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VOL 4, NO 7
CANCER CENTER PROFILE
Hallmark Health Hematology and Oncology Center Face-to-Face Communication with Oncology Pharmacists
Oral Chemotherapeutic Agents in Patients with Renal Dysfunction By Melinda Tran, PharmD; Emily Mackler, PharmD, BCOP Department of Pharmacy, University of Michigan Health System, Ann Arbor
By Dawn Lagrosa
ral chemotherapeutic agents have transformed the management of cancer treatment— transitioning the primary location of care to the ambulatory setting and pro-
viding patients with a convenient, noninvasive option to manage their malignancy. Despite the growing availability of oral chemotherapeutic agents, data describing the management of these Continued on page 28
Bevacizumab in Metastatic Breast Cancer: Is This the End of the Line? From left: Oncology Pharmacy Coordinator Meredith Harper, PharmD, BCPS; Oncology Pharmacy Technician Tina Motta, CPhT; System Director of Pharmacy Services Michelle Corrado, PharmD; and Oncology Staff Pharmacist Jon Jankun, RPh.
ffering medical, surgical, and radiation oncology, the Hallmark Health Hematology and Oncology Center provides local access to personalized, comprehensive, high-quality cancer care. Located in Stoneham, Massachusetts, about 7 miles north of Boston, the center is part of Hallmark Health System, which also includes 2 community hospitals, Lawrence Memorial Hospital of Medford and Melrose-Wakefield Hospital.
Continued on page 26
By Joanna Schwartz, PharmD, BCOP Assistant Professor, Albany College of Pharmacy and Health Science Colchester, Vermont Maggie Charpentier, PharmD, BCPS Clinical Associate Professor, College of Pharmacy University of Rhode Island, Kingston
evacizumab (Avastin; Genentech) for metastatic breast cancer may be one of the most widely debated, media-reported, and editorialized agents in oncology. This is certainly understand-
able in an era when targeted therapy such as bevacizumab, a monoclonal antibody against the vascular endothelial growth factor, holds high expectations to provide a much-needed treatment option for Continued on page 14
CONFERENCE NEWS: AACR
Genetic Differences Linked to Higher Risk, Severity of Prostate Cancer in African-American Men Understanding Molecular Mechanisms Underlying Disparities May Lead to Strategies for Personalized Treatment
Update on Non-Hodgkin Lymphoma: Alignment of the Current Treatment Landscape and Value-Based Care ConferenCe news
By John Schieszer
WASHINGTON, DC—Genetic differences among African-American and white men seem to be root causes of the prostate cancer disparities between the 2 groups, according to new data. Prostate cancer is the second most
common cancer among men in the United States, with occurrences and mortality rates higher in AfricanAmerican men compared with white men. Studies show that prostate cancer
American Association for Cancer Research . . . . . . . . . . . . . . . . 9 American Society of Clinical Oncology Breast Cancer Symposium . . . . . . . . . . . . . . . . . . . . . 13
Continued on page 10
©2011 Green Hill Healthcare Communications, LLC
reader survey results
Do people receiving treatment talk to you about the cost of their oncology drugs?
Ne Featuw re
Shooting from the Hip
Will Anybody Be Making Cancer Drugs in the Future? Page 34
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A S T HE C OMP L E X I T Y O F H E ALT H C AR E EV OLV ES , HOS PIR A G E M C I TAB I N E I N J E C T I O N D ELIV ER S ON E S O L UT I O N F O R AL L .
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200 mg/5.26 mL single-dose vial
U N IQU E O NCO - TA IN S A F ET Y F EAT U R ES
FOR PHARMACISTS—SAME CONCENTRATION WITH MORE EFFICIENCY
PVC BOTTOM offers shatter resistance.
SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.
GLASS CLARITY allows for easy inspection of the vial as a final safety check before administration.
PREWASHED VIALS reduce cytotoxic residue.
FOR PATIENTS—A HIGH-QUALITY MEDICATION AT A LOWER COST FOR CLINICIANS—UNIQUE ONCO-TAIN™ VIALS REINFORCE SAFETY 1
For reimbursement support, contact the Hospira Reimbursement Support Line at 1-800-340-8667. Contact your representative today to learn more or to place an order at e.hospira.com. Please refer to boxed warning below and see Brief Prescribing Information on back page. Warnings and Precautions Patients receiving therapy with Gemcitabine Injection should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Reference: 1. Data on file. Hospira, Inc. Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045
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BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Gemcitabine Injection safely and eﬀectively. See full prescribing information for Gemcitabine Injection.
Gemcitabine Injection For Intravenous Infusion Only. Must Be Diluted Before Use. Initial U.S. Approval: 1996 CONTRAINDICATIONS Patients with a known hypersensitivity to gemcitabine (4) WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1) • Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7) • Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3) • Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4) • Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1) • Radiation toxicity. May cause severe and life-threatening toxicity. (5.8) ADVERSE REACTIONS The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at ProductComplaintsPP@hospira.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USPSTF Updates Prostate Cancer Screening and Treatment Guidelines Prostate-specific antigen (PSA)-based screening has not been shown to reduce prostate cancer–specific mortality, but is associated with harms related to subsequent evaluation and treatments, some of which may be unnecessary, according to a new analysis of the evidence by the US Preventive Services Task Force (USPSTF) published online in the Annals of Internal Medicine. The new guidelines will downgrade PSA screening from “I—inconclusive” to “D—no benefit” for men younger than 75, basically stating that younger, healthy men should not undergo this testing. The Prostate Cancer Foundation and the American Cancer Society continue to support better communication and processes of informed patient decision-making prior to, and after, PSA screening in healthy men.
Everolimus and Exemestane Combination Prolonged PFS for Advanced Postmenopausal Breast Cancer Patients For women with advanced breast cancer resistant to hormonal therapy, combining everolimus and exemestane improves progression-free survival (PFS) by nearly 7 months compared with exemestane alone, according to phase 3 trial results reported at the European Multidisciplinary Cancer Conference. The Breast Cancer Trials of Oral Everolimus (BOLERO) randomized 724 patients in 24 countries who had been treated previously with letrozole or anastrozole. Previous therapy also included tamoxifen, fulvestrant, and chemotherapy. The trial was stopped early when interim analysis revealed that patients receiving the combination regimen did not experience tumor progression for nearly 11 months, whereas patients receiving exemestane alone progress after approximately 4 months.
Trastuzumab Emtansine Delays Progression of HER2-Positive Metastatic Breast Cancer The antibody-guided drug conjugate trastuzumab emtansine (T-DM1) as initial therapy prolonged progression-free survival (PFS) for patients with HER2-positive metastatic breast cancer compared with docetaxel plus trastuzumab, according to trial results reported at the European Multidisciplinary Cancer Conference. The conjugate delivers trastuzumab directly to tumor cells by attaching the drug to DM1 using a stable linker. This limits the drug’s exposure to normal cells, thus producing fewer side effects than the drug delivers through traditional means. The phase 2 trial randomized 137 patients who were chemotherapy-naïve to either T-DM1 or trastuzumab plus docetaxel chemotherapy. Median PFS was 14.2 months in the T-DM1 group compared with 9.2 months in the trastuzumab/docetaxel group. In the T-DM1 arm, only 7.2% of patients discontinued treatment because of side effects; 28.8% discontinued treatment in the trastuzumab/docetaxel arm.
5-Year Z-FAST Results Show Maintenance of Bone Density with Zoledronic Acid and Letrozole Combination Upfront zoledronic acid significantly and progressively increases bone mineral density (BMD) in postmenopausal women with early breast cancer receiving letrozole for 5 years, according to results of the Zoledronic Acid–Letrozole Adjuvant Synergy Trial (Z-FAST). This finding did not hold true if the zoledronic acid use was delayed (if a postbaseline lumbar spine or total hip T score decreased to less than -2.0, any clinical nontraumatic fracture occurred, or an asymptomatic vertebral fracture was identified at the 36-month follow-up). Patients in the delayed zoledronic acid group who were treated with zoledronic acid after bone loss had occurred did benefit by subsequent increases in BMD. Coadministration of zoledronic acid and letrozole was found to be well tolerated over 5 years, with fracture and disease recurrence rates similar in both groups.
ADT Did Not Increase Cardiovascular Mortality
Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia
Adding androgen-deprivation therapy (ADT) to radiation in men with clinically localized prostate cancer was not associated with increased cardiovascular mortality compared with radiation therapy alone, according to results of a multivariate analysis presented at the annual meeting of the American Society for Radiation Oncology. Older age (≥70 years), cardiovascular disease, and diabetes mellitus remained strong risk factors for cardiovascular death. To help quell the controversy surrounding the FDA’s request to add safety labeling of risk of cardiovascular disease to gonadotropin-releasing hormone agonists, the researchers analyzed data from a phase 3 trial that included 1979 men with clinically localized stage T1-2 prostate cancer. The cumulative 10-year incidence of cardiovascular death was 9.8% in the combined ADT and radiation group and 10.7% in the radiation alone arm, which the researchers noted was not statistically significant. Univariate analysis, however, determined that adding ADT improved overall and disease-specific survival but did not worsen cardiovascular mortality. ●
OCTOber 2011 I VOL 4, NO 7
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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
Indiana University Hospital Indianapolis, IN
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, BSPh
USC/Norris Cancer Hospital Los Angeles, CA
OncologyPharmacist.net Warwick, RI
Laura Boehnke Michaud, PharmD, BCOP, FASHP
Steven L. Dâ&#x20AC;&#x2122;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
John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
The University of Texas M. D. Anderson Cancer Center Houston, TX
University of Nebraska College of Pharmacy Omaha, NE
Burt Zweigenhaft, BS BioPharma Partners LLC New York, NY
Marlo Blazer, RPh, PharmD 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 2011 I VOL 4, NO 7
Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
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Taking a broader view — charting a unique course in cancer care
At Genentech BioOncology, not only are we leading the fight against cancer with innovative science, but we’re also dedicated to supporting patients and others within the oncology community. A commitment to patients — We created Genentech BioOncology™ Access Solutions®, a single source for all access and reimbursement issues, so healthcare providers can remain focused on patient care. Reducing barriers to treatment — We help make treatment possible for patients in financial need through our BioOncology Co-pay Card Program and ongoing charitable donations to various independent, nonprofit organizations in support of co-pay assistance. A commitment to care — Our first product was approved in 1985, and since then we have donated approximately $2.3 billion in medicine to uninsured patients through the Genentech® Access to Care Foundation and other donation programs. Our goal is to fundamentally change the way that cancer is treated by personalizing solutions to patient care.
© 2011 Genentech USA, Inc. All rights reserved. BIO0000330901 Printed in USA.
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From the Editor
quick look at the National Cancer Institute’s news releases finds 15 items in just 1 week. These include studies on drugs, supplements, and behaviors that can influence cancer risk; trials of new anticancer agents; and results of new regimens and dosing schedules on existing drugs. As always, The Oncology Pharmacist strives to make this information Patrick Medina, relevant to you. PharmD, BCOP In addition, there is, what seems Editor-in-Chief like, constant media coverage of controversial reports and decisions by various committees within the US government. I look forward to seeing how
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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 ©2011 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. BPA Worldwide membership applied for April 2011.
OcTOber 2011 I VOL 4, NO 7
they affect you, and encourage you to weigh in on our reader poll (see this month’s question, page 16). In this issue, our colleagues Joanna Schwartz and Maggie Charpentier give a pharmacist’s take on the current bevacizumab situation and how it affects the everyday practice of oncology pharmacy. Melinda Tran and Emily Mackler provide a comprehensive review of oral oncolytic dosing in patients with renal dysfunction. As pharmacists, ensuring that each patient gets the right dose is of paramount importance. With this issue, Jim Koeller continues to provide us his insights on key developments in oncology pharmacy practice. His views on the drug shortage not only provide information, but also offer pathways to possible solutions. As always, I hope this issue benefits your practice. We look forward to hearing from you. ●
Denosumab to Increase Bone Mass The US Food and Drug Administration (FDA) has approved denosumab (Prolia, Amgen) to increase bone mass in patients at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. This monoclonal antibody that binds to RANKL was approved based on results of 2 randomized, double-blind, placebo-controlled trials. One trial randomized 1468 men with prostate cancer. Men aged younger than 70 years were required to have either a baseline bone mineral density (BMD) T score at the lumbar spine, total hip, or femoral neck between -1.0 and -4.0, or history of osteoporotic fracture. The other trial randomized 252 women with breast cancer. Women were required to have a baseline BMD T score at the lumbar spine, total hip, or femoral neck between -1.0 and -2.5 and to have not experienced fracture after age 25. Denosumab use resulted in changes in lumbar spine BMD of +5.6% at 24 months in men and +4.8% at 12 months in women. Those on placebo experienced changes of -1.0% and -0.7%, respectively. Common adverse reactions included arthralgia and back pain. Pain in extremities and musculoskeletal pain were also noted. Hypocalcemia (serum calcium <8.4 mg/dL) was observed only in denosumab-treated patients (2.4%) at the 1-month visit. In Vitro Diagnostic Assay for Change in ProstateSpecific Antigen Over Time The FDA has granted 510k marketing clearance to an invitro diagnostic assay (NADiA ProsVue, Iris International) for determining rate of change of serum total prostate-specific antigen over a period of time. A slope of 3 assays is indicated for use as a prognostic marker in conjunction with clinical evaluation to aid in identifying those patients at reduced risk for recurrence of prostate cancer for the 8-year period following prostatectomy. This nucleic acid detection immunoassay identifies
extremely low concentrations of proteins that have not been routinely used as a diagnostic or prognostic aid. Clearance was based on a retrospective study of 304 patients that evaluated the slope of 3 successive tests over a period of at least 10 months after prostatectomy to identify patients with no evidence of disease or clinical progression. The assay correctly identified 92.7% of stable patients and 78.0% of patients with recurrence.
Bevacizumab Label Changes The FDA issued a statement warning physicians of changes in the package insert for bevacizumab (Avastin, Genentech) regarding newly identified risks. • Increased risk for ovarian failure. New cases of ovarian failure were identified in 34% of women receiving bevacizumab in combination with chemotherapy compared with 2% of women receiving chemotherapy alone. After discontinuation of bevacizumab, recovery of ovarian function was demonstrated in 22% of these women. • Osteonecrosis of the jaw. Postmarketing, osteonecrosis of the jaw was reported in patients receiving bevacizumab but not bisphosphonates. The pathogenesis is unclear, but it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis. • Venous thromboembolic event (VTE) and bleeding in patients receiving anticoagulation therapy after first VTE event. In patients with metastatic colorectal cancer, prospective evaluation found the overall incidence of first VTE was higher with bevacizumab (13.5%) than with chemotherapy alone (9.6%). Among patients treated with anticoagulants following an initial VTE event, the overall incidence of subsequent VTEs was also higher among those treated with bevacizumab (31.5% vs 25.6%, respectively) and the overall incidence of bleeding was higher in the bevacizumab group (27.4% vs 20.9%, respectively). ●
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Help stop CINV before it starts, with a regimen including EMEND, a 5-HT3 antagonist, and a corticosteroid
Have you included EMEND from Cycle 1?
These highly and moderately emetogenic chemotherapy regimens increase the risk of CINV. Breast Cancer1,2
AC (doxorubicin + cyclophosphamide) TAC (docetaxel + doxorubicin + cyclophosphamide) TC (docetaxel + cyclophosphamide) CMF (cyclophosphamide + methotrexate + fluorouracil) TCH (docetaxel + carboplatin + trastuzumab)
ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) ± rituximab CVP (cyclophosphamide + vincristine + prednisone)
Carbo-Tax (carboplatin + paclitaxel) Cisplatin + vinorelbine Cisplatin + gemcitabine Cisplatin + pemetrexed
FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) FOLFIRI (irinotecan + leucovorin + 5-fluorouracil) CapeOX (capecitabine + oxaliplatin) Irinotecan Cisplatin-based regimens
Head and Neck Cancer1,4
Cisplatin-based regimens Carboplatin-based regimens
Carbo-Tax (carboplatin + paclitaxel) IP cis (intraperitoneal cisplatin) Cisplatin
EMEND, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high - dose cisplatin ; and for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND is not recommended.
Selected Important Safety Information EMEND should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased ef ficac y of aprepitant. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND 125 mg/80 mg was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND 125 mg /80 mg did not influence the pharmacokinetics of docetaxel or vinorelbine. Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.
The efficacy of hormonal contraceptives may be reduced during coadministration with EMEND and for 28 days after the last dose of EMEND. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month after the last dose of EMEND. Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle. Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence greater than 10%, in patients receiving highly emetogenic chemotherapy were asthenia /fatigue (17.8% EMEND vs 11.8% standard therapy), nausea (12.7% vs 11.8%), hiccups (10.8% vs 5.6%), diarrhea (10.3% vs 7.5%), and anorexia (10.1% vs 9.5%). In clinical trials of EMEND, the most common adverse events reported at a frequency greater than with standard therapy in patients receiving moderately emetogenic chemotherapy were alopecia (12.4% EMEND vs 11.9% standard therapy), dyspepsia (5.8% vs 3.8%), nausea (5.8% vs 5.1%), neutropenia (5.8% vs 5.6%), asthenia (4.7% vs 4.6%), and stomatitis (3.1% vs 2.7%). In clinical trials, EMEND increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2.2-fold; therefore, the dexamethasone dose administered in the regimen with EMEND should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND. See PRECAUTIONS, Drug Interactions, in the Prescribing Information for EMEND for additional information on dosage adjustment for methylprednisolone when coadministered with EMEND. Please read the Brief Summary of the Prescribing Information for EMEND on the following pages.
References : 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: antiemesis—V.1.2011. w w w.nccn.org/professionals/physician_gls/ f_guidelines.asp. Accessed January 5, 2011. 2. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer—V.2.2011. www.nccn.org/ professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 4. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: head and neck cancers—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 5. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: Hodgkin lymphoma—V.2.2010. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: colon cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. 7. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: rectal cancer—V.2.2011. w w w.nccn.org/professionals/ physician_gls/f_guidelines.asp. Accessed January 5, 2011. 8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: ovarian cancer—V.2.2011. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed January 5, 2011. CINV=chemotherapy-induced nausea and vomiting.
An antiemetic regimen including
Merck Oncology Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1012122-0000 emend.com
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Brief Summary of the Prescribing Information for
INDICATIONS AND USAGE Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV): EMEND, in combination with other antiemetic agents, is indicated for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC), including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses of moderately CAPSULES emetogenic cancer chemotherapy (MEC). Prevention of Postoperative Nausea and Vomiting (PONV): EMEND is indicated for prevention of postoperative nausea and vomiting. Limitations of Use: EMEND has not been studied for treatment of established nausea and vomiting. Chronic continuous administration is not recommended. CONTRAINDICATIONS EMEND is contraindicated in patients who are hypersensitive to any component of the product. EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Moderate inhibition of CYP3A4 by aprepitant, 125-mg/80-mg regimen, could result in elevated plasma concentrations of these concomitant medications. Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced and this may result in decreased efficacy of EMEND [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when EMEND (125-mg/80-mg regimen) was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of EMEND with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with EMEND, the efficacy of hormonal contraceptives during and for 28 days following the last dose of EMEND may be reduced. Alternative or backup methods of contraception should be used during treatment with EMEND and for 1 month following the last dose of EMEND [see Drug Interactions]. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when EMEND is administered in these patients. Chronic Continuous Use: Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. ADVERSE REACTIONS The overall safety of aprepitant was evaluated in approximately 5300 individuals. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials Experience: Chemotherapy-Induced Nausea and Vomiting: Highly Emetogenic Chemotherapy: In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the Multiple-Cycle extension for up to 6 cycles of chemotherapy. EMEND was given in combination with ondansetron and dexamethasone. In Cycle 1, clinical adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 68% of patients treated with standard therapy. Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Body as a whole/Site unspecified: asthenia/fatigue: 17.8, 11.8; dizziness: 6.6, 4.4; dehydration: 5.9, 5.1; abdominal pain: 4.6, 3.3; fever: 2.9, 3.5; mucous membrane disorder: 2.6, 3.1 Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; heartburn: 5.3, 4.9; gastritis: 4.2, 3.1; epigastric discomfort: 4.0, 3.1 Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8 Hemic and lymphatic system: neutropenia: 3.1, 2.9 Metabolism and nutrition: anorexia: 10.1, 9.5 Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1 Respiratory system: hiccups: 10.8, 5.6 In addition, isolated cases of serious adverse experiences, regardless of causality, of bradycardia, disorientation, and perforating duodenal ulcer were reported in highly emetogenic CINV clinical studies. Moderately Emetogenic Chemotherapy: During Cycle 1 of 2 moderately emetogenic chemotherapy studies, 868 patients were treated with the aprepitant regimen and 686 of these patients continued into extensions for up to 4 cycles of chemotherapy. In the combined analysis of Cycle 1 data for these 2 studies, adverse experiences were reported in approximately 69% of patients treated with the aprepitant regimen compared with approximately 72% of patients treated with standard therapy. In the combined analysis of Cycle 1 data for these 2 studies, the adverse-experience profile in both moderately emetogenic chemotherapy studies was generally comparable to the highly emetogenic chemotherapy studies. Following are the percentage of patients receiving moderately emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=868) and standard therapy (n=846), respectively: Blood and lymphatic system disorders: neutropenia: 5.8, 5.6 Metabolism and nutrition disorders: anorexia: 6.2, 7.2 Psychiatric disorders: insomnia: 2.6, 3.7 Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4 Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7 Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9 General disorders and general administration site conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6 In a combined analysis of these 2 studies, isolated cases of serious adverse experiences were similar in the 2 treatment groups. Highly and Moderately Emetogenic Chemotherapy: The following additional clinical adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen in either HEC or MEC studies: Infections and infestations: candidiasis, herpes simplex, lower respiratory infection, oral candidiasis, pharyngitis, septic shock, upper respiratory infection, urinary tract infection Neoplasms benign, malignant, and unspecified (including cysts and polyps): malignant neoplasm, non–small-cell lung carcinoma Blood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopenia Metabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemia Psychiatric disorders: anxiety disorder, confusion, depression Nervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremor Eye disorders: conjunctivitis Cardiac disorders: myocardial infarction, palpitations, tachycardia Vascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotension Respiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbance Gastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increased Skin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rash Musculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgia Renal and urinary disorders: dysuria, renal insufficiency Reproductive system and breast disorders: pelvic pain General disorders and administrative site conditions: edema, malaise, pain, rigors Investigations: weight loss Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another CINV study. Laboratory Adverse Experiences: Following are the percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with laboratory adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: Proteinuria: 6.8, 5.3 ALT increased: 6.0, 4.3 Blood urea nitrogen increased: 4.7, 3.5 Serum creatinine increased: 3.7, 4.3 AST increased: 3.0, 1.3
EMEND® (aprepitant) capsules The following additional laboratory adverse experiences (incidence >0.5% and greater than standard therapy), regardless of causality, were reported in patients treated with the aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, erythrocyturia, leukocyturia. The adverse-experience profiles in the Multiple-Cycle extensions of HEC and MEC studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1. Postoperative Nausea and Vomiting: In well-controlled clinical studies in patients receiving general anesthesia, 564 patients were administered 40-mg aprepitant orally and 538 patients were administered 4-mg ondansetron IV. Clinical adverse experiences were reported in approximately 60% of patients treated with 40-mg aprepitant compared with approximately 64% of patients treated with 4-mg ondansetron IV. Following are the percentage of patients receiving general anesthesia with clinical adverse experiences reported at an incidence of ≥3% in the combined studies for aprepitant 40 mg (n=564) and ondansetron (n=538), respectively: Infections and infestations: urinary tract infection: 2.3, 3.2 Blood and lymphatic system disorders: anemia: 3.0, 4.3 Psychiatric disorders: insomnia: 2.1, 3.3 Nervous system disorders: headache: 5.0, 6.5 Cardiac disorders: bradycardia: 4.4, 3.9 Vascular disorders: hypotension: 5.7, 4.6; hypertension: 2.1, 3.2 Gastrointestinal disorders: nausea: 8.5, 8.6; constipation: 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9 Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4 General disorders and general administration site conditions: pyrexia: 5.9, 10.6 The following additional clinical adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant: Infections and infestations: postoperative infection Metabolism and nutrition disorders: hypokalemia, hypovolemia Nervous system disorders: dizziness, hypoesthesia, syncope Vascular disorders: hematoma Respiratory, thoracic, and mediastinal disorders: dyspnea, hypoxia, respiratory depression Gastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsia Skin and subcutaneous tissue disorders: urticaria General disorders and administrative site conditions: hypothermia, pain Investigations: blood pressure decreased Injury, poisoning, and procedural complications: operative hemorrhage, wound dehiscence Other adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included: Nervous system disorders: dysarthria, sensory disturbance Eye disorders: miosis, visual acuity reduced Respiratory, thoracic, and mediastinal disorders: wheezing Gastrointestinal disorders: bowel sounds abnormal, stomach discomfort There were no serious adverse drug-related experiences reported in the postoperative nausea and vomiting clinical studies in patients taking 40-mg aprepitant. Laboratory Adverse Experiences: One laboratory adverse experience, hemoglobin decreased (40-mg aprepitant 3.8%, ondansetron 4.2%), was reported at an incidence ≥3% in a patient receiving general anesthesia. The following additional laboratory adverse experiences (incidence >0.5% and greater than ondansetron), regardless of causality, were reported in patients treated with aprepitant 40 mg: blood albumin decreased, blood bilirubin increased, blood glucose increased, blood potassium decreased, glucose urine present. The adverse experience of increased ALT occurred with similar incidence in patients treated with aprepitant 40 mg (1.1%) as in patients treated with ondansetron 4 mg (1.0%). Other Studies: In addition, 2 serious adverse experiences were reported in postoperative nausea and vomiting (PONV) clinical studies in patients taking a higher dose of aprepitant: 1 case of constipation, and 1 case of subileus. Angioedema and urticaria were reported as serious adverse experiences in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postmarketing use of aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Aprepitant is a substrate, a weak-to-moderate (dose-dependent) inhibitor, and an inducer of CYP3A4. Aprepitant is also an inducer of CYP2C9. Effect of Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Weak inhibition of CYP3A4 by a single 40-mg dose of aprepitant is not expected to alter the plasma concentrations of concomitant medications that are primarily metabolized through CYP3A4 to a clinically significant degree. However, higher aprepitant doses or repeated dosing at any aprepitant dose may have a clinically significant effect. As a moderate inhibitor of CYP3A4 at a dose of 125 mg/80 mg, aprepitant can increase plasma concentrations of concomitantly administered oral medications that are metabolized through CYP3A4 [see Contraindications]. The use of fosaprepitant may increase CYP3A4 substrate plasma concentrations to a lesser degree than the use of oral aprepitant (125 mg). 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: EMEND, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and EMEND when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate, by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen), to achieve exposures of dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical chemotherapy-induced nausea and vomiting studies with EMEND reflects an approximate 50% reduction of the dose of dexamethasone. A single dose of EMEND (40 mg) when coadministered with a single oral dose of dexamethasone 20 mg, increased the AUC of dexamethasone by 1.45-fold. Therefore, no dose adjustment is recommended. Methylprednisolone: EMEND, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The IV methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with EMEND (125-mg/80-mg regimen) to achieve exposures of methylprednisolone similar to those obtained when it is given without EMEND. Although the concomitant administration of methylprednisolone with the single 40-mg dose of aprepitant has not been studied, a single 40-mg dose of EMEND produces a weak inhibition of CYP3A4 (based on midazolam interaction study) and it is not expected to alter the plasma concentrations of methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. Chemotherapeutic agents: [see Warnings and Precautions] Docetaxel: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of docetaxel. Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree. CYP2C9 substrates (warfarin, tolbutamide): Aprepitant has been shown to induce the metabolism of S(–) warfarin and tolbutamide, which are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs that are known to be metabolized by CYP2C9, such as phenytoin, may result in lower plasma concentrations of these drugs. Warfarin: A single 125-mg dose of EMEND was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of EMEND on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as international normalized ratio or INR) 5 days after completion of dosing with EMEND. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting. Tolbutamide: EMEND, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND, when given as a 40-mg single oral dose on Day 1, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 8% on Day 2, 16% on Day 4, 15% on Day 8, and 10% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of EMEND 40 mg and on Days 2, 4, 8, and 15. This effect was not considered clinically important. Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norethindrone was administered on Days 1 through 21, and EMEND was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10 with ondansetron 32 mg IV on Day 8 and oral dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of EMEND on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. In another study, a daily dose of an oral contraceptive containing ethinyl estradiol and norgestimate (which is converted to norelgestromin) was administered on Days 1 through 21, and EMEND 40 mg was given on Day 8. In the study, the AUC of ethinyl estradiol decreased by 4% and 29% on Day 8 and Day 12, respectively, while the AUC of norelgestromin increased by 18% on Day 8 and decreased by 10% on Day 12. In addition, the trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following coadministration of the oral contraceptive with EMEND 40 mg on Day 8 compared to the trough levels following administration of the oral contraceptive alone. The coadministration of EMEND may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of EMEND. Alternative or backup methods of contraception should be used
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EMENDÂŽ (aprepitant) capsules during treatment with EMEND and for 1 month following the last dose of EMEND. Midazolam: EMEND increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of EMEND 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with EMEND (125 mg/80 mg). A single dose of EMEND (40 mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this effect was not considered clinically important. In another study with intravenous administration of midazolam, EMEND was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of EMEND and on Days 4, 8, and 15. EMEND increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of EMEND on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline. An additional study was completed with intravenous administration of midazolam and EMEND. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of EMEND 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (eg, elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with EMEND for the chemotherapy-induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3). Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of EMEND with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of EMEND with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations of aprepitant that may result in decreased efficacy of EMEND. Ketoconazole: When a single 125-mg dose of EMEND was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of EMEND was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of EMEND with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy of EMEND. Additional Interactions: EMEND is unlikely to interact with drugs that are substrates for the P-glycoprotein transporter, as demonstrated by the lack of interaction of EMEND with digoxin in a clinical drug interaction study. Diltiazem: In patients with mild to moderate hypertension, administration of aprepitant once daily, as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and C max by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC 0â&#x20AC;&#x201C;24hr OF MCGsHR M, ABOUT TIMES THE HUMAN EXPOSURE AT THE RECOMMENDED DOSE AND IN RABBITS AT ORAL DOSES UP TO MG KG day (plasma AUC 0â&#x20AC;&#x201C;24hr OF MCGsHR M, ABOUT TIMES THE HUMAN EXPOSURE AT THE RECOMMENDED DOSE AND HAVE REVEALED NO EVIDENCE OF IMPAIRED fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of EMEND in pediatric patients have not been established. Geriatric Use: In 2 well-controlled chemotherapy-induced nausea and vomiting clinical studies, of the total number of patients (N=544) treated with EMEND, 31% were 65 and over, while 5% were 75 and over. In well-controlled postoperative nausea and vomiting clinical studies, of the total number of patients (N=1120) treated with EMEND, 7% were 65 and over, while 2% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC 0â&#x20AC;&#x201C;24hr ) of 0.7 to 1.6 times the human exposure (AUC 0â&#x20AC;&#x201C;24hr MCGsHR M, AT THE RECOMMENDED DOSE OF 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test. Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/ kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling.] Instructions: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed. Patients should be instructed to take EMEND only as prescribed. For prevention of chemotherapy-induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40-mg capsule of EMEND) within 3 hours prior to induction of anesthesia. Allergic reactions, which may be serious, and may include hives, rash, and itching, and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction. EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting. Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND. For detailed information, please read the Prescribing Information. Rx only
Copyright ÂŠ 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1012122-0000
Conference News The following articles are based on presentations at the Fourth American Association for Cancer Research Conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved held September 18-21, 2011, in Washington, DC.
Secondary Breast Cancer Rates Higher in AfricanAmerican Women Contralateral Second Primary Cancer Found in About 4% of All Breast Cancer Patients By John Schieszer
WASHINGTON, DCâ&#x20AC;&#x201D;The overall incidence of breast cancer is generally higher among white women than black women. The incidence of a second breast cancer in the opposite breast, however, is higher among black women, according to new data. Researchers have found that, when cancer is diagnosed in women aged younger than 45 years, the incidence of primary breast cancer is higher among blacks than among whites. In addition, â&#x20AC;&#x153;when the disease does occur in blacks early on, it tends to be more aggressive, more likely to be estrogen-receptor negative, and it is more likely to cause death,â&#x20AC;? said lead researcher NsouliMaktabi Hala, who is a PhD graduate of George Washington University, Washington, DC. She and her colleagues found that when cancer is diagnosed at an older age, the incidence is higher among white women. Because most breast cancers are diagnosed in older women, the overall incidence is higher in whites. â&#x20AC;&#x153;While the incidence of breast cancer is generally higher among whites for first-time diagnosis, we found the incidence of the second contralateral diagnosis was higher among blacks,â&#x20AC;? said Hala. â&#x20AC;&#x153;This was unexpected. Blacks usually have a higher mortality rate than whites from the first cancer, so you would expect blacks to have lower rates of second cancers.â&#x20AC;? She said usually about 4% of all breast cancer patients will present with a second primary cancer contralaterally. The researchers used Surveillance, Epidemiology, and End Results Registry 9 data to evaluate breast cancer incidence among 415,664 white women and 39,887 black women diagnosed with primary breast cancer aged 19 years or older and possible development of a second cancer in the opposite breast. Results showed that 22,290 (40.7%) developed a second pri-
mary breast cancer, of which 18,142 (4%) occurred in the opposite breast. Incidence of second primary cancers of the opposite breast was higher among black women, and 15,101 (83.2%) of second contralateral cancers developed in those who were diagnosed with first breast cancer at age 45 or older.
â&#x20AC;&#x153;A cancer in one breast should lead to a careful examination of the other breast over a long period, just in case a cancer develops.â&#x20AC;? â&#x20AC;&#x201D;Nsouli-Maktabi Hala, PhD
The researchers also found that the average age of the second primary contralateral cancer diagnosis tended to be lower in blacks (59 years of age) than in whites (67 years of age). Contralateral breast cancer tended to occur within the first 2 years of the primary breast cancer diagnosis. â&#x20AC;&#x153;This should alert the physician to watch patients very carefully,â&#x20AC;? Hala said. â&#x20AC;&#x153;A cancer in one breast should lead to a careful examination of the other breast over a long period, just in case a cancer develops.â&#x20AC;? Study coinvestigator Donald Henson, MD, who is with George Washington Cancer Institute, said these findings should be of particular interest to oncology nurses. â&#x20AC;&#x153;African-American women need to be more closely followed and longer than what we usually do. So they need to be followed past 6 years,â&#x20AC;? said Henson. â&#x20AC;&#x153;I think these data are something that you need to know as an oncology nurse and counsel your patients about. It is important to know some statistics about this so the nurses can better counsel their patients.â&#x20AC;? â&#x2014;?
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Stress Linked to Breast Cancer Aggressiveness Association More Pronounced in Blacks and Hispanics By John Schieszer
WASHINGTON, DC—Psychosocial stress may play a role in the etiology of breast cancer aggressiveness, particularly among minority populations, according to study results. In a cross-sectional study, greater levels of fear, anxiety, or isolation were found to be associated with more aggressive breast cancer; however, no clear driver for the association is yet identified. “We found that after diagnosis, black and Hispanic breast cancer patients reported higher levels of stress than whites, and that stress was associated with tumor aggressiveness,” said study investigator Garth Rauscher, PhD, associate professor of epidemiology in the division of epidemiology and biostatistics at the School of Public Health, University of Illinois at Chicago. Rauscher and his colleagues studied patient-reported perceptions of fear,
anxiety, and isolation, together referred to as psychosocial stress, and associations with breast cancer aggressiveness. The patients’ stress levels were examined 2 to 3 months after diagnosis. The
“Stress increases certain hormone levels in the body and hormones affect breast cancer risk.” —Garth Rauscher, PhD
study included 989 breast cancer patients who were recently diagnosed (411 were non-Hispanic black, 397 were nonHispanic white, and 181 were Hispanic). Results showed that psychosocial
stress scores were higher for both black and Hispanic patients compared with white patients. “Those who reported higher levels of stress tended to have more aggressive tumors. However, what we don’t know is if we had asked them the same question a year or 5 years before diagnosis, would we have seen the same association between stress and breast cancer aggressiveness?” said Rauscher. “It’s not clear what’s driving this association. It may be that the level of stress in these patients’ lives influenced tumor aggressiveness. It may be that being diagnosed with a more aggressive tumor, with a more worrisome diagnosis and more stressful treatments, influenced reports of stress. It may be that both of these are playing a role in the association. We don’t know the answer to that question.” Patient-reported psychosocial stress
was one third of a standard deviation higher for patients with receptor-negative versus -positive disease, and higher for patients with high- versus low- or intermediate-grade disease (difference = 0.17). Compared with whites, psychosocial stress scores were higher for black patients (difference = 0.22), and higher for Hispanic patients (difference = 0.44). “There are reasons that the breast may be more vulnerable to effects of stress. Stress increases certain hormone levels in the body and hormones affect breast cancer risk,” Rauscher said in an interview with The Oncology Pharmacist. “Stress may be an important prognostic factor, but it is not clear what the process is. We need to figure out what we need to do to intervene. There are all kinds of reasons to help people lower their stress, and this study suggests there may be a benefit in terms of breast cancer.” ●
Genetic Differences Linked to Higher Risk... Continued from cover is a disease conferred by multiple gene mutations, numerous alterations in gene expression, and changes in genome composition. Researchers, therefore, are investigating the genetic predispositions and oncogenic networks associated with observed prostate cancer disparities. “There are a lot of socioeconomic and environmental factors that create differences in levels of prostate cancer in these 2 groups,” said one study investigator BiDar Wang, PhD, assistant research professor of pharmacology and physiology at George Washington University, in Washington, DC. “We’ve found that genetic elements play a role in these disparities as well.” Wang and colleagues analyzed normal and cancerous prostate tissue samples from African-American and white men who underwent prostate biopsies. They looked at 2 key genetic pieces: messenger RNA (mRNA), which carries codes from DNA that then are used to make proteins; and microRNA, shorter RNA strands that regulate that process by binding to mRNA and interrupt the gene expression. The results showed enough differences between African-American and white men to determine that each race has “population-specific” mRNA and microRNA. Overall, the researchers found nearly 400 mRNAs were expressed differentially between the cancerous prostate tissues of African-American and white men. These differences are crucial because mRNA and microRNA affect the biolog-
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“The genomic analyses of prostate cancers have revealed that differential mRNA and microRNA expression and the associated gene network rewriting may be critical in prostate cancer health disparities.” —Bi-Dar Wang, PhD
ical pathways by which prostate cancer tumor formation is either promoted or stopped, according to Wang. “It is still too early to conclude any novel treatment strategy based on our results. However, the genomic analyses of prostate cancers have revealed that differential mRNA and microRNA expression and the associated gene network rewriting may be critical in prostate cancer health disparities,” said Wang. He said these findings will help lead to a better understanding of the molecular mechanisms underlying prostate cancer disparities and may lead to the development of novel strategies for prostate cancer detection and personalized treatment for African-American men. “We may be able to identify better biomarkers for early detection and treatment in African Americans. Their tumors are slightly different in terms of genetic factors,” Wang said in an interview with The Oncology Pharmacist.
In a separate study just released, investigators found that a high intake of calcium causes prostate cancer among African-American men who are genetically good absorbers of the mineral (J Bone Miner Res. September 1, 2011. Epub ahead of print). “High dietary intake of calcium has long been linked to prostate cancer but the explanation for this observation has been elusive,” said study investigator Gary Schwartz, PhD, associate professor of cancer biology, urology, and public health sciences at Wake Forest Baptist Medical Center, WinstonSalem, North Carolina. Schwartz and his team studied 783 African-American men, 533 of whom were diagnosed with prostate cancer. The investigators studied the effects of genotype, calcium intake, and diet– gene interactions. The study is one of the few to explore genes related to calcium absorption or to examine diet in a large African-American population.
Although prostate cancer is 36% more common among African Americans than in non-Hispanic whites, data on the diet–cancer link primarily come from populations of Caucasian origin. The team targeted a genetic allele that is more common in populations of African origin than in other populations and is associated with regulating the absorption of calcium. The study found that men who reported the highest intake of calcium were 2 times more likely to have localized and advanced prostate cancer than those who reported the lowest. Men with a genotype associated with poor calcium absorption were 59% less likely to have been diagnosed with advanced prostate cancer than men who genetically were the best absorbers of calcium. The researchers found that among men with calcium intake below the median, genetically poor absorbers had a 50% decreased risk of having advanced prostate cancer than the best absorbers. “It may be possible in the future to personalize prevention using this type of genetic knowledge,” said Schwartz. “We now have a better understanding of why calcium in the diet may increase the risk for prostate cancer and who is at increased risk. If our results are confirmed, it gives much better insight into the preventable causes of prostate cancer. So if I know I’m a good absorber of calcium, I may want to be careful about my diet and about the use of calcium supplements.” ●
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Overall Survival Advantage Sustained at 3-Year Median Follow-up In Previously Untreated Multiple Myeloma (MM) VISTTA VISTA* A* OVER OVERALL RALL SURVIV SURVIVAL VAL AL (OS) ANAL ANALYSIS: LY YSIS: VcMP† vs MP (36.7-month median follow-up)
MEDIAN OS NOT REACHED FOR VcMP
% PPatients atients Without Event
80 70 60 50 40 30 20 10
VELCADE+MP ■ VE LCADE+MP (n=344) ■ MP (n=338)
HR 0.65 (95% CI, 0.51-0.84); PP=0.00084 =0.00084 =
Months Kaplan-Meier Kaplan-Meier estimate. estimate.
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hanks to medical research, there are nearly 12 million cancer survivors living in the United States today. And the research continues: There are approximately 400 new cancer therapies in preclinical and clinical development. As progress continues to treat those with cancer, let’s examine the statistics related to clinical trial participation.
From 1996 through 2002, National Cancer Institute (NCI)-sponsored cooperative group nonsurgical treatment trials for breast,
colorectal, lung, and prostate cancers enrolled 75,215 patients: • 85.5% white • 9.2% black
• 3.1% Hispanic • 1.9% Asian/Pacific Islander • 0.3% American Indian/Alaskan Native…
Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS:
VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:
VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.
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Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:
Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).
Cancer incidence was divided evenly among 3 participating age-groups (30-64, 65-74, ≥75 years) in the NCIsponsored treatment trials; however, trial participant representation was heavily skewed toward the young est age-group (68%). Fewer than 5% of cancer patients participate in clinical trials… If 10% participated, studies potentially could be completed in 1 year, instead of the current 3 to 5 years. Common cancer patient concerns regarding joining a clinical study include: • Fear of a reduction in quality of life • Reluctance to accept the possibility of receiving a placebo • Potential side effects • Treatments under study are not the best option.
Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Please see full Prescribing Information for VELCADE at www.VELCADE.com
VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. V-11-0041 All rights reserved. Printed in USA
Unfortunately, fewer than 4% of US physicians participate in clinical trials… Therefore, although most trial participants are highly satisfied with their experience, 8 of 10 cancer patients may be unaware that a clinical trial was a possible option. After identifying an appropriate trial, 40% of cancer patients either enroll or try to enroll… Sources: The Center for Information & Study on Clinical Research Participation; National Cancer Institute.
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Conference News The following articles are based on presentations at the American Society of Clinical Oncology Breast Cancer Symposium 2011 held September 8-10 in San Francisco, California.
Chemoprevention in Breast Cancer: Which Agents for Which Patients? Choice of Agent Depends on Patient Variables By Caroline Helwick
SAN FRANCISCO—A number of interventions can help reduce breast cancer among women at high risk, but uptake is sluggish, and there can be confusion about which agent to prescribe to a given patient. Seema Khan, MD, professor of surgery at Northwestern University Feinberg School of Medicine, Chicago, addressed the topic of pharmacologic risk reduction at the 2011 Breast Cancer Symposium. “It’s clear that selective estrogen receptor modulators [SERMs; tamoxifen and raloxifene] reduce risk, but uptake is poor. High on our priority list is better risk assessment of women at sufficiently high risk to benefit from such preventive therapy,” she said. Even in high-risk women, fewer than 15% use any means of chemoprevention, and this rate falls to about 5% when patients in clinical trials are excluded. But many women could benefit. An example is a 45-year-old woman with 1 first-degree relative with breast cancer and 1 biopsy showing atypical hyperplasia. Her 5-year risk is almost 5% (compared with 1% for an average-risk peer) and her lifetime risk is 37% (vs 12%), Khan noted. Choosing an Agent For such women, the type of pharmacologic intervention depends on menopausal status and age, hysterectomy status, bone mineral density status,
mutation carrier status, and whether ductal carcinoma in situ (DCIS) has been found (Figure). For premenopausal women, tamoxifen is the preferred agent. Tamoxifen has been shown to cut risk by at least two thirds in women with lobular carcinoma in situ or atypical hyperplasia. For postmenopausal women, raloxifene or the aromatase inhibitor exemestane are recommended (based on recent data); patients who have had a hysterectomy also may consider tamoxifen (because adverse effects on the uterus are moot). “Women at risk for sporadic breast cancer are most likely to benefit from SERMs, and BRCA2 carriers are more likely to benefit than BRCA1 carriers. Data also are emerging to suggest that estrogen receptor (ER)-positive patients are more likely to benefit than ER-negative ones and, for women with DCIS, tamoxifen is marginally better than raloxifene,” she said. A recent analysis determined the relative risks and benefits of tamoxifen and raloxifene in a variety of clinically relevant scenarios (Freedman AN, et al. J Clin Oncol. 2011;29:2327-2333). Over a 5-year period, postmenopausal women with an intact uterus had a better benefit–risk ratio for raloxifene than with tamoxifen, but for those without a uterus the ratio was similar. In particular, the analysis showed that regardless of ethnicity, older women
High Risk Premenopausal
Tamoxifen Surgical prevention
Exemestane Tamoxifen Exemestane
Figure. Summary of Pharmacologic Agents to Prevent Sporadic Breast Cancer
(aged 70-79 years) with a lower risk of breast cancer seem to derive little benefit from either agent. Non-Hispanic white women aged 50 to 70 years at high risk, with an intact uterus, have a more favorable benefit–risk ratio with raloxifene. In the absence of a uterus, both tamoxifen and raloxifene are reasonable options in many scenarios. In black women, the pattern is similar. Freedman and colleagues summarized the benefits and risks into an index, which can complement clinical evaluation in deciding whether to initiate chemoprevention and in comparing the benefits and risks of raloxifene
versus tamoxifen. Based on recent data showing a 65% risk reduction for ER-positive breast cancer, “exemestane can certainly be introduced into the category of drugs to consider for chemoprevention,” Khan added, but she had concerns about adverse effects and short follow-up in the MA.3 trial (Goss PE, et al. N Engl J Med. 2011;364:2381-2391). In the future, other options may prove effective for chemoprevention, she said, including low-dose tamoxifen, tamoxifen gel, the bisphosphonates, metformin, fenretinide, and poly [ADP-ribose] polymerase (PARP) inhibitors. ●
Do people receiving treatment talk to you about the cost of their oncology drugs?
n the September issue, we published an article entitled Patients Want to Discuss Cost of Cancer Care, Oncologists Often Avoid It. We wondered if patients were talking to their pharmacists about the cost of their oncology drugs. Here’s how our online reading community responded:
• 14% indicated they are never asked about drug costs • 48% said patients occasionally talk to them about drug costs • 38% are regularly talking with patients about drug costs
Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 16 for details.
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Breast Cancer Bevacizumab in Metastatic... Continued from cover thousands of women with metastatic breast cancer. It is currently the bestselling anticancer drug in history, even with its high price tag—the annual sales have exceeded $6 billion, with $1 billion per year used in breast cancer.1 The main sources of controversy leading to the US Food and Drug Administration’s (FDA) reversal of its approval for this indication, as outlined in the timeline (Table 1), surround several very important as yet unanswered questions that may determine the fate of many investigational agents in the future. The most important and most contested question concerns what is an appropriate, clinically significant end point in clinical trials of new agents to decide their FDA approval: progression-free survival (PFS) or overall survival (OS). Furthermore, when considering the adverse event profile in relation to any apparent benefit, what is an acceptable risk-to-benefit ratio? Adding to the controversy is the valid arguments on both sides of the
Initial Study Achieves Accelerated Approval The historical timeline of bevacizumab for metastatic breast cancer starts in 2005 when the Eastern Cooperative Oncology Group (ECOG, or E) 2100 study was presented amid much excitement at a large international meeting2 and was subsequently published in the New England Journal of Medicine in 2007.3 The E2100 study was a multicenter, randomized, clinical trial of bevacizumab as initial therapy in metastatic breast cancer. This open-label trial enrolled 722 patients with treatmentnaïve metastatic breast cancer to either weekly paclitaxel 90 mg/m2, or to weekMaggie Charpentier, PharmD, BCPS Joanna Schwartz, PharmD, BCOP ly paclitaxel plus bevacizumab 10 mg/kg issues, with breast cancer experts, organi- representing cancer and statistics ex - every 2 weeks until progression. The primary end point was PFS; seczations, and even members within organ- perts, industry, and the public that is izations such the FDA and its Oncologic charged by the FDA to evaluate study ondary end points included objective Drugs Advisory Committee (ODAC) data and to make recommendations to response rate, toxic effects, OS, and appear to be split on these issues. ODAC the FDA about the approval of new quality of life. Patients with HER2-positive breast cancer were eligible, prois a committee that consists of members cancer medications. vided they had received trastuzumab. Ultimately, few patients with HER2Table 1 Timeline of Bevacizumab for Metastatic Breast Cancer positive disease were enrolled. Patients Date Action who received previous taxane therapy as adjuvant or neoadjuvant therapy December 2005 The randomized, phase 3 E2100 trial presented at a national meeting, showing a were required to have received their 5.5-month increase in median PFS with the addition of bevacizumab to paclitaxel for last dose at least 12 months before metastatic breast cancer.a (Results published in the New England Journal of Medicine in enrollment. 2007.b) Results demonstrated a significant improvement in median PFS with the December 2007 ODAC recommends against approval of bevacizumab for metastatic breast cancer to addition of bevacizumab (11.8 months FDA, citing the lack of OS benefit in the E2100 study. vs 5.9 months; hazard ratio [HR], 0.60; February 2008 FDA grants conditional accelerated approval for bevacizumab with paclitaxel as P <.001). Median OS, however, was first-line therapy for metastatic breast cancer contingent upon confirmatory trials to similar between groups (25.2 months further define benefits. in the paclitaxel-alone group vs 26.7 c,d months in the combined therapy July 2010 ODAC meets to review the 2 confirmatory trials, and recommends to FDA to group; HR, 0.88; P = .16). On subremove the breast cancer indication from the label, citing an unfavorable risk-togroup analysis, no subgroup was idenbenefit profile. tified as most likely to benefit from the September 2010 FDA announces it will delay its decision regarding converting the accelerated combination therapy. approval to a full approval or removing the breast cancer indication. Grade 3 and 4 toxicities were more frequent in the combination group than December 2010 FDA proposes removing the metastatic breast cancer indication from in the paclitaxel-alone group, including bevacizumab label. neuropathy, infection, and fatigue; January 2011 The manufacturer (Genentech) files an appeal with FDA and requests an hypertension, cerebrovascular ischemia, administrative hearing that is open to the public. and headaches were all more frequent in June 28, 2011 FDA and ODAC conduct 2-day public hearing involving data presentations from the combination arm. Treatment-related deaths were similar in both groups. the manufacturer and testimonials from patients and physicians, accompanied by Table 2 summarizes trial-related serious expansive media coverage and patient advocacy group demonstrations. adverse events. June 30, 2011 ODAC votes unanimously against allowing the breast cancer indication to remain The debate began in December 2007 on the label; however, the FDA allows public comments to be submitted until when ODAC recommended, in a split July 28, 2011. decision, against approval of bevacizuAugust 5, 2011 The manufacturer files an appeal of decision in its posthearing summary, with mab. The FDA, in a move rare in its history, overrode its own committee in proposed labeling changes. granting conditional accelerated apSeptember 2011 A final decision is awaited from FDA Commissioner. proval on the basis of the pivotal E2100 a Miller KD, Wang M, Gralow A, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: study in 2008. This suggested that the a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Presented at: 28th Annual San Antonio Breast Cancer Symposium; December 8-11, 2005; San Antonio, TX. FDA accepted the end point of imb Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676. c provement in PFS, even with a lack of Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247. OS benefit, as observed in the E2100 d Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human study, for approval of an oncology agent, epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260. although most ODAC members apFDA indicates US Food and Drug Administration; ODAC, Oncologic Drugs Advisory Committee; OS, overall survival; PFS, progression-free survival. peared to disagree with this decision.
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Breast Cancer Confirmatory Studies Arrive Amid End Point Controversy The controversy is complicated by the seemingly unclear or even contradictory stance by the FDA about what it considers a “gold standard” study end point for FDA approval; however, the role of conditional or provisional accelerated ap proval, as opposed to full approval, must be put in perspective. Introduced in 1992, the accelerated approval process was originated so the FDA could grant marketing authorization, or provisional approval based on surrogate end points such as PFS, conditional on additional studies to further define clinical benefit, for agents that fulfill unmet medical needs, such as for HIV/AIDS and cancer. This process provides for more rapid access of these medications to populations with few treatment options, but does not guarantee a conversion to full approval after further studies are complete. An agent that was available, therefore, could be later taken off the market when its approval is rescinded, such as the case with the antileukemia agent gemtuzumab ozogamicin.4 For bevacizumab, not only was full approval not granted, but also withdrawal of approval was determined. This decision was based on 2 factors: an unclear clinical benefit when evaluating the end point of PFS compared with OS; and concern about the benefit-to-risk ratio. These evaluations were based on the release of 2 manufacturersponsored confirmatory trials: Avastin and Docetaxel (AVADO) and Regimens in Bevacizumab for Breast Oncology (RIBBON)-1. The randomized, double-blind, phase 3 AVADO study evaluated the use of bevacizumab in patients with HER2negative breast cancer who were treatment-naïve for metastatic disease.5 A total of 736 patients were enrolled into 1 of 3 treatment arms: docetaxel (100 mg/m2 every 3 weeks) plus placebo every 3 weeks; docetaxel plus 7.5 mg/kg bevacizumab every 3 weeks; or docetaxel plus 15 mg/kg bevacizumab every 3 weeks. Entry criteria were similar to the E2100 trial. Unlike the E2100 trial, however, patients whose disease progressed were given the option to receive bevacizumab in combination with second-line chemotherapy; approximately 34% of the docetaxel-alone group received bevacizumab after progression. There was significant improvement in PFS in the docetaxel plus bevacizumab 15-mg/kg arm (8.1 months vs 10.1 months; HR, 0.77; P = .006), although the PFS was nonsignificant in the docetaxel plus bevacizumab 7.5-mg/kg arm (9.0 months vs 8.1 months; HR, 0.86, P = .12). OS was not statistically different among treatment groups: 31.9 months in the docetaxel plus placebo group; 30.8 months in the docetaxel
plus bevacizumab 7.5-mg/kg group; and 30.2 months in the docetaxel plus bevacizumab 15-mg/kg group. Similar to the E2100 trial, more patients in the bevacizumab arms experienced grade 3 and 4 toxicity, especially neutropenia, febrile neutropenia, and hypertension (Table 2).
The controversy is complicated by the seemingly unclear or even contradictory stance by the FDA about what it considers a “gold standard” study end point for FDA approval.
The second trial, RIBBON-1, was an international, phase 3, multicenter, placebo-controlled study in treatmentnaïve patients.6 Before enrollment, the investigators selected the chemotherapy regimen of either capecitabine, or taxane/anthracycline. Patients then were randomized 2:1 to bevacizumab or placebo. The bevacizumab dose was 15 mg/kg every 3 weeks. Patients in this trial were permitted to receive open-label bevacizumab 5 mg/kg per week as secondline therapy after progressive disease. The RIBBON-1 trial used the same primary and secondary end points as the E2100, along with similar schedules and criteria to assess patients. RIBBON-1 enrolled a total of 1237 patients, 615 in the capecitabine arm and 622 in the taxane/anthracycline arm. The PFS was 5.7 months in the capecitabine plus placebo arm and 8.6 months in the capecitabine plus bevacizumab arm (HR, 0.69; P <.001). In the taxane/anthracycline plus placebo arm, median PFS was 8 months compared with 9.2 months in the bevacizumab group (HR, 0.64; P <.001). When evaluating a planned subset of taxane versus taxane plus bevacizumab, the PFS was 8.2 months compared with 9.2 months, respectively; the PFS of anthracycline versus anthracycline plus bevacizumab was also significant, 7.9 months compared with 9.2, respectively (HR, 0.55; P <.001). Again, the OS was not statistically significant among groups. In the capecitabine group, the HR for OS was 0.85 (P = .27), whereas in the taxane/ anthracycline cohort, the HR for OS was 1.03 (P = .83). Of note, after progression, 54.4% of the capecitabinealone patients and 50.7% of the taxane/anthracycline patients received open-label bevacizumab. Similar to AVADO and E2100, grade
3 and 4 adverse events in the RIBBON1 trial were significantly higher in the bevacizumab arms. Hypertension and proteinuria were increased with bevacizumab. There were more treatment discontinuations resulting from adverse effects in the bevacizumab arm. Deaths related to treatment were similar among groups. Both RIBBON-1 and AVADO did not appear to confirm the impressive 5.5-month median PFS increase seen in E2100 and confirmed a lack of OS benefit. In July 2010, therefore, ODAC met to consider these 2 trial results to recommend to the FDA either the conversion to full approval or withdrawal of approval. The committee voted 12:1 to recommend that the FDA remove the indication for metastatic breast cancer from the label, citing that the data demonstrated that PFS did not appear to act as a surrogate for OS and, therefore, a lack of favorable risk-to-benefit profile. Approval Review Following an extended review period by the FDA, which heightened expectations and resulted in emotionally charged media coverage of the impending decision, the FDA announced its plan to withdraw approval in December 2010. However, the manufacturer soon appealed by filing an opposition petition to request an administrative hearing open to the public. The focus of the appeal was mainly contingent upon the increase in PFS shown in the E2100 trial, although that trial had been criticized for being open label, making quality-of-life data less meaningful.7 Also, they argued E2100, RIBBON-1, and AVADO used PFS as the primary end point based on the assumption that the
FDA accepted this end point for approval and, therefore, the trials may have been underpowered to address OS. Furthermore, PFS may be considered an important end point for patients, because it may delay symptoms and improve quality of life. In addition, in metastatic colorectal cancer, PFS is considered a valid end point for drug approval. Additional points outlined in the appeal were that the large difference observed in PFS in the E2100 trial was not replicated in subsequent trials because of the lower dose intensity of docetaxel compared with the E2100 paclitaxel trial, which resulted from increased toxicity of docetaxel, and that there is a potentially synergistic effect between paclitaxel and bevacizumab that may not occur with other combinations. There are no data to substantiate these claims, however. The confusion by the public over the seeming back and forth on bevacizumab’s efficacy is certainly understandable when many experts, organizations, and agencies—not just the FDA and ODAC—remain divided on many issues. Other agents for metastatic cancers have been FDA-approved on the basis of a median PFS increase alone. Indeed, bevacizumab remains approved for breast cancer in several European countries and remains on the list of preferred regimens (with paclitaxel) for HER2-negative breast cancer by the National Comprehensive Cancer Network (NCCN) 2011 breast cancer guidelines, albeit with a statement that it does not increase OS.8 Additional debate also concerns whether OS is measurable in future metastatic breast cancer trials. This is especially challenging, because patients
Table 2 Serious Adverse Events (Grade 3-5) with Bevacizumab Total Control Group, %
Total Bevacizumab Group, %
Number of patients
Fatal adverse events
Thrombosis Sensory neuropathy
Left ventricular dysfunction
Bleeding events Febrile neutropenia Gastrointestinal perforation
0.3 3.4 0.3
1.2 6.3 0.5
Total serious adverse events
Data compiled from: Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676; Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247; Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260.
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Breast Cancer have several options for treatment of refractory disease that cannot be standardized in trials, as well as the crossover or access to the study agent after trial completion. Another valid argument is that sponsors should still be encouraged to design studies to address this very important end point. Despite these concerns, the recent FDA approvals of other agents for metastatic breast cancer, such as eribulin, were approved on the basis of statistically significant increases in OS.9 Unlike metastatic breast cancer, PFS recently has been validated statistically as a surrogate end point for OS in metastatic colorectal cancer.10 In addition, not all regimens recommended in NCCN guidelines for every cancer site and stage, or treatment line, are FDAapproved regimens. Unfortunately, there are not strong data to support the connection between quality-of-life data and extension of PFS in breast cancer, although this should be a research focus of the near future. Certainly the patient’s perspective about the understandable desire to access alternative treatment options should be considered strongly; and it was considered by the FDA and ODAC officials, during the 2-day public hearing in June 2011. This hearing not only included the manufacturer’s as well as patient perspectives, but also provided for physician testimonials along with much media interest.
The ODAC opinion regarding the lack of OS benefit and the questionable PFS benefit in light of the risk of serious adverse effects remained unchanged as the FDA members voted unanimously against allowing the breast cancer indication to remain on the label. Again, the manufacturer soon appealed, this time proposing labeling changes to enable a continuation of the conditional accelerated approval until a confirmatory trial of paclitaxel plus bevacizumab—the apparent preferred combination—powered to
Even the definitions of serious adverse events and “unmet medical need” are now a source of debate. assess OS can be completed.11 The proposal includes revising the labeling to restrict treatment to women with an “unmet medical need, that have fewer treatment options,” which is detailed in their proposal as women with triple receptor (estrogen/progesterone receptor [ER/PR] and HER2 receptor)-negative breast cancer, or ER-positive women with aggressive (rapidly progressing) disease with symptomatic visceral metastases. They also propose to restrict bevacizumab use to be with paclitaxel only, with updated trial data about differing
efficacy with other chemotherapy partners, and to commence a Risk Evaluation and Mitigation Strategy that would require distribution of a medication guide to every physician and patient containing detailed safety information, including serious adverse events. An Unknown Future The final chapter of this controversy is not written yet, as the FDA Commissioner has not made a final decision on the process of withdrawal of the breast cancer indication, and the date of this decision remains unknown. Even the definitions of serious adverse events and “unmet medical need” are now a source of debate—the manufacturer argues that the risks appear manageable, whereas others report that bleeding and thrombotic events carry significant risks. Experts continue to argue that there are other treatment options for metastatic breast cancer; therefore, bevacizumab is not fulfilling an unmet need. The highrisk subpopulations as defined previously have not been identified statistically to have greater responses to bevacizumab in the clinical trials. Certainly, there is an argument made by patients who have had a good response to this treatment and want to continue to have access to as many options as possible for the treatment of a serious, incurable disease. The impact of this decision also remains unknown and leaves many questions unanswered.
Reader Poll ©iStockphoto.com/YinYang
Have patients asked you about the situation with bevacizumab and the FDA? To weigh in on this question, please log on to www.TheOncologyPharmacist.com. 16
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• What is the gold standard study end point required by the FDA: PFS or OS? • Should PFS be considered a clinically meaningful end point and, if so, what is an appropriate risk-tobenefit ratio? • How will the decision impact insurance coverage for women already on bevacizumab for metastatic breast cancer and, until this is known, should any new patients be started on this regimen? • Will this decision impact accrual to clinical trials in breast cancer using bevacizumab? Clearly studies need to continue to clarify whether PFS may be a surrogate for OS in metastatic breast cancer, and whether an increased PFS confers any benefit on quality of life. Ultimately, the goal would be to identify women through genetic or other markers who will most benefit from treatment. Until then, questions remain regarding the use of bevacizumab, including is this the end of the line for this agent in breast cancer? ● References 1. Goren M. Roche may keep some Avastin sales if US breast cancer label lost. Wall Street Journal. June 27, 2011. http://online.wsj.com/article/BT-CO-20110627704044.html. Accessed September 8, 2011. 2. Miller KD, Wang M, Gralow A, et al. A randomized phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group (E2100). Presented at: 28th Annual San Antonio Breast Cancer Symposium; December 8-11, 2005; San Antonio, TX. 3. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676. 4. US Food and Drug Administration. FDA: Pfizer voluntarily withdraws cancer treatment Mylotarg from U.S. market. June 21, 2010. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm216448.htm. Accessed September 1, 2011. 5. Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28:3239-3247. 6. Robert NJ, Diéras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011;29:1252-1260. 7. Horning SJ, Labson MS, Schmidt PW. Submission of Genentech, Inc. in response to the Food and Drug Administration’s Notice of Opportunity for a hearing and proposal to withdraw approval of AVASTIN® (bevacizumab) in combination with weekly paclitaxel for the first-line treatment of patients with metastatic breast cancer. Docket No. FDA-2010-N-0621. January 16, 2011. www.gene.com/gene/news/news-events/avastin/ documents/NOOH-Prim-Sub-Doc_FINAL_ 16JAN2011.pdf. Accessed September 10, 2011. 8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2011. www.nccn.org/professionals/physician_gls/pdf/breast. pdf. Accessed September 5, 2011. 9. US Food and Drug Administration. Eribulin mesylate. November 23, 2010. www.fda.gov/AboutFDA/Centers Offices/CDER/ucm234527.htm. Accessed September 23, 2011. 10. Grothey A, Hedrick EE, Mass RD, et al. Responseindependent survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Oncol. 2008;26:183-189. 11. Horning SJ, Labson MS, Schmidt PW. Post-hearing submission of Genentech, Inc. in support of maintaining the accelerated approval of AVASTIN® (bevacizumab) in combination with paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer. Docket No. FDA-2010-N-0621. August 4, 2011. www.cancerletter.com/downloads/20110812_1/down load. Accessed August 30, 2011.
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CONTINUING EDUCATION PROGRAM P1108 • RELEASE DATE: FEBRUARY 28, 2011 • EXPIRATION DATE: FEBRUARY 28, 2012 ESTIMATED TIME TO COMPLETE: 1.0 HOUR • COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM
Update on Non-Hodgkin Lymphoma: Alignment of the Current Treatment Landscape and Value-Based Care TARGET AUDIENCE This activity was developed for pharmacists and other healthcare professionals practicing in a managed care environment. LEARNING OBJECTIVES After completing this activity, the reader should be able to: • Explain the impact of key clinical data presented at ASH 2010 on payers and providers in the treatment and management of non-Hodgkin lymphoma (NHL) • Identify patient/disease-associated factors, as well as economic factors that may affect the choice of a therapeutic agent and be able to formulate a management strategy using a riskadapted approach to the treatment of NHL • Construct informed treatment decisions for the purpose of improving the long-term outlook for patients with NHL across the lifecycle of the disease • Identify and discuss the future of NHL treatment and the potential clinical, business, and regulatory changes that could affect the cost-value benefit design
This activity is jointly sponsored by the Medical Learning Institute, Inc. (a nonprofit medical accreditation company), and Center of Excellence Media, LLC.
Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 04689999-11-003-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 For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc., at 609-333-1693 or cgusack@ mlicme.org.
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. • John Fox, MD, and James T. Kenney, RPh, MBA, have nothing to disclose. • Caroline Helwick has stock ownership at Micronet.
The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CE activity for any amount during the past 12 months. 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. COmmERCIAL SUPPORT ACkNOwLEDGmENT This activity is supported by an educational grant from Genentech.
Payers’ Perspectives on Non-Hodgkin Lymphoma: Aligning Current Treatments with Value-Based Patient Care By Caroline Helwick
t the 2010 annual meeting of the American Society of Hematology (ASH), many presentations focused on current and new therapies for non-Hodgkin lymphoma (NHL), the benefits and risks of these therapies and the associated costs and their impact on health insurance plans and patients. The following article provides updates on key presentations delivered at the 2010 ASH meeting, focusing on value-based care for patients with NHL and the associated cost issues that are of concern for payers and patients. The article highlights concerns relevant to the alignment of best available cancer therapies with the needs of patients, payers, and other healthcare stakeholders involved in the management of this disease.
Early Rituximab Therapy in Asymptomatic Follicular Lymphoma Shows Benefit An early course of rituximab can help to defer chemotherapy for nearly 3 years for patients with follicular lymphoma (FL), according to a key study presented at ASH 2010.1 FL is the most common of the indolent lymphomas, accounting for nearly one fourth of the NHL cases in North America. Previous research has shown
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little benefit for treating patients with FL who have not developed symptoms; the disease typically presents at an advanced stage, and patients are often asymptomatic. “Follicular lymphoma is a slowgrowing cancer that is usually widespread when it is diagnosed. It is generally considered to be incurable, and patients have an average life expectancy of 10 to 12 years. Many people feel very well when they are first diagnosed and do not have any symptoms. We know from previous studies that there is no benefit in starting treatment early when patients have no symptoms, compared to waiting until symptoms develop,” said Kirit M. Ardeshna, MD, of University College London Hospitals, United Kingdom. As a result, most physicians normally defer treatment for NHL and monitor patients closely until the disease progresses, usually at around 2.5 years, although a growing number of American clinicians have already begun early treatment, according to Ardeshna. This study supports that practice.1 Ardeshna added that although “watchful waiting” delays the side effects of treatment, it creates anxiety in many patients. Early treatment would be an option for these patients.
Study Details The study randomized 462 patients into 3 treatment arms: • Watch and wait (ie, no rituximab; n = 186) • Rituximab (375 mg/m²) weekly for 4 weeks (rituximab induction; n = 84). This arm was closed midway through the trial, because of slow recruitment and because several other studies were showing a benefit to rituximab maintenance • Rituximab induction followed by ri tuximab maintenance (n = 192), which consisted of 1 dose of rituximab given every 2 months for 2 years, starting at month 3 and given until month 25. The primary end point of the study was time to initiation of new chemotherapy or new radiotherapy at 3 years. Overall, only 48% of patients in the watch-and-wait arm had not started chemotherapy or radiotherapy, whereas in the rituximab induction arm, 80% of patients were treatment free, and in the rituximab maintenance arm, 91% of patients were free of treatment (Figure 1).1 Median time to initiation of chemotherapy was not reached at 4 years in the rituximab arms. Progression-free survival (PFS) at 3 years was 81% for the maintenance arm versus 33% for the
observation arm, representing a 79% reduction in risk (P <.001; Figure 2), Ardeshna reported. Rituximab was well tolerated, with few adverse events. There were 7 infections (all grade 3 that required intravenous antibiotics); 5 cases of allergic reactions that resulted in bronchospasm in 2 patients; and 4 cases of neutropenia. “Our study has shown that we can defer chemotherapy by a long time in patients who have asymptomatic follicular lymphoma,” Ardeshna commented. He predicted that such an approach will prove attractive to patients, because they can defer chemotherapy and avoid the associated side effects for a longer time. “I imagine this will become the standard of care,” he said. The trial answered questions that have been on the minds of hematologists for some time: should asymptomatic patients, or those who have low tumor burden, be watched or treated? Does early treatment offer a clinical benefit to them? asked Nancy Valente, MD, global head of the hematology development at Genentech/Roche. In this study, early treatment was shown to benefit patients who normally would be followed carefully, offering an alternative to the current care standard, Valente said.
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Multiple Studies Confirm Benefit of Maintenance Rituximab in Follicular Lymphoma For several years, treatment with rituximab for patients who respond to induction therapy has been widely recommended. Studies of patients with FL presented throughout the meeting confirmed the benefit of maintenance therapy with rituximab and offered data on safety and outcomes with longterm use.
nance and in 24% not receiving maintenance rituximab. Grade 3 or 4 adverse events were found in 24% and 17% of patients, respecTheOncologyPharmacist.com tively, and patients in the maintenance arm experienced more neutropenia (4%) than patients not in the rituximab maintenance arm (1%).
Three Years of Maintenance Delays Progression A retrospective population-based analysis using the British Canadian Cancer Agency Lymphoma Cancer Database confirmed better outcomes with maintenance rituximab versus observation.4 The study included 251 patients receiving R-CVP as induction therapy up to January 2010. Outcomes of responders who received maintenance therapy versus observation were compared. With a median follow-up of 3 years, Figure 1
87% of patients were alive and 13% had died; 11% developed progressive disease while receiving rituximab maintenance, and within this subset of patients, 23% of patients in PR converted to CR/CRu while receiving maintenance therapy, reported Alden A. Moccia, MD. The 3-year PFS estimate was significantly higher for patients receiving maintenance compared with those observed after having responded to
Time to Initiation of New Therapy 1.0 0.9
Proportion of patients with no new treatment initiated
Benefit Sustained at 2 Years in PRIMA In 2009, the Primary Rituximab and Maintenance (PRIMA) trial firmly established the benefit of 2 years of maintenance therapy with rituximab in patients with FL who respond to induction immunochemotherapy.2 At ASH 2010, PRIMA investigators reported that after 3 years of follow-up, maintenance therapy sustained these benefits.3 “Rituximab maintenance therapy improved PFS and response rates, with no unexpected toxicities. All patients randomized to maintenance therapy have excellent survival to date,” said Gilles Andre Salles, MD, of the Centre Hospitalier Lyon-Sud, Pierre-Benite, France. “The take-home message is that for patients who need treatment, efficacy can be improved by adding 2 years of maintenance therapy with rituximab. The PRIMA results indicate that rituximab maintenance should be considered in all FL patients who respond to firstline immunochemotherapy.” “For patients with a high tumor burden, the PFS of 79% seen 3 years after randomization has not been seen before in large studies of follicular lymphoma,” he added. Salles presented data on 1193 patients randomized to induction chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone; n = 805), R-CVP (rituximab, cyclophosphamide, vincristine, prednisone; n = 272), or RFCM (rituximab, fludarabine, cyclophosphamide, and mitoxantrone; n = 45). Patients in complete remission (CR), unconfirmed CR (CRu), or partial remission (PR) were eligible for randomization to either rituximab maintenance therapy (n = 505) or observation (n = 513). Rituximab was given as 1 infusion of 375 mg/m2 every 8 weeks for 2 years. At the time of randomization, the CR rate was 39%, the CRu rate was 31%, and the PR rate was 29%.3 The overall response rate (ORR) to maintenance rituximab was robust: 52% of patients in PR after induction converted to CR/CRu after 2 years of maintenance compared with 30% of the observation arm (P = .0001). The 3-year PFS was 60.3% in the observation arm and 78.6% in the rituximab maintenance arm (P <.001). The effect of rituximab was consistent across age-groups, sex, Follicular Lymphoma International Prognostic Index score, induction chemotherapy type, and response to induction chemotherapy. At the time of data cut-off, mortality rates were similar between groups: 5% in the rituximab maintenance arm and 6% in the observation arm. Infection was the most common adverse event, occurring in 39% of patients receiving rituximab mainte-
0.8 0.7 0.6 0.5 0.4 0.3 0.2
W+W R4 R4 + RM
0.1 0.0 0
Events Totals 83 187 19 84 19 192
% not requiring Rx at 3 yrs W + W = 48% R4 = 80% R4 + RM = 91% 3
Years from randomization HR (rituximab vs W + W) = 0.37; 95% CI = 0.25, 0.56; P <.001 HR (rituximab + M vs W + W) = 0.20; 95% CI = 0.13, 0.29; P <.001 HR (rituximab + M vs rituximab) = 0.57; 95% CI = 0.29, 1.12; P = .10 CI indicates confidence interval; HR, hazard ratio; M, maintenance; R4, rituximab induction arm; RM, rituximab maintenance arm; W + W, watch and wait.
Progression-Free Survival 3-yrs PFS W + W = 33% R4 = 60% R4 + RM = 81%
Proportion of patients progression-free
Commentary and Concerns The new data come from “a very highquality study” and show that there is a clear advantage to starting rituximab therapy early on, even before symptoms arise,1 said Charles Abrams, MD, of the University of Pennsylvania, Philadel phia, who is Secretary of ASH. “These data will lead to changes in clinical practice, perhaps not so much in the United States as elsewhere in the world,” Abrams predicted. He explained that in the United States, some clinicians are already taking this approach, whereas in Europe and Canada clinicians treat more conservatively. The study, or at least the preliminary analysis, also did not address quality-of-life (QOL) issues, which was of concern to some ASH attendees. The study also did not show an overall survival (OS) benefit, with 96% of patients in both arms alive at 3 years.1 Ardeshna stressed that this was a preliminary analysis and that QOL measurements, as well as OS, would be part of the next phase of research. Other hematologists raised concerns about the cost of treating patients with many more courses of rituximab, and some questioned whether early treatment with rituximab may blunt a patient’s response to immunochemotherapy down the line, when it may be more warranted. Ardeshna said that he believes early treatment will not compromise future response, speculating that it may lead to tumor shrinkage and reduce genetic mutations, thus setting up patients to be even better candidates for therapy. He also pointed out that some patients—perhaps 1 of 5—will never develop full-blown disease, because their tumor will remain indolent for many years. “At the moment, however, we can’t identify them,” Ardeshna said. “We have no way of knowing who will progress and who won’t.” Future research may refine the patient subgroups that will benefit most from treatment in the asymptomatic state, thus sparing some patients a long and expensive therapy. “We are going to be following these patients, and the study will be ongoing for several years. We are in this for the long term,” he said.
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0.8 0.7 0.6 0.5 0.4 0.3 0.2
W+W R4 R4 + RM
0.1 0.0 0
Events Totals 108 181 33 83 33 189 2
Years from randomization HR (rituximab vs W + W) = 0.46, 95% CI = 0.33, 0.65, P <.001 HR (rituximab + M vs W + W) = 0.21, 95% CI = 0.15, 0.29, P <.001 HR (rituximab + M vs rituximab) = 0.43, 95% CI = 0.24, 0.72, P = .001 CI indicates confidence interval; HR, hazard ratio; M, maintenance; PFS, progression-free survival; R4, rituximab induction arm; RM, rituximab maintenance arm; W + W, watch and wait.
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CONTINUING EDUCATION R-CVP: 83% versus 62%, respectively (P = .002). The 3-year OS was similar, at approximately 92%. “This population-based analysis confirms the benefit of rituximab maintenance following immunochemotherapy in patients with untreated follicular lymphoma,” Moccia said. In addition, the R-CVP regimen produced outcomes that compared favorably with more intensive combinations and appeared less toxic. Patients whose disease was refractory to R-CVP had a poor prognosis.
2 or more years, of which 48 have been treated for at least 3 years. According to Taverna, 2 patients have completed 5 years of maintenance rituximab. He acknowledged concerns about infections associated with long-term rituximab use, and pointed out that the low incidence of infections observed in the SAKK trial might be attributed to the fact that induction was accomplished with rituximab monotherapy—not in combination with chemotherapy, as in previous studies.
Safety Demonstrated Over 3-Plus Years The safety of 3 or more years of “prolonged maintenance” was validated in the phase 3 Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) 35/03 trial, which was led by Swiss investigators.5 “We found that rituximab maintenance beyond 2 years is feasible, without evidence of increased toxicity,” said Christian Taverna, MD, of Kantonsspital Munsterlingen, although he advised close monitoring of such patients. All 270 patients (untreated, chemotherapy-resistant, or relapsed) received rituximab induction, and responders were randomized to a short maintenance of 4 doses every 2 months or prolonged maintenance with rituximab given every 2 months for up to 5 years. Safety was assessed after 3.3 years. During maintenance therapy, 899 adverse events were observed, only 28 of which were grade 3, and 8 were grade 4. Grade 3 neutropenia occurred in 5 patients and grade 4 occurred in 1 patient. Seven grade 3 or 4 infections were reported, primarily pneumonia, appendicitis, and diverticulitis. Five patients developed subsequent cancers. In the prolonged maintenance arm, 2 patients discontinued treatment because of unacceptable toxicity after 16 and 42 months, respectively, and 1 discontinued treatment because of subsequent breast cancer after 20 months. Of the patients, 63 remain on maintenance for
Rituximab Peritransplant Improves Outcomes Autologous stem cell transplantation (ASCT) significantly improves PFS and OS in patients with relapsed or resistant FL compared with chemotherapy alone, and studies have suggested that rituximab given around the time of transplant further improves survival outcomes. However, in contrast to maintenance rituximab post chemotherapy in untreated FL, the true benefit and safety of maintenance rituximab after ASCT is unknown.
FDA Approved Rituximab for Advanced Follicular Lymphoma On January 28, 2011, the US Food and Drug Admin is tra tion ap proved rituximab as a maintenance treatment for pa tients with advanced FL who responded to initial therapy with this drug plus chemotherapy (ie, induction therapy). This approval echoed the recommendation by the European Commission in Oct ober 2010 to approve rituximab for this indication.
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Studies of patients with FL presented throughout the meeting confirmed the benefit of maintenance therapy with rituximab and offered data on safety and outcomes with long-term use. Investigators from the United Kingdom evaluated this approach, which is called in vivo purging pretransplant with immediate posttransplant maintenance.6 They found that rituximab in vivo purging and maintenance resulted in superior PFS compared with no rituximab, although OS was not improved, and 80% of patients in both arms were alive at 5 years. The drug did not compromise peripheral blood stemcell harvesting or engraftment, reported Ruth Pettengell, MD, of St. George’s University of London. The study included 280 rituximabnaïve patients in their first, second, or third remission (80% had 2 prior lines of therapy) who responded to induction chemotherapy and were randomized to rituximab purging (375 mg/m2 4 times weekly) versus no purging. Both were followed by stem cell collection and high-dose therapy, then randomization to maintenance rituximab 375 mg/m2 every 3 months for 2 years or to observation. Transplant was accomplished in 70%
of patients. No graft failures or late neutropenia were reported. Transplant-related mortality was 0.5%. Only 3 infectionrelated deaths were reported within 5 years, Pettengell said. Results showed that 5-year PFS was highest when patients received rituximab purging plus maintenance: 62.9% versus 37.6%, for patients receiving no rituximab purging or maintenance, respectively, for a 24% significant reduction in risk (P = .004). Maintenance also provided significant benefits in delaying disease progression. The 5-year PFS in patients on maintenance therapy was 54.9% versus 42.0% without maintenance therapy, respectively, a 35% risk reduction (P = .01), although OS was similar at around 81% per arm, Pettengell said. “Rituximab in vivo purging and maintenance resulted in superior PFS compared with no rituximab,” she said, “and posttransplant maintenance significantly improved PFS compared with observation. The PFS curve at 6 years suggested that a subset of patients may achieve durable disease control.” Lymphoma: Rituximab Efficacy Shown in Several Treatment Combinations Rituximab has become an almost universally useful agent in NHL treatment. The biologic agent is designed to be highly specific for its target: cancerous B-cells of the immune system. The targeting is so precise that rituximab is able to approximate, if not surpass, the rates of efficacy for chemotherapeutic agents while having none of the chemotherapy-related toxicities. These qualities make it a very attractive candidate for combination regimens in the setting of NHL. Three such regimens were highlighted at ASH 2010. GELA: Study of Elderly Patients A growing number of patients with NHL are elderly, and the Groupe d’Etude Des Lymphomes De L’Adulte (GELA) study evaluated a regimen that may prove effective and less toxic in patients aged ≥80 years.7 “In Western Europe, an 80-year-old man presently has a remaining 9.5 years of life expectancy,” said Frederic Peyrade, MD, of the Centre Antoine Lacassagne, Nice, France. “That means that by 2050, there will be twice as many individuals in this age bracket as there are now, and that will represent greater than 15% of the overall population.” The lymphoma caseload among the elderly will inevitably increase, he concluded, yet little data are available to guide treatment choice or even the decision of whether to treat these patients at all. To evaluate a tolerable treatment regimen, GELA enrolled 149 treatment-
naïve, diffuse large B-cell lymphoma (DLBCL) patients and treated them with rituximab in combination with a reduced-dose version of CHOP, termed “R-mini-CHOP,” given every 21 days for 6 cycles. After a median follow-up of 20 months, the ORR was an impressive 74%, with 40% of patients having a CR; this success translated into a 2year survival rate of 59%. Grade 3 and 4 toxicities were uncommon and generally occurred within the first treatment cycle. Reflecting on the quality of the responses, Peyrade stated, “It means that even with these very old patients, obtaining the best response possible remains crucial in terms of overall survival.” In general, he said, these results indicate that even patients aged >80 years should be considered for treatment. Rituximab/Bendamustine Mathias J. Rummel, MD, PhD, of JustusLiebig Universität Giessen, Germany, reported final results of NHL 2-2003 from the Study Group of Indolent Lymphomas.8 The trial examined the use of rituximab in combination with bendamustine (R-Bd), an alkylating agent available for years in Europe but not approved in the United States until 2008. NHL 2-2003 compared this combination with a standard regimen of rituximab/fludarabine (R-F). The purpose of the study was a so-called “noninferiority” determination between the 2 therapeutic approaches. NHL 2-2003 enrolled 219 patients with a variety of lymphomas, mostly FL (47%) and mostly advanced disease for which patients had received prior treatment. Results for the R-Bd combination were more favorable than those achieved with standard R-F, with ORRs of 82% versus 49%, respectively, and CRs of 39% versus 16%. Event-free survival (EFS) was 30.4% for R-Bd versus 11.2% for R-F. Best responses were observed in the FL subgroup. Side effects were less common than previously seen with this regimen, said Rummel. Grade 3 and 4 toxicity was uncommon, and most complaints were for nausea and fatigue. Slightly more infectious complications occurred with R-Bd, but the difference was not significant; no dose reductions were required. OS was similar for the 2 regimens; however, the protocol was amended midstudy to implement the newly established paradigm of 2 years of rituximab maintenance. It is uncertain what effect, if any, this had on the comparisons of eventual outcome for study patients, he said. Rituximab/Bortezomib Bortezomib, a proteasome inhibitor cur-
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rently indicated for use in multiple myeloma and advanced mantle-cell lymphoma, was combined with rituximab (R-Bt) in a large phase 3 trial that enrolled 676 patients with relapsed, rituximab-naïve, or rituximab-sensitive FL.9 Results for the combination versus rituximab alone were reported by Bertrand Coiffier, MD, PhD, of the Hospices Civils de Lyon, France. Because bortezomib had previously shown activity in heavily pretreated patients with indolent lymphoma, and preclinical evidence suggested promise for the R-Bt combination, Coiffier and colleagues predicted a therapeutic response with R-Bt in patients with FL, he explained. Patients were randomized to rituximab or the R-Bt combination, treated for 25 weeks, and followed for a median of 33.9 months. As expected, because of advanced disease, discontinuation rates in this study were high (29%); however, response was good in light of considerable pretreatment, Coiffier reported. The ORR was 63% with the combination versus 49% with rituximab alone, and CRs were achieved in 25% and 18%, respectively. Differences in PFS, however, were slight: PFS was 12.8% for R-Bt versus 11% for rituximab alone. Patients with the worst prognosis at baseline, however, fared significantly better with the combination. “This is important for me,” said Coiffier, “that the patients with the higher risk to progress still do better with the combination.” Toxicity for R-Bt was higher than for rituximab alone, but grade 3 and 4 side effects were uncommon and transient. Based on these results, Coiffier said that he hoped that future efficacy could be boosted with a combination of R-BtCHOP. Radioimmunotherapy in NHL Various novel approaches have been tested in an attempt to improve CR rates and achieve a survival advantage in indolent NHL. A regimen that combines chemotherapy induction (fludarabine and mitoxantrone), consolidation with radioimmunotherapy (90Y- ibritumomab tiuxetan), and maintenance with rituximab produced durable responses without additional toxicity in a small study of 22 patients with FL presented at the meeting by Reem Karmali, MD, of Rush University Medical Center, Chicago.10 The ORR to induction was 95%, and 19 patients continued to radioimmunotherapy, all of whom responded. Radioimmunotherapy converted 60% of PRs to CRs. During or after maintenance rituximab, the response rate was 80%, and 75% of the responses were CRs. The lower response rate—from 95% to 80% during maintenance—reflects relapses, Karmali reported.10
At a median follow-up of 49.6 months, median PFS was 47.2 months. Seven patients relapsed, and 2 of these patients died. Of the remaining patients, 24% are stable and 76% are in CR. Approximately 80% are alive at 6 years. Karmali suggested that, “This regimen is a viable option in the frontline treatment of FL patients with high tumor burden and intermediate-high FL scores.” R-CHOP Plus Radioimmunotherapy Effective Karmali also led a phase 2 study in 20 patients with DLBCL that evaluated a regimen combining R-CHOP-14 (RCHOP every 2 weeks for 6-8 cycles) cycles with radioimmunotherapy consolidation with 90Y-ibritumomab tiuxetan given 6 to 8 weeks after immunochemotherapy was completed.11 After R-CHOP-14 induction, the PR rate was 25% and the CR rate was 75% (ie, all patients responded). After radioimmunotherapy, 4 patients converted to CR, for a conversion rate of 80%. At a median follow-up of 44.2 months, the relapse rate was only 15%. “All these patients had high-risk features and received further treatment,” he said. “One is now in CR.” Median PFS was 92.6 months, and median OS has not been reached. To date, 17 patients remain alive, all in CR, making the estimated median OS 125 months. Grade 3 or 4 neutropenia developed in 50% of patients, but no patients developed neutropenic fever. There were no cases of myelodysplastic syndrome/ acute myeloid leukemia. “Dose-dense R-CHOP followed by Zevalin [ibritumomab injection] consolidation maintains durable responses with good tolerability,” Karmali said. “An 80% conversion rate of PR to CR was achieved after radioimmunotherapy.” Karmali said that he believes both novel regimens his group is studying warrant further investigation in randomized trials. Progression of FL Is Costly Disease progression is associated with significantly higher costs and healthcare utilization for patients with FL compared with those with stable disease, and treatment that prevents or delays progression not only improves clinical outcomes but also provides economic benefits in lowering the cost of care, a study from Genentech and US Oncology showed.12 “Follicular lymphoma accounts for approximately 70% of indolent lymphomas. We estimated the marginal cost of progression for patients with FL treated in the outpatient community setting,” said Sacha-Satram Hoang, PhD, of Genentech, South San Francisco. Using US Oncology’s iKnowMed electronic medical record (EMR), inves-
tigators identified 1002 patients with FL who achieved CR or stable disease. The database captures information from a network of approximately 1200 community-based oncologists who treat patients according to usual clinical practice, with no criteria for therapy selection and no schedule of visits imposed. To estimate outpatient cost of care, the study linked the EMR data to US Oncology’s claims data warehouse. Patients were categorized into 2 cohorts based on whether they experienced disease progression. Costs per patient per month (estimated based on outpatient claims and normalized to 2007 Medicare reimbursement rates) were compared between patients who did and did not progress. Econometric regression analysis was used to compare healthcare costs after adjusting for potential confounders. The study also compared resource utilization as measured by outpatient physician visits, chemotherapy visits, laboratory procedures, and acute care visits. Of the 1002 patients with FL, 204 progressed and 798 did not. At baseline, patients with disease progression were more likely to have been diagnosed with advanced disease, have 4 or more positive lymph nodes, have worse performance status, and have high lactate dehydrogenase and low hemoglobin levels compared with patients whose disease did not progress.12 The mean overall costs per patient per month over the 6-month follow-up period were significantly higher for patients who progressed: $3612 versus
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$965, respectively, for a very significant difference of $2647 (P <.001).12 Differences in cost were significant in all categories (Table 1). This resulted in a relative cost that was nearly 4 times higher for patients who experienced disease progression. After adjusting for differences in clinical factors, disease progression was associated with a 2-fold increased cost (P <.001). The cumulative 6-month total cost for patients who progressed was $21,496 versus $5165 for nonprogression,12 Hoang reported. Patients with disease progression had significantly higher frequencies of outpatient physician visits and laboratory procedures compared with patients without progression and were significantly more likely to receive chemotherapy and be admitted to the hospital and/or emergency department. The investigators believe these costs may be underestimated. “We followed patients for a maximum of 6 months, which may have led to an underestimation of reported costs and the rate of treatment failure of progressive disease. Also, costs for radiologic services and inpatient consultation visits may be
NICE Recommends Maintenance Treatment for Follicular NHL Coinciding with ASH 2010, the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) issued preliminary draft guidance recommending the use of rituximab as a first-line maintenance treatment for certain patients with advanced FL, based on evidence that rituximab delays disease progression. The recommendation pertains to patients with advanced FL that have responded to first-line induction therapy with rituximab in combination with chemotherapy. Peter Littlejohns, Clinical and Public Health Director at NICE, commented, “A maintenance treatment is used to stop a cancer from returning following initial chemotherapy. For FL, no such maintenance treatment has so far been available, and therefore rituximab could be a valuable treatment option. The evidence highlighted that it could keep a patient’s cancer in remission after they have had chemotherapy and therefore delay the need for further chemotherapy. This should mean that patients have fewer chemotherapy-associated side effects long-term and so improve their quality of life. “However,” he continued, “the evidence submitted by the manufacturer did include some uncertainties, mostly around the extent to which rituximab can extend a patient’s life expectancy and the impact of this assumption on its costeffectiveness. While the committee felt that the drug is likely to be an appropriate use of NHS [National Health Service] resources, it expects that the manufacturer will confirm this by providing further, more specific, information.” The NICE Appraisal Committee is particularly interested in obtaining a revised cost-effectiveness analysis for patients aged 60 to 65 years (the age at which most people are first treated in the United Kingdom) at the start of treatment and in which the duration of clinical benefit from rituximab maintenance treatment is 3 to 4 years. Once all questions have been answered, NICE will issue full guidance on maintenance rituximab.
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CONTINUING EDUCATION underestimated since patients may have received these outside the US Oncology Network,” Hoang suggested. The implications of the findings, according to the researchers, are that therapies that delay disease progression for FL may provide substantial economic benefits in addition to improvements in clinical outcomes. Rituximab Maintenance Shown Cost-Effective in UK Study The phase 3 PRIMA study demonstrated that rituximab maintenance therapy after induction immunochemotherapy in patients previously untreated for FL significantly improves PFS, with little additional toxicity.2 Using clinical evidence from PRIMA, an economic analysis presented at ASH 2010 evaluated whether rituximab maintenance after a response to rituximab-chemo therapy induction is a cost-effective option compared with observational practices in the United Kingdom’s National Health Service (NHS).13 The findings were presented by Konstantinos Papadakis, MD, of Hoffmann-LaRoche, Welwyn Garden City, United Kingdom. The study used a transition state (Markov) model in which patients with FL and complete or partial response to first-line immunochemotherapy induction were assigned across 4 health states reflecting their disease status—PFS in first-line maintenance, PFS in secondline maintenance, progressive disease, or death. The model incorporated a 25-year horizon to capture the lifetime of an average patient. Data from key trials and treatment guidelines were used to develop probabilities. It was assumed that the treatment benefit of maintenance was sustained for 72 months. Beyond that point, treated patients have the same probability of progression to second-line maintenance as patients who were only observed. Costs associated with the average dose of rituximab maintenance, postprogression treatments, and management of grade 3 and 4 adverse events observed in PRIMA were incorporated into the rele-
Rituximab in vivo purging and maintenance resulted in superior PFS compared with no rituximab, although OS was not improved, and 80% of patients in both arms were alive at 5 years.
vant health state. Drug administration, patient monitoring, and pharmacy costs were informed by expert opinion and the NHS schedule of reference costs. The average OS in the first-line maintenance cohort was projected to be 1.27 years longer on average than with observation (10.31 years vs 9.05 years), and to be associated with an additional 1.17 quality-adjusted life-years (QALYs). “This is largely due to patients treated with first-line rituximab maintenance spending more time progressionfree in the first line (1.17 years),” Papadakis said. Total costs were £14,129 higher with first-line maintenance than with observation and were driven by the cost of the study drug and its administration. However, this was partially compensated by the lower costs of rituximab therapy in the second line, where the cost-savings were £198, as well as lower costs of supportive care incurred at disease progression, where £906 was saved, he said. The incremental cost-effectiveness ratio (ICER) for first-line rituximab maintenance was £14,712 per life-year gained and £15,983 per QALY gained, “well below an assumed willingness to pay the threshold of £30,000,” he noted. Although there is uncertainty associated with the cost of FL progression and relapse treatment, the ICER did not exceed £21,155 per QALY despite a wide variation in each parameter value used in the probabilistic and deterministic sensitivity analyses, he added. “The cost-effectiveness of rituximab maintenance in follicular lymphoma patients after response to immuno chemotherapy is well within the acceptable willingness-to-pay ceiling and remains valid under most plausible sensi-
Drug Regimens R-CHOP: Rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone R-CVP: Rituximab, cyclophosphamide, vincristine, prednisone R-FCM: Rituximab, fludarabine, cyclophosphamide, mitoxantrone R-Bd: Rituximab, bendamustine R-F: Rituximab, fludarabine R-Bt: Rituximab, bortezomib
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tivity scenarios,” he said. “This provides adequate reassurance that the superior clinical benefits of first-line maintenance are sufficient to justify the additional costs over observational practice.” Practice Makes Perfect Two sessions presented under the “Practice Makes Perfect” banner at ASH 2010 drew attendees concerned about emerging requirements that providers and payers demonstrate “quality care.” New Models for Payment: Pathways Pathways take clinical guidelines a step further, not only evaluating treatments for their evidence basis and toxicity but—these factors being equal—also determining (and advocating) treatments that are more cost-effective, said Gerald Robbins, MD, of Florida Cancer Institute, New Port Richey, who presided over a session called “New Models for Payment, Pathways, and Insurers.” “Many people view pathways as something thrown together,” he said in an interview “but to construct pathways correctly requires a tremendous amount of effort and structure.” Therefore, he added, not all pathways are equal. Two of the most well-known pathways come from US Oncology and the University of Pittsburgh Medical Center (UPMC). These pathways started within committees that were already established for disease management. The committee members reviewed data; developed, reviewed, and voted on the pathways; had the larger membership vote on the pathways; and had a built-in structured review of the pathways every 3 to 6 months. In other words, the pathways stand up to scrutiny, Robbins emphasized. “There are practice-changing findings that emerge, and you have to be prepared to alter the pathway on the basis of new data. You need to be fluid; you need to have a process for reevaluation and physician input,” he pointed out. The Florida Society of Clinical Oncology (FLASCO) has been interested in choosing a pathway program and has evaluated those offered by US Oncology, UPMC, P4 Healthcare, and others. The aim is to find a pathway that will be acceptable to all members and that will mesh well with payers’ needs, noted Robbins, who is President of
FLASCO. “We will be writing a report on various pathway programs and our recommendations, but will not make one single endorsement,” he said. “We are looking at various pilot programs, with the goal of improving quality and controlling costs.” “We are trying to be very proactive with the payers. Our membership also feels a global responsibility for controlling healthcare costs. Physicians see the same growth in the cost curve and a nonsustainable trend,” Robbins emphasized. “And we are trying to change the typically adversarial relationship with payers to one of more cooperation.” That change can be seen in several forms—a payer relations committee intended to improve communications with payers, meetings with medical directors, and a “payer’s summit,” to which the medical directors of several companies were invited to meet with FLASCO representatives. “We discussed what is important to payers and to FLASCO members,” he said. For example, FLASCO and its members want to avoid having to use a pathway for one payer, and another for a different payer, he offered. “This would be a nightmare.” By the same token, Robbins continued, “what if a group decides on a pathway and the carrier responds that it cannot scale up so that each practice uses its own pathway?” The summit laid bare such scenarios and facilitated transparency, he explained. “For payers and providers to work together you have to have a comfort zone and transparency. We are taking baby steps. Several payers have reciprocated and have shown an interest in working with us on these details. Admittedly, it’s strange territory for doctors to partner with insurance companies, as much as the opposite,” Robbins commented. The session provided for discussion about how pathways are being developed and used in hematology and allowed an opportunity for some venting, he said. “The attendees were very concerned about the future of outpatient hematology/oncology, and how these pathways will impact their practices. They were interested in learning about them, because they realize they are one of the most important ways of controlling costs,” Robbins pointed out. Pay-for-Performance and PQRI Participation in so-called physician quality reporting initiatives (PQRIs) has not been particularly robust and may not be the best way to encourage quality care, according to Steven L. Allen, MD, Assistant Chief of Hematology, North Shore Long Island Jewish Health System, Manhasset, New York. Allen led a session on pay-for-performance programs and PQRI, noting that
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“Participation has so far been poor in the PQRI program of the CMS [Centers for Medicare & Medicaid Services]. However, for those who have become involved, about 90% successfully complete the 4 measures.” The metrics, which Allen helped to develop, gauge whether hematologists perform flow cytometry and cytogenetic tests appropriately at diagnosis, prescribe bisphosphonates for multiple myeloma, and screen for iron levels when prescribing erythropoiesis-stimulating agents in patients with myelodysplastic syndrome. Physicians who successfully complete these measures (ie, appropriately conduct at least 80% of cases submitted to CMS for payment in 2009) receive, as a bonus, 2% of their Medicare Part B billing. This bonus was decreased to 1% in 2011, and will decrease to 0.5% in the following 2 years. After that, not only will any bonus be eliminated, but hematologists will actually be penalized for not participating in PQRI, he said. There are approximately 150 metrics with PQRI, and clinicians can participate in any of them. The 4 mentioned above were designed to be relevant to hematology practices, Allen noted. “Attendees at the session were concerned about what they can do to meet the criteria and to receive the incentive payment. They were also concerned about how to properly complete the necessary paperwork,” Allen said. “Not many hematologists have signed up,” Allen reported. “They are concerned about the time it takes. The learning curve is difficult, and there have been delays in payment, but this past year more doctors got paid.” Physicians in large groups do not have to participate (and do the work) individually, he noted. “The group can do it as a whole.” The definition of a “group” is changing, so that 2 or more physicians now constitute a group. Allen believes this may ease the burden and encourage more physicians to become involved in PQRI. It has been more common for institutions, rather than physicians, to get on board. “They want to get ready for the time when PQRI becomes mandatory,” he said. But there is a downside. “It is costing institutions—hospitals and health systems—more to do the paperwork than they are getting back, even at the 2% level. Perhaps with experience and new technology, the cost of doing the paperwork will decrease.” The bottom line, according to Allen, is that PQRI “is not as good as it sounds,” at least at this point. “En couraging quality is what we all want— physicians, payers, and the public,” he said. “But shortly we will be penalizing people, and I don’t know that philosophically this is the best way to encourage quality care. All physicians
want to provide quality care; it’s why we go into medicine. But we can encourage this through education. Assistance in understanding the current standards of care, and what is expected of physicians, might be better received and be more successful than this financial incentive model.” Benefit and Cost-Effectiveness of Growth Factors Examined The hematopoietic granulocyte colonystimulating growth factors (G-CSFs) filgrastim and pegfilgrastim accelerate neutrophil engraftment and decrease the number of days of febrile neutropenia after chemotherapy and ASCT. Cancer delivery models are under pressure to become more efficient in an increasingly cost-restrictive environment, and because these agents are expensive, there is a need to establish their true benefit and cost. The following are among a number of studies presented at ASH that looked at these issues. Pegfilgrastim Cost-Effectiveness Shown Filgrastim is used daily for up to 2 weeks per chemotherapy cycle, whereas pegfilgrastim is used once per cycle. A single dose of pegfilgrastim, the newer agent, is as effective as many doses of filgrastim in patients with cancer treated with conventional chemotherapy, but there are no convincing comparative studies assessing the efficacy, safety, and economic impact of 1 injection of pegfilgrastim after reinjection of stem cells. In a French open-label randomized phase 2 trial comparing one 6-mg dose of pegfilgrastim to multiple doses (mean of
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7) of filgrastim 5 µg/kg/day in 80 patients with lymphoma who underwent ASCT, outcomes TheOncologyPharmacist.com favored pegfilgrastim.14 The investigators suggested, therefore, that pegfilgrastim be considered “a standard of care” after high-dose chemotherapy and ASCT. The results were reported by Catherine Sébban, MD, of the Centre Leon Bérard, Lyon, France. “We found that pegfilgrastim after i3 Innovus, Lakeland, Tennessee.15 “Little is known regarding the use of ASCT is at least as efficient as filgrastim on clinical outcomes, especially on dura- practice resources needed to deliver thertion of febrile neutropenia, and as safe as apy with growth factors. We constructed filgrastim,” Sébban said (Table 2). “In an empirical model to calculate the terms of economic outcomes, pegfilgras- human resource time and cost associated tim strictly dominates filgrastim, that is, with the delivery of filgrastim and pegfiloffers better effectiveness and lower costs grastim,” Taylor said. The study used a practice-level model on the primary end point, febrile neuto detail staff tasks required over 1 tropenia” (Table 3). month in administering G-CSF. Specific clinic characteristics were included (eg, number of patients receiving G-CSF, number of filgrastim injections per cycle, Various novel hourly pay rates for staff). Interviews approaches have were conducted with 400 medical professionals at 20 community oncology pracbeen tested in an tices to provide data for the time and perattempt to improve sonnel required for various tasks (ie, CR rates and achieve scheduling, front desk, phlebotomy, laboratory, triage, injection, and billing). a survival advantage The costs of the drugs were not included in indolent NHL. in the model. The base-case scenarios contrasted 1 patient versus 30 patients per month. The use of prophylactic pegfilgrastim Labor Costs Are Lower with resulted in substantial savings, in a comPegfilgrastim parison with filgrastim given as either 6 A cost model of expenses associated with or 11 injections per cycle and in scenargrowth factor use found an advantage ios based on 1 or 30 patients per month. with pegfilgrastim use compared with fil- Nursing hours involved in treating 1 grastim, according to Douglas Taylor, of patient per month with 6 injections were
Six-Month Mean Cost of Care Overall and by Category
No progression, $ (N = 798)
Disease progression, $ (N = 204)
CP – CNPa
CP – CNP indicates the cost of progressing minus cost of not progressing. Inpatient and emergency department visits.
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Days of febrile neutropenia (lymphoma), N
Days with fever, N
Days to reach absolute neutrophil count ≥1.0 G/L, N
FDG-PET results. The management of early-stage follicular lymphoma is surprisingly heterogeneous and varies across NCCN centers, but it is not influenced by the use of FDG-PET scan at staging. Given the widespread use and high cost of FDG-PET, its clinical utility in earlystage disease should be further evaluated,” Abou-Nassar maintained. ●
Days with platelets <20 G/L, N
Days of hospitalization from reinjection, N
Days of antibiotics, N
Patients without fever, %
Patients with grade 3-4 adverse events, %
Selected Clinical Outcomesa
Data also reflect outcomes in 71 multiple myeloma patients included in the population.
Mean Costs of Primary In-Hospital Care (in 2009 Euros) Pegfilgrastim,
9.4 versus 1.5 hours for pegfilgrastim; for 11 injections nursing hours were 17.3 versus 1.5, respectively.15 When extrapolated to 30 patients per month, this entailed 283 and 519 nursing hours for filgrastim, respectively, compared with 1.5 and 45 total hours for pegfilgrastim, respectively, Taylor reported. The 30-patient model predicted that monthly opportunity costs (labor needed for filgrastim minus pegfilgrastim) were more favorable for pegfilgrastim compared with 6 and 11 days of filgrastim, respectively. Staff hours would be reduced from 756 to 378, and staff costs would be reduced from $18,000 to $9000.15 On a per-patient basis, the monthly opportunity costs were more favorable for pegfilgrastim: staff hours would be reduced from 25 to 13 hours, and staff costs would be reduced from $600 to $300.15 “The use of pegfilgrastim as compared with filgrastim was associated with substantial savings in time and labor costs,” Taylor said, acknowledging that the model did not include the cost of purchasing the drugs. “We think future medical care delivery models should consider practice resource requirements as a means of increasing efficiency and cost-effectiveness.”
OctOber 2011 I VOL 4, NO 7
FDG-PET Use Widespread, Despite Little Evidence of Utility The use of fluorodeoxyglucose-positron emission tomography (FDG-PET) for the initial staging of FL varies by cancer center and is widespread, despite a paucity of evidence supporting its use, most notably in terms of an association with better treatment outcomes.
“We think future medical care delivery models should consider practice resource requirements as a means of increasing efficiency and costeffectiveness.” —Douglas Taylor
This was the conclusion of a multicenter study that examined data from the National Comprehensive Cancer Network (NCCN) NHL Outcomes Database, a repository of comprehensive clinical, treatment, and outcomes data for patients treated at 7 participating NCCN centers.16
“The management of follicular lymphoma can vary according to stage at presentation. The use of FDG-PET for initial staging may result in upstaging and/or changes in treatment strategy,” said Karim E. Abou-Nassar, MD, of the Dana-Farber Cancer Institute, Boston. “In this study, we describe the patterns of use of FDG-PET for the initial staging of patients with newly diagnosed disease and its potential impact on treatment.” The population included 953 persons diagnosed with low-grade FL between 2001 and 2009. All patients received staging imaging within 6 weeks of diagnosis and were followed for at least 6 months. Baseline characteristics, clinical characteristics, and treatment were compared according to receipt of FDGPET for initial staging. The study showed that 56% of patients underwent FDG-PET as part of the initial staging work-up, and the use of this varied significantly across NCCN centers. Among patients undergoing imaging, 82% received early treatment (ie, within 180 days of diagnosis) compared with 61.5% of those who were staged with conventional computed tomography scanning only. By disease stage, among the 189 patients who had early-stage disease, 63.5% underwent FDG-PET for initial staging, again with the use significantly varying across centers. Of all the early-stage patients, 29.1% were treated with radiotherapy alone, 36% received chemoimmunotherapy alone, 14.8% were treated with combined radiotherapy and chemoimmunotherapy, and 20.1% were observed (ie, no treatment yet).16 “The choice of the initial treatment strategy for early-stage FL did not vary significantly by the use of FDG-PET,” Abou-Nassar reported. “Patients who undergo FDG-PET scan for initial staging appear more likely to receive early therapy although this may not be directly attributed to the
NOTE: All abstracts in this reference list were presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. 1. Ardeshna KM, Smith P, Qian W, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2, and 3a). A preliminary analysis. Abstract 6. 2. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:4-6. 3. Salles GA, Catalano J, Feugier P, et al. Updated results of the PRIMA study confirms the benefit of 2-years rituximab maintenance in follicular lymphoma patients responding to immunochemotherapy. Abstract 1788. 4. Moccia AA, Hoskins P, Klasa R, et al. Front-line therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) followed by 2 years of rituximab maintenance for follicular lymphoma (FL) is associated with excellent outcomes and improved progression-free survival (PFS) in comparison to no maintenance. Abstract 1803. 5. Taverna CJ, Bassi S, Hitz F, et al. Rituximab maintenance treatment for a maximum of 5 years in follicular lymphoma: safety analysis of the randomized phase III trial SAKK 35/03. Abstract 1802. 6. Pettengell R, Schmitz N, Gisselbrecht C, et al. Rituximab purging and maintenance improves progression free survival but not overall survival in patients with relapsed or resistant follicular lymphoma prior to receiving an autologous transplant. Abstