new Kaiser Family Foundation report. In addition,
the report estimates that 11 million low-income Americans will no longer be uninsured. The Urban Institute, which prepared the report for the Kaiser Family Foundation, projected enrollment at two levels of participation. The “enhanced outreach scenario” increases those numbers to 22.8 million people added to Medicaid and 17.5 million people newly insured. The cost of these expansions is estimated to be $464.7 billion by 2019. Only $443.5 billion will be covered by the federal government; state governments will need to pay the remainder. Under the enhanced scenario, the cost rises to $575 billion, with $532 billion paid by the federal government. ●
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TOP_June2010_v2_TOP 6/15/10 11:54 AM Page 18
ONCOLOGY DRUG CODES Supplied by: RJ Health Systems
Medications Used for the Treatment of Lung Cancer Lung cancer forms in tissues of the lung, usually in the cells lining the air passages. The two main types are small-cell lung cancer and non– small-cell lung cancer. The following section will assist healthcare professionals and payers by providing appropriate coding, billing, and reimbursement information associated with the management of lung cancer. The following sections include: • Associated ICD-9-CM codes used for the classification of lung cancer • Drugs that have been FDA-approved in the treatment of lung cancer • Drugs that are compendia listed for off-label use for lung 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
amifostine (Ethyol) bevacizumab (Avastin) carboplatin (Paraplatin) cetuximab (Erbitux) cisplatin (Platinol AQ) cisplatin (Platinol AQ) cyclophosphamide (Cytoxan) cyclophosphamide (Cytoxan)
J0207: injection, amifostine, 500mg J9035: injection, bevacizumab, 10 mg J9045: injection, carboplatin, 50 mg J9055: injection, cetuximab, 10 mg J9060: cisplatin, powder or solution, per 10 mg J9062: cisplatin, 50 mg
J8530: cyclophosphamide, oral, 25 mg J9070: cyclophosphamide, 100 mg (All 100 mg NDCs inactive—500 mg NDCs used to calculate code price) J9080: cyclophosphamide, 200 mg (All 200 mg NDCs inactive—500 mg NDCs used to calculate code price) J9090: cyclophosphamide, 500 mg
June 2010 I VOL 3, nO 4
Associated ICD-9-CM Codes Used for Lung Cancer 162 Malignant neoplasm of trachea, bronchus, and lung 162.0 Trachea Cartilage of trachea Mucosa of trachea 162.2 Main bronchus Carina Hilus of lung 162.3 Upper lobe, bronchus or lung 162.4 Middle lobe, bronchus or lung 162.5 Lower lobe, bronchus or lung 162.8 Other parts of bronchus or lung Malignant neoplasm of contiguous or overlapping sites of bronchus or lung whose point of origin cannot be determined 162.9 Bronchus and lung, unspecified
FDAapproved for lung cancer
Compendia listed off-label use for lung cancera
Current code price (AWP-based pricing), effective 6/1/10
Medicare allowable (ASP + 6%), effective 4/1/10-6/30/10
CPT administration codes
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
96374 96413, 96415 96409, 96413, 96415 96413, 96415
TOP_June2010_v2_TOP 6/15/10 11:54 AM Page 19
ONCOLOGY DRUG CODES Supplied by: RJ Health Systems
generic (Brand) name
HCPCS code: code description
cyclophosphamide (Cytoxan) cyclophosphamide (Cytoxan) docetaxel (Taxotere) doxorubicin HCl (Adriamycin) erlotinib (Tarceva)
J9091: cyclophosphamide, 1.0 gram J9092: cyclophosphamide, 2.0 gram J9171: injection, docetaxel, 1 mg J9000: injection, doxorubicin hydrochloride, 10 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J8560: etoposide, oral, 50 mg J9181: injection, etoposide, 10 mg J8565: gefitinib, oral, 250 mg J9201: injection, gemcitabine hydrochloride, 200 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0176: hydroxyurea, oral, 500 mg
etoposide (Vepesid) etoposide (Toposar) gefitinib (Iressa) gemcitabine (Gemzar) hydroxyurea (Hydrea) hydroxyurea (Hydrea) ifosfamide (Ifex) irinotecan (Camptosar) mechlorethamine HCl (Mustargen)
J9208: injection, ifosfamide, 1 gram J9206: injection, irinotecan, 20 mg J9230: injection, mechlorethamine hydrochloride (nitrogen mustard), 10 mg methotrexate J8610: methotrexate, oral, 2.5 mg methotrexate sodium J9250: methotrexate sodium, 5 mg methotrexate sodium J9260: methotrexate sodium, 50 mg mitomycin J9280: mitomycin, (Mutamycin) 5 mg mitomycin J9290: mitomycin, (Mutamycin) 20 mg mitomycin J9291: mitomycin, (Mutamycin) 40 mg paclitaxel J9265: injection, (Taxol) paclitaxel, 30 mg paclitaxel J9264: injection, protein-bound paclitaxel protein-bound particles particles, 1 mg (Abraxane) panitumumab J9303: injection, (Vectibix) panitumumab, 10 mg
FDAapproved for lung cancer
Compendia listed off-label use for lung cancera
Current code price (AWP-based pricing), effective 6/1/10
Medicare allowable (ASP + 6%), effective 4/1/10-6/30/10
CPT administration codes
96409, 96413, 96415
96409, 96413, 96415
NDC level pricing $47.64
none reported $145.10
96413, 96415 N/A 96413
NDC level pricing $1.28
NDC level pricing S0176 not payable by Medicare $30.76
96372, 96374, 96401, 96409, 96450 96372, 96374, 96401, 96409, 96450 96409
96413, 96415 96413, 96415
96413, 96415 96413
Continued on page 20 www.TheOncologyPharmacist.com
June 2010 I VOL 3, nO 4
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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Continued from page 19
generic (Brand) name
HCPCS code: code description
pemetrexed (Alimta) porfimer sodium (Photofrin) procarbazine (Matulane)
J9305: injection, pemetrexed, 10 mg J9600: injection, porfimer sodium, 75 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0182: procarbazine HCl, oral, 50 mg
procarbazine (Matulane) tamoxifen (Nolvadex) tamoxifen (Nolvadex) teniposide (Vumon) topotecan (Hycamtin) topotecan (Hycamtin) trastuzumab (Herceptin) vinBLAStine vinCRIStine (Vincasar) vinCRIStine (Vincasar) vinCRIStine (Vincasar) vinorelbine tartrate (Navelbine) a
FDAapproved for lung cancer
