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VOL 3, NO 7
The Official Newspaper for the Hem/Onc Pharmacist
CANCER CENTER PROFILE
Reducing Disparities in Cancer Care: St. Luke’s Mountain States Tumor Institute Embraces NCCCP Pillar By Dawn Lagrosa
Revisiting the Use of IV Iron in Patients with Cancer By Michael Auerbach, MD Auerbach Hematology Oncology Associates, Baltimore, Maryland
he role of intravenous (IV) iron as an addition to erythropoiesisstimulating agents (ESAs) to optimize therapy in patients with anemia from cancer or chemotherapy-induced anemia has been examined in nine prospective, randomized trials,1-9 all of which showed improvement in ESA response, time to maximal response, reduction in ESA dose to reach maximal response, and improvement in quality-oflife parameters (when measured). The observed benefit was independent of baseline iron parameters, and although responses were greater in iron-depleted
patients, significant benefit was seen in patients who were iron replete at study entry. One study, which was powered to show a difference in red blood cell transfusions, found a 36% reduction in the number of patients transfused.5 In all these studies, which represent data on more than 1200 patients, no significant toxicity was noted. Despite these data, there remains resistance to the addition of IV iron to the standard treatment paradigm for cancer and chemotherapy-induced anemia. This resistance is, in large part, due to misinformation and misinterpretation about the Continued on page 24
PHARMACY PRACTICE Members of St. Luke’s Mountain States Tumor Institute, from left: Dan Zuckerman, MD; Alicia Rosales, LMSW; Jill Winschell, RN; and Paul G. Montgomery, MD, FACP.
It May Be Time to Rethink Drug Dosing in Your Obese Patients By John Schieszer
t. Luke’s Mountain States Tumor Institute (MSTI) provides advanced cancer care to patients at clinics in Boise, Fruitland, Meridian, Nampa, and Twin Falls, Idaho. Spanning more than 180 miles across southwestern Idaho, MSTI cares for patients from rural areas and from metropolitan areas. Because of geographic isolation, many people in rural areas present at later stages of disease. In addition, large Hispanic populations in the rural counties of the state are not getting screened for cancers on recommended timelines. “Reduce cancer healthcare disparities” is the first of seven pillars with which National Cancer Institute Community Cancer Centers Program (NCCCP) sites are tasked. These inequalities of care include access to cancer screening, treatment, and research. The staff at MSTI hopes to reduce disparities in care for their patients with help from their new contract as a member of the NCCCP.
BOSTON—New data presented at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) suggest that standard doses of antibiotics may not be the right dose for obese individuals and that obese patients may need higher doses for some agents. In addition, the researchers said that more studies are needed to determine correct dosages of drugs for the obese. “Stop using the ideal body weight equations and its derivative (adjusted body weight). Consider using lean body
Continued on page 25
Continued on page 20
Inside Continuing Education ASCO 2010 Update on CML Page 12
Hematologic Cancers Dasatinib vs Imatinib Study in Treatment-Naïve CML
weight–2005 (LBW2005) when estimating kidney function in the morbidly obese subject. Oncology pharmacists need to study the role of LBW2005 for dosing cancer chemotherapy agents as a potential surrogate of body surface area. This is important because body surface area is not estimated differently for men and women of equal height and weight. LBW2005 gives you estimates by sex, which is important due to known physiological differences,” said Manjunath Pai, PharmD, an associate professor at
Dasatinib 100 mg once daily in second-line CP-CML
Pharmacy Careers Business Management Programs
Supportive Care Routine HBV Screening in Cancer Immunosuppressive Recipients
Oncology Pharmacist Seeks MBA to Prepare for Future of Healthcare Page 28
Pharmacist/Nurse Model for Delivery of Supportive Care Page 22 ©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 guidelines.3,4 Extravasation management is now a chemotherapy administration safety standard.5
For more information, call 866-478-8274 or visit our website at www.totect.com To order Totect®, contact one of our authorized distributors. ASD Healthcare Cardinal Specialty McKesson/OTN Oncology Supply US Oncology (800) 482-6700 (800) 633-7555 (888) 987-6679 (800) 746-6273 (866) 677-4844 1
Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane). Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550. 2 Totect® package insert. 3 Polovich M, White JM, Olsen, M (eds.). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice (ed 3). Pittsburgh, PA, Oncology Nursing Society, 2009. 4 Alexander M, Corrigan A, Gorski L, Hankins J, Perucca R. (eds). Infusion Nurses Society Infusion Nursing an Evidence-Based Approach (ed 3). Boston, MA, Infusion Nurses Society, 2009. 5 Jacobsen J., et al. American Society of Clinical Oncology/Oncology Nursing Society Chemotherapy Administration Safety Standards. Oncology Nursing Forum, 2009; 36:651-658. © 2010 Topotarget USA. All rights reserved. TOT0111/7-10 Totect and its logo mark are registered trademarks of Topotarget A/S Image is copyright © Photo Researchers, Inc. Pharma Chemo Ad 11x14FINAL 4 26 10 indd 1
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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
TOT0111/7-10 © 2010 Topotarget USA
Drug Interactions: No drug interactions have been identified. Based on anecdotal reports concurrent use of topical dimethyl sulfoxide (DMSO) at the site of tissue injury may reduce the benefit of Totect. Additionally, nonclinical studies using a mouse model that simulates extravasation of anthracyclines has shown that concomitant treatment with topical DMSO decreases the efficacy of systemic dexrazoxane. Use in Specific Populations: Nursing Mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. Renal Impairment: Reduce the Totect dose by 50% In patients with creatinine clearance values <40 mL/min. Pediatric Use: The safety and effectiveness of Totect in pediatric patients have not been established. Geriatric Use: This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Overdosage: There are no data on overdosage. There is no known antidote for dexrazoxane. Carcinogenesis, Mutagenesis, Impairment of Fertility: The carcinogenic potential of dexrazoxane has not been investigated. Nevertheless, a study by the National Cancer Institute has reported that long term dosing with razoxane (the racemic mixture of dexrazoxane, ICRF-187, and its enantiomer ICRF-186) is associated with the development of malignancies in rats and possibly in mice. Dexrazoxane was not mutagenic to bacteria in vitro (Ames assay), but caused significant chromosomal aberrations in mammalian cells in vitro. It also increased the formation of micronucleated polychromatic erythrocytes in mice. Thus, dexrazoxane is mutagenic and clastogenic. The possible adverse effects of Totect on the fertility of humans and experimental animals, male or female, have not been adequately studied. Testicular atrophy was seen with dexrazoxane administration at doses as low as 30 mg/kg weekly for 6 weeks in rats (about 1/5 the human dose on a mg/m2 basis) and as low as 20 mg/kg weekly for 13 weeks in dogs (about half the human dose on a mg/m2 basis).
Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Hameln Pharmaceuticals GmbH 31789 Hameln Germany
Manufactured for: Topotarget A/S Fruebjergvej 3 DK-2100 Copenhagen Denmark
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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 Institute Cleveland, OH
Jim Koeller, MS University of Texas at Austin San Antonio, TX
Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA
Christopher 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
OcTOber 2010 I VOL 3, NO 7
Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
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FROM THE EDITOR
The Official Newspaper for the Hem/Onc Pharmacist
survey just released shows that more than 40% of US adults will forego a flu vaccine this year and 33% do not plan to get their children vaccinated. Somewhat surprisingly, the survey, by the National Foundation for Infectious Diseases, found that awareness of the vaccine’s effectiveness does not increase acceptance. In cancer care, use of intravenous Patrick Medina, (IV) iron in patients receiving an PharmD, BCOP erythropoiesis-stimulating agent Editor-in-Chief for anemia has met with resistance despite evidence of its safety and efficacy. Dr Michael Auerbach explains reasons for this lack of acceptance and discusses new agents, which may lead to wider use of IV iron. Another topic that has generated much discussion is appropriate dosing for the obese. The report in this issue from the Interscience Conference on Antimicrobial Agents and Chemotherapy suggests a new approach to this problem.
PUBLISHING STAFF Publisher Philip Pawelko email@example.com Editorial Director Karen Rosenberg firstname.lastname@example.org Associate Editor Dawn Lagrosa email@example.com Director, Client Services John W. Hennessy firstname.lastname@example.org Production Manager Stephanie Laudien Business Manager Blanche Marchitto email@example.com Executive Administrator Andrea Boylston Circulation Department firstname.lastname@example.org Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938
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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2010 by Green Hill Healthcare Communications LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: 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.
OcTOber 2010 I VOL 3, NO 7
In addition to clinical issues, many pharmacists have administrative responsibilities, which has led some to seek management training to complement their clinical knowledge and experience. Several schools of business are now offering programs specifically geared for students with an interest in healthcare. In an interview, Scott Soefje of the University of Texas Health Science Center discusses his own decision to enroll in a master’s of business administration program after many years as a pharmacist and teacher. Additionally, he notes that residents at his institution attend monthly management training sessions to increase the administrative capabilities. This trend in pharmacy education may continue, especially in oncology pharmacy, where a pharmacist often administratively handles reimbursement of drug. As the demand for oncology services grow, pharmacists will assume increasing responsibilities for patient care and education, for helping their institutions function efficiently, and for training the new generation of pharmacists. A broad education encompassing many aspects of pharmacy practice will be needed to prepare students and residents to fulfill these multifaceted roles.●
OcTOber 2010 • VOL 3, NO 7
8 Genetic profiling changing clinical practice in some areas of oncology DIAGNOSIS
8 Undiagnosed cancer clinic helps patients deal with the unknown CONTINUING EDUCATION
12 ASCO 2010 update on chronic myelogenous leukemia: payers’ and providers’ perspectives
18 DASISION: more responses faster with frontline dasatinib in CML in chronic phase Dasatinib 100 mg once daily is best dose in second-line CP-CML 34 New “tip sheets” help NHL patients communicate with the oncology team
21 Routine HBV screening in cancer immunosuppressive recipients finds evidence of virus in some 22 Pharmacist/nurse model for delivery of supportive care improves patient symptoms 38 Single-dose IV regimen comparable with 3-day regimen for prevention of CINV Palonosetron demonstrates benefits over other 5-HT3 receptor antagonists in lung cancer patients
23 Business management programs help clinicians improve healthcare delivery 28 Experienced oncology pharmacist seeks MBA to better prepare for future of healthcare
23 Meta-analysis of bevacizumab trials in breast cancer show longer PFS 28 Combination of agents shows promise in MBC SKIN CANCER
36 High responses in melanoma for wool dye/ocular stain Rose Bengal DEPARTMENTS
10 26 30 34 41
News Notes Personal Finance Oncology Drug Codes International News Meetings
Erratum: In the article in the August issue on cabazitaxel for prostate cancer, the dosage was incorrectly stated as “three times weekly.” It should read “every 3 weeks,” as indicated in the package insert.
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Genetic Profiling Changing Clinical Practice in Some Areas of Oncology By John Schieszer
CHICAGO—Gene-expression profiling, combined with a novel chemoradiation regimen, may predict pathologic complete response in patients with esophageal cancer, according to new data presented at the 46th annual meeting of the American Society of Clinical Oncology. New studies presented at this meeting highlighted several new “genetic fingerprinting” techniques that may improve and guide chemotherapy in specific cancer populations. Researchers looked at pathologic complete response rate and toxicity in a phase 2 trial involving 36 patients with stage II to IVa esophageal cancer, 29 (81%) of whom had undergone surgery in the course of their treatment. The treatment consisted of three 85mg/m2 doses of oxaliplatin over the course of a month, a 625-mg/m2 twicedaily dose of oral capecitabine, and radiation therapy, followed by surgery 4 to 6 weeks later. Two cycles of oxaliplatin and capecitabine were given postoperatively. Gene-expression profiling (using microarrays by Agilent Technology) was conducted on primary tumor tissue. The researchers have found that eight of the 29 patients who had their esophagus removed following the oxaliplatin regimen had no cancer in the surgical specimen (a 28% pathologic complete response rate). “Another clear result is that this regimen is very well-
tolerated by patients without significant side effects,” said study investigator Nikhil Khushalani, MD, who is an assistant professor of medicine at Roswell Park Cancer Institute. “There appear to be several gene pathways that are enriched when studying different subgroups, the pathologic complete response group versus the nonpathologic complete response group.” The study continues to accrue pa tients, and Khushalani expects to have mature survival data by fall 2010. “I believe this is an efficacious regimen, and it’s definitely well-tolerated,” he said. “We hope that the exploratory gene-expression profiling results will translate into clinically meaningful hypotheses that can be validated in a large, preferably multicenter study.” Genetic profiling to identify trastuzumab resistance in breast cancer patients Other researchers at Roswell Park Cancer Institute are hoping to determine whether genetic profiling may effectively identify which breast cancer patients are most likely to respond to the drug trastuzumab. Trastuzumab interferes with a protein, known as the human epidermal growth factor receptor type 2 (HER2), which is linked to breast cancer. However, a high number of breast cancer patients (approximately 50%)
The differentially expressed genes for recurrence or nonrecurrence were distinct between the group treated with trastuzumab and the group that was not treated with the drug.
don’t respond to the drug and experience recurrence. Currently, there is great interest in research that might elicit factors that drive responses. Over the past 2 years, researchers looked at 41 breast carcinoma cases in which amplified HER2 levels were seen and for which fresh frozen tissue was available. Of these patients, 12 were treated with trastuzumab and three (25%) experienced recurrence. Among the 11 patients not treated with the drug, six (55%) had recurrence. Gene microarrays were used to identify differentially expressed genes for trastuzumab (responsive vs resistant). The investigators found that the differentially expressed genes for recurrence or nonrecurrence were distinct between the group treated with trastuzumab and the group that was not treated with the drug. The researchers hope that differential expression of key genes identified in this study may offer insights into trastuzumab resistance among breast cancer patients. It is hoped that this type
of technology fingerprinting can lead to new potential biomarkers for diagnosis, prognosis, and treatment. “The group that was treated with trastuzumab and developed recurrence had a genetic makeup different from those who were not treated and developed recurrence,” said study investigator Thaer Khoury, MD, who is an assistant professor of pathology and laboratory medicine at Roswell Park Cancer Institute. “The idea from the beginning was to know why these patients who are treated with trastuzumab develop recurrence and why the others did not. There is definitely something going on, and we’re starting to understand these mechanisms.” Khoury, who presented the study findings at the meeting, said they should be of particular interest to clinicians working in this area of cancer. The message about treatment and how it should be guided is now changing, as molecular markers are complementing clinical markers. ●
Undiagnosed Cancer Clinic Helps Patients Deal with the Unknown By John Schieszer
team of oncology clinicians in New York has now started what they call “The Undiagnosed Cancer Clinic.” The clinic was launched more than 1 year ago, and it has become an important new resource for primary care providers and their patients in cases where cancer is suspected but a clear diagnosis is not indicated by symptom presentation and/or diagnostic tests. In many respects, the clinic is something that is long overdue and may start a new trend in oncology. The Undiagnosed Cancer Clinic has been set up by a team of oncology experts at Roswell Park Cancer
OcTOber 2010 I VOL 3, NO 7
Institute, Buffalo, New York, to help improve the efficiency of diagnosis and care of cancer for people living in and around western New York. However, because of its success, other clinics like this may sprout up around the United States. “It’s about efficiency and decreased wait times for these patients and their families, and the ability to drill down to what the issue is,” said Martin Mahoney, MD, PhD, who helps run the clinic. In many of the patients presenting at this clinic, cancer is suspected or an abnormality has been found on a radiogram or computed tomography scan
that is consistent with cancer, but further testing and a biopsy is needed to confirm what type of cancer it is. The
This clinic is designed to …get these patients diagnosed and started on a treatment plan as quickly as possible.
clinic’s multidisciplinary team of specialists can obtain a biopsy using the
most appropriate method, make a diagnosis, and refer the patient for care with one of the disease-site experts at Roswell Park Cancer Institute. Mahoney pointed out often valuable time can be lost as care providers try to determine what to do next, and which type of biopsy may be the least invasive and yield rapid results. In some cases, he said, patients can be referred from specialist to specialist in the effort to make a definitive diagnosis. The Undiagnosed Cancer Clinic is designed to combat that problem and get these patients diagnosed and started on a treatment plan as quickly as possible. ●
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ALOXI provides powerful CINV prevention that can’t be ignored. ®
ALOXI is the only IV 5-HT3 receptor antagonist specifically approved for the prevention of both acute and delayed CINV s Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy1,2 s Lasts long against nausea following moderately emetogenic chemotherapy 3 s Powerful acute CINV prevention following highly emetogenic chemotherapy 4
Eisai offers: s Contracting opportunities
Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.
Important Safety Information s !,/8) IS CONTRAINDICATED IN PATIENTS KNOWN TO HAVE HYPERSENSITIVITY TO THE DRUG OR ANY of its components s -OST COMMONLY REPORTED ADVERSE REACTIONS IN CHEMOTHERAPY INDUCED NAUSEA AND VOMITING include headache (9%) and constipation (5%) Please see the brief summary of the Full Prescribing Information on the adjacent page. References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on file. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.
STARTS STRONG. LASTS LONG.
ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license. Distributed and marketed by Eisai Inc. © 2010 Eisai Inc. All rights reserved. Printed in USA. ALO000083C 08/10
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News Notes Final Rule on Safety Informa tion during Clinical Trials The US Food and Drug Administration (FDA) issued a final rule that clarifies what safety information must be reported during clinical trials of investigational drugs and biologics. The new rule requires that certain safety information that previously had not been required to be reported to the FDA be reported within 15 days of
becoming aware of an occurrence. These reports include: • Findings from clinical or epidemiologic studies that suggest a significant risk to study participants • Serious suspected adverse reactions that occur at a rate higher than expected • Serious adverse events from bioavailability studies and bioequivalence studies.
NCCN Launches Guidelines for Patients The National Comprehensive Cancer Network (NCCN) now offers a series of NCCN Guidelines for Patients, consumer-friendly translations of the NCCN Clinical Practice Guidelines in Oncology. The first two guidelines released cover breast and lung cancers. “While there are a number of good resources available to these women, only
the NCCN Guidelines for Patients provide the level of highly specific, current information that patients want and need. We are very proud to take a leadership role in supporting these guidelines and making them available to breast cancer patients,” said Diana Rowden, Survivorship and Outcomes Vice President at Susan G. Komen for the Cure, which supported the breast cancer guidelines through grant funding. The NCCN Guidelines for Pa tients are available at NCCN.com, which also features enhanced content for patients and caregivers. A link to the NCCN Guidelines for Patients: Breast Cancer will also be available at komen.org.
TRUST Study Confirms Safety and Efficacy of Erlotinib Patients previously believed unlikely to benefit from erlotinib treatment may benefit from this treatment, according to recently released results of the Tarceva Lung Cancer Survival Treatment (TRUST) study (J Thorac Oncol. 2010;10:1616-1622). This global phase 4 open-label study in previously treated patients with advanced non–small-cell lung cancer (NSCLC) confirmed the favorable efficacy and safety profile of erlotinib in a large heterogeneous NSCLC population. In a study of 6580 patients with advanced NSCLC, progression-free survival and overall survival in this study were 3.25 months and 7.9 months, respectively, and the disease control rate. ●
Recent FDA Approval FDA Approves Docetaxel Injection One-Vial Formulation The US Food and Drug Administration (FDA) has approved a new one-vial formulation of docetaxel injection concentrate (Taxotere, sanofi-aventis). This new formulation eliminates the initial dilution step, as well as the second vial containing the diluent. With the one-vial formulation, the pharmaceutical ingredients and the 1hour intravenous infusion administration remain unchanged. Docetaxel is approved for use in treating patients at specific stages of metastatic and adjuvant breast cancer, metastatic androgen-independent prostate cancer, advanced non–small-cell lung cancer, advanced gastric adenocarcinoma, and locally advanced squamous cell carcinoma of the head and neck.
OctOber 2010 I VOL 3, NO 7
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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 control exploding healthcare Hollywood, Hollywood,FLâ€”Clinical FLâ€”Clinicalpractice practice of frustration of frustration costs, told attendees, issued by by thethe National never been guidelines issued National hashas never been costs,DrDrBergstrom Bergstrom told attendees, guidelines and because increased cost control Comprehensive Cancer Network higher in cancer and because increased cost control Comprehensive Cancer Network higher in cancer â€œToo many was areare followed by by conscienwasinevitable, 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 areare developed young. WeWe â€œItâ€œIt is is anan important topic, because dying young. important topic, because practice, practice,butbutthey they developed dying this is one of of those things, if we donâ€™t on on clinical efficacy andand without innovations andand a cure,â€? he said. 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 treata handle going to happen regard regard costs. a roundtable held ButBut inadequacy of current treatto 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 sugGoodman, PhD, Senior Vice President gested, is finding a means to pay for dictating how we provide cancer care, 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 us,â€? Dr Goodman commented. the healthcare system.â€? the healthcare system.â€? us,â€? Dr Goodman commented.
Value-Based Value-BasedCancer CancerCare Care will willbebeatatthe theASCO ASCOAnnual Annual Meeting, June 4-8, in Chicago. Meeting, June 4-8, in Chicago.
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Please visit usus atat booth 18121 Please visit booth 18121
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Breast Cancer Conference (EBCC7). Breast Cancer Conference (EBCC7). This improvement, the researchers By Rosemary Frei, MSc This improvement, the researchers By Rosemary Frei, MSc Barcelonaâ€”Survival for patients with suggest, is due to increased use of The 2010 Genitourinary Cancers Barcelonaâ€”Survival for patients with suggest, is due to rise increased use of San Francisco, CAâ€”The popularity of The 2010 Progress Genitourinary Cancers metastatic breast cancer has improved anthracyclines and the of targeted Symposium: in Multi San Francisco, CAâ€”The metastatic breast cancer has improved anthracyclines and the rise of targeted minimally Symposium: Progresswas in held Multidramatically in the last 20 years, espe- therapies. Management invasive radical popularity prostatec- of disciplinary minimally radical prostatec- March dramatically in the last 20 years,with espe- â€œThere therapies. disciplinary Management cially in the subgroup of patients is no doubt that trastuzu- tomy 5-7 in San Francisco. Allwas ses-held (MIRP),invasive intensity-modulated tomy (MIRP), cially in the subgroup patients with is no which doubt that trastuzu March 5-7 in San Francisco. All sesHER2-positive tumors, of according to mab â€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 analysis to take off associated broughtwith out the cost for andgenitourivalue issues Continued on page 27 after caring a new database 2002, a new database analysis nary associated cancers. with caring for genitourihasafter confirmed. hasthe confirmed. nary cancers. At American Society of Clinical At the American Society of Can Clinical Oncologyâ€™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 cofoundBoston, MIRP and jumped MD, the Paul resultsL. of his investigators MD, analysis presentedof the investigators found MIRP jumped teamâ€™s dataresults from of thehis from 1.5% of radical prostatectomies teamâ€™s analysis of dataand from from of 28.7% radicalinprostatectomies Surveillance, Epidemiology Endthe (RPs) in 1.5% 2002 to 2005. They Surveillance, Epidemiology and End also(RPs) in 2002 28.7% in 2005. They Results (SEER)-Medicare database. found that to IMRT soared from also found that IMRT treatments soared from Results (SEER)-Medicare Dr Nguyen, director of database. Prostate 8.7% of external radiation Dr Nguyen, director of Prostate 8.7% of external radiation treatments addiBrachytherapy, Dana-Farber/Brigham for prostate cancer to 81.7%. In Brachytherapy, Dana-Farber/Brigham for prostate cancer to 81.7%. In 24 addiContinued on page
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A new publication for your new vocabulary
TOP_October 2010_v6_TOP 10/15/10 2:45 PM Page 12
CONTINUING EDUCATION PROGRAM P10057 • RELEASE DATE: SEPTEMBER 15, 2010 • EXPIRATION DATE: SEPTEMBER 15, 2011 ESTIMATED TIME TO COMPLETE: 1.0 HOUR
ASCO 2010 Update on Chronic Myelogenous Leukemia: Payers’ and Providers’ Perspectives TARGET AUDIENCE
This activity was developed for pharmacists and other healthcare professionals. LEARNING OBJECTIVES
Upon completion of this activity, participants will be able to: • Explain the impact of key data from ASCO 2010 on payers and providers regarding chronic myelogenous leukemia (CML) • Assess potential clinical, business, and regulatory changes in CML • Discuss patient-centered, value-based care for CML
istorically, payers have not been important participants in oncology drug utilization. As oncology costs have escalated, however, payer involvement in oncology drug management has increased. Reimbursement and coverage models are emerging to grapple with the massive financial burden associated with oncology treatment. Payers have become coparticipants with providers, and recent experience has shown that these two stakeholder groups can be poles apart in their strategic goals. A meaningful dialogue between payers and providers will occur if payers recognize provider management strategies that provide optimal outcomes. Complex issues comprise the basis for provider clinical approaches, including an understanding of the disease state, pharmacotherapeutic options, clinical objective options, adherence to guidelines, and regulatory issues. Alignment of goals—clinical and monetary—is essential for oncology care to achieve the progress made possible by the impressive advancements in therapy, and to provide patients with value-based treatments that balance cost, quality, and access.
Advances in Ph+ CML Approximately 0.6 to two cases of Philadelphia chromosome–positive chronic myelogenous leukemia (Ph+ CML) are diagnosed globally per 100,000 persons each year. In the United States, 1.5 cases per 100,000 persons are diagnosed annually.1,2 Historically, chemotherapy with alkylating agents and hydroxyurea provided a median survival of only 3 to 4 years.3 Median survival improved to 6 to 7 years in the early 1980s with the advent of interferon-alpha, but 10-year survival rates were still only between 30% and 40%, and patients had few options after the failure of first-line therapy.
OcTOber 2010 I VOL 3, NO 7
The introduction of imatinib, a selective BCR-ABL tyrosine kinase inhibitor (TKI), has revolutionized management strategies for patients with chronicphase CML.4,5 By 2007, the annual mortality rate decreased to approximately 1% to 2%, and the estimated 5-year survival rate increased to approximately 90%.2,3 This translates to an increasing disease prevalence that may exceed 200,000 cases within the next 20 years. With a median age of 65 years at diagnosis, providing treatment that maintains quality of life and valued productivity is of major concern. Optimal response and standard of care Much has been learned regarding accepted first-line therapy response milestones and the timing of those responses in patients with chronicphase CML since the introduction of imatinib to clinical practice in 2001. A key CML treatment strategy is to quickly, and as completely as possible, eradicate cells harboring the Philadelphia chromosome, thus avoiding or delaying the development of mutations in the BCR-ABL gene that result in imatinib resistance. Patients with CML who have suboptimal or no response to treatment are far more likely to experience early disease progression to advanced phase or blast crisis, in which long-term responses to TKIs are unlikely to occur.6 In the International Randomised Study of Interferon versus STI571 (IRIS), 98% of patients who had achieved a complete cytogenetic response (CCyR) and major molecular PHARMACISTS DESIGNATION
Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 468-999910-045-H01-P. INSTRUCTIONS FOR CREDIT
1. Read the article in its entirety 2. Log on to www.TheOncologyPharmacist.com 3. Select “Continuing Education” 4. Click on this article’s title from the list shown 5. Select “Click here to complete the posttest and obtain a CE certificate online” 6. Complete and submit the CE posttest and CE Activity Evaluation 7. Print your Statement of Completion
response (MMR) by 12 months were free from progression to advanced phase or blast crisis at 4 years compared with 90% of patients who achieved CCyR without MMR by 12 months and 75% of patients who did not achieve CCyR by 12 months.7 Another significant piece of evidence from the IRIS trial came from the 8-year follow-up (Figure 1).8 By year 8, patients responding to imatinib had a low overall risk of progression to advanced phase or blast crisis.8 As seen in Figure 1, imatinib was effective in preventing risk of prospective progression events but not loss of response or progression events that occur early (within years 1-4). A large proportion of patients who fail to achieve adequate or optimal response to first-line imatinib harbor resistance-conferring BCR-ABL mutations.9,10 Therefore, to improve longterm outcomes, treatment strategies should be more contingent on prompt and early optimal response than on the identification of patients who develop resistance and relapse. Second-generation TKIs designed to overcome imatinib resistance include nilotinib, dasatinib, bosutinib, and others.11 Although these agents have proved to be effective second-line or “salvage” options, patients already harboring BCR-ABL mutations have been shown to have an increased likelihood of relapse, as a result of the development of additional mutations.12 Because the goals of first-line therapy should include preventing the emergence of therapy resistance and providing the best possible option for longThis activity is provided free of charge to participants. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. FACULTY DISCLOSURES
Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speaker’s bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. The associates of Medical Learning Institute, Inc., and Center of Excellence Media, LLC, have no financial relationships to disclose. Michael Mauro, MD, has received research grants
term survival, researchers have hypothesized that early diagnosis of CML, paired with immediate treatment with more potent TKIs, may improve the rate of early CCyR and further MMR (3-log reduction in BCR-ABL transcripts below standard baseline), and thus improve long-term outcomes in patients with CML. Key presentations on CML at ASCO 2010 The 2010 American Society of Clinical Oncology (ASCO) annual meeting provides the perfect forum for the discussion of emerging data that affect patient outcomes and treatment strategies, as well as the changing paradigm of standard of care. This article provides a review of several key presentations that may provide the basis for future decisions and policies as more agents become available for the treatment of CML. First-line treatment strategies: nilotinib The Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Ph+ CML Patients (ENESTnd) trial is a global, multicenter, randomized, phase 3 trial comparing nilotinib 300 mg twice daily and 400 mg twice daily with imatinib 400 mg/day as first-line therapy in newly diagnosed patients with chronic-phase CML (N = 846).13,14 Patients were stratified by the Sokal risk score, with 28% of patients in each arm in the high-risk category.15 The primary end point is the MMR rate at 12 months, and a key secondary end point is the durability of from, and is a consultant to, Bristol-Myers Squibb and Novartis Oncology. Gary M. Owens, MD, is a consultant to Auxilium, Genzyme, GlaxoSmithKline, and Eli Lilly and Company. DISCLAIMER
The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. SPONSOR
This activity is jointly sponsored by Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC. COMMERCIAL SUPPORT ACKNOWLEDGMENT
This activity is supported by an educational grant from Novartis Pharmaceuticals.
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Figure 1 Annual Event Rates for Patients Receiving Imatinib in the IRIS Trial 8
Event: loss of CHR; loss of MCyR; AP/BC; death during treatment AP/BC
Patients with event, %
7 6 4.8
Years of receiving imatinib AP indicates advanced phase; BC, blast crisis; CHR, complete hematologic response; IRIS, International Randomised Study of Interferon versus STI571; MCyR, major cytogenetic response. Source: Reference 8.
Figure 2 The ENESTnd Trial: MMR and CCyR, by 12 Months Nilotinib 300 mg bid (n = 282)
Nilotinib 400 mg bid (n = 281)
Imatinib 400 mg/day (n = 283)
Patients responding to therapy, %
were rare in patients receiving either nilotinib or imatinib, and there was no clinically relevant prolongation in QT interval or decrease in left-ventricular ejection fraction in patients receiving either study drug. Lipase and amylase elevations, abnormal liver function tests, and hyperglycemia were higher in the nilotinib arms, and some of these events were grade 3/4 (â‰¤1% to 9%). Grade 3 and 4 hematologic events that occurred any time during the study are shown in Figure 3.14 Rates of grade 3/4 anemia and thrombocytopenia in patients receiving nilotinib (4% and 4%, respectively; and 10% and 12%, respectively) were similar to those experienced by patients receiving imatinib (5% and 9%), while the rate of neutropenia was approximately half (12% and 10%, respectively, vs 20%). On June 17, 2010, the US Food and Drug Administration (FDA) granted accelerated approval to nilotinib for the treatment of adult patients with newly diagnosed chronic-phase Ph+ CML. The recommended nilotinib dose for this indication is 300 mg twice daily, orally.16
Pericardial and pleural effusion events were rare in patients receiving either nilotinib or imatinib.
P <.001 P <.001
40 30 22
20 10 0
First-line treatment strategies: dasatinib The Dasatinib versus Imatinib Study in Treatment-NaĂŻve CML Patients (DASISION) is a multinational study that randomized 519 patients with newly diagnosed chronic-phase CML to receive either dasatinib 100 mg/day (n = 259) or imatinib 400 mg/day (n = 260).17,18 Patients were stratified according to the Hasford risk score, with 19% of patients categorized as high risk in each arm.17-19 Note that the Hasford categorization places fewer patients in the high-risk group than does the Sokal risk score. The primary end point was the rate of confirmed CCyR at 12 months, and secondary end points included rate of MMR, time to confirmed CCyR and MMR, and duration of confirmed CCyR.17,18 Median time from diagnosis to study entry was 1 month.18 Results after a minimum followup of 12 months and a median treatment duration of 14 months were reported during an oral abstract session by Hagop Kantarjian, MD, Chair, Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston.17 Of patients receiving dasatinib, 77% had a confirmed CCyR by 12 months compared with 66% of patients receiv-
BCR-ABL transcript level â‰¤0.1% in peripheral blood on RQ-PCR assay, as expressed on the International Scale. Patients who did not undergo RQ-PCR assessment at 12 months were considered to have had no response. CCyR indicates complete cytogenetic response; MMR, major molecular response; RQ-PCR, real-time quantitative polymerase chain reaction. Source: Reference 14.
Figure 3 The ENESTnd Trial: Grade 3/4 Hematologic Toxicities Nilotinib 300 mg bid (n = 282) 25
Patients with hematologic toxicities, %
MMR at 24 months. Median time from diagnosis to study entry was 31 days. Results after a median follow-up of 18.5 months were reported during an oral abstract session by Richard Larson, MD, Director, Hematologic Malignancies Clinical Research Program, University of Chicago Medical Center, Illinois.13,14 Results for the primary end point, MMR rates at 12 months, are shown in Figure 2.13,14 The rates for nilotinib 300 mg twice daily (44%) and 400 mg twice daily (43%) were significantly higher and twice that for imatinib (22%, P <.001 for both comparisons).13 Rates of MMR at 12 months among patients with a high Sokal risk score were 41%, 32%, and 17%, respectively.14 MMR rates continued to rise, and with a median follow-up of 18.5 months, remain significantly higher for the two nilotinib arms compared with the imatinib arm (66%, 62%, and 40%, respectively; P <.001 for both comparisons).13 For patients who have had a real-time quantitative polymerase chain reaction assessment after receiving 24 months of study drug (N = 145), 86% (n = 49), 88% (n = 48), and 48% (n = 48) achieved MMR, respectively. As reported by Saglio and colleagues, after a median follow-up of 13.8 months, 50% of the intent-to-treat population had achieved MMR 8.6 (nilotinib 300 mg) and 11.0 (nilotinib 400 mg) months after randomization (median not yet achieved for patients receiving imatinib).14 As seen in Figure 2, CCyR rates by 12 months were 80%, 78%, and 65% (P <.001 for both comparisons).13,14 Also, significantly fewer patients receiving nilotinib have progressed to advanced phase or blast crisis compared with those receiving imatinib (0.7%, 0.4%, and 4.2%; P = .006 and P = .003, respectively).13 No patient who had progressed to advanced phase or blast crisis had achieved an MMR. Nilotinib and imatinib both had good safety and adverse event profiles. Overall, grade 3 or grade 4 nonhematologic adverse events were uncommon in the safety population (patients who received at least one dose of the study drug; N = 836).13,14 Rates of any grade nausea (33%), muscle spasms (26%), diarrhea (24%), and vomiting (16%) were higher for patients in the imatinib arm than for those in either nilotinib arm (12%, 7%, 8%, and 5%, 300 mg twice daily; and 20%, 6%, 6%, and 9%, 400 mg twice daily).13 Rash (32% and 37%, respectively), headache (14% and 22%, respectively), pruritus (15% and 13%, respectively), and alopecia (8% and 13%, respectively) were more common in the nilotinib arms (vs 12%, 8%, 5%, and 4%, respectively, for patients receiving imatinib).13 Fluid retention events of any grade were more common in the imatinib arm. Pericardial and pleural effusion events
Nilotinib 400 mg bid (n = 281)
Imatinib 400 mg/day (n = 283)
Source: Reference 14.
ing imatinib (P = .067; Figure 4).17 The MMR rate at 12 months was also significantly higher for the dasatinib arm compared with the imatinib arm (46% vs 28%, P <.001), as was the rate of an MMR at any time (52% vs 34%, P <.001). Patients receiving dasatinib also
achieved MMR earlier than did patients receiving imatinib. Considering only the patients who achieved MMR, the median time to MMR for patients receiving dasatinib was 6.3 months (vs 9.2 months for patients who achieved Continued on page 14
OctOber 2010 I VOL 3, NO 7
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CONTINUING EDUCATION Continued from page 13
ASCO 2010 Update on Chronic Myelogenous Leukemia: Payers’ and Providers’ Perspectives Figure 4 The DASISION Trial: Confirmed CCyR and MMR, by 12 Months (n = 258 in each group)
Patients responding to therapy, %
Dasatinib 100 mg/day Imatinib 400 mg/day
P = .067
30 20 10 0
Confirmed CCyRa a
Confirmed on 2 consecutive assessments at least 28 days apart. Patients who had a first assessment of CCyR at 12 months that was confirmed on a second assessment thereafter were considered to have had a confirmed CCyR by 12 months. b BCR-ABL transcript level ≤0.1% in peripheral blood on RQ-PCR assay, as expressed on the International Scale. CCyR indicates complete cytogenetic response; MMR, major molecular response; RQ-PCR, real-time quantitative polymerase chain reaction. Source: Reference 17.
Figure 5 The DASISION Trial: Grade 3/4 Hematologic Toxicities Dasatinib 100 mg/day Imatinib 400 mg/day
Patients with hematologic toxicities, %
25 21 20
Source: Reference 17.
Figure 6 Common Adverse Events Associated with Bosutinib
Patients with adverse events, %
Any grade Grade 3/4 84
80 70 60 50
30 20 10
Source: Reference 21.
MMR receiving imatinib, hazard ratio = 2.01; P <.001). Rates of MMR at 12 months among patients receiving dasatinib by Hasford risk score were 56% (low risk), 45% (intermediate risk), and 31% (high risk)
who achieved an MMR has progressed to advanced phase or blast crisis. The rates of grade 3/4 cytopenias are shown in Figure 5.17 In particular, the rate of grade 3/4 neutropenia (21%) was comparable to that observed in patients receiving imatinib (20%) and lower than that observed in patients receiving dasatinib second-line after imatinib resistance or intolerance (36%).17,20 The rate of thrombocytopenia was 19% among patients receiving dasatinib compared with 10% among those receiving imatinib. This, too, is lower than that experienced by patients receiving dasatinib second-line. Grade 3/4 nonhematologic adverse events were rare for both treatment arms.17 Several events of any grade occurred less frequently among patients receiving dasatinib than among those receiving imatinib, including nausea (8% vs 20%, respectively), vomiting (5% vs 10%, respectively), rash (11% vs 17%, respectively), muscle inflammation (4% vs 17%, respectively), and fluid retention (19% vs 42%, respectively). Similar rates were seen with both agents for any grade diarrhea (17% for both), fatigue (8% vs 10%), and headache (12% vs 10%). Pleural effusion was reported only in the dasatinib arm (10%), with all being grade 1/2.17 Three patients in the dasatinib arm discontinued treatment because of grade 2 pleural effusion.
OcTOber 2010 I VOL 3, NO 7
compared with patients receiving imatinib (36%, 28%, and 16%, respectively). Fewer patients receiving dasatinib have progressed to advanced phase or blast crisis compared with those receiving imatinib (1.9% vs 3.5%). No patient
Several events of any grade occurred less frequently among patients receiving dasatinib than among those receiving imatinib, including nausea. Laboratory abnormalities, including lipase and amylase elevations and abnormal liver function tests, were rare on both arms, as was clinically relevant prolongation in QT interval. On July 12, 2010, the FDA granted a priority review designation to the application for dasatinib for the treatment of adult patients with newly diagnosed chronic-phase Ph+ CML. A decision is expected by late October 2010. Following resistance or intolerance to first-line therapy: bosutinib Bosutinib is an orally bioavailable dual SRC/ABL TKI that is active against the vast majority of imatinib-resistant BCR-ABL mutations, excluding T315I. Jorge Cortes, MD, Chair, CML Section of the Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center,
Houston, reported preliminary results from a phase 1/2 study that is investigating the efficacy and safety of bosutinib in patients with chronic-phase CML who failed treatment with imatinib. A total of 294 patients are enrolled in this study— 18 from the phase 1 portion (bosutinib 400, 500, or 600 mg/day) and 276 in the phase 2 portion (bosutinib 500 mg/day).21 Patients with complete hematologic response (CHR), CCyR, or MMR at baseline and patients lacking either a baseline or a postbaseline assessment were considered nonevaluable for the respective response. After a median treatment duration of 13.7 months and a median follow-up of 23.8 months, 91% of evaluable patients had achieved a CHR, 50% of patients had achieved CCyR, and 52% had achieved MMR. Median time to CCyR was 12.3 months. Median progression-free survival has not been reached, and 94% of patients are still alive at month 24. Treatment with bosutinib was generally well tolerated (Figure 6).21 Diarrhea was the most common nonhematologic toxicity, reported in 84% of patients (9%, grade 3/4). It was most frequently observed within the first few weeks of treatment, and was manageable and subsided quickly. Twenty-five percent of patients required a dose reduction and 2% of patients had to discontinue bosutinib because of diarrhea. Rash of any grade was observed in 34% of patients, with 9% of patients experiencing rash of grade 3/4. Rash responded favorably to symptomatic management strategies and seldom required dose reductions, interruptions, or therapy discontinuation. Fluid retention was minimal. The most common grade 3/4 toxicity was myelosuppression. Grade 3/4 thrombocytopenia was observed in 24% of patients, grade 3/4 neutropenia in 16%, and grade 3/4 anemia in 12%. As with other TKIs, myelosuppression most often occurred within the first few months of therapy and did not require dose reductions or interruptions in most patients. Grade 3/4 laboratory abnormalities, including hypermagnesemia (12%), hypophosphatemia (8%), lipase elevations (7%), and abnormal liver function tests (10% elevated alanine aminotransferase and 5% elevated aspartate aminotransferase) were also observed.21 These results demonstrate that bosutinib has clinical efficacy in patients with chronic-phase CML who are resistant or intolerant to imatinib. A phase 3 randomized clinical trial comparing the efficacy of bosutinib with that of imatinib in newly diagnosed, previously untreated patients with chronic phase CML has finished accrual. Results should be available by the end of 2010.
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www.TheOncologyPharmacist.com Conclusion These updates highlight the recent advances in the treatment of CML; they can help payers and providers to develop new approaches to the management of this chronic disease and encourage multistakeholder collaboration to provide value-based care for patients with CML. ● References 1. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol. 2009;22:295-302. 2. Altekruse SF, Kosary CL, Krapcho M, et al, eds. SEER cancer statistics review, 1975-2007. National Cancer Institute, 2010. http://seer.cancer.gov/csr/1975_2007/. Accessed August 10, 2010. 3. Kantarjian H, O’Brien S, Cortes J, et al. Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years. Cancer. 2008;113(7 suppl):1933-1952. 4. Druker BJ. Translation of the Philadelphia chromosome into
therapy for CML. Blood. 2008;112:4808-4817. 5. O’Brien SG, Guilhot F, Larson RA, et al; for the IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004. 6. Soverini S, Martinelli G, Rosti G, et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with upfront cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia. J Clin Oncol. 2005;23:4100-4109. Epub 2005 May 2. 7. Hughes TP, Kaeda J, Branford S, et al; for the International Randomised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423-1432. 8. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114:abstract 1126. 9. Branford S, Rudzki Z, Walsh S, et al. Detection of BCRABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis. Blood. 2003;102:276-283. Epub 2003 Mar 6.
10. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20:1767-1773. Epub 2006 Jul 20. 11. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009;114:5426-5435. Epub 2009 Oct 30. 12. Soverini S, Gnani A, Colarossi S, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Abl kinase domain mutations have a higher likelihood of developing additional mutations associated with resistance to secondor third-line tyrosine kinase inhibitors. Blood. 2009;114:21682171. Epub 2009 Jul 9. 13. Larson RA, le Coutre PD, Reiffers J, et al. Comparison of nilotinib and imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd beyond one year. J Clin Oncol. 2010;28(suppl 15):abstract 6501. 14. Saglio G, Kim DW, Issaragrisil S, et al; for the ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259. Epub 2010 Jun 5. 15. Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63:789-799.
16. Tasigna (nilotinib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2010. 17. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib compared to imatinib (IM) in patients (pts) with newly diagnosed chronic-phase chronic myelogenous leukemia in chronic phase (CML-CP): twelve-month efficacy and safety from the phase III DASISION study. J Clin Oncol. 2010;28(suppl 18):abstract LBA6500. 18. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub 2010 Jun 5. 19. Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst. 1998;90:850-858. 20. Sprycel (dasatinib) package insert. Princeton, NJ: BristolMyers Squibb Company; June 2009. 21. Cortes JE, Kantarjian H, Brümmendorf T, et al. Safety and efficacy of bosutinib (SKI-606) in patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (IM). J Clin Oncol. 2010;28(suppl 15):abstract 6502.
Linda Ritter, PhD, participated in the development of this article.
Redefining the Best Approach to CML Therapy By Michael Mauro, MD Associate Professor of Medicine, Oregon Health & Science University Knight Cancer Institute, Center for Hematological Malignancies, Portland
he International Randomised Study of Interferon versus STI571 (IRIS) provided proof of principle that a small molecule, BCR-ABL inhibitor, could be very effective and durable therapy for chronic-phase chronic myelogenous leukemia (CML).1 Response kinetics were clearly predictive of outcome—timely complete cytogenetic response (CCyR) and molecular response are protective against relapse and progression. Disease risk, as assessed by the prognostic Sokal and Hasford scores, has historically been predictive of lower response to interferon-alpha and chemotherapy, as well as relapse, regardless of response to therapy. In the IRIS trial, we saw that although high-risk disease was associated with reduced response, achievement of relevant response, such as CCyR, mitigated subsequent risk of relapse or progression. Unlike resistance to traditional chemotherapy, which typically involves activation of a salvage molecular pathway, identified resistance to imatinib is most often associated with kinase domain mutations altering or precluding imatinib binding, which can restore BCR-ABL activity. Perhaps the most favorable element of response kinetics to imatinib has been the finding that the modest number of loss-ofresponse and progression events in the IRIS trial occurred early and declined sharply thereafter rather than persisting as a continual or growing threat. What have we learned from the two studies, Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Ph+ CML Patients (ENESTnd)2 and Dasatinib versus Imatinib Study in
Treatment-Naïve CML Patients (DASISION)3? Nilotinib and dasatinib are both superior to imatinib for treating newly diagnosed patients with chronicphase CML. Both drugs provided higher rates of CCyR faster than imatinib. Better molecular responses were also observed with these agents when compared with imatinib, and optimal responses were seen across all prognostic groups. These two agents provided reduction in rates of progression to advanced phase or blast crisis at early time points.2,3 Emerging questions The investigational second-generation tyrosine kinase inhibitor (TKI), bosutinib, may soon represent an additional option for patients who are imatinib-resistant or -intolerant, although its common toxicities are different from those experienced by patients receiving imatinib, dasatinib, or nilotinib, and with comparable efficacy, toxicity comparison prominence increases. As new second-generation TKIs gain approval by the US Food and Drug Administration, we need to determine their place in our management strategies. Relevant questions in the context of this clinical debate include: • Why not continue to use imatinib as first-line therapy and then switch to a second-generation TKI at the earliest sign of inadequate response or intolerance? • Will early use of second-generation TKIs lead to more high-level resistance? • Does the benefit match the expense?
1. Why not continue to use imatinib as first-line therapy and then switch to a second-generation TKI at the earliest sign of inadequate response or intolerance? Waiting to use a more potent and more effective agent may simply be too risky. Aside from the Sokal and Hasford risk categorization scores, there is no prognostic tool available that will identify patients needing more potent firstline therapy. Treating patients with second-generation TKIs at suboptimal response or failure needs to be recognized as salvage therapy—disease biology has likely changed or resistance mechanisms have become dominant by this point, and optimal long-term outcomes are thus compromised, given lower response and uncertainty regarding response duration. In the absence of the ability to select or personalize therapy, the best strategy is to provide all patients every opportunity to achieve an early and deep response that is protective against progression by using secondgeneration TKIs as primary therapy. 2. Will early use of second-generation TKIs lead to more high-level resistance? We do not yet know if there is a plateau in progression-free survival (PFS) curves for the ENESTnd and DASISION trials, nor do we fully understand the kinetics of late resistance with the second-generation TKIs. We do know that mutations related to drug resistance, as well as emergence of additional mutations over time, increase after an initial suboptimal response or treatment failure, necessitating the increasing use of a third TKI or of stem-cell transplantation. The ENESTnd and DASISION trials
demonstrated that optimal response rates were significantly greater in patients receiving nilotinib or dasatinib compared with those receiving imatinib. Such significant gains in early response should functionally reduce the number of patients at risk for development of resistance, because the genesis of resistant disease is linked to disease volume. Although time will add strength to this argument, the early (12-18 months) differences in PFS, in light of the depth of these responses, may prove to be quite relevant, because increasing the rapidity of response may shorten the time frame during which resistance emerges. 3. Does the benefit match the expense? To answer this question, we must look ahead to one important, yet theoretical future benefit—will we be able to eventually discontinue therapy and essentially “cure” chronic-phase CML? The Stop Imatinib (STIM) study evaluated the persistence of complete molecular remission after stopping imatinib.4 In this pilot study, patients were required to be in complete molecular remission (then defined as polymerase chain reaction undetectable) for at least 2 years before entering the study. Of the 69 patients included in the study, 34 had previous interferon-alpha treatment and 35 were treated only with imatinib. Median follow-up was 17 months. Of these 69 patients, 41 patients relapsed (loss of complete molecular response) within the first 7 months, 37 relapsed within the first 6 months, and two relapsed after more than 6 months. At month 12, the probability of remainContinued on page 16
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CONTINUING EDUCATION Continued from page 15
Redefining the Best Approach to CML Therapy ing in complete molecular response was 45%.4 These results are quite intriguing and suggest a subgroup of patients with undetectable disease that is sustained by continued TKI therapy; the definition of such a group can be reached rapidly after drug withdrawal. Although it is not currently recommended to stop therapy outside of a closely monitored clinical trial, as the number of patients living with chronic-phase CML grows and more patients achieve deeper and long-lasting responses, the magnitude of this potential increases. If greater proportions of patients achieve better
quality remissions with first-line use of second-generation TKIs, and this quality facilitates the ability to discontinue therapy, second-generation TKIs will unequivocally prove their worth. 2010 marks a redefinition of “best therapy” for chronic-phase CML How do we manage chronic-phase CML in 2010? I recommend the continued use of imatinib in patients who have already achieved an optimal response in the absence of clinical toxicity, because there is currently no basis to switch a patient to a second-generation TKI in the face of optimal re-
sponse to imatinib. I do, however, recommend monitoring such patients appropriately, and we should immediately switch patients to a second-generation TKI at the first clear sign of developing resistance. For patients who have recently initiated imatinib, consideration of switching to a second-generation TKI should be made in the setting of suboptimal response or any sign of intolerance, more carefully defined given the availability of multiple therapy options. We are obligated to provide newly diagnosed chronic-phase CML patients with the best opportunity to achieve a
deep and long-lasting response, and first-line use of second-generation TKIs should be the new gold standard. ● References 1. Hughes TP, Kaeda J, Branford S, et al; for the International Randomised Study of Interferon versus STI571 (IRIS) Study Group. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2003;349:1423-1432. 2. Saglio G, Kim DW, Issaragrisil S, et al; for the ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:22512259. Epub 2010 Jun 5. 3. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub 2010 Jun 5. 4. Mahon F-X, Rea D, Guilhot F, et al. Discontinuation of imatinib therapy after achieving a molecular response in chronic myeloid leukemia patients. Blood (ASH Annual Meeting Abstracts). 2009;114:abstract 859.
Chronic Myelogenous Leukemia: Is It Time for a Change? By Gary M. Owens, MD President, Gary Owens Associates, Philadelphia, Pennsylvania
he multiple forms of leukemia, both acute and chronic, represent a diverse group of hematologic malignancies that can affect patients from childhood onward; however, leukemia is primarily a disease that affects older individuals. According to the National Cancer Institute Surveillance, Epidemiology and End Results data, the incidence of all types of leukemia is less than 10 cases per 100,000 persons until the age of 50, when the incidence begins to rise sharply and reach 65 per 100,000 persons by age 75.1 As we learn in this article, Philadelphia chromosome–positive chronic myelogenous leukemia (Ph+ CML) accounts for about 1.5 new cases annually, or approximately 15% of all newly diagnosed leukemia cases in the United States. The average age for CML is about 65 years. More important, since the introduction of imatinib in 2001 for the treatment of CML, the 5-year survival rate for patients with CML has reached 90%. Health plan medical and pharmacy directors have often used the example of imatinib for CML when speaking of “breakthrough” clinical products. Although the significant clinical advance in treatment of CML has been lauded by health plans, they also have reason to be concerned, because of the potential for increasing numbers of patients with this disease, and the accompanying growth in the cost of caring for what has now become a long survival span for this chronic condition. Until now, plan management of this condition has been
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minimal, with management strategies mostly centering on prior authorization of the tyrosine kinase inhibitor (TKI) agents used to treat CML and management of distribution through specialty pharmacy. In the main article, we learn about the importance of an early complete cytogenetic response (CCyR) and major molecular response. Early CCyR and major molecular response are indicative of the eradication of the Philadelphia chromosome harboring cells, thus potentially avoiding the development of mutations in the BCR-ABL gene that can lead to treatment resistance. According to data presented at the recent 2010 American Society for Clinical Oncology meeting, there appears to be a basis for a treatment paradigm shift for newly diagnosed patients with CML. The Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Ph+ CML Patients (ENESTnd) trial showed superior CCyR and major molecular response rates for newly diagnosed patients treated with nilotinib compared with imatinib. Similarly, the Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients (DASISION) trial showed superior CCyR and major molecular response rates with dasatinib compared with imatinib.2,3 The second-generation TKI, bosutinib, if approved, is likely to be initially reserved for treatment-resistant patients. The key question for health plans to consider when managing benefits for the treatment of CML is—What is the proper therapeutic strategy for newly diagnosed and for existing patients?
Data from the ENESTnd and DASISION trials were published in the June 17, 2010, issue of the New England Journal of Medicine, documenting that nilotinib and dasatinib are each superior to imatinib for patients with newly diagnosed Ph+ CML.2,3 Does this mean plans should require one of these treatments for all newly diagnosed patients, or should the initial treatment still be left up to the oncologist, even if that may result in use of a product that has been shown to be clinically inferior? In general, health plans would prefer to preferentially pay for more effective treatments at the outset, even if the cost is increased. The dilemma for plans is how to provide the best therapeutic option for their members, while working collaboratively with treating physicians. The next obvious question will be— Where will bosutinib be useful and how does it compare to the existing TKIs for CML? These are just a few of the many unanswered questions that health plan decision makers face daily. With clinical outcomes being so critical, and the cost of these agents being a major factor, we cannot afford to get this wrong. And the care of CML and other leukemias is only getting more complex. According to the Pharmaceutical Research and Manufacturers of America, 129 agents are under development for the treatment of leukemia, second only to the 202 drugs under development for solid organ tumors.4 The questions of what works on whom, and when, will only become geometrically more complex for clinicians and health plans.
We therefore should invest in research on genetic markers, comparative effectiveness research, and head-to-head trials, such as the ENESTnd and DASISION trials, to determine the best therapies. The dilemma is, who will bear the cost of this kind of research? We know that manufacturers are hesitant to do such head-to-head trials, government funding is limited for these trials, and health plans, with their relatively narrow profit margins, cannot afford to sponsor such trials. Yet as the need for this information continues to grow, we need to be increasingly efficient in the use of our healthcare resources. The healthcare system can no longer afford to fund less-than-effective treatments when better options exist. In addition to funding research on the development of new drugs, we need to find ways to fund the basic research needed to determine their place (if any) in therapy. Now is the time for all stakeholders to come together and find ways to accomplish this before the cost crisis worsens, and access to the best medical care is compromised. ● References 1. Surveillance Research Program, National Cancer Institute. Surveillance, Epidemiology and End Results: fast stats. http://seer.cancer.gov/faststats. Accessed August 10, 2010. 2. Saglio G, Kim DW, Issaragrisil S, et al; for the ENESTnd Investigators. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:22512259. Epub 2010 Jun 5. 3. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270. Epub 2010 Jun 5. 4. Pharmaceutical Research and Manufacturers of America. 2009 report medicines in development for cancer. www.phrma.org/files/attachments/meds_in_dev/09-046 PhRMACancer09_0331.pdf. Accessed August 11, 2010.
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DASISION: More Responses Faster with Frontline Dasatinib in CML in Chronic Phase By Walter Alexander
CHICAGO—“Dasatinib 100 mg once daily should become frontline therapy in newly diagnosed chronic-phase chronic myelogenous leukemia,” said DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients; CA180-056) lead investigator Hagop M. Kantarjian, MD, The University of Texas, M. D. Anderson Cancer Center, Houston. Kantarjian’s statement was based on findings from the DASISION comparison of firstline dasatinib with first-line imatinib in patients with chronic-phase chronic myelogenous leukemia (CP-CML). Imatinib is the current gold standard for CP-CML, Kantarjian pointed out in a presentation at the 2010 annual meeting of the American Society of Clinical Oncology. Once-daily dasatinib, in earlier research, has induced high rates of complete cytogenetic response (CCyR) and progression-free survival (PFS) in CML after imatinib failure. Investigations also have shown that patients receiving imatinib who achieve a CCyR and a major molecular response (MMR) by 12 months have longer PFS and reduced risks of disease progression or death. MMR, the highest standard of
response, was defined by the presence of ≤0.1% BCR-ABL transcripts. In a phase 2 study of first-line dasatinib, CCyR and MMR rates were high. DASISION, a phase 3 study, was conducted at 108 centers in 26 countries among 519 patients (mean age, 47 years)
Hagop M. Kantarjian, MD
with newly diagnosed CML. Patients were randomized to either dasatinib 100 mg/day (n = 259) or imatinib 400 mg/day (n = 260). Dose escalations to dasatinib 140 mg once daily and to imatinib 600 mg to 800 mg once daily were permitted for suboptimal response.
Patients were all enrolled within 1 month of their initial diagnosis. Mean duration of therapy was 14 months. The primary end point was confirmed CCyR by 12 months, with confirmed CCyR defined as a CCyR detected in two consecutive assessments. Dose escalations were reported in 5% of patients receiving dasatinib and in 14% of patients receiving imatinib. Data analyses revealed CCyRs in 83% and 72% of patients in the dasatinib and imatinib arms, respectively (P = .0011), and confirmed CCyRs in 77% and 66% of patients in the two groups, respectively (P = .0067) at 12 months. An analysis of CCyR rates at 3, 6, 9, and 12 months revealed that the likelihood of achieving a CCyR at all points remained at ~50% higher with dasatinib than with imatinib throughout (P <.001; hazard ratio, 1.53). MMR rates followed a similar pattern, with the 12-month rates at 46% for dasatinib 100 mg once daily and 28% for imatinib 400 mg once daily (P <.0001). Patients were twice as likely to achieve MMR at any time with dasatinib versus imatinib. Median time to achieving MMR was 6.3 months for dasatinib and 9.2 months for imatinib.
Also, progression to accelerated or blast phase was less frequent with dasatinib (1.9%) than with imatinib (3.5%). No patients who achieved MMR progressed to accelerated or blast phase. Twelve-month overall survival was similar for both groups (dasatinib, 97.2%; imatinib, 98.8%). Rates of thrombocytopenia and anemia were higher with dasatinib (thrombocytopenia, 19% vs 10%; anemia, 10% vs 7%). Neutropenia occurred in about 20% of patients with both agents. Adverse event–related discontinuations were low at 1.2% for dasatinib and 0.4% for imatinib. Discontinuations for treatment failure occurred in 5% of patients treated with dasatinib and 8.9% of those treated with imatinib. Pleural effusion was more common with dasatinib (10% vs 0%), and superficial edema was more common with imatinib (9% for dasatinib vs 36% for imatinib). Kantarjian concluded that dasatinib 100 mg/day should be first-line therapy for newly diagnosed CP-CML and commented, “Based on the predictive value of complete cytogenetic responses, longer follow-up of first-line dasatinib may demonstrate better longterm outcomes than imatinib.” ●
Dasatinib 100 mg Once Daily Is Best Dose in Second-line CP-CML CHICAGO—Four-year follow-up of patients with chronic-phase chronic myelogenous leukemia (CP-CML) who have been resistant, suboptimally re sponsive, or intolerant to prior imatinib therapy showed that dasatinib 100 mg once daily has the most favorable risk–benefit profile, with 66% progression-free survival (PFS) and 82% overall survival (OS). The findings also demonstrated that responses to dasatinib 100 mg once daily at 12 months are predictive of PFS at 48 months, said Neil P. Shah, MD, assistant professor of medicine at the University of California, San Francisco, at the 2010 annual meeting of the American Society of Clinical Oncology. Dasatinib, a potent tyrosine kinase inhibitor, is indicated for treating imatinib-resistant or -intolerant patients with CML (all phases) or Philadelphia chromosome–positive acute lymphoblastic leukemia. “These findings argue, in general for this population of patients, that a trial
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of dasatinib for 1 year to see if they can achieve a CCyR [complete cytogenetic response] is reasonable. With a CCyR, you can expect a 4% to 5% chance of their disease transforming to accelerated or blast phase,” Shah said. Patients were randomized using a 2 ¥ 2 factorial design to one of four dasatinib treatment arms: 100 mg once daily (n = 167), 50 mg twice daily (n = 168), 140 mg once daily (n = 167), and 70 mg twice daily (n = 168). Prior analysis of the study had resulted in a change of the approved dose from 70 mg twice daily to the 100-mg once-daily dose. The current analysis evaluated efficacy and safety in patients with a minimum followup of 48 months. Similar percentages of patients achieved the highest standard of response, major molecular responses (MMRs) (44%, 100 mg once daily; 43%, 70 mg twice daily; 42%, 140 mg once daily; 41%, 50 mg twice daily). Fifty percent achieved CCyR in the 100-mg once-daily group (49%-53%
for other doses). PFS, defined as no loss of complete hematologic response or major cytogenetic response, development of advanced disease, elevated white blood cells, or death, was 66% for 100 mg once daily and 57% to 69% for other doses. OS was 82% for 100 mg once daily and 75% to 83% for other doses. Rates of progression to accelerated or blast phase for the 100mg once-daily dose were 1.2% for each of the first 3 years and 0% for year 4. Landmark analysis of PFS according to response at 12 months with 100 mg once daily showed that 93% of patients who achieved an MMR (+ CCyR) had PFS at 48 months, as compared with a PFS rate of 77% among patients who achieved a CCyR but not an MMR at 12 months. PFS for patients without a cytogenetic response at 12 months was 45%. In general, first occurrence of an adverse event (AE) was encountered early in the treatment course (<24 months). AEs were typically mild to moderate. First occurrences of pleural
effusions (all grades) tended to occur at <24 months (15% by 24 months, 7% between 24 and 36 months, and 2% beyond 36 months). Neutropenia and thrombocytopenia (grade 3-4) occurred mostly within the first 12 months of treatment (33% and 22% by 12 months, decreasing to 0% for both between 36 and 48 months). Discontinuations due to drug toxicity were lowest with the 100-mg once-daily dose (16% vs 19%26% for other doses). Shah concluded that dasatinib 100 mg once daily offers a more favorable 4-year risk–benefit profile with similar efficacy but better tolerability than other doses. He pointed out that this analysis is the longest follow-up reported for any tyrosine kinase inhibitor. He commented further, “I think the less than 4% rate of transformation to accelerated or blast phase in a secondline setting, along with the 82% overall survival, is rather encouraging.” ● —WA
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Cancer Center Profile Reducing Disparities in Cancer Care... Continued from cover Making it a reality MSTI has “plans to beef up programs that are partly already in place but need greater funding, whether that is getting early screening with mammography at a greater intensity or getting more education within the communities,” said Paul G. Montgomery, MD, FACP, a medical oncologist. “There has been some education, there needs to be more. There have been some mobile mammography units going to rural areas, there needs to be more.” Funding from the NCCCP contract should help MSTI provide these additional services and “allow us to make an impact.” The action plans start by analyzing data on their patients. These data show where MSTI needs to focus, including geographic areas and ethnic populations. Then, areas with disparities are targeted for what is needed. Montgomery gave this example: Geographic areas where patients disproportionately pre-sent in the later stages of cancers can be targeted for patient education, hopefully leading to improved early diagnosis and screening. To help get information and services out to people, MSTI plans to expand its services beyond the Boise clinic, where most of the specialized clinics are currently housed. With the high-risk breast cancer clinic, for example, all patients must travel to Boise. But, the plan is to expand into the Twin Falls area, which is about 130 miles away, and at a future date, perhaps into the Fruitland area, according to Jill Winschell, RN, a breast cancer nurse navigator.
“These rural navigators will be situated in those areas and begin to develop community resources and community outreach to occur directly in their communities.” —Jill Winschell, RN Nurse Navigator Navigation services will expand beyond the new clinic. MSTI is currently looking to fill several positions for new navigators, starting with a navigator for the Twin Falls area and one for the Fruitland area in the western end of the Treasure Valley, which is home to a large Hispanic and rural population. A third breast care navigator will be hired for additional western Idaho locations.
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“These rural navigators will be situated in those areas and begin to develop community resources and community outreach to occur directly in their communities,” said Winschell. A second mobile mammography coach also is in the works. The current coach is booked every day, except when it is down for service, according to Winschell. “In fact, they have traveled up to Grangeville, which is 220 miles north. And we will be traveling into Oregon, which will be new for us.” Disparities meet supportive care Psychosocial and survivorship resources are expected to expand into all five sites as well, which will help MSTI embrace another of the NCCCP pillars—“Enhance cancer survivorship and palliative care services.” In addition, “we have the opportunity to provide supportive oncology clinics to meet the advanced disease population,” said Alicia Rosales, LMSW, an oncology social worker. A supportive care oncology clinic was opened in May in the Boise location. “It is not in replacement of the patients’ visits to their primary oncologist, but something that is linked in parallel,” said Dan Zuckerman, MD, medical director for the supportive care and survivorship clinics. With this clinic, patients who require help from multiple supportive disciplines now have a place to go. The clinic offers dietitians, social workers, and physical therapists. There are plans to increase psychiatric services by hiring someone with a specific interest in psycho-oncology. Although dedicated psychosocial oncology personnel can be difficult to staff in rural areas, Zuckerman is hoping to use funding from the NCCCP for this purpose. This funding may also allow a supportive oncology clinic to open in each of the five sites. Rosales envisions a half- day clinic of survivorship and a half-day clinic of advanced disease patients, staffed by a multidisciplinary team. The clinics would offer a dietitian, a social worker, a psychiatrist, a pharmacist, a nurse practitioner, and referrals to financial counselors and physical therapists. The rural location of its patients affects survivorship services as well. With patients in remote areas, survivorship services means “making sure that patients have the information, the resources, and the tools they need to empower themselves to lead healthy lives. We have to take into account that all of them may not have the opportunity to participate in exercise classes. We have to give them the information about how they can do it on their own in their own geographic setting,” said Rosales.
St. Luke’s Mobile Mammography Service brings mammography to the rural areas of southwestern Idaho.
Patient education is a similar challenge. In the Hispanic community, many believe that cancer cannot be
“Many of our patients cannot come into our main center in Boise, so our goal and our responsibility is to provide care in their own communities.” —Dan Zuckerman, MD Medical Director, Supportive Care and Survivorship Clinics cured. “It is even harder when these groups of workers are spread over a large area, to be able to reach out and have them understand that cancer can be cured. A great deal of time and effort will be needed to communicate that early diagnosis is important,” said Montgomery. “We are hoping that we can do more community outreach and interaction with the people in those communities to deal with a lot of those disparities and get the rural and Hispanic population into the healthcare system in a timely manner,” echoed Winschell. MSTI employs both Hispanic and Spanish-speaking oncologists and nurses to help with these efforts. Clinical trials and biospecimen research NCCCP sites are also tasked to “increase participation in clinical trials”
and “participate in biospecimen research initiatives to support personalized medicine.” Using funding from the contract, MSTI will be able to start a phase 1 clinical trial program within the next 2 years, “which will be a huge thing because there is no place in Idaho or in our surrounding area that offers phase 1 trials,” said Zuckerman. At current, MSTI accrues only to phase 3 trials, usually from one of the cooperative groups—Southwest Oncology Group, Radiation Therapy Oncology Group, National Surgical Adjuvant Breast and Bowel Project, Eastern Cooperative Oncology Group, and Cancer and Leukemia Group B—as well as to a limited number of industry-sponsored and investigator-initiated phase 2 trials. Biospecimen processing is already under way. In conjunction with Boise Veterans Affairs Medical Center and Boise State University, MSTI has broken ground on the building where biospecimens will be stored. “I think one of the things nationally is the NCI [National Cancer Institute] is trying to standardize how biospecimens are stored and to enable researchers from anywhere in the country to access these biospecimens,” said Zuckerman. Meeting the challenge “The challenge is not only to deliver best standards of care, but also to implement that across our multiple sites. Many of our patients cannot come into our main center in Boise, so our goal and our responsibility is to provide care in their own communities,” explained Zuckerman. Along with fellow NCCCP site Billings Clinic Cancer Center in Billings, Montana, MSTI hopes to meet the NCI’s challenge of providing the best evidence-based care to all Americans. ●
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Routine HBV Screening in Cancer Immunosuppressive Recipients Find Evidence of Virus in Some By Wayne Kuznar
CHICAGO—Routine screening for hepatitis B virus (HBV) in all patients being started on immunosuppressive therapy uncovers a significant percentage with HBV surface antigen (HBsAg) and HBV core antibody (HBcAb), said Emmy Ludwig, MD, at the 2010 annual meeting of the American Society of Clinical Oncology (ASCO). As such, she recommends a universal screening program for HBV at all cancer centers. Chemotherapy and immunosuppressive drugs can cause reactivation of HBV in persons who have the virus, with morbid and potentially fatal consequences. The recommendation for universal screening in this population is at odds with ASCO, which recently issued a provisional clinical opinion stating that the net benefits and harms of routine screening for HBV are not known for cancer patients who are about to receive cytotoxic or immunosuppressive therapy as part of their cancer therapy. The official stance of ASCO, therefore, is that HBV screening in cancer patients requires clinical judgment. The opinion was published online on June 1 in the Journal of Clinical Oncology. All patients at Memorial SloanKettering Cancer Center who were started on immunosuppressive therapy (chemotherapy and/or corticosteroids) were screened for HBV from June to December 2009, consisting of serologies for HBsAg and HBcAb and subsequent measurement of HBV polymerase chain reaction (PCR) if either test was positive. The screening program was begun after Ludwig and her colleagues identified cases in their center in which HBV was reactivated after immunosuppressive therapy, four of whom died (three who had solid tumors) and 19 of whom were hospitalized (one who required liver transplant). Two of the patients were being treated with steroids. In all, 1720 patients were screened prior to immunosuppressive therapy. During those 6 months, 1.1% were positive for HBsAg and 9.2% were positive for HBcAb. Less than half with HBsAg were born in Asia, where HBV is pandemic. More than nine (91%) of 10 positive tests were in patients with a solid tumor.
Four of the 155 patients in whom HBcAb was positive but HBsAg was negative had a positive HBV PCR, meaning that new HBV was being made despite the negative HBsAg test.
If screening was positive, patients were treated with prophylactic antiviral therapy with entecavir, 0.5 mg/day, which has proved 100% effective in preventing reactivation, said Ludwig, a
gastroenterologist at Memorial-Sloan Kettering. Entecavir prophylaxis is given for the entire duration of cancer therapy and continued for an additional 6 months. ●
In the treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible
Making the Case for INFeD ®
Broad usage1 • Allows FDA-approved treatment of a wide range of patients with documented iron deficiency anemia
Proven safety profile of iron dextran • In a retrospective analysis of 841,252 doses, dyspnea, hypotension, and neurological symptoms were the most common major adverse drug events (ADEs)2 — The most common minor ADEs were nausea, vomiting, flushing, and pruritus2 • Serious adverse events are rare — In a nonuremic population, 3 serious adverse events occurred in 481 patients (0.6%) receiving 2099 iron dextran injections (0.1%), with no fatalities reported3 — In a retrospective analysis of 61,950 hemodialysis patients, the incidence of reactions requiring resuscitative medications was 0.0016% (7 episodes in 440,406 exposures)4 • Iron dextran products are not clinically interchangeable1 — Differ in chemical characteristics and may differ in clinical effects Important Safety Information1 Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. A test dose should be administered prior to the first therapeutic dose, followed by the full therapeutic dose if no signs or symptoms of anaphylactic-type reactions are seen. Resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions must be readily available during all INFeD® administrations. Patients should be observed for signs or symptoms of anaphylactic-type reactions during all INFeD® administrations. Fatal reactions have followed the test dose and have also occurred in situations where the test dose was tolerated. Use INFeD® only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactictype reactions. INFeD® should be used with caution in individuals with histories of significant allergies and/or asthma, and is contraindicated in patients with hypersensitivity to the product and patients with all anemias not associated with iron deficiency. INFeD® should be used with extreme care in patients with serious impairment of liver function, and should not be used during the acute phase of infectious kidney disease. Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis, which is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias. Please see next page for references and brief summary of full Prescribing Information.
Did You Know? Of the 1.63 billion prescriptions written in the United States in 2009, 12% (190 million) were written electronically, ac cording to a Surescripts audit.
© 2009, Watson Pharma, Inc., Morristown, NJ 07960. All rights reserved. 06107 11/09
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Pharmacist/Nurse Model for Delivery of Supportive Care Improves Patient Symptoms By Karen Rosenberg
CHICAGO—Implementation of a roving pharmacist/nurse model for supportive care at the North Carolina Cancer Hospital resulted in a significant improvement in patient symptoms, re-
searchers reported at a poster session at the 2010 annual meeting of the American Society of Clinical Oncology. The multidisciplinary Oncology Supportive Care Consult Service was start-
ed at the hospital in 2008. Members of the team include a medical oncologist, a clinical pharmacist practitioner, and a clinical nurse specialist. A novel feature of the service is that the pharmacist and
References: 1. INFeD® full Prescribing Information. Watson Pharma, Inc. September 2009. 2. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis. 2001;37:743-749. 3. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726-1731. 4. Walters BAJ, Van Wyck DB. Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients. Nephrol Dial Transplant. 2005;20:1438-1442.
BRIEF SUMMARY: For full Prescribing Information, see package insert. WARNING: RISK FOR ANAPHYLACTIC-TYPE REACTIONS Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. Have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during INFeD administration. Administer a test INFeD dose prior to the first therapeutic dose. If no signs or symptoms of anaphylactic-type reactions follow the test dose, administer the full therapeutic INFeD dose. During all INFeD administrations, observe for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran injection. Fatal reactions have also occurred in situations where the test dose was tolerated. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions to INFeD. INDICATIONS AND USAGE: Intravenous or intramuscular injections of INFeD are indicated for treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible. CONTRAINDICATIONS: Hypersensitivity to the product. All anemias not associated with iron deficiency. WARNINGS: Risk for Anaphylactic-type Reactions: Anaphylactic-type reactions, including fatalities have followed the parenteral administration of iron dextran. Always have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during INFeD administration. Prior to the first therapeutic dose, administer a test INFeD dose of 0.5 mL. (See DOSAGE AND ADMINISTRATION.) Although reactions are usually evident within a few minutes, observe patients for at least one hour before administering the therapeutic dose. During all INFeD administrations, observe patients for signs or symptoms of anaphylactictype reactions. Fatal reactions have followed the test dose of iron dextran and have also occurred in situations where the test dose was tolerated. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies. Additionally, concomitant use of angiotensin-converting enzyme inhibitor drugs may increase the risk for reactions to an iron dextran product. The extent of risk for anaphylactic-type reactions following exposure to any specific iron dextran product is unknown and may vary among the products. Iron dextran products differ in chemical characteristics and may differ in clinical effects. Iron dextran products are not clinically interchangeable. Delayed Reactions: Large intravenous doses, such as used with total dose infusions (TDI), have been associated with an increased incidence of adverse effects. The adverse effects frequently are delayed (1-2 days) reactions typified by one or more of the following symptoms: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is usually 24-48 hours after administration and symptoms generally subside within 3-4 days. The etiology of these reactions is not known. The potential for a delayed reaction must be considered when estimating the risk/benefit of treatment. The maximum daily dose should not exceed 2 mL undiluted iron dextran. Risk in Patients with Underlying Conditions: INFeD should be used with extreme care in patients with serious impairment of liver function. It should not be used during the acute phase of infectious kidney disease. Adverse reactions experienced following administration of INFeD may exacerbate cardiovascular complications in patients with pre-existing cardiovascular disease. Carcinogenesis: A risk of carcinogenesis may attend the intramuscular injection of iron-carbohydrate complexes. Such complexes have been found under experimental conditions to produce sarcoma when large doses or small doses injected repeatedly at the same site were given to rats, mice, and rabbits, and possibly in hamsters. The long latent period between the injection of a potential carcinogen and the appearance of a tumor makes it impossible to measure accurately the risk in man. There have, however, been several reports in the literature describing tumors at the injection site in humans who had previously received intramuscular injections of iron-carbohydrate complexes. PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias that might be erroneously diagnosed as iron deficiency anemias. INFeD should be used with caution in individuals with histories of significant allergies and/or asthma. Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of iron dextran injection. Therefore, administer a test dose prior to the first therapeutic dose of INFeD. (See BOXED WARNING and DOSAGE AND ADMINISTRATION: Administration.) Epinephrine should be immediately available in the event of acute hypersensitivity reactions. (Usual adult dose: 0.5 mL of a 1:1000 solution, by subcutaneous or intramuscular injection.) Note: Patients using beta-blocking agents may not respond adequately to epinephrine. Isoproterenol or similar beta-agonist agents may be required in these patients. Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the administration of INFeD. Reports in the literature from countries outside the United States (in particular, New Zealand) have suggested that the use of intramuscular iron dextran in neonates has been associated with an increased incidence of gram-negative sepsis, primarily due to E. Coli. Information For Patients: Patients should be advised of the potential adverse reactions associated with the use of INFeD. Drug/Laboratory Test Interactions: Large doses of iron dextran (5 mL or more) have been reported to give a brown color to serum from a blood sample drawn 4 hours after administration. The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. Serum iron determinations (especially by colorimetric assays) may not be meaningful for 3 weeks following the administration of iron dextran. Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of INFeD and slowly returns to baseline after about 3 weeks.
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Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following iron dextran therapy because residual iron dextran may remain in the reticuloendothelial cells. Bone scans involving 99m Tc-diphosphonate have been reported to show a dense, crescentic area of activity in the buttocks, following the contour of the iliac crest, 1 to 6 days after intramuscular injections of iron dextran. Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal activity, and excessive blood pool and soft tissue accumulation. Carcinogenesis, Mutagenesis, Impairment Of Fertility: See WARNINGS. Pregnancy: Pregnancy Category C: Iron dextran has been shown to be teratogenic and embryocidal in mice, rats, rabbits, dogs, and monkeys when given in doses of about 3 times the maximum human dose. No consistent adverse fetal effects were observed in mice, rats, rabbits, dogs and monkeys at doses of 50 mg iron/kg or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a 14 day period. Similar effects were observed in mice and rats on administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deficient. There are no adequate and well-controlled studies in pregnant women. INFeD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated inconclusive results with respect to the placental transfer of iron dextran as iron dextran. It appears that some iron does reach the fetus, but the form in which it crosses the placenta is not clear. Nursing Mothers: Caution should be exercised when INFeD is administered to a nursing woman. Traces of unmetabolized iron dextran are excreted in human milk. Pediatric Use: Not recommended for use in infants under 4 months of age. (See DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS: Severe/Fatal: Anaphylactic reactions have been reported with the use of iron dextran injection; on occasions these reactions have been fatal. Such reactions, which occur most often within the first several minutes of administration, have been generally characterized by sudden onset of respiratory difficulty and/or cardiovascular collapse. Because fatal anaphylactic reactions have been reported after administration of iron dextran injection, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available. (See BOXED WARNING and PRECAUTIONS: General, pertaining to immediate availability of epinephrine.) Cardiovascular: Chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycardia, flushing, arrhythmias. (Flushing and hypotension may occur from too rapid injections by the intravenous route.) Dermatologic: Urticaria, pruritus, purpura, rash, cyanosis. Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea. Hematologic/lymphatic: Leucocytosis, lymphadenopathy. Musculoskeletal/soft tissue: Arthralgia, arthritis (may represent reactivation in patients with quiescent rheumatoid arthritis – See PRECAUTIONS: General), myalgia; backache; sterile abscess, atrophy/fibrosis (intramuscular injection site); brown skin and/or underlying tissue discoloration (staining), soreness or pain at or near intramuscular injection sites; cellulitis; swelling; inflammation; local phlebitis at or near intravenous injection site. Neurologic: Convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia, febrile episodes, chills, dizziness, disorientation, numbness, unconsciousness. Respiratory: Respiratory arrest, dyspnea, bronchospasm, wheezing. Urologic: Hematuria. Delayed reactions: Arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea, vomiting. (See WARNINGS.) Miscellaneous: Febrile episodes, sweating, shivering, chills, malaise, altered taste. OVERDOSAGE: Overdosage with iron dextran is unlikely to be associated with any acute manifestations. Dosages of iron dextran in excess of the requirements for restoration of hemoglobin and replenishment of iron stores may lead to hemosiderosis. Periodic monitoring of serum ferritin levels may be helpful in recognizing a deleterious progressive accumulation of iron resulting from impaired uptake of iron from the reticuloendothelial system in concurrent medical conditions such as chronic renal failure, Hodgkins disease, and rheumatoid arthritis. The LD50 of iron dextran is not less than 500 mg/kg in the mouse. Rx Only Revised: September 2009 Address medical inquiries to: WATSON Medical Communications P.O. Box 1953 Morristown, NJ 07962-1953 800-272-5525
Distributed by: Watson Pharma, Inc. Morristown, NJ 07962 Manufactured by: Patheon Italia S.p.A. Ferentino, Italy 03013 251279 S0909
nurse travel to the individual outpatient adult oncology clinics (hematology/oncology, gynecologic oncology, surgical oncology, radiation oncology), resulting in more timely consults and less travel and inconvenience for patients, explained Stephen Bernard, MD. Service is available 5 days a week. A designated Oncology Supportive Care Clinic was added when a need was identified to accommodate complex cases and patients needing ongoing follow-up.
A novel feature of the service is that the pharmacist and nurse travel to the individual outpatient adult oncology clinics, resulting in more timely consults and less travel and inconvenience for patients.
In the first 18 months, the service saw 89 new patients and there were 292 encounters, including both new and return visits. Referrals were received from radiation oncology, medical oncology, gynecologic oncology, and surgical oncology and were for patients with a variety of malignancies. Pain management was the primary reason for consults (75%); others were constipation (11%), nausea/vomiting (8%), anxiety/mood (4%), and spiritual (2%). New consults and established visits with the service increased by 50% in the second 6 months compared with the first 6 months. The most common recommendations by the Oncology Supportive Care Consult Service were dosage increases and addition of new medications. Improvements in symptom scores were evident by the second visit and were maintained beyond that visit. In a sample of 49 patients, pain scores decreased from 4 to 2.7 (5 being the maximum), nausea from 4 to 1.4, and constipation from 2 to 1.6. The researchers noted that the service allowed the primary oncologist to focus on disease management while the supportive care consult team focused on managing symptoms of the disease and treatment. A study using a formal tool to evaluate patient satisfaction with the service is under way. ●
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Meta-analysis of Bevacizumab Trials in Breast Cancer Show Longer PFS By Caroline Helwick
CHICAGO—The benefit of bevacizumab in metastatic breast cancer was made clear in a meta-analysis of key trials presented by Joyce O’Shaughnessy, MD, of Baylor-Sammons Cancer Center and US Oncology, during the 2010 annual meeting of the American Society of Clinical Oncology. Three randomized trials—E2100, AVADO, and RIBBON-1—that include a total of 2447 patients have demonstrated significantly improved progression-free survival (PFS) for bevacizumab combined with different chemotherapy regimens for frontline treatment of metastatic breast cancer. In the pooled analysis, median PFS improved by 2.5 months when bevacizumab was combined with chemotherapy compared with chemotherapy alone, regardless of hormone receptor status, sites of metastasis, disease-free interval, or prior adjuvant taxane use, O’Shaughnessy said. The chemotherapy regimens for metastatic breast cancer included weekly paclitaxel; every-3-week docetaxel; and capecitabine, docetaxel or nanoparticle albumin-bound (nab)-paclitaxel, and doxorubicin or epirubicin. Approximately 50% had received adjuvant therapy. Median follow-up was 23 months to 35 months. An overview of efficacy is shown in the Table. O’Shaughnessy and colleagues pooled the individual results and arrived at an
overall PFS of 9.2 months with bevacizumab versus 6.7 months with chemotherapy alone, for a 36% reduction in risk. All subgroups derived benefit from bevacizumab, including patients with adverse prognostic features. Response rates increased by an absolute 17% versus controls. Overall survival (OS), however, was not significantly improved in either the individual trials or the pooled analysis. In the pooled population, OS was 26.7 months with bevacizumab and 26.4 months with chemotherapy alone; 1year survival rates were 82% and 77%, respectively. There were no survival differences by subsets. “But in general, patients received multiple treatments upon progression,” O’Shaughnessy noted, which has a wellknown effect on survival and thus makes it very difficult to show survival differences between arms. In the nonbevacizumab arms, 71% of patients received additional chemotherapy after the study, as did 65% of patients in the bevacizumab arm. O’Shaughnessy pointed out that 50% of the chemotherapy-alone arm received bevacizumab. An additional four anticancer agents were given to 25% of patients. Bevacizumab use has been proved safe, with treatment-related deaths reported for 2.1% of patients. Grade 3 or higher adverse events included neutropenia, sensory neuropathy, and
Table Efficacy of Bevacizumab in Individual Trials Trial
Median PFS Non-BV arm BV arm
BV indicates bevacizumab; HR, hazard ratio; PFS, progression-free survival.
hypertension in approximately 10% of patients; febrile neutropenia in 6.5% of patients; venous thromboembolism in 2.8% of patients; and proteinuria in 2.3% of patients. OS benefit uncertain Hope Rugo, MD, of the University of California, San Francisco, posed some reasons for the lack of OS benefit shown in the trials. “Line of therapy is important,” she pointed out. Studies are less likely to show a survival benefit in the first-line unselected population, whose biology is “extremely heterogeneous.” Late-line studies are more likely to enroll a more homogeneous group of patients who have likely responded to prior treatments, have a good performance status, and have tumors associated with rapid relapse, which makes development of resistance less likely, she said.
In addition, observation of an OS benefit is dependent on survival time postprogression, and short follow-up as well as crossover treatments (50% of the control group received bevacizumab) make it highly unlikely for this to be observed. Rugo said the future studies need to hone in on which patients are more likely to benefit from taking bevacizumab. “Collaborative research and tumor biopsies are required to answer the critical question of which patients benefit most from antiangiogenic therapy,” she concluded. ●
Did You Know? The number of prescription drugs abandoned by patients at the pharmacy rose 55% in the second quarter of 2010 compared with 4 years earlier, The Wall Street Journal reports.
Business Management Programs Help Clinicians Improve Healthcare Delivery By Eileen Koutnik-Fotopoulos
ealthcare is more than medicine and patient care. Physicians, pharmacists, nurses, and hospital administrators are realizing that healthcare is also a business. As a result, healthcare professionals are looking for ways to improve quality of care while lowering costs. College and universities are answering the call with business management courses geared toward medical professionals. “Healthcare has traditionally set itself apart from other industries. It’s extremely important to take best practices from across all industries and disciplines and learn everything we can to deliver the highest quality of care more efficiently,” says Judy Smith, MD, FACS, medical
director for the Roswell Park Cancer Institute in Buffalo, New York. The cost of cancer care and how to best treat the disease are concerns for clinical professionals treating cancer patients. “The high cost of cancer care in general is an issue. Our patients and providers have high expectations, and we have to learn how to manage the business of cancer better,” explains Smith. She notes how cancer is treated by providers has changed. “It’s not just managing acute cancer but also longterm care.” Furthermore, the demand for cancer care is increasing because “of the aging population and the high number of cancer survivors,” adds Smith.
In an effort to improve Roswell Park’s operations and optimize patient care, Smith is one of 68 students enrolled in Harvard Business School’s Managing Healthcare Delivery executive education program. Launched in October 2009, the $22,000 nondegree program consists of three 1-week sessions over 9 months. “More and more clinicians, particularly clinical leaders, are recognizing that a significant portion of their job is not only to deliver excellent care, but also to manage and allocate resources appropriately,” says Cara M. Sterling, director of the healthcare initiative at Harvard Business School. “Clinicians tend to be fact-based
learners who appreciate the body of knowledge related to managing people, applying information technologies, and understanding and designing management metrics, to name just a few, that business schools have to offer. The majority, however, don’t have 2 years to invest in an MBA program. This program was developed specifically for healthcare delivery professionals who want an immersive management education experience, but want to do it in the context of their current job,” explains Sterling. Sessions cover developing effective operational models, teams, and delivery strategies; managing performance of Continued on page 25
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Supportive Care Revisiting the Use of IV Iron in Patients with Cancer Continued from cover clinical nature of serious adverse events (AEs) associated with the administration of IV iron. This brief overview aims to change this perception. History In the early 20th century, Goetsch and colleagues introduced colloidal ferric hydroxide for IV infusion as therapy for patients with hypochromic anemias.10 Toxic reactions to this preparation were frequent and severe and set the stage for the admonition that IV iron be reserved for only extreme clinical circumstances. In the 1940s, iron saccharides—and shortly thereafter iron dextran—were introduced for clinical use and were associated with an acceleration of IV iron use for those situations in which oral iron was not adequate. In 1964, Marchasin and Wallerstein showed the felicitousness of total dose infusions of up to 3000 mg of a high-molecular-weight (HMW) iron dextran in 45 iron-deficient patients (Imferon, Fisons PLC; no longer available). All patients responded, and no serious toxicity was observed.11 Yet, it was not until 1980, when Hamstra and colleagues published their prospective experience with 471 iron-deficient patients who received IV iron dextran (Imferon), that the first large series appeared.12 In this study, three patients were considered to have had “anaphylactoid” reactions, with symptoms and signs including respiratory arrest, hypotension, purpura, cyanosis, dyspnea, syncope, wheezing, and hives. There were no deaths. The authors concluded that IV iron should be reserved for conditions in which oral iron could not be used.12 IV iron remained on the pharmacopeia, but its use was limited. In 1989, recombinant human erythropoietin (EPO) became available for the treatment of dialysis-associated anemia. Shortly thereafter, numerous studies showed the benefit of IV iron in optimizing responses to EPO-treated patients, and the addition of IV iron to the treatment paradigm in dialysis-associated anemia became standard practice. At the end of 1991, low-molecularweight (LMW) iron dextran (INFeD, Schein, now Watson Pharma) was released for clinical use and rapidly replaced HMW iron dextran, which was removed from markets in 1992, as the IV iron formulation used in dialysis centers. In 1996, the initial review of safety was published. The authors concluded that AEs with LMW iron dextran were rare, and only a history of allergies predicted otherwise infrequent AEs.13 At the same time, another HMW iron dextran (Dexferrum, American Regent) was approved as an alternative to INFeD. No comparison
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safety data were, or subsequently are, available. In 2002, ferric gluconate (Ferrlecit, Schein, now Watson Pharma) and shortly thereafter iron sucrose (Venofer, American Regent) were introduced as alternatives to iron dextran in patients on dialysis. In two retrospective studies, Michael and colleagues as well as Coyne and colleagues concluded that serious AEs were much more common with iron dextran than with ferric gluconate,14,15 which rapidly replaced iron dextran for dialysis-associated anemia. In 2004, however, Chertow and colleagues published a retrospective review of 30 million doses of IV iron, reporting
The NCCN recommends that if iron is indicated, it should be given intravenously. The guidelines specifically proscribe HMW iron dextran by brand and state that the preferred product is LMW iron dextran. that serious AEs were much more likely to occur with the HMW formulation and concluding that when this product is avoided, the other preparations (LMW iron dextran, iron sucrose, ferric gluconate) are safe with an incidence of serious AEs of <1:200,000.16 Five studies, albeit all retrospective, corroborated these findings.17-21 However, a sixth retrospective analysis reported no difference.22 Nonetheless, use of iron dextran in nephrology patients, for all intents and purposes, remains negligible. Barriers to IV iron use Despite the safety and efficacy demonstrated in the nine prospective oncology studies, the clinical community’s larger perception of danger associated with the use of IV iron persists. Although AE rates may be driven high-
er by HMW iron dextran, all iron supplementation products suffer the stigma.23 This incorrect perception is further driven by the near lack of prospective comparison studies. Only two small prospective studies and one meta-analysis compared the efficacy and safety of LMW iron dextran with iron sucrose; no difference was seen.24-26 Another reason contributing to the sparse use of IV iron in oncology may be the lack of consensus on how best to administer the different products and the benefit or lack thereof of premedication. Premedication, which has been shown to be responsible for more side effects than IV iron itself27 and of no other clinical benefit, continues to be widely used before IV iron administration. After a test dose, acute myalgias (chest and back tightness) occur infrequently without tachycardia, hypotension, stridor, or periorbital edema.28 This reaction abates within minutes and rarely recurs with rechallenge. It is not rare for physicians and nurses unfamiliar with the innocuous nature of the reaction to intervene with antihistamines and pressors, which cause significant vasoactive reactions that are subsequently attributed to the IV iron. Lastly, inconvenience may contribute to the lack of widespread use of IV iron. In the United States (but not in Europe), payers do not allow the administration of ESAs and IV iron on the same day. This unsubstantiated regulation is fueled by the lack of ICD-9-CM codes for iron-restricted erythropoiesis or functional iron deficiency. For absolute iron deficiency, ESAs are contraindicated until iron is replete. For those common situations in chemotherapy-induced anemia when iron parameters suggest iron repletion, however, functional iron deficiency is often present, and addition of IV but not oral iron to the treatment paradigm, routinely improves responses to ESAs. If the only ICD-9-CM code for iron deficiency, 280.9, is placed on the billing form, the ESA will not be reimbursed; if omitted, however, the IV iron will not be covered. This conundrum remains. Recent developments The recent update to the National Comprehensive Cancer Network (NCCN) guidelines provides new optimism.29 The NCCN recommends that if iron is indicated, it should be given intravenously. The guidelines specifically proscribe HMW iron dextran by brand and state that the preferred product is LMW iron dextran (ie, INFeD). Principals at the US Food and Drug Administration (FDA), however, recently published a review of the AE reporting on iron dextrans using the
FDA AE reporting system, death certificates, and emergency department visits. They concluded that reactions with all of the products are possible and, using the current system, it is not possible to determine the relative rates of serious AEs with the absence of head-to-head trials.30 Furthermore, three new IV iron products promise to allow complete replacement of iron intravenously in 15 minutes or less. Of these, ferumoxytol (Feraheme, AMAG Pharmaceuticals) is approved in the United States as a 510-mg bolus injection administered over 17 seconds for patients with iron deficiency and chronic renal diseases. Data with higher doses are anticipated in the near future as are safety and efficacy data in other conditions associated with iron deficiency. The other two products, iron carboxymaltose (Ferinject, Vifor Pharma) and iron isomaltoside (MonoFer, Pharmacosmos), are approved in Europe. Iron carboxymaltose can be administered as a 1-g infusion over 15 minutes, and iron isomaltoside as a 15-minute infusion in doses up to 20 mg/kg. The safety and efficacy of IV iron have been demonstrated with transferrin saturation up to 50% and serum ferritin levels up to 1000 ng/mL. Although all IV irons are associated with serious AEs, current reporting mechanisms tell us nothing about relative frequency of AEs. Based on the preponderance of published literature, it appears prudent to use HMW iron dextran with caution. These data suggest it may be time to revisit the treatment paradigm to include the routine use of IV iron within these parameters. ● References 1. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol. 2004;22:1301-1307. 2. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12:231-242. 3. Hedenus M, Birgegård G, Näsman P, et al. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia. 2007;21:627-632. 4. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. J Clin Oncol. 2008;26:1619-1625. 5. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26:1611-1618. 6. Auerbach M, Silberstein PT, Webb RT, et al. Darbepoetin alfa 300 or 500 mmg once every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. Am J Hematol. June 4, 2010. Epub ahead of print.
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Pharmacy Practice 7. Kim YT, Kim SW, Yoon BS, et al. Effect of intravenously administered iron sucrose on the prevention of anemia in the cervical cancer patients treated with concurrent chemoradiotherapy. Gynecol Oncol. 2007;105: 199-204. 8. Beguin Y, Maertens J, De Prijck B, et al. Darbepoetin-alfa and I.V. iron administration after autologous hematopoietic stem cell transplantation: a prospective randomized multicenter trial. Blood (ASH Annual Meeting Abstracts). 2008;112:54. 9. Dangsuwan P, Manchana T. Blood transfusion reduction with intravenous iron in gynecologic cancer patients receiving chemotherapy. Gynecol Oncol. 2010; 116:522-525. 10. Goetsch AT, Moore CV, Minnich V. Observations on the effect of massive doses of iron given intravenously to patients with hypochromic anemia. Blood. 1946;1:129-142. 11. Marchasin S, Wallerstein RO. The treatment of iron-deficiency anemia with intravenous iron dextran. Blood. 1964;23:354-358. 12. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243:1726- 1731. 13. Fishbane S, Ungureanu VD, Maesaka JK, et al. The safety of intravenous iron dextran in hemodialysis patients. Am J Kidney Dis. 1996;28:529-534. 14. Michael B, Coyne DW, Fishbane S, et al; for the Ferrlecit Publication Committee. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002;61:1830-1839. 15. Coyne DW, Adkinson NF, Nissenson AR, et al; for the Ferrlecit Investigators. Sodium ferric gluconate complex in hemodialysis patients. II. Adverse reactions in iron dextran-sensitive and dextran-tolerant patients. Kidney Int. 2003;63:217-224. 16. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant. 2004;19:1571-1575. 17. Mamula P, Piccoli DA, Peck SN, et al. Total dose intravenous infusion of iron dextran for iron-deficiency anemia in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2002;34:286-290. 18. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis. 2001; 37:743-749. 19. McCarthy JT, Regnier CE, Loebertmann CL, Bergstralh EJ. Adverse events in chronic hemodialysis patients receiving intravenous iron dextran––a comparison of two products. Am J Nephrol. 2000;20:455-462. 20. Auerbach M. Finding a safe and effective intravenous iron treatment for restless legs syndrome. Sleep Med. 2010;11:429-430. 21. Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med. 2010; 11:494-496. 22. Walters BA, Van Wyck DB. Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients. Nephrol Dial Transplant. 2005;20:1438-1442. 23. Auerbach M, Glaspy J. What is the right balance between iron and erythropoiesis stimulating agents in chemotherapy induced anemia? European Journal of Clinical & Medical Oncology. 2009;1:17-20. 24. Sav T, Tokgoz B, Sipahioglu MH, et al. Is there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran? Ren Fail. 2007;29:423-426. 25. Moniem KA, Bhandari S. Tolerability and efficacy of parenteral iron therapy in hemodialysis patients, a comparison of preparations. Transfus Alternat Transfus Med. 2007;9:37-42. 26. Critchley J, Dundar Y. Adverse events associated with intravenous iron infusion (low-molecular-weight iron dextran and iron sucrose): a systematic review. Transfus Alternat Transfus Med. 2007;9:8-36. 27. Barton JC, Barton EH, Bertoli LF, et al. Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am J Med. 2000;109:27-32. 28. Auerbach M, Ballard H, Glaspy J. Clinical update: intravenous iron for anaemia. Lancet. 2007;369(9572): 1502-1504. 29. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Cancer- and Chemotherapy-induced Anemia. V.2.2011. www.nccn.org/pro fessionals/physician_gls/PDF/anemia.pdf. Accessed September 13, 2010. 30. Wysowski DK, Swartz L, Borders-Hemphill BV, et al. Use of parenteral iron products and serious anaphylactic-type reactions. Am J Hematol. 2010;85:650-654.
It May Be Time to Rethink Drug Dosing... Continued from cover the Albany College of Pharmacy and Health Sciences, New York. He said oncology pharmacists need to be fully aware of the LBW2005 equation. Pharmacists have historically used the Devine formula, which was based on ideal body weight. Pai said that the Devine formula was not derived on solid scientific grounds. Along with Paloucek, he has published a paper outlining the history of this formula (Ann Pharmacother. 2000; 34:1066-1069). “The goal of calculating ideal body weight was to get an estimate of lean body weight. It is important to recognize that many equations have been generated over time to estimate lean body weight. All these previous equations are limited in that they are linear equations. That is to say that the estimate of lean body weight increases in proportion to total body weight as one goes from 50 kg to say 250 kg,” Pai explained.
The LBW2005 equation is superior to previous equations because it is nonlinear and gives better estimates of lean body weight according to Pai. Simply put, the estimate of an individual subject’s lean body weight using LBW2005 increases by approximately twofold even though their total body weight increases by fourfold (50-200 kg). Pai applied this equation and demonstrated its superiority when dosing aminoglycosides, ertapenem, daptomycin, and voriconazole. Several investigators have demonstrated this for agents other than antibiotics as well. At the ICAA meeting, Pai presented the findings from his current study that showed estimated lean body weight was more useful than measured total body weight to decrease the pharmacokinetics of the drug ertapenem in normal weight and obese individuals. Lean body weight represents the “nonfat” or “fat-free weight” of a patient
based on his or her sex. This information may be helpful because it could be used to estimate the dose of drugs that are similar to ertapenem. The researchers found that a higher dose of ertapenem may be necessary in obese patients compared with nonobese patients. Ertapenem is commonly given before surgery to prevent infections. When most drugs now on the market were approved for commercial use, little information was available on dosing obese patients. For antibiotics, using a dose that is too low could lead to treatment failure and increase bacterial resistance, resulting in superinfections. Pai said that an antimicrobial dose that is too high could also lead to avoidable side effects. He and his colleagues noted that improving outcomes in obese patients with infections by using the appropriate antibiotic dose could reduce morbidity and mortality, and result in significant cost savings. ●
OCTO BER 20 10 www.Th eOncolo gyPhar macist .com
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Memb ers Zuckerm of St. Luke ’s Moun Montg an, MD; Ali tain Sta cia Ro omery tes , MD, sales, FACP. LMSW Tumor Institu ; Jill Wi te, fro m nschell, t. Luke RN; an left: Dan d Paul advanc ’s Mountain CE G. on pag ed canc Sta e 24 tes Me 180 mi ridian, Namper care to pa Tumor Ins titu les ac tie a, te nts at and (MSTI) ross so rural are clinics uthwe Twin Falls, provid in By John Bo lation, as and from stern Ida es Idaho. ise Schiesze ma Spannin , Fruitland addition ny people metropolitan ho, MSTI r , g mo ca in BOSTON are no , large Hispa rural areas areas. Beca res for patie re than t ge use pre nic nts 50th Int —New dat a “Reduc tting screene population sent at later of geograp from s in the hic iso microbia erscience Co presented at stages d for ca with wh e cancer nfe the of rur ncers he (ICAA l Agents an rence on An we on rec al counties disease. In Progra ich Nationa althcare dis C) d Chem ti- ma ight–2005 (LB omme of the m pa l antibiot suggest tha ting kid W access (NCCCP) sit Cancer Ins rities” is the nded timelin state t stand otherapy ics ney fun 2005) when titu es ard doses to ob obese es firs te Co ese ind may not be are tas . cancer ction MSTI est sub mmun t of seve ked. sc ho may ne ividuals and the right dose of need to ject. Oncol in the morbi ifrom the pes to reduc reening, tre These inequ ity Cancer n pillars tha ed highe dly for do ogy ph stu atmen e ir new In add r doses t obese patien armaci sing can dy the role t, and alities of ca Centers contrac disparities itio for ts re includ res som in more stu n, the res potentia cer chemoth of LBW2005 sts t as a e earchers e agents. memb care for the earch. The for l surrog erapy age die s are cor Th er of the sta ir pa ate sai rect do is ff at sages of needed to det d that are is important of body surfacnts as a NCCC tients with “Stop P. a help dru erm bec e is are gs no ause bo ine equation using the ide for the obese and wo t estimated dy surfaca. Continu dif . me s al fer e ed on pag ently for body we body we and its der LBW20 n of equal e 20 he men ight 05 giv iva ight). Co which es you ight and we nsider tive (adjusted ight. is est using lea Viewpo iological important du imates by Hemat n body sex e A New int Pai, Ph differences,” to known ph , Dasatini ologic Canc Rx for Me armD, ysers Page an associsaid Manjuna dicine Treatmentb vs Imatinib Stu 6 th ate -Naïve dy Ph pro in armacist/N fessor CML Dasatini Continu at urs Su ed b
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How to Keep Your Money Earning Interest By Eileen Koutnik-Fotopoulos
s the economy slowly recovers from the financial crisis, you may be looking for ways to boost the minuscule interest payments you are earning on your money. Although many different options and strategies for increasing your income stream are available, they may not be appropriate for your situation. Before making any decisions, do research and shop around for the best rates.
Savings accounts A savings account is the most convenient place to save money whether it is with your local bank or credit union. Most people also have this account linked directly to their primary checking account to make it easy to transfer money to savings. It is important to look at the interest rate you are earning from this account. Depending on where you bank and the type of account you have, the interest rate could be anywhere from less than 1% up to 4% or more. The national average for a basic savings account is about 0.80%. You may find that community banks are offering better
interest rates, compared with the big national banks. Visit www.bankrate.com to find the top-yielding bank and credit union savings deals. Money markets If you are not satisfied with the interest rates from your savings accounts, consider a money market account. This type of account can serve as your checking account in many situations and can average 3% to 4% interest. If you decide to link your money market account to your checking account, make all deposits to the money market account. Keep the minimum needed in the checking account to avoid fees and transfer money to the checking account only when necessary. A money market account does have restrictions. Because the money held in this account is invested differently, higher balance requirements, a limited number of withdrawals per month or quarter, and a limited number of checks to be written per month may apply. Checking accounts An interest-bearing checking account
is another option. How much money you regularly keep in your checking account and how often you need to access the money or write checks will help determine whether you will benefit from this type of account. The average interest earned with regular checking accounts is less than 1.5%, with most checking accounts earning 0.5% interest. Although the low rate of return is not going to maximize your earnings even with a high balance in your checking account, some interest is better than none. Keep in mind that most checking accounts that earn interest also charge monthly fees if you do not maintain a minimum balance. This may not be an issue if you always keep a large balance in your checking account. Local and national banks also offer what is called reward checking accounts. You can earn higher interest (about 4%) with no principal risk. To earn this higher yield, you typically have to make one monthly direct deposit into your account and use your debit card at least 10 times per month. A word of caution: If you cannot meet
the account requirements, your interest rate can drop to 0.25%. Certificate of deposit If your financial situation allows for locking up some of your money to get a higher interest rate, consider a certificate of deposit (CD). A CD is a time deposit, which means you are tying up some of your money for a specific amount of time before you can withdraw it. If you withdraw early, you will lose interest and possibly principal. This fixed-income investment is most often issued by banks. You can purchase short- or long-term CDs ranging from 1 month to years. This option guarantees a fixed amount of interest, which is added to your account periodically throughout the term of the CD. If you decide to purchase a longerterm CD, you can withdraw the interest payments as they are received. You may decide that you want several options for saving money depending on your financial situation. Whatever you decide, make sure your money is working as hard as it can and providing you with a return on your investment. ●
Business Management Programs... Continued from page 23 daily operations and processes; and fostering an environment of learning and leadership. Between the modules, participants work on projects that are relevant to their organization and relate to the curriculum. In the first session, students complete a series of exercises that are meant to encourage self-reflection and help identify areas of organizational opportunity. Participants also complete online tutorials in finance and accounting. In the second session, participants write a business plan for a new service line or rewrite the plan for an existing one. Faculty keep in touch with the students by sending periodic “healthcare in the news” articles, recommended readings, and surveys about specific management issues, according to Sterling. “Managing healthcare delivery has become increasingly complex,” says Harvard Business School professor Richard Bohmer, MBChB, MPH, faculty chair of the Managing Healthcare Delivery program. “Individuals who attend this program are looking for the right balance between clinical management and science. “If you want to run an organization more effectively, you have to design an organization that runs well,” explains
OcTOber 2010 I VOL 3, NO 7
Bohmer. He points out that individuals in a nonmanagerial role, such as in a practice with oncologists, also can benefit from the Harvard program. In an oncology practice, for example, staff needs to have an appreciation for baseline managerial principles to bring people together to work effectively and to get the highest quality outcomes for the practice and patients. Managing Healthcare Delivery is not the only program available for the medical community. Duke University’s Fuqua School of Business has just started a 1-year Master of Management in Clinical Informatics degree program in partnership with the Duke Center for Health Informatics. The cost of the program is around $48,000. The program will allow students to develop business knowledge in tandem with advanced health information technology (IT) skills. Curriculum requirements include seven management courses and five informatics courses, including a new practicum experience to be completed in a realworld setting at Duke. Duke has a long history in business management and healthcare management programs. This new graduate program is the “intersection of those two,” according to Randy Sears, assistant direc-
tor of Masters of Management in Clinical Informatics. “IT alone is not a panacea to improve the patient experience or to impact the cost of healthcare. IT needs to be married to process improvement and organization innovation to change paradigms. Bringing this all together is our focus at Fuqua,” comments Kevin A. Schulman, MD, director of Duke’s Health Sector Management program. At the University of St. Thomas in St. Paul, Minnesota, students complete nine programs over 24 months to receive a certificate in Advanced Health Care Management. The university, in partnership with the Minnesota Medical Group Management Association, developed this educational program to help organizations prepare for the future of healthcare. The cost is $375 per program. Program topics meet seven core competencies determined by the University of St. Thomas and the Minnesota Medical Group Management As sociation. Core competencies include leadership, finance, operations, marketing, IT, human resources, and care delivery and policy. Participants will be educated on new ideas, strategies, and tools to improve their organization; learn theory and participate in experiential instruction that will provide the tools to
integrate knowledge learned into organizations’ operations; gain education and exposure to ideas and concepts beyond what healthcare professionals experience in their daily role; and network with other healthcare professionals. Vanderbilt University’s Owen Graduate School of Management graduated its first Master of Management in Health Care class in September 2009. The 1-year, part-time, 30-credit-hour degree program targets physicians, nurses, and other clinical professionals. The program cost for the 2008-2009 academic year was $43,000, according to the university’s website. The program is organized into three main components: core general business classes, healthcare-focused business classes, and a yearlong team strategy project. Specific courses include managerial economics, services marketing, managerial accounting, finance, operations, and healthcare leadership. ●
Did You Know? It is estimated that the generic oncology market in the United States will be $35 billion after 2011, The Economic Times/ India Times reports.
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The Official Newspaper for the Hem/Onc Pharmacist
Whoâ€™s Your Nominee for
Pharmacist? The Oncology Pharmacist is pleased to announce the inaugural T.O.P. Pharmacist award. The award will recognize an oncology pharmacist nominated by his/her peers for an outstanding contribution to oncology pharmacy practice, research, or education in 2010. The four leading nominees will be profiled in the February issue of The Oncology Pharmacist. Readers will have an opportunity to vote for the winner online at www.TheOncologyPharmacist. com/award or by visiting The Oncology Pharmacist booth at the 2011 HOPA meeting. The winner will be announced in the April issue of The Oncology Pharmacist.
Nomination forms are available at
TOP_October 2010_v6_TOP 10/15/10 2:51 PM Page 28
Experienced Oncology Pharmacist Seeks MBA to Better Prepare for Future of Healthcare An interview with Scott A. Soefje, PharmD, BCOP By Karen Rosenberg
cott A. Soefje, PharmD, BCOP, has more than 20 years of pharmacy experience. He started as a hospital staff pharmacist, has held several positions in academia, and worked briefly in industry. Currently, he is director of pharmacy operations and director of the oncology residency program at The University of Texas Health Science Center at San Antonio. Just this past summer, however, he embarked on a new venture—a master of business administration (MBA) program at George Washington University. Soefje is part of a new trend, with more business schools offering programs geared specifically to students with an interest in healthcare administration [see story on page 24]. He hopes that with a combination of clinical experience and management training, he will be able to help his institution deal with the financial and administrative challenges in oncology practice today.
How did you get started in oncology pharmacy? I got my bachelor of science in pharmacy back in the ’80s. I then worked in a hospital pharmacy and, during that time, I started working on a master’s in hospital administration thinking that the administrative route was the way I wanted to go. But I was accepted to the doctor of pharmacy program at the University of Texas before I finished the master’s, and I felt that I couldn’t do both programs at the same time. I chose the doctor of pharmacy program and then went on to a residency at The University of Texas Health Science Center at San Antonio and a fellowship at The M. D. Anderson Cancer Center. When I completed the fellowship there were no oncology jobs, and I
heard about a position at Texas Tech University in Lubbock, where they were just starting a pharmacy school. I was the first pharmacy practice faculty to arrive on campus, 6 months before my boss. After a few years, a position opened up at the Veterans Affairs hospital in San Antonio, which is my home town, and I moved there. I took a position in industry for awhile and then moved to my current position at The University of Texas Health Science Center in San Antonio, where I am director of pharmacy operations and also director of the oncology residency program.
So why did you decide to go back to school at this point in your career? I’ve always enjoyed the administrative side of things and found I understand it. But in my role as a director, I began to realize that there were things that I was discussing with the CEOs, CFOs, and accountants that I didn’t fully understand. I thought I had two options. I could do on-the-job training or I could get formal training. About 1 year ago, I started looking into online MBA programs and, ultimately, enrolled in the George Washington University program in August. It has a healthcare focus and a very strong leadership focus, and it offers classes that I think will be very relevant to my job. There are 120 people in the program, all with an interest in healthcare. Some are just out of a bachelor’s degree program, while others are quite advanced in their careers. There are several physicians in the group, some clinicians who want to be better able to manage their practice, and some hospital administrators who want more formal training.
“We’ve set up monthly management training sessions where we sit down with the residents and go over things like strategic planning, pharmacoeconomics, and budgeting to help prepare them to deal with these issues. ” —Scott A. Soefje, PharmD, BCOP Do you think now with the current economy and concerns about healthcare reform concerns it’s more important than ever before for pharmacists to have management experience as well as clinical training? Yes. I remember back in the ’80s when I was talking to Roger Anderson at M. D. Anderson he said that in the future, those who reach the level of director will be clinically trained people who understand the business side of hospital administration, not someone with an MBA or a master’s degree who doesn’t understand the clinical side. That’s one of the reasons I went back to school. With the changes coming in healthcare, I figured that someone with a clinical background who understands clinical practice and has an MBA, has to be marketable. Considering that cancer care is not going to get cheaper over the next few years and that we’re going to have to make decisions about what drugs to use and when, about how to integrate all of these factors into oncology protocols, somebody with both clinical and administration training is going to be in a good position. Some schools are now offering programs that combine pharmacy training and business administration. For in-
stance, the University of Florida has an online program in conjunction with Stetson University that offers a combined degree, an MBA and a master’s in hospital pharmacy. I can already see how I can apply what I’m learning in my present position. Even though the Cancer Therapy and Research Center is part of The University of Texas Health Science Center, we practice as a physicians’ practice, much like community practices. We’re not part of a hospital system, so we’re dealing with the same sort of economic issues they’re facing on a daily basis. We’re thinking of opening a retail pharmacy here, and this program will prepare me to do that. Just taking the marketing class has gotten me thinking about how I can apply marketing to clinical pharmacy practice, even within the institution. As part of our oncology residency program, we’ve set up monthly management training sessions where we sit down with the residents and go over things like strategic planning, pharmacoeconomics, and budgeting to help prepare them to deal with these issues. I think this will serve them well in the future, whatever direction their careers take. ●
Combination of Agents Shows Promise in MBC NATIONAL HARBOR, MD—Pre liminary results of an ongoing trial suggest that a combination of trastuzumab, bevacizumab, and docetaxel is safe and effective as first-line therapy in women with metastatic breast cancer (MBC). Fourteen of the 18 patients treated to date had a partial response or stable disease, a clinical benefit rate of 77.7, the investigators reported. Previous studies have demonstrated the efficacy of trastuzumab combined with bevacizumab in MBC but the high
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rate of cardiotoxicity was a concern. Docetaxel has also been shown to be effective alone or combined with trastuzumab or bevacizumab. In the current study, Bhuvaneswari Ramaswamy, MD, of Ohio State University, Col umbus, and her colleagues studied the safety and efficacy of the three drugs combined in previously untreated women with HER2-positive MBC. Their findings on the first 18 patients enrolled in the ongoing trial were reported at the 2010 American Society
of Clinical Oncology Breast Cancer Symposium. All patients received six cycles of trastuzumab, bevacizumab, and docetaxel, after which docetaxel could be discontinued at the physician’s discretion. The other two agents were continued until disease progression or development of unacceptable toxicity. Median progression-free survival was 56 weeks. Eight patients had a partial response and six had stable disease. Grade 3 and 4 nonhematologic tox-
icities included nausea, fatigue, diarrhea, wound dehiscence, retinal edema, pulmonary embolism, neuropathy, nephrotic syndrome, and hypertension. Grade 3 and 4 hematologic toxicities were neutropenia and febrile neutropenia. One patient had an asymptomatic drop in left ventricular ejection fraction after three cycles of therapy, but no grade 3 or 4 cardiotoxicity was observed. Accrual in the study is continuing at two institutions. ●
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ONCOLOGY DRUG CODES
Medications Used for the Treatment of Breast Cancer Breast cancer forms in tissues of the breast, usually the ducts (tubes that carry milk to the nipple) and lobules (glands that make milk). It occurs in both men and women, although male breast cancer is rare. The following sections will assist healthcare professionals and payers by providing appropriate coding, billing, and reimbursement information associated with the management of breast cancer. The following sections include: • Associated ICD-9-CM codes used for the classification of breast cancer • Drugs that have been FDA-approved in the treatment of breast cancer • Drugs that are compendia listed for off-label use for breast cancer based on clinical studies that suggest beneficial use in some cases. Please note: if a check mark appears in the FDA column it will NOT appear in the compendia off-label use column • Corresponding HCPCS/CPT® codes and code descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable), if applicable • Possible CPT® Administration Codes for each medication
generic (Brand) name
HCPCS code: code description
J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0170: anastrozole, oral, 1 mg
anastrozole (Arimidex) bacillus Calmette-Guerin (Tice BCG, TheraCys) bevacizumab (Avastin) capecitabine (Xeloda) capecitabine (Xeloda) carboplatin (Paraplatin) cisplatin (Platinol AQ) cisplatin (Platinol AQ) cyclophosphamide (Cytoxan) cyclophosphamide (Cytoxan)
Associated ICD-9-CM Codes Used for Breast Cancer 174 Malignant neoplasm of female breast Includes: breast (female) connective tissue soft parts Paget’s disease of: breast nipple Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes: skin of breast (172.5, 173.5) 174.0 Nipple and areola 174.1 Central portion 174.2 Upper-inner quadrant 174.3 Lower-inner quadrant 174.4 Upper-outer quadrant 174.5 Lower-outer quadrant 174.6 Axillary tail 174.8 Other specified sites of female breast Ectopic sites
This information was supplied by:
FDAapproved for breast cancer
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175 Malignant neoplasm of male breast Use additional code to identify estrogen receptor status (V86.0, V86.1) Excludes: skin of breast (172.5, 173.5) 175.0 Nipple and areola 175.9 Other and unspecified sites of male breast Ectopic breast tissue, male
PO BOX 290616, Wethersfield, CT 06109 T: (860) 563-1223 • F: (860) 563-1650 www.RJHealthSystems.com
Compendia listed off-label use for breast cancera
Current code price (AWP-based pricing), effective 10/1/10 NDC level pricing $13.48
Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10
CPT ® administration codes
NDC level pricing S0170: not payable by Medicare $114.93
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
J9031: bCG (intravesical) per installation J9035: injection, bevacizumab, 10 mg J8520: capecitabine, oral, 150 mg J8521: capecitabine, oral, 500 mg J9045: injection, carboplatin, 50 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)
Inner breast Lower breast Malignant neoplasm of contiguous or overlapping sites of breast whose point of origin cannot be determined Midline of breast Outer breast Upper breast Breast (female), unspecified
N/A 96409, 96413, 96415
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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems
generic (Brand) name cyclophosphamide (Cytoxan)
cyclophosphamide (Cytoxan) cyclophosphamide (Cytoxan) cyclophosphamide (Cytoxan) daunorubicin citrate liposome (DaunoXome) docetaxel (Taxotere) doxorubicin (Adriamycin) doxourubicin HCl liposome (Doxil) epirubicin (Ellence) estradiol (Estrace) etoposide (Vepesid) exemestane (Aromasin) exemestane (Aromasin)
HCPCS code: code description J9080: cyclophosphamide, 200 mg (all 100-mg NDCs inactive: 500-mg NDCs used to calculate code price) J9090: cyclophosphamide, 500 mg J9091: cyclophosphamide, 1 gram J9092: cyclophosphamide, 2 gram J9151: injection, daunorubicin citrate, liposomal formulation, 10 mg J9171: injection, docetaxel, 1 mg J9000: injection, doxorubicin hydrochloride, 10 mg J9001: injection, doxorubicin hydrochloride, all lipid formulations, 10 mg J9178: injection, epirubicin HCl, 2 mg J8499b: prescription drug, oral, non-chemotherapeutic, not otherwise specified J8560: etoposide, oral, 50 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0156: exemestane, 25 mg
fluorouracil (Adrucil) fluoxymesterone (Androxy)
J9190: injection fluorouracil, 500 mg J8499b: prescription drug, oral, non-chemotherapeutic, not otherwise specified fulvestrant J9395: injection, fulvestrant, (Faslodex) 25 mg gemcitabine J9201: injection, (Gemzar) gemcitabine hydrochloride, 200 mg goserelin acetate J9202: goserelin acetate (Zoladex 3.6 mg ONLY) implant, per 3.6 mg hydroxyurea J8999b: prescription drug, (Hydrea) oral, chemotherapeutic, not otherwise specified hydroxyurea S0176: hydroxyurea, oral, (Hydrea) 500 mg ifosfamide (Ifex)
J9208: injection, ifosfamide, 1 gram
Current code price (AWP-based pricing), effective 10/1/10 $21.15
96409, 96413, 96415
96409, 96413, 96415
96409, 96413, 96415
NDC level pricing $57.33
NDC level pricing $28.48
NDC level pricing S0156: not payable by Medicare $1.74
NDC level pricing $13.50
NDC level pricing $97.29
NDC level pricing $83.02
FDAapproved for breast cancer
Compendia listed off-label use for breast cancera
NDC level pricing $1.28
Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10 $11.92
CPT ® administration codes 96409, 96413, 96415
NDC level pricing S0176: not payable by Medicare $34.15
Continued on page 32 www.TheOncologyPharmacist.com
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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems Continued from page 31
generic (Brand) name
HCPCS code: code description
irinotecan (Camptosar) ixabepilone (Ixempra) lapatinib ditosylate (Tykerb)
J9206: injection, irinotecan, 20 mg J9207: injection, ixabepilone, 1 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J0640: injection, leucovorin calcium, per 50 mg J9217: leuprolide acetate (for depot suspension), 7.5 mg J9218: leuprolide acetate, per 1 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0178: lomustine, oral, 10 mg
letrozole (Femara) leucovorin calcium (Wellcovorin) leuprolide (Eligard, Lupron Depot) leuprolide (Lupron) lomustine (CeeNu) lomustine (CeeNu)
medroxyprogesterone J1051: injection, (Depo-Provera) medroxyprogesterone acetate, 50 mg megestrol J8999b: prescription drug, (Megace) oral, chemotherapeutic, not otherwise specified megestrol S0179: megestrol acetate, (Megace) oral 20 mg melphalan (Alkeran) melphalan (Alkeran) methotrexate sodium methotrexate sodium methotrexate sodium mitomycin (Mutamycin) mitomycin (Mutamycin) mitomycin (Mutamycin) mitoxantrone (Novantrone) oxaliplatin (Eloxatin)
J8600: melphalan, oral, 2 mg J9245: injection, melphalan hydrochloride, 50 mg J8610: methotrexate, oral, 2.5 mg J9250: methotrexate sodium, 5 mg J9260: methotrexate sodium, 50 mg J9280: mitomycin, 5 mg J9290: mitomycin, 20mg J9291: mitomycin, 40 mg J9293: injection, mitoxantrone hydrochloride, per 5 mg J9263: injection, oxaliplatin, 0.5 mg
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Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10
CPT ® administration codes
NDC level pricing NDC level pricing $3.60
NDC level pricing NDC level pricing $1.05
NDC level pricing S0178: not payable by Medicare $8.12
NDC level pricing $10.59
NDC level pricing $0.66
FDAapproved for breast cancer
Compendia listed off-label use for breast cancera
Current code price (AWP-based pricing), effective 10/1/10
NDC level pricing S0179: not payable by Medicare $4.80
96372, 96374, 96409
96372, 96374, 96401, 96409, 96450 96372, 96374, 96401, 96409, 96450 96409
N/A 96409, 96413 N/A
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ONCOLOGY DRUG CODES Supplied by: RJ Health Systems
generic (Brand) name
HCPCS code: code description
paclitaxel (Taxol) paclitaxel protein-bound particles (Abraxane) pemetrexed (Alimta) prednisone
J9265: injection, paclitaxel, 30 mg J9264: injection, paclitaxel protein-bound particles, 1 mg J9305: injection, pemetrexed, 10 mg J7506: prednisone, oral, per 5 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified S0187: tamoxifen citrate, oral, 10 mg
tamoxifen (Nolvadex) tamoxifen (Nolvadex) testolactone (Teslac) thiotepa (Thiotepa) toremifene citrate (Fareston) trastuzumab (Herceptin) triptorelin (Trelstar Depot, Trelstar LA) topotecan (Hycamtin) topotecan (Hycamtin) vinBLAStine vinCRIStine (Vincasar) vinCRIStine (Vincasar) vinCRIStine (Vincasar) vinorelbine (Navelbine)
J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J9340: injection, thiotepa, 15 mg J8999b: prescription drug, oral, chemotherapeutic, not otherwise specified J9355: injection, trastuzumab, 10 mg J3315: injection, triptorelin pamoate, 3.75 mg J8705: topotecan, oral, 0.25 mg J9350: injection topotecan, 4 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
FDAapproved for breast cancer
Compendia listed off-label use for breast cancera
Current code price (AWP-based pricing), effective 10/1/10
Medicare allowable (ASP + 6%), effective 10/1/10-12/31/10
CPT ® administration codes
NDC level pricing $1.89
NDC level pricing $138.00
NDC level pricing S0187: not payable by Medicare NDC level pricing $114.09
NDC level pricing $78.26
NDC level pricing $68.28
51720, 96409 N/A
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 Nolvadex) 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 (CPT © copyright 2010 American Medical Association. All rights reserved. CPT® is a registered trademark of the American Medical Association) • ICD-9-CM for Professionals Volumes 1 and 2, 2010 • The Drug Reimbursement Coding and Pricing Guide by RJ Health Systems International, LLC, Volume 7, Number 4, 4th Quarter 2010 • FDA-approved indication (from the product’s prescribing information) • National Cancer Institute® • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMS (Centers for Medicare & Medicaid Services), Medicare Allowable 4th Quarter 2010 (effective dates 10/1/10-12/31/10). Prices listed herein are effective as of October 1, 2010.
OcTOber 2010 I VOL 3, NO 7
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New “Tip Sheets” Help NHL Patients Communicate with the Oncology Team By Caroline Helwick
research-based educational program aimed at enhancing communication between nonHodgkin lymphoma patients and their healthcare providers has just been launched and is available for healthcare providers. Framing Life With Lymphoma was developed by the Cancer Support Community, which unites The Wellness Community and Gilda’s Club Worldwide, and was supported by a grant from Cephalon. “Non-Hodgkin lymphoma is the seventh most common cancer, yet the majority of people who are diagnosed have very little information on the disease and how it may impact their
lives,” said David Henry, MD, clinical professor of medicine at Pennsylvania Hospital and the physician advisor for Framing Life With Lymphoma. The program contains simple tip sheets outlining ways to approach each conversation the patient is likely to encounter from diagnosis through treatment. The information was created through input from an expert steering committee and a national survey of 150 hematologists/ oncologists and 133 patients with indolent lymphoma. The survey found that 96% of physicians and 86% of patients felt their communication could be made more efficient with informational aids. The survey also revealed that about two in
five patients do not ask all their intended questions during visits, usually because they don’t remember. “This survey shows that it is critical that patients have resources to help them understand their condition and treatment options. This helps them communicate more effectively with their physicians,” Henry said. “In addition to providing information, physicians need to work with their patients to create a team-based approach to treatment,” he added. “Working as a team creates an environment where informed patients are more comfortable addressing their concerns and questions, and this can have a positive impact on their overall
treatment experience.” Kim Thiboldeaux, president and CEO of the Cancer Support Community, also applauded the program.“We hope Framing Life With Lymphoma will become an important resource for the lymphoma community,” she said. “A clear majority of patients and physicians reported that discussion materials would improve their conversations. That is what this program aims to do.” The patient tip sheets for newly diagnosed patients and those undergoing treatment, along with the survey results and other program information, can be downloaded at www.Framing LifeWithLymphoma.org. ●
Reports from the European Society of Cardiology Congress and the Joint Annual Meeting of the International Continence Society and International Urogynecological Association By Jill Stein
Western Lifestyle Responsible for UK Breast Cancer Surge LONDON—A Western lifestyle characterized by an excess of food and alcohol and a lack of exercise may explain increasing breast cancer rates in the United Kingdom, new data suggest. Findings from the World Cancer Research Fund (WCRF) show that the breast cancer rate in the United Kingdom is more than four times higher than in eastern Africa, which has the lowest breast cancer rate worldwide. The organization recently reported that 87.9 women per 100,000 in the United Kingdom were diagnosed with breast cancer in 2008 versus only 19.3 women per 100,000 women in eastern Africa, which includes Kenya and Tanzania. Cancer experts have suggested that the growing gap in breast cancer rates between rich and poor countries may be partly a function of better surveillance and diagnosis in wealthier countries. They also emphasize, however, that lifestyle is an important contributor. In fact, it is estimated that 40% of breast cancer cases in the United Kingdom, or more than 18,000 cases per year, could be avoided if women adopted a healthier lifestyle involving a better diet, more exercise, and less alcohol. Women in eastern Africa consume less alcohol than UK women and are less likely to be obese. They are also more
OctOber 2010 I VOL 3, NO 7
likely to breastfeed, and breastfeeding has been associated with a lower rate of breast cancer. Rachel Thompson, MD, with the WCRF, said that breast cancer is not the only cancer for which lifestyle may be a contributor. In fact, roughly a third of the most common cancers in the United Kingdom could be prevented by lifestyle changes, she noted.
No Evidence that Statins Cause Cancer STOCKHOLM—Statins do not increase the risk of cancer, according to the results of a large meta-analysis released at the European Society of Cardiology Congress 2010. Researchers from the University of Oxford, United Kingdom, and the University of Sydney, Australia, said in a news release that their results will “reassure the millions of people worldwide who are taking statins to lower cholesterol levels and clarify earlier research that had raised concerns of a causal link.” The data are from the Cholesterol Treatment Trialists’ Collaboration, which reviewed data from 170,000 patients enrolled in 26 trials. Overall, 10,000 patients developed cancer and more than 3500 died of cancer. “Statin therapy had no adverse effect on cancer at any site or in any group of individuals, irrespective of their cholesterol levels,” said principal investigator
Statin therapy had no adverse effect on cancer at any site or in any group of individuals, irrespective of their cholesterol levels. Jonathan Emberson, MD, of the University of Oxford. “There was also no association of cancer with statin dose or duration.” The study was funded by the UK Medical Research Council, the British Heart Foundation, and the National Health and Medical Research Council (Australia).
Overactive Bladder without Hematuria May Be Cancer Symptom TORONTO—Overactive bladder (OAB) symptoms without hematuria may be a presenting symptom of bladder cancer, researchers reported at the joint annual meeting of the International Continence Society and International Urogynecological Association. Most patients with bladder cancer present with hematuria. Jeffrey Weiss, MD, of State University of New York Downstate College of Medicine in Brooklyn, and colleagues searched a database for the years 1998 through 2008 to identify patients without hematuria who underwent cystoscopy as part of an evalua-
tion for refractory OAB. Overall, 1420 patients underwent cystoscopy, and eight were found to have bladder cancer. The mean duration of OAB symptoms was 3.3 years. In all cases, the initial biopsy in patients with bladder cancer demonstrated low-grade Ta transitional carcinoma that, in most cases, resembled a typical papillary transitional cell tumor on cystoscopy. At a mean follow-up of 5.2 years, four (50%) patients had experienced one or two recurrences and two had disease progression—in one case to carcinoma in situ and in the other case to high-grade T3 disease. The study also found that bladder cancer was 10 times more common in women with OAB than men with OAB despite the fact that it is two to three times more common in men than in women in the general population. Because OAB symptoms without hematuria may be an initial symptom of bladder cancer, patients with OAB symptoms even without hematuria should be advised to undergo cystoscopy to rule out underlying bladder cancer, the authors said. ●
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High Responses in Melanoma for Wool Dye/Ocular Stain Rose Bengal By Walter Alexander
ositive findings in treatment of metastatic melanoma were among the highlights of June’s 2010 annual meeting of the American Society of Clinical Oncology (ASCO). For ipilimumab, there was the remarkable achievement of being the first to show a survival advantage in a randomized clinical trial. But whereas ipilimumab is an investigational human monoclonal antibody and a product of the most sophisticated of modern medical technologies, the agent in the second successful metastatic melanoma trial, Rose Bengal, has a more humble pedigree. The clinical trial of Rose Bengal injections (PV-10, a 10% Rose Bengal solution) revealed a 79% response rate in metastatic melanoma patients, and showed responses in “bystander” lesions that were not injected, suggesting a systemic immune response, according to Sanjiv Agarwala, MD, who is section chief of oncology and hematology at St. Luke’s Cancer Center in Bethlehem, Pennsylvania. But for the story of how Rose Bengal evolved in stages over more than 130 years from its original application as a coal tar–derived wool dye, Eric Wachter, PhD, Provectus cofounder and
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senior vice president, provided a history in an interview at ASCO. History of Rose Bengal In 1882, German patent No. 32584 was granted to Ghnem for a new family of wool dyes. Ghnem took different halogens and added them to fluorescein to produce molecules with different colors. The name, Rose Bengal, arose presumably from the fact that the deep rosy red color was similar to that of the middle-of-the-forehead dot indicating marriage in women of the Bengali region of India. In Chemistry of the Organic Dyestuffs (Nietzki R. London, UK: Gurney & Jackson; 1892), the principal constituents of Rose Bengal were identified as iodine derivatives of di- and tetrachlorofluorescein, with those prepared from tetrachlorophthalic acid being the bluest. The original Rose Bengal version combined two iodines, and subsequent modifications through the 1920s adding two more iodines led to the current form. It was its color-imparting properties, however, that led to Rose Bengal’s predominant medical use; in 1914 Römer, Cobb, and Lohlein reported on its role
in combating ocular pneumococcal infections when added to Safranin Victoria Yellow. Kleefeld’s discovery, in 1919, that Rose Bengal was an effective stain for visualizing corneal ulcers opened the door to its widespread use as an ocular biological staining agent. As Rosettes and Minims, that use continues today, based on separate improvements over many decades by Sjögren, Norn, and Marsh. A parallel development of Rose Bengal as an intravenous marker for impaired liver function began in the 1920s through the work of Delprat. In the 1950s, Taplin devised a more sensitive radioisotope labeling with 131I RB Diagnostic. By the late 1980s, radiolabeling had been eclipsed and replaced as the preferred diagnostic strategy when direct visualization of the liver was afforded by magnetic resonance imaging and computed tomography scanning. None of this, of course, suggests antineoplastic efficacy. The application of Rose Bengal as a cancer treatment came about indirectly. Wachter and colleagues, all of whom had met working at Oak Ridge National Laboratory, were looking at photodynamic therapy, a process in which agents become cytotoxic when exposed to light (usually from lasers), and in the late 1990s while looking for a candidate agent with antineoplastic activity, they hired a commercial data search service that identified several hundred potential substances. Through their own internal screening process they narrowed the candidates to only those agents with powerful effects, and among these was Rose Bengal. At the same time that the Provectus preclinical tests were showing Rose Bengal to be worthy of deeper study, the researchers stumbled on a three-line sentence in a 1986 journal article (Ito A, et al. J Natl Cancer Inst. 1986;77: 277-281) on a study that was, in essence, a failed attempt to show cancer-stimulating properties in Rose Bengal, which was then used in Japan as a food-coloring agent (Red Food No. 105). The Japanese researchers noted no tumorigenicity for Rose Bengal in a strain of particularly tumor-prone mice, but offhandedly mentioned without comment that the higher the concentration of the Rose Bengal solution, the lower the tumor rate. This further fired the Provectus Rose Bengal investigations and the next test, for Wachter, was giving up on the photodynamic treatment aspect. “I was a laser expert, and I was very psyched
about finding this perfect molecule to go with our exciting laser techniques.” His cofounders, Craig Dees (a molecular virologist) and Tim Scott (a chemical engineer), were worried that the laser/photodynamic technology was too sophisticated for routine use in the clinic, and that severe phototoxicity, requiring patients to stay not only out of direct sunlight but also away from intense indoor lighting for up to several weeks, would hamper wide acceptance. Dees and Scott, after a few months of modifications and testing, presented Wachter with incontrovertible proof that the laser/photodynamic aspect was unnecessary to the dramatic anticancer effect of Rose Bengal, now in its PV-10 form. Subsequent animal and human studies confirmed that agent’s potency and selectivity for ablating cancers. Rose Bengal for melanoma The phase 2 trial presented at ASCO enrolled 80 patients with measurable stage III-IV melanoma, all of whom received initial treatment with PV-10 in up to 20 cutaneous, subcutaneous, or nodal lesions. Investigators were allowed to leave one or two lesions untreated. The primary end point was response rate of injected lesions. Agarwala reported that among the first 40 subjects to complete the study, 33% achieved complete remission, 28% partial remission, and 20% stable disease in their target lesions. Also, 33% of 21 subjects with evaluable bystander lesions achieved complete remission of these lesions, along with 10% achieving partial remission, and 14% achieving stable disease. Mean progression-free survival for all subjects was 8.5 months. Patients with complete remissions achieved significantly longer progression-free survival (11.1 months) than those with stable disease or progressive disease (2.8 and 2.7 months, respectively). No grade 4 or 5 adverse events were attributed to PV-10, and overall, adverse events were predominantly mild to moderate. Agarwala concluded that, “The safety and efficacy profile of PV-10 compares favorably with available and emerging options for this patient population.” Beyond melanoma, PV-10 is currently being evaluated in treatment of primary and metastatic tumors of the liver. Ultimately, systemic administration of PV-10 may be explored for certain indications, Wachter said. ●
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Single-dose IV Regimen Comparable with 3-Day Regimen for Prevention of CINV By John Schieszer
CHICAGO—Findings of a new study suggest that an antiemetic regimen containing a single intravenous (IV) 150mg dose of fosaprepitant dimeglumine in combination with a 5-hydroxytryptamine type 3 (5-HT3) antagonist and dexamethasone appears to be comparable with a 3-day regimen of aprepitant with a 5-HT3 antagonist and dexamethasone for the prevention of chemotherapy-induced nausea and vomiting (CINV). The findings from the Evaluation of Fosaprepitant in Single-dose Schedule (EASE)-017 study, which were presented at the 46th annual meeting of the American Society of Clinical Oncology, showed that the regimen containing 150-mg fosaprepitant dimeglumine was not inferior to the regimen with oral aprepitant. “The results of this study demonstrate that an antiemetic regimen with a single, 150-mg injection of fosaprepitant provides similar protection against CINV as a 3-day regimen of oral aprepitant, which has become part of the standard of care for patients receiving highly emetogenic chemotherapy,” said lead study investigator Steven Grunberg, MD, a professor of
medicine and pharmacology at the University of Vermont, Burlington. “These findings are important because prevention of CINV is a major concern, and this formulation of aprepitant could potentially provide dosing flexibility to prevent CINV.” Currently, aprepitant is approved as a part of a 3-day regimen for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic and highly emetogenic cancer chemotherapy, including high-dose cisplatin. In this phase 3, randomized, double-blind, parallel-group, noninferiority study, researchers studied 2322 patients, all of whom were naïve to cisplatin therapy and were scheduled to receive cisplatin-based chemotherapy at a dose of 70 mg/m2 or higher. Of the patients randomized, 2247 patients were included in the analysis. The study’s primary end point was the proportion of patients who reported no vomiting and no use of rescue therapy (complete response) in the overall phase (0-120 hours after initiation of cisplatin-based chemotherapy). The secondary end point was the proportion of patients who reported a complete response (no vomiting and no
use of rescue therapy) in the delayed phase (25-120 hours after initiation of cisplatin-based chemotherapy). The investigators found that 71.9% of patients who received an antiemetic regimen that included a single, 150-mg dose of fosaprepitant plus ondansetron 32 mg IV and dexamethasone 12 mg orally on day 1, and dexamethasone 8 mg orally on day 2, and dexamethasone 8 mg orally twice daily on days 3 and 4 achieved a complete response in the overall phase of chemotherapy (0120 hours after initiation of cisplatin chemotherapy). That was comparable with the 72.3% of those receiving an antiemetic regimen containing a 3-day oral regimen of fosaprepitant (fosaprepitant 125 mg orally, ondansetron 32 mg IV, and dexamethasone 12 mg orally on day 1, fosaprepitant 80 mg orally once daily on days 2 and 3, and dexamethasone 8 mg orally once daily on days 2 through 4). In addition, 74.3% of patients treated with the regimen containing the single, 150-mg dose of fosaprepitant achieved a complete response in the delayed phase (25-120 hours after cisplatin-based chemotherapy), compared with 74.2% of patients treated
with a regimen containing a 3-day dose of fosaprepitant. The overall incidence and types of adverse events were generally consistent between the two treatment groups. The most frequently reported drug-related clinical adverse events in both the group receiving a single, 150mg dose of fosaprepitant and the group receiving oral aprepitant were asthenia, constipation, anorexia, diarrhea, and nausea. “With the intravenous treatment, there was some venous irritation, but the numbers were very small,” said Grunberg in an interview with The Oncology Pharmacist. “In terms of efficacy, there is equivalence. With the single dose, it is going to add convenience because the patients won’t have to take the pills at home. A lot of policies require preauthorization and, if there is just one single IV, there are no pills going home so there is no authorization and so it is a benefit to the patient. There is also benefit for the office because they are sure the patient is compliant and they don’t have to deal with getting preauthorization for getting a tripack. So, there are economic, social, and medical advantages with this single dose.” ●
Palonosetron Demonstrates Benefits over Other 5-HT3 Receptor Antagonists in Lung Cancer Patients By Caroline Helwick
CHICAGO—Among patients with lung cancer on highly emetogenic chemotherapy, those receiving palonosetron throughout all cycles of chemotherapy had a 31% lower risk of chemotherapy-induced nausea and vomiting (CINV) associated with an emergency department or hospital visit, than patients receiving other 5hydroxy tryptamine type 3 (5-HT3) re ceptor antagonists (RAs). The study was presented by Hind T. Hatoum, PhD, of the Center of Pharmacoeconomic Research at the University of Illinois at Chicago during the 46th annual meeting of the American Society of Clinical Oncology. The study compared the risk of serious CINV among 1692 lung cancer patients initiated on cisplatin-based chemotherapy who were started and maintained on a 5-HT3–based prophylactic strategy, including palonosetron, dolasetron,
OcTOber 2010 I VOL 3, NO 7
granisetron, or ondansetron. Patients were identified from claims data (PharMetrics) between 2005 and 2008 and stratified into one of two groups: palonosetron throughout all cycles of chemotherapy (n = 390) and any other 5-HT3–based regimen (n = 1302). CINV events were identified from emergency department and hospital claims with codes of nausea, vomiting, and/or dehydration. The two groups were compared for the risk of CINV, controlling for age, sex, comorbidity, and chemotherapy treatment days. The two treatment groups had comparable comorbidities, with no significant differences in the Charlson Comorbidity Index. The most widely represented chemotherapy regimens were cisplatin/etoposide (25%), cisplatin alone (7%), and cisplatin/docetaxel/etoposide (6%). In what Hatoum called a “real-
world practice,” the average patient receiving palonosetron had significantly fewer claims of both 5-HT3 RAs and all antiemetics, as compared with patients receiving all other 5-HT3 RAs: 6.4 versus 12.4 for other 5-HT3 RA claims (P <.0001), and 8.5 versus 14.7 in all antiemetic claims (P <.0001). This represents 42% fewer antiemetic claims and 58% fewer 5-HT3 RA claims for palonosetron compared with patients who received other agents, Hatoum noted. With palonosetron, fewer patients experienced CINV events leading to emergency department or hospital visits: 16.4% versus 22.6% (P <.01) in the unadjusted analysis, which remained a significant 31% reduction (P <.05) in the adjusted analysis. Palonosetron-treated patients also had, on average, significantly fewer cis-
platin treatment days: 4.9 versus 5.7 days (P <.0001). “We cannot ascertain with 100% certainty what this means, but we suspect these patients were able to have the dose pushed higher because they had less nausea and vomiting. They did not have to delay treatment; and therefore, there were fewer treatment days,” Hatoum suggested. In addition, 51.0% of patients used palonosetron without combining it with the neurokinin-1 (NK1) antagonist aprepitant and/or dexamethasone, compared with 45.6% of the alternate group. Palonosetron, in contrast to other 5-HT3 RAs, differentially inhibits “crosstalk” between NK1 receptors and 5-HT3 signaling pathways, and exhibits prolonged inhibition of receptor function, Hatoum explained, suggesting that “it may have properties such that you don’t need the NK1 antagonist.” ●
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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
TOP_October 2010_v6_TOP 10/15/10 2:55 PM Page 40
A Friday Satellite Symposium preceding the 52nd ASH Annual Meeting
Challenging Cases in Multiple Myeloma A Dialogue Between Community and Academic Clinicians to Improve Patient Care and Outcomes December 3, 2010 Rosen Centre Hotel Ballrooms A & B, Orlando, Florida
Register online today at www.myelomacases.com/register PROGRAM DESCRIPTION
This continuing medical education symposium will serve as a forum for discussion of current questions and concerns regarding the treatment and management of patients through the multiple myeloma (MM) life cycle. A panel of domestic and international myeloma experts will be joined by representatives from community cancer care facilities and private oncology practices. By thoroughly engaging participants with interactive cases and physician point-counterpoint-style discussions, this symposium will provide evidence-based treatment and management recommendations and address new treatment regimens and management strategies based on recent clinical trials and emerging data. In addition to considering differences in domestic and international care, barriers and/or limitations faced by community cancer centers and private-practice oncologists will be debated.
Registration and Lunch Service
Welcome and Introduction Sundar Jagannath, MD - Chair
CASE PRESENTATIONS Each case will be presented by an expert faculty member and discussed by the international and community panel. 1:10 – 1:40 PM
Case 1: Difficult diagnosis G. David Roodman, MD, PhD
1:40 – 2:10 PM
Case 2: Newly diagnosed, stem cell transplant eligible patient Sundar Jagannath, MD
2:10 – 2:40 PM
Case 3: First-line therapy in a non-SCT eligible patient Stefan Knop, MD
2:40 – 3:10 PM
Case 4: Multiple risk factors Jonathan L. Kaufman, MD
3:10 – 3:40 PM
Case 5: Treatment of MM across the life cycle Noopur Raje, MD
Question & Answer Session
Closing Remarks Sundar Jagannath, MD
LEARNING OBJECTIVES At the end of this activity participants will be able to: • Apply early management strategies that consider new diagnostic and staging criteria for SMM, MGUS, and MM and new imaging studies in order to improve prognosis for your patients. • Evaluate novel therapeutic regimens as induction therapy for your patients considering an SCT in order to provide the most rapid response and allow the largest amount of stem cell collection, while maintaining safety and tolerance. • Integrate novel agent-based regimens that provide optimal outcomes and a survival benefit into your management strategy for patients ineligible for SCT after appraising emerging data from clinical trials. • Identify patient- and disease-associated factors that impact choice of therapeutic agent and formulate management strategies using a risk-adapted approach to treatment of MM. • Construct optimal treatment regimens based on novel combinations and make informed treatment decisions in order to improve the long-term outlook for myeloma patients across the life cycle of the disease.
TARGET AUDIENCE This activity has been developed for hematologists and medical oncologists, as well as nurses, pharmacists, and other allied health professionals who are interested in meeting the challenges faced when treating patients with multiple myeloma in academic and community settings.
ACCREDITATION INFORMATION Physician Accreditation The University of Cincinnati designates this activity for a maximum of 3 AMA PRA Category 1 Credits ™. The University of Cincinnati is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity. Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 3.0 contact hours. Registered Pharmacy Designation Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 3.0 contact hours (0.3 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-10-058-L01-P.
FACULTY CHAIR: Sundar Jagannath, MD Professor, Hematology and Medical Oncology Mount Sinai School of Medicine’s Tisch Cancer Institute Director of the Multiple Myeloma Program, The Mount Sinai Medical Center New York, NY Leon Dragon, MD, FACP Medical Director Kellogg Cancer Center Northshore University HealthSystem Highland Park, IL Charles M. Farber, MD, PhD Section Chief of Hematology and Oncology Department of Medicine Carol G. Simon Cancer Center, Morristown, NJ Shoba Kankipati, MD Associate Physician EPIC Care East Bay Partners in Cancer Care San Francisco Bay Area, CA Jonathan L. Kaufman, MD Assistant Professor Blood and Marrow Transplantation Department of Hematology and Medical Oncology Emory University School of Medicine Member, Winship Cancer Institute Emory University, Atlanta, GA
ACKNOWLEDGMENT This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.
This activity is jointly sponsored by the University of Cincinnati, Medical Learning Institute, Inc., a nonprofit medical accreditation company, and Center of Excellence Media, LLC.
Stefan Knop, MD University Hospital Würzburg Würzburg, Germany Noopur Raje, MD Associate Professor of Medicine Harvard Medical School Director, Center for Multiple Myeloma Massachusetts General Hospital Boston, MA G. David Roodman, MD, PhD Professor of Medicine Vice Chair for Research Department of Medicine Director, Myeloma Program Director, Bone Biology Center University of Pittsburgh Medical Center Pittsburgh, PA Ari Umutyan, MD Redwood Regional Medical Group Hematology and Medical Oncology Napa, CA
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Meetings MARCH 2011
NEW YORK, NY Chemotherapy Foundation Symposium www.chemotherapyfoundationsympo sium.org
4-7 ORLANDO, FL American Society of Hematology Annual Meeting www.hematology.org
ANAHEIM, CA American Society of Health-System Pharmacists Midyear Clinical Meeting www.ashp.org
SAN ANTONIO, TX San Antonio Breast Cancer Symposium www.sabcs.org
20-22 SAN FRANCISCO, CA Gastrointestinal Cancers Symposium www.gicasymposium.org
ORLANDO, FL Genitourinary Cancers Symposium www.gucasymposium.org
HOLLYWOOD, FL National Comprehensive Cancer Network Annual Congress www.nccn.org
SALT LAKE CITY, UT Hematology/Oncology Pharmacy Association 7th Annual Conference www.hoparx.org
WASHINGTON, DC Association of Community Cancer Centers Annual National Meeting www.accc-cancer.org
RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), patients who develop cytopenias. [See Adverse Reactions]. s The duration of cytopenias SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL caused by Rituxan can extend months beyond the treatment period. ADVERSE LEUKOENCEPHALOPATHY (PML) REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) Infusion Reactions: Rituxan administration can result in serious, including observed in clinical trials of patients with NHL were infusion reactions, fever, fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have lymphopenia, chills, infection, and asthenia. The most common adverse reactions of occurred. Approximately 80% of fatal infusion reactions occurred in Rituxan (incidence ≥25%) observed in clinical trials of patients with CLL were: infusion association with the first infusion. Carefully monitor patients during reactions and neutropenia. Clinical Trials Experience in Lymphoid Malignancies infusions. Discontinue Rituxan infusion and provide medical treatment for Because clinical trials are conducted under widely varying conditions, adverse reaction Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse rates observed in the clinical trials of a drug cannot be directly compared to rates in the Reactions]. s Tumor Lysis Syndrome (TLS): Acute renal failure requiring clinical trials of another drug and may not reflect the rates observed in practice. The data dialysis with instances of fatal outcome can occur in the setting of TLS described below reflect exposure to Rituxan in 2282 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan active-controlled trials (n = 356 and n = 1926). The population included 679 patients [see Warnings and Precautions, Adverse Reactions]. s Severe Mucocutaneous with low-grade follicular lymphoma, 927 patients with DLBCL, and 676 patients with Reactions: Severe, including fatal, mucocutaneous reactions can occur in CLL. Most NHL patients received Rituxan as infusion of 375 mg/m2 per infusion, given as patients receiving Rituxan [see Warnings and Precautions, Adverse a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 Reactions]. s Progressive Multifocal Leukoencephalopathy (PML): JC virus doses, or following chemotherapy for up to 16 doses. CLL patients received Rituxan 375 infection resulting in PML and death can occur in patients receiving Rituxan mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with [see Warnings and Precautions, Adverse Reactions]. s fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. Infusion INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is Reactionss In the majority of patients with NHL, infusion reactions consisting of fever, indicated for the treatment of patients with: Relapsed or refractory, low-grade or chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after beginning the first infusion and resolved with slowing or interruption of the Rituxan first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. saline). The incidence of infusion reactions was highest during the first infusion (77%) Chronic Lymphocytic Leukemia (CLL) Rituxan® (rituximab) is indicated, in and decreased with each subsequent infusion. [See Boxed Warning, Warnings and combination with fludarabine and cyclophosphamide (FC), for the treatment of patients Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, with previously untreated and previously treated CD20-positive CLL. Limitations of use occurred in less than 5% of patients with NHL in the single-arm studies. The overall Rituxan is not recommended for use in patients with severe, active infections. incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan including fatal, infusion reactions. Severe reactions typically occurred during the first was administered following chemotherapy for the treatment of follicular or low-grade infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and NHL, the rate of infection was higher among patients who received Rituxan. In diffuse sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, large B-cell lymphoma patients, viral infections occurred more frequently in those who pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, received Rituxan. Cytopenias and hypogammaglobulinemiaa In patients with NHL ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in patients with an antihistamine and acetaminophen prior to dosing. Institute medical 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia reactions as needed. Depending on the severity of the infusion reaction and the required was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). interventions, temporarily or permanently discontinue Rituxan. Resume infusion at a A single occurrence of transient aplastic anemia (pure red cell aplasia) and two minimum 50% reduction in rate after symptoms have resolved. Closely monitor the occurrences of hemolytic anemia following Rituxan therapy occurred during the singlefollowing patients: those with pre-existing cardiac or pulmonary conditions, those who arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in experienced prior cardiopulmonary adverse reactions, and those with high numbers of 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and of these patients. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1 Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Acute renal failure, occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. [See some fatal, can occur within 12–24 hours after the first infusion of Rituxan in patients Clinical Studies.] Most patients received Rituxan 375 mg/m2 weekly for 4 doses. with NHL. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden Table 1 confers a greater risk of TLS. Administer aggressive intravenous hydration and anti- Incidence of Adverse Reactions in ≥5% of Patients with Relapsed or Refractory, Lowhyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b monitor renal function and fluid balance, and administer supportive care, including dialysis as All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous Any Adverse Events 99 57 Respiratory p y System y 38 4 reactions, some with fatal outcome, can occur in patients treated with Rituxan. These Bodyy as a Whole 86 10 Increased Cough 13 1 Fever 53 1 Rhinitis 12 1 reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid Chills 33 3 Bronchospasm 8 1 dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these Infection 31 4 Dyspnea 7 1 Asthenia 26 1 Sinusitis 6 0 reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan Headache 19 1 Metabolic and Nutritional in patients who experience a severe mucocutaneous reaction. The safety of Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 readministration of Rituxan to patients with severe mucocutaneous reactions has not Back Pain 10 1 Hyperglycemia 9 1 been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Throat Irritation 9 0 Peripheral Edema 8 0 5 0 LDH Increase 7 0 Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur HemeFlushing and Lymphatic y p System y 67 48 Digestive g System y 37 2 in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. Lymphopenia 48 40 Nausea 23 1 Leukopenia 14 4 Diarrhea 10 1 The majority of patients with hematologic malignancies diagnosed with PML received Neutropenia 14 6 Vomiting 10 1 Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell Thrombocytopenia 12 2 Nervous System y 32 1 Anemia 8 3 Dizziness 10 1 transplant. The patients with autoimmune diseases had prior or concurrent Skin and Appendages Anxiety 5 1 pp g 44 2 immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of Night Sweats 15 1 Musculoskeletal System y 26 3 Rash 15 1 Myalgia 10 1 their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting Arthralgia Pruritus 14 1 10 1 with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited Urticaria 8 1 Cardiovascular System y 25 3 Hypotension 10 1 to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituxan Hypertension 6 1 and consider discontinuation or reduction of any concomitant chemotherapy or a b immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Adverse reactions observed up to 12 months following Rituxan. Adverse reactions graded for severity Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation by NCI-CTC criteria. with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and up to malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was 6 months after Rituxan infusion. Previously Untreated Low-Grade NHL In Study 4, approximately 4 months after the initiation of Rituxan and approximately one month after patients in the R-CVP arm experienced a higher incidence of infusional toxicity and the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. neutropenia compared to patients in the CVP arm. The following adverse reactions Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: infection for several months following Rituxan therapy. Discontinue Rituxan and any rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), concomitant chemotherapy in patients who develop viral hepatitis, and institute pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In appropriate treatment including antiviral therapy. Insufficient data exist regarding the Study 5, the following adverse reactions were reported more frequently (≥5%) in safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV patients receiving Rituxan following CVP compared to patients who received no further reactivation. [See Adverse Reactions.] Infections Serious, including fatal, bacterial, therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory fungal, and new or reactivated viral infections can occur during and up to one year neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. following the completion of Rituxan-based therapy. New or reactivated viral infections 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only West Nile virus, and hepatitis B and C. Discontinue Rituxan for serious infections and Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm institute appropriate anti-infective therapy. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform compared with those who received no further therapy (4% vs. 1%). [See Clinical Studies.] DLBCLL In Studies 6 and 7, [see Clinical Studies] s the following adverse reactions, cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. [See regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder administration in patients with NHL. Renal toxicity has occurred in patients who (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed experience tumor lysis syndrome and in patients with NHL administered concomitant safety data collection in these studies was primarily limited to Grade 3 and 4 adverse cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity approved treatment regimen. Monitor closely for signs of renal failure and discontinue determined that supraventricular arrhythmias or tachycardia accounted for most of Rituxan in patients with a rising serum creatinine or oliguria. Bowel Obstruction and the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading following Grade 3 or 4 adverse reactions occurred more frequently among patients in to death, can occur in patients receiving Rituxan in combination with chemotherapy. In the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. postmarketing reports, the mean time to documented gastrointestinal perforation was 6 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and more frequently among patients receiving R-CHOP were viral infection (Study 7), institute appropriate treatment for complaints of abdominal pain. [See Adverse neutropenia (Studies 7 and 8), and anemia (Study 8). CLLL The data below reflect Reactions.] Immunization The safety of immunization with live viral vaccines following exposure to Rituxan in combination with fludarabine and cyclophosphamide in 676 s The age range was Rituxan therapy has not been studied and vaccination with live virus vaccines is not patients with CLL in Study 9 or Study 10 [see Clinical Studies]. recommended. Laboratory Monitoring In patients with lymphoid malignancies, during 30–83 years and 71% were men. Detailed safety data collection in Study 9 was limited treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related
adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. In Study 9, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 10, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC–treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. <1%). Fifty-nine percent of R-FC–treated patients experienced an infusion reaction of any severity. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human antichimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in Rituxan-treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during post-approval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/ Autoimmune Events:: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. In patients with CLL, Rituxan did not alter systemic exposure to fludarabine or cyclophosphamide. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breast-feeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHLL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituxan-treated patients (36%) were 65 years of age or older; of these, 100 Rituxan-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 9 or in Study 10; there was also no observed benefit from the addition of Rituxan to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 10 [see Clinical Studies]. s Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of Rituxan. In Study 9, the dose intensity of Rituxan was similar in older and younger patients, however in Study 10 older patients received a lower dose intensity of Rituxan. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 9); 56% vs. 39% (Study 10)], febrile neutropenia [16% vs. 6% (Study 9)], anemia [5% vs. 2% (Study 9); 21% vs. 10% (Study 10)], thrombocytopenia [19% vs. 8% (Study 10)], pancytopenia [7% vs. 2% (Study 9); 7% vs. 2% (Study 10)] and infections [30% vs. 14% (Study 10)]. OVERDOSAGE There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituxan or to determine potential effects on fertility in males or females. PATIENT COUNSELING INFORMATION Patients should be provided the Rituxan Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient’s overall health be assessed at each visit and the risks of Rituxan therapy and any questions resulting from the patient’s reading of the Medication Guide be discussed. Rituxan is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituxan therapy. Revised 02/2010 (4851501) Jointly Marketed by: Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 ©2010 Biogen Idec Inc. and Genentech, Inc. 7140919 February 2010
OctOber 2010 I VOL 3, NO 7
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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.