Compendia listed off-label use for lung cancera
Current code price (AWP-based pricing), effective 6/1/10
Medicare allowable (ASP + 6%), effective 4/1/10-6/30/10
CPT administration codes
J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0187: tamoxifen citrate, oral, 10 mg
NDC level pricing $1.89
Q2017: injection, teniposide, 50 mg J8705: topotecan, oral, 0.25 mg J9350: injection topotecan, 4 mg J9355: injection, trastuzumab, 10 mg J9360: injection, vinblastine sulfate, 1 mg J9370: vincristine sulfate, 1 mg J9375: vincristine sulfate, 2 mg J9380: vincristine sulfate, 5 mg J9390: injection, vinorelbine tartrate, per 10 mg
NDC level pricing S0182 not payable by Medicare NDC level pricing S0187 not payable by Medicare $324.55
NDC level pricing $55.68
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 Tarceva) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 in order to ensure appropriate reimbursement.
References HCPCS Level II Expert 2010 • Current Procedural Terminology (CPT) 2010 • 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 2, 2nd 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 and Medicaid Services)—Medicare Allowable 2nd Quarter 2010 (effective dates 4/1/106/30/10). Prices listed herein are effective as of June 1, 2010. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS, Healthcare Common Procedure Coding System; 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
June 2010 I VOL 3, nO 4
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CONTINUING EDUCATION CREDITS
Current activities at www.COEXM.com include:
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New Treatments for Chronic Idiopathic Thrombocytopenic Purpura. Part 2. Eltrombopag By Starla J. Sweany, PharmD, BCOP The University of Texas M. D. Anderson Cancer Center, Houston
haracterized by thrombocytopenia and bleeding manifestations, particularly mucocutaneous, idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder seen in both adults and children. Although the majority of ITP cases in children are considered acute and typically resolve within 6 months often without therapy, adult ITP is generally chronic and requires therapeutic interventions to raise platelet counts.1 ITP can be associated with other disorders, including malignancy and infections, and is referred to as secondary ITP. However, the etiology of primary ITP is still largely unclear.1,2 Production of antiplatelet autoantibodies leading to platelet destruction by macrophages, coupled with the inhibition of megakaryocyte platelet production, leads to an overall decrease in platelet counts in patients with ITP. Several studies have also demonstrated that antibody production may be driven by T-cell and B-
cell clones. Because of the risk of hemorrhagic complications associated with severe thrombocytopenia, the general goal in the treatment of patients severely affected with ITP is to maintain platelet counts at or above 30 ¥ 109/L to 50 ¥ 109/L. Corticosteroids have long been the first-line treatment and are considered the standard of care for the initial management of ITP. Response rates to corticosteroids range from 50% to 75%; however, this response is often short-term, and only up to 30% of patients have a prolonged response.1,3 Intravenous immunoglobulin (IVIG) is often the next step in the treatment of ITP after failure of corticosteroid therapy or development of hemorrhagic complications. Although splenectomy remains the most effective and possibly curative option for chronic ITP, with two thirds of patients having a sustained response,4 the postsurgical period can be complicated with infections, and many questions still remain
regarding optimal timing and patient selection.3 Refractory ITP is defined as persistent thrombocytopenia after initial treatment including splenectomy that requires further treatment to maintain a safe platelet count. For these patients, options available include rituximab, danazol, cyclophosphamide, immunosuppressive agents (eg, cyclosporine, azathioprine), mycophenolate mofetil, and vinca alkaloids, all of which exhibit varying degrees of effectiveness and adverse event profiles.1,4 Despite several effective treatment strategies for patients with chronic or relapsed ITP, a need for more salvage treatment options has prompted additional research on the biology of thrombopoiesis. This research has led to the development of agents that work by stimulating the production of platelets, in contrast to traditional therapies, which aim at inhibiting the production of antiplatelet antibodies. Endogenous thrombopoietin (TPO) is synthesized in
Table 1. Dosing and Monitoring Eltrombopag Therapy Monitoring parameters Laboratory values
Complete blood count, including platelet count; peripheral blood smear
Weekly until stable platelet count (>50 ¥ 109/L) achieved, then monthly thereafter
Liver function tests, including AST, ALT, and bilirubin
Prior to initiation, every 2 weeks during dose adjustment, and monthly once stable dose achieved • If abnormal laboratory value, repeat in 3 to 5 days; following confirmation of abnormality, monitor weekly until resolution, stabilization, or return to baseline • Discontinue therapy if ALT ≥3 ¥ ULN and: • Progressive, or • Persistent (≥4 weeks), or • Accompanied by increased direct bilirubin, or • Accompanied by clinical symptoms Dose adjustment
<50 ¥ 109/L after at least 2 weeks of therapy
Increase daily dose by 25 mg, up to a maximum of 75 mg daily
≥200 ¥ 109/L to ≤400 ¥ 109/L anytime during therapy
Decrease daily dose by 25 mg; allow 2 weeks before assessing effects of new dose
>400 ¥ 109/L
Stop eltrombopag; monitor platelets twice weekly and reinitiate therapy at a daily dose reduced by 25 mg when platelets are <150 ¥ 109/L
>400 ¥ 109/L after 2 weeks of therapy at lowest dose (25 mg)
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal. Source: Reference 7.
June 2010 I VOL 3, nO 4
the liver, releases into the circulation, and binds to TPO receptors on stem cells, progenitor cells, and platelets. Activation of these receptors leads to downstream signaling pathways and, ultimately, to proliferation of megakaryocytes, thus increasing the release of platelets into the bloodstream. Most patients with ITP have low or normal levels of endogenous TPO,5 despite the compensatory reaction that normally occurs—increasing TPO levels in situations with low platelet counts. Initial clinical trials using thrombopoietin analogs were halted due to immunogenicity reactions and antibody formation leading to secondary thrombocytopenia and bleeding.6 Secondgeneration thrombopoiesis-stimulating agents that developed out of this setback have provided two new commercially available agents, which have minimal immunogenicity and are not structurally similar to endogenous TPO. Romiplostim was the first thrombopoiesis-stimulating agent approved by the US Food and Drug Administration, followed closely by eltrombopag for the treatment of patients with chronic ITP who have insufficient response to corticosteroids, IVIG, or splenectomy. Eltrombopag is a small-molecule, nonpeptide TPO receptor–agonist that binds to the transmembrane domain of human TPO receptors, thus inducing proliferation and differentiation of cells in the megakaryocytic lineage.7 Eltrombopag in the treatment of ITP The results of two multicenter, randomized, double-blind, placebo-controlled trials have served as the platform for approval of eltrombopag for use in refractory ITP. The initial trial was a phase 2 dose-ranging trial designed to assess whether eltrombopag could safely increase platelet counts. This study included 118 patients with at least a 6month history of ITP, who were at least 18 years of age (median age, 50 years), had received at least one previous therapy (47% with prior splenectomy), and had a platelet count <30 ¥ 109/L (48% had platelet count ≤15 ¥ 109/L) at enrollment. Patients were enrolled in a 1:1:1:1 manner into the placebo, 30-mg, 50-mg, or 75-mg eltrombopag groups to be taken orally once per day for up to 6 weeks. Maintenance immunosuppressive therapy, mainly glucocorticoids, with stable doses was allowed, but other Continued on page 24
TOP_June2010_v2_TOP 6/15/10 11:54 AM Page 23
value-focused www.ValueBasedCancer.com www.ValueBasedCancer.com
New NewTools ToolsArriving ArrivingtotoMeasure Measureand and NCCN NCCNRoundtable: Roundtable:Clinical Clinicaland and Manage Economic ManageChemotherapy ChemotherapyCare Care EconomicIssues IssuesImpacting Impacting Business, Cancer Business,clinical clinicalconcerns concernsnow nowconnected connectedinin CancerCare CareDelivery Delivery value-focused value-focusedapproach approach ByBy Daniel Denvir Daniel Denvir
Baltimore, MDâ€”A long-held business Baltimore, MDâ€”A long-held business truism is is that â€œifâ€œif you canâ€™t measure it, it, truism that you canâ€™t measure you it.â€?it.â€? The application youcanâ€™t canâ€™tmanage manage The application ofofthis belief to the oncology setting this belief to the oncology setting was of of thethe wasdemonstrated demonstratedat ata session a session Association AssociationofofCommunity CommunityCancer Cancer Cen tersâ€™ 36th Annual National Cen tersâ€™(ACCC) (ACCC) 36th Annual National Meeting. Kimberly Bergstrom, PharmD, Meeting. Kimberly Bergstrom, PharmD, chief chiefclinical clinicalofficer officerforforMcKesson McKesson Specialty Care Solutions, told attendees Specialty Care Solutions, told attendees ofof thethe growing importance of of developing growing importance developing and using standardized chemotherapy and using standardized chemotherapy treatment regimens, and of of thethe tools that treatment regimens, and tools that
clinical practice guidelines
â€œCollision â€œCollisioncourseâ€? courseâ€?ininsight sight cancan benchmark performance andand foster benchmark performance foster compliance with treatment guidelines. Dr DrGoodman Audrey Andrews Goodman compliance with treatment guidelines. By By Audrey Andrews Public and private payers areare movalluded to atolevel Public and private payers movalluded a level ingingto tocontrol exploding healthcare thatthat of frustration control exploding healthcare Hollywood, Hollywood,FLâ€”Clinical FLâ€”Clinicalpractice practice of frustration never been costs, told attendees, issued by by thethe National costs,DrDrBergstrom Bergstrom told attendees, guidelines guidelines issued National hashas never been and because increased cost control Comprehensive Cancer Network higher in cancer and because increased cost control Comprehensive Cancer Network higher in cancer was areare followed by by conscienâ€œToo many wasinevitable, inevitable,it itis isin inprovidersâ€™ providersâ€™ (NCCN) (NCCN) followed conscien- care. care. â€œToo many interest to to getget a seat at at thethe table. tious oncologists in in their everyday areare stillstill interest a seat table. tious oncologists their everyday patients patients â€œItâ€œIt is is anan important topic, because areare developed young. WeWe important topic, because practice, practice,butbutthey they developed dying dying young. on on clinical efficacy andand without innovations andand a cure,â€? he said. this is one of of those things, if we donâ€™t this is one those things, if we donâ€™t based based clinical efficacy without need need innovations a cure,â€? he said. getget a handle onon it, it, itâ€™sitâ€™s going to happen to to costs. At At a roundtable held thethe inadequacy of current treatinadequacy of current treata handle going to happen regard regard costs. a roundtable held ButBut to to us,â€? sheshe said. â€œPeople and groups NCCNâ€™s 15th Annual for for cancer is no the the main us,â€? said. â€œPeople and groups during duringthethe NCCNâ€™s 15th Annual ments ments cancer is longer no longer main and organizations are going to start Conference, moderator Clifford problem. Equally challenging, he sugand organizations are going to start Conference, moderator Clifford problem. Equally challenging, he sugdictating how we provide cancer care, Goodman, PhD, Senior Vice President gested, is finding a means to pay for dictating how we provide cancer care, Goodman, PhD, Senior Vice President gested, is finding a means to pay for and wewe canâ€™t letlet that happen.â€? at The Lewin Group, predicted, â€œThe ever-costlier carecare thatthat threatens to to and canâ€™t that happen.â€? at The Lewin Group, predicted, â€œThe thethe ever-costlier threatens appropriate use of evidence-based bankrupt the healthcare system. Continued on page 8 appropriate use of evidence-based bankrupt the healthcare system. Continued on page 8 guidelines is on a collision course As society struggles to find soluAs society struggles to find soluguidelines is on a collision course with the financial nonsustainability of tions, â€œthe ground is shaking beneath with the financial nonsustainability of tions, â€œthe ground is shaking beneath the healthcare system.â€? us,â€? Dr Goodman commented. the healthcare system.â€? us,â€? Dr Goodman commented.
Value-Based Value-BasedCancer CancerCare Care will willbebeatatthe theASCO ASCOAnnual Annual Meeting, Meeting,June June4-8, 4-8,ininChicago. Chicago.
Continued on page 19 Continued on page 19
Please visit usus atat booth 18121 Please visit booth 18121
SEER-Medicare SEER-MedicareDatabase DatabaseAnalysis Analysis Confirms Expensive Prostate Confirms Expensive Prostate Breast BreastCancer CancerSurvival SurvivalImproves, Improves, Cancers CancersGaining GainingSupremacy Supremacy Photo by ÂŠ ASCO/Todd Buchanan 2009 Photo by ÂŠ ASCO/Todd Buchanan 2009
Thanks ThankstotoNew NewTherapies Therapies
But remains to to Butcost-effectiveness cost-effectivenessofofthis thismove move remains bebedetermined determined
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€”Survival for patients with suggest, is due to increased use of The 2010 Genitourinary Cancers Barcelonaâ€”Survival with anthracyclines suggest, is due to rise increased use of San Francisco, CAâ€”The popularity of The 2010 Progress Genitourinary Cancers metastatic breast cancerfor haspatients improved and the of targeted Symposium: in Multi San Francisco, CAâ€”The metastatic breast has improved anthracyclines and the rise of targeted minimally Symposium: Progresswas in held Multidramatically in the cancer last 20 years, espe- therapies. Management invasive radical popularity prostatec- of disciplinary minimally invasive radical prostatecdramatically in the last 20 years, espetherapies. disciplinary Management cially in the subgroup of patients with â€œThere is no doubt that trastuzu- tomy (MIRP), intensity-modulated March 5-7 in San Francisco. Allwas ses-held 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€œThere (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 to take off brought out the cost andgenitourivalue issues Continued on page 27 after associated with caring for a new database analysis 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€™s 2010 Genitourinary - and Womenâ€™s Hospital, Harvard Oncologyâ€™s 2010Paul Genitourinary Can- Medical and Womenâ€™s Hospital, Harvard cers Symposium, L. Nguyen, School, Boston, and his cocerspresented Symposium, Nguyen, Medical School, his coMD, the Paul resultsL. of his investigators foundBoston, MIRP and jumped investigators found MIRP jumped MD, analysis presentedof the teamâ€™s dataresults from of thehis from 1.5% of radical prostatectomies teamâ€™s analysis of data from the from 1.5% of radical prostatectomies Surveillance, Epidemiology and End (RPs) in 2002 to 28.7% in 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 for 8.7% of external radiation treatments Brachytherapy, Dana-Farber/Brigham prostate cancer to 81.7%. In addiBrachytherapy, Dana-Farber/Brigham for prostate cancer to 81.7%. In addiContinued on page 24
By Colin Gittens By Colin Gittens
ÂŠ2010 Engage Healthcare Communications, LLC ÂŠ2010 Engage Healthcare Communications, LLC
Continued on page 24
A new publication for your new vocabulary
TOP_June2010_v2_TOP 6/15/10 11:54 AM Page 24
Drug Therapy New Treatments for Chronic Idiopathic Thrombocytopenic... Continued from page 22 Table 2. Adverse Events Associated with the Use of Eltrombopag Eltrombopag 50 mg (n = 106)
Placebo (n = 67)
ALT indicates alanine aminotransferase; AST, aspartate aminotransferase. Sources: References 8 and 9.
treatments for ITP had to be discontinued at least 2 weeks before enrollment. In the 109 patients evaluated for efficacy data, the primary end point (platelets ≥50 ¥ 109/L on day 43) was achieved in 11%, 28%, 70%, and 81% in the placebo, 30-mg, 50-mg, and 75mg groups, respectively. By day 15 of therapy, more than 80% of patients in the 50-mg and 75-mg groups had reached platelet counts ≥50 ¥ 109/L. Platelet counts rose to ≥200 ¥ 109/L in 28 patients (26%), at which time eltrombopag was discontinued. After cessation of therapy, platelet counts returned to near baseline levels within 2 weeks. The incidence of bleeding also decreased as platelet counts increased, particularly in the patients receiving the 50-mg and 75mg doses of eltrombopag.8 A phase 3 trial was conducted as a follow-up to assess the efficacy, safety, and tolerability of eltrombopag 50 mg orally once per day compared with placebo. Inclusion criteria were similar in the two studies. The 114 patients enrolled were randomized 2:1 to eltrombopag therapy for up to 6 weeks or placebo. Eltrombopag could be increased to 75 mg daily after 3 weeks if platelet counts had not reached 50 ¥ 109/L. The primary end point (platelets ≥50 ¥ 109/L after 6 weeks of therapy) was reached by more patients in the eltrombopag arm than the placebo arm (59% vs 16%, P <.0001). Of the 34 patients who received a dose increase to 75 mg, 29% met the primary end point; however, none of these patients reached platelet counts ≥200 ¥ 109/L. Prior history of splenectomy, concomitant drugs for ITP, or baseline platelet count ≤15 ¥ 109/L did not have a significant effect on response rates to eltrombopag compared with placebo. As is the goal in the treatment of ITP, a significant reduction in bleeding symptoms was seen in the treatment group compared with the
June 2010 I VOL 3, nO 4
placebo group (39% vs 60%, P = .029). As seen in the phase 2 trial, platelet counts returned to baseline following discontinuation of eltrombopag, as did the risk for bleeding complications.9 Dosing, administration, and toxicity Eltrombopag should be started at a dose of 50 mg orally once per day on an empty stomach (1 hour before or 2 hours after a meal) and should be separated by at least 4 hours from antacids, calcium-rich food, and supplements containing polyvalent cations (iron, calcium, magnesium, aluminum, selenium, and zinc).7 Patients of East-Asian decent (Chinese, Japanese, Korean, and Taiwanese) should be started at 25 mg orally daily because of pharmacokinetic data showing this population had a 70% increased exposure compared with nonAsian subjects. Moderate to severe hepatic impairment (as determined by Child-Pugh criteria) will require dose reduction of eltrombopag to 25 mg orally once per day. The lowest dose of eltrombopag should be used to maintain a platelet count >50 ¥ 109/L. Dose adjustments and monitoring parameters can be found in Table 1. Because eltrombopag is metabolized by cytochrome P450 (CYP) 1A2, CYP2C8, and several uridine diphosphate-glucuronosyltransferases, patients receiving concomitant therapy with moderate or strong inhibitors of these metabolizers and eltrombopag should be monitored closely for signs and symptoms of excessive eltrombopag exposure. In vitro studies also show that eltrombopag is an inhibitor of the organic anion transporting polypeptide 1B1 and can increase systemic exposure to drugs that use this transport system, such as atorvastatin, fluvastatin, pravastatin, rosuvastatin, methotrexate, nateflinide, repaglinide, and rifampin. Although no specific dose reductions
have been given, caution should be used with administering these drugs concomitantly.7 The most common adverse effects associated with eltrombopag use were headache, nausea, vomiting, and diarrhea. Adverse events associated with the 50-mg dose of eltrombopag combined from the two randomized studies are summarized in Table 2. The incidence of grade 3/4 adverse events during treatment in both studies was similar for patients receiving eltrombopag and placebo, 11 (7%) versus five (7%).8,9 Reticulin fiber deposition, without cytopenias, was reported in the bone marrow biopsies of seven patients. This observation prompted the manufacturer to warn prescribers to monitor patients closely by examining peripheral blood smears and to discontinue therapy if the patient develops new or worsening morphologic abnormalities or cytopenias.7 Thrombotic complications have also been observed in patients receiving eltrombopag and are likely a result of excessive increases in platelet counts. Distribution program Promacta Cares is a restricted distribution program that was designed to promote risk-benefit decisions before eltrombopag is dispensed to patients as well as to require prescribers to report baseline and periodic safety information for each patient enrolled. Before distribution of eltrombopag, each prescriber must complete a one-time enrollment form, which can be found on the Promacta Cares website.10 In addition, a completed enrollment form and patient baseline form must be sent in for each patient before the patient can receive the medication. Twice yearly, a consultant from Promacta Cares will contact the prescriber to collect safety information, verify the patient is still receiving eltrombopag, and verify whether the patient should continue therapy. To help establish long-term data regarding safety and use, registered prescribers must report any adverse events to the program. In particular, the risk for hepatotoxicity, bone marrow reticulin formation and fibrosis, worsened thrombocytopenia upon cessation of therapy leading to serious hemorrhage, thromboembolic/thrombotic complications, and increased risk or progression of hematologic malignancies are the focus of the registry program. In addition to proper counseling regarding the use and side effects of eltrombopag, a mandatory medication guide must be distributed to each patient and can be found on the Promacta Cares website.10 Conclusion With up to 10% of ITP patients
developing refractory disease, the need for agents to reduce mortality from bleeding complications in this population has encouraged many researchers to delve into new mechanisms in the pathogenesis of ITP. Second-generation thrombopoiesis-stimulating agents were developed to provide an additional mechanism of increasing platelets by stimulating the production of platelets in the bloodstream. Eltrombopag has shown substantial efficacy in maintaining platelets above 50 ¥ 109/L in patients with chronic ITP in two randomized controlled trials. Its long-term efficacy has not been established, however, as the duration of these trials was only 6 weeks. Several ongoing studies are looking at long-term use of eltrombopag in patients with chronic ITP. Preliminary data from the Eltrombopag Extended Dosing Study (EXTEND) have shown that 73% of patients with baseline platelets <30 ¥ 109/L achieved platelet counts ≥50 ¥ 109/L during a median treatment duration of 151 days, and the adverse event profile was similar to that in previous studies.11 The study also seeks to determine whether tapering of concomitant medications for ITP will maintain platelet counts while on eltrombopag, thus allowing patients to receive less corticosteroid therapy. Based on these favorable re sults, the use of eltrombopag and romiplostim is currently being studied in other disease states causing thrombocytopenia, including myelodysplastic syndrome and chemotherapy-induced thrombocytopenia.12-14 Continued re search in the use of thrombopoiesisstimulating agents may identify which patients are more likely to respond to these therapies as well as determine whether these agents should be used as frontline therapy. ● References 1. Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346:9951008. 2. Cines DB, McMillan R. Pathogenesis of chronic thrombocytopenia purpura. Curr Opin Hematol. 2007;14:511-514. 3. Godeau B, Provan D, Bussel J. Immune thrombocytopenic purpura in adults. Curr Opin Hematol. 2007;14:535-556. 4. Kojouri K, Vesely SK, Terrell DR, George JN. Splenectomy for adult patients with idiopathic thrombocytopenic purpura: a systematic review to assess long-term platelet count responses, prediction of response, and surgical complications. Blood. 2004;104:2623-2634. 5. Porcelijn L, Folman CC, Bossers B, et al. The diagnostic value or thrombopoietin level measurements in thrombocytopenia. Thomb Haemost. 1998;79:1101-1105. 6. Li J, Yang C, Xia Y, et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood. 2001;98:3241-3248. 7. Promacta (eltrombopag) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.
Continued on page 26
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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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National Safe Handling Initiative Serves as Reminder of Need for Precautions when Handling Hazardous Drugs By Karen Rosenberg
pril 2010 was the second Nat- we don’t know if that’s acceptable. ional Safe Handling Month, a There’s also the question of how much campaign designed to further contamination—if any—is acceptable. education about the risks associated At what level are we going to get into with handling hazardous drugs and safe- trouble? There may be multiple threshty measures that can prevent olds, and until we can say this exposure to these agents. The is the unsafe level at which initiative was supported by an some percentage of the popuunrestricted educational grant lation will be at risk for develprovided by Carmel Pharma, oping a malignancy, people Inc, the maker of the PhaSeal are going to ask why they closed-system drug transfer should spend large sums of device (CSTD) and includmoney to comply when it may ed regional and national not be necessary. The twoeducational activities. The pronged approach is to either Oncology Pharmacist recently provide reimbursement from Timothy Tyler, spoke with Timothy Tyler, the payers, Medicare, MediPharmD, FCSHP PharmD, FCSHP, director of caid, and the third-party paypharmacy services, Comprehensive Can- ers, for using CSTDs or to be able to cer Center, Desert Regional Medical demonstrate the level at which contamCenter, Palm Springs, California, about ination will cause harm. his institution’s decision to implement a So, the barriers to compliance with CSTD to protect their personnel. the standards are basically cost and the fact that we don’t know what Why is there still a need to raise exactly the safety threshold is. We’re awareness of safe handling? running a business with very little The 2004 National Institute for margin left these days in healthcare. Occupational Safety and Health There are a lot of issues with reim(NIOSH) alert raised awareness of the bursement, so the idea of adding problem, but NIOSH has no executive another expense when we’re not posienforcement arm. The US Pharma - tive about the level of risk is not copeia (USP) <797> regulations are attractive to hospital or business enforceable, but who is going to enforce administrators. I think people will them? We are all trying to comply, but divide into those who say “if there’s we know from listservs and what we hear any potential risk, we want to offer from our colleagues that there are facili- personal protective equipment for all ties that are not fully complying with all of our staff to be on the safe side,” and of the USP <797> regulations. those who say “we don’t have the And a lot of questions remain. For money for this unless you can demoninstance, CSTDs are mentioned in the strate that there’s a defined risk.” One NIOSH alert and briefly in USP <797>. of the reasons for an awareness month We know that if these devices are truly is to keep raising this issue with the closed systems, they are effective in people who are actually involved in reducing contamination, but some of handling of the cytotoxins and other them are filtered, not truly closed, and hazardous drugs.
At your own institution you decided to use a CSTD. What led to that decision? Data from a study conducted at the Huntsman Cancer Center in Salt Lake City, Utah, were instrumental in making that decision. The Huntsman study showed a significant reduction in surface contamination and positive urine samples from pharmacists, technicians, and nurses after implementation of the PhaSeal system (Wick C, et al. Am J Health Syst Pharm. 2003;60:23142320). In 2000, we had just moved into a fairly low-volume, brand new facility and had only one pharmacy technician preparing chemotherapy. We thought we were doing everything right and decided to do wipe testing to document it. Much to our surprise, we did test positive, which made me believe that even under the very best circumstances, you can still have contamination. When we tested again after 6 months of use of the PhaSeal system, all areas tested showed a reduction in contamination. Did the staff accept the new device readily? We surveyed the nurses and technicians after the first week of use and they said it slowed them down, but after 60 days of use that was no longer the case. It just became part of our standard operating procedure. It is important though to train new personnel how to use the system appropriately. It does require a concerted effort with everyone from administration to pharmacy to nursing agreeing on what the important issues are, doing the training, and sticking to it, making sure that the product is being used appropriately.
What are some of the remaining issues with safe handling? Of course the 800-pound gorilla in the room is that nearly all of the chemotherapy vials or hazardous drug vials that come to doctors’ offices and clinics come contaminated on the outside. The manufacturers have said their hands are tied. They’re concerned that if they put vials through an extra washing that gets rid of that contamination, they’d be heating the vials, and the US Food and Drug Administration would then require them to do studies to prove that they haven’t damaged the drug inside. The Hematology/Oncology Pharmacy Association and other organizations are looking into this situation. As I mentioned before, the cost of CSTDs remains a concern too. I think probably the only way it’s going to be solved is by mandating the use of some system. And that cost has to be reimbursed by the payer community —by Medicare, Medicaid, or thirdparty insurance companies. We need legislative involvement and we need to lobby the payer community to convince them that this is a legitimate use of technology to keep employees safe. As Luci Power stated in an editorial, “demand clean vials” (Power LA. Am J Health Syst Pharm. 2005; 62:471). ● For more information on safe handling of hazardous drugs, please view the archived Safe Handling Awareness Day CE webinar at www.carmelpharmausa.com/CE. Free CE credit for this archived webinar is available for pharmacists, pharmacy technicians, nurses, and risk managers.
New Treatments for Chronic Idiopathic Thrombocytopenic... Continued from page 24 8. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for the treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med. 2007;357:2237-2247. 9. Bussell JB, Provan D, Shamsi T, et al. Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, doubleblind, placebo-controlled trial. Lancet. 2009; 373:641-648. 10. Promacta Cares. www.promactacares.com. Accessed September 1, 2009. 11. Bussel JB, Cheng G, Kovaleva L, et al. Long-term
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safety and efficacy of oral eltrombopag for the treatment of subjects with idiopathic thrombocytopenic purpura (ITP): preliminary data from the EXTEND study. Blood (Annual Meeting Abstracts). 2007;110:Abstract 566. 12. Tiu RV, Sekeres MA. The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes. Expert Opin Biol Ther. 2008;8:1021-1030. 13. GlaxoSmithKline. Eltrombopag treatment of thrombocytopenia in subjects with advanced
myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia after MDS (sAML/ MDS). Clinicaltrials.gov identifier: NCT009 034 22. http://clinicaltrials.gov/ct2/show/NCT009 03422?term=eltrombopag&rank=11. Accessed September 1, 2009. 14. Amgen, Inc; M.D. Anderson Cancer Center. AMG 531 in patients with advanced malignancy receiving treatment with carboplatin. Clinical trials.gov identifier: NCT00147225. http://clinical trials.gov/ct2/show/NCT00147225?term=romi plostim&rank=6. Accessed September 1, 2009.
Did You Know? Medicare covers only 56% of the costs of administering chemotherapy and providing infusion room services to elderly patients, according to a study of cancer care in community practices.
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Reports from the European Breast Cancer Conference and the European Association of Urology Congress CEP17 Breast Cancer Tumors Are More Likely to Respond to Anthracyclines BARCELONA—Breast cancer patients with the chromosome enumeration probe 17 (CEP17) alpha satellite abnormality are more likely to have good outcomes from chemotherapy involving anthracycline antibiotics than women without the abnormality, according to new data released at the Seventh European Breast Cancer Conference. John Bartlett, MD, with the University of Edinburgh in Scotland presented the results of a meta-analysis of four adjuvant breast cancer trials that enrolled a total of nearly 3000 women. Women with CEP17 tumors that were treated with anthracyclines were roughly two thirds more likely to survive without recurrent cancer than those who did not receive anthracyclines. Recurrence-free survival was 67%, and overall survival was 63%. Prior research by the same investigators had shown that duplication of CEP17 predicts sensitivity to anthracyclines. “CEP17 can be readily assessed in fluorescent in situ hybridization analysis of human epidermal growth factor receptor type 2 [HER2] status and may repre-
sent a clinically useful biomarker for the selection of patients likely to benefit from anthracycline-containing therapies,” Bartlett pointed out. He added that the research is important because there has been conflicting evidence on the best way to predict response to anthracyclines and because it has not been clear whether any of the known biomarkers like HER2 and topoisomerase 2 alpha were accurate indicators of response to these drugs.
High BMI Is No Reason to Exclude Prostate Cancer Patients from Minimally Invasive Surgery BARCELONA—Minimally invasive prostate cancer surgery known as robotic-assisted laparoscopic prostatectomy (RALP) is an effective and safe treatment option in obese patients, investigators announced at the 25th Anniversary European Association of Urology Congress. David Samadi, MD, and colleagues at Mount Sinai Medical Center in New York presented results in 1112 men who underwent RALP by a single surgeon. Of the study population, 870 patients had a low body mass index (BMI; <30) and
242 patients had a high BMI (≥30). The results showed similar perioperative, pathologic, oncologic, and functional outcomes in the two groups. Continence and potency rates were also similar. Samadi noted that surgeons have voiced concern that obese patients might develop worse outcomes than nonobese patients because surgery is technically more challenging in this population. “Surgeons should approach these cases with more confidence,” he said.
Breast Cancer Patients Prefer “Buddy System” to Photographs When Discussing Reconstruction BARCELONA—Women with breast cancer say they would rather meet with other patients who have undergone breast reconstructive surgery than view clinical photographs before they decide on the particulars of their procedure, new data show. Clinical photographs are the surgeons’ preferred method for showing patients preoperatively the outcomes of various types of breast reconstruction. Anushka Chaudhry, MD, with
Frenchay Breast Care Centre in Bristol, United Kingdom, interviewed 30 women who were planning to undergo reconstructive procedures at her institution. All patients were seen at the center’s dedicated breast reconstruction clinic. In addition to viewing clinical photographs of their surgeon’s breast reconstruction procedures, patients were offered the opportunity to meet face-to-face with other women who had undergone similar procedures or talk to them by telephone or e-mail. Contact between the women was made by the breast cancer nurse. Twenty-five women reported that they preferred meeting other patients to “simply seeing clinical photographs.” The other five women said that they, too, preferred meeting other women who had undergone reconstructive surgery but that contact by phone or e-mail was best for them. “A key part of the decision-making process is support, and patients are often the best advocates for others at this time of great personal anguish,” Chaudhry said. She reported the findings at the Seventh European Breast Cancer Conference. ●
Is It Time to Jump on the Credit Union Bandwagon? By Eileen Koutnik-Fotopoulos
re you tired of the poor interest rates your bank is offering? Have you had it with bank fees? Are you worried your bank could fail? Perhaps, it’s time you consider switching to a credit union. More than 90 million Americans belong to a credit union, according to the Credit Union National Association. A credit union is a financial cooperative that offers a wide array of services similar to those offered by banks, such as checking and saving accounts, credit cards with low interest rates and low or no annual fees, and loans. Nowadays, membership is not limited to specialized groups because the National Credit Union Administration (NCUA) has relaxed its regulations on joining. NCUA is an indepedent federal organization that supervises and charters credit unions, as well as insures participants’ savings. Each credit union serves what is called their “field of mem-
June 2010 I VOL 3, nO 4
bership”—that is the commonality between the members, according to NCUA. You may be eligible to join a credit union based on your: • Employer—many employers sponsor their own credit unions • Geographic location—many credit unions serve anyone who lives in a particular geographic area • Family—most credit unions allow members’ families to join • Membership in a group, such as a church, labor union, school, or alumni. Here are some advantanges of belonging to a credit union: • Credit unions are not-for-profit organizations. The profits incurred by the credit union directly benefit its members, and NCUA insures deposits up to $250,000. • The biggest distinction between credit unions and banks is that credit unions are owned and run by
its members. Therefore, if you have an account with a credit union, you are a member and owner. As a member, you have a say in how the credit union is run and can vote on a board of directors. • Interest rates, for example, on car loans, mortgages, and money market accounts, are often attractively low. Credit unions can offer these lower interest rates because they are exempted from most state and federal income taxes. Additionally, credit unions are in a better position to lend money because they are not as tangled up in the subprime credit crisis, compared with commercial banks. • Fees can be fewer and lower. Customer fees generated by banks help generate profits. Credit unions, however, charge nominal fees or no fees at all for many of their services.
• Minimum balance requirements are low. Most credit unions require a deposit of $5 to $25 to join, open an account, and be eligible for free checking. Banks, however, typically require a larger deposit to open an account and often require a minimum balance for free checking. If you decide to join a credit union, keep in mind that you may have limited access to branch offices and automated teller machines (ATMs). However, many credit unions have formed a network of “shared branch” locations throughout the country that members can use without incurring ATM fees. Before opening an account, visit your credit union’s website for ATM locations. It is also a good idea to talk with your credit union to make sure you have a full understanding of their services. To learn more about whether a credit union is right for you, visit NCUA’s website at www.ncua.gov. ●
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June 30-July 3 BARCELONA, SPAIN 12th World Congress on Gastrointestinal Cancer www.esmo.org
RANCHO PALOS VERDES, CA 11th International Lung Cancer Congress www.cancerlearning.com
WASHINGTON, DC 10th International Congress on Genitourinary Malignancies www.cancerlearning.com
LA JOLLA, CA Ninth International Congress on the Future of Breast Cancer www.cancerlearning.com
BORDEAUX, FRANCE Congress of the European Society of Surgical Oncology www.ecco-org.eu
WASHINGTON, DC Breast Cancer Symposium www.asco.org
MONTREAL, QUEBEC 18th International Congress on Palliative Care www.pal2010.com
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 8 3 Dizziness 10 1 transplant. The patients with autoimmune diseases had prior or concurrent Skin Anemia Anxiety 5 1 and Appendages 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 NHLL In Study 4, approximately 4 months after the initiation of Rituxan and approximately one month after patients in the R-CVP arm experienced a higher incidence of infusional toxicity and the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. neutropenia compared to patients in the CVP arm. The following adverse reactions Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: infection for several months following Rituxan therapy. Discontinue Rituxan and any rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), concomitant chemotherapy in patients who develop viral hepatitis, and institute pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In appropriate treatment including antiviral therapy. Insufficient data exist regarding the Study 5, the following adverse reactions were reported more frequently (≥5%) in safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV patients receiving Rituxan following CVP compared to patients who received no further reactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial, therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory fungal, and new or reactivated viral infections can occur during and up to one year neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. following the completion of Rituxan-based therapy. New or reactivated viral infections 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm institute appropriate anti-infective therapy. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform compared with those who received no further therapy (4% vs. 1%). [See Clinical s the following adverse reactions, cardiac monitoring during and after all infusions of Rituxan for patients who develop Studies.] DLBCLL In Studies 6 and 7, [see Clinical Studies] clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with NHL. Renal toxicity has occurred in patients who (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity approved treatment regimen. Monitor closely for signs of renal failure and discontinue determined that supraventricular arrhythmias or tachycardia accounted for most of Rituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading following Grade 3 or 4 adverse reactions occurred more frequently among patients in to death, can occur in patients receiving Rituxan in combination with chemotherapy. In the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. postmarketing reports, the mean time to documented gastrointestinal perforation was 6 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and more frequently among patients receiving R-CHOP were viral infection (Study 7), institute appropriate treatment for complaints of abdominal pain. [See Adverse neutropenia (Studies 7 and 8), and anemia (Study 8). CLL The data below reflect Reactions.] Immunization The safety of immunization with live viral vaccines following exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 s The age range was Rituxan therapy has not been studied and vaccination with live virus vaccines is not patients with CLL in Study 9 or Study 10 [see Clinical Studies]. recommended. Laboratory Monitoring In patients with lymphoid malignancies, during 30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related
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 NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. s Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of 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
June 2010 I VOL 3, nO 4
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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
21.7 months FC
improvement in median
improvement in median
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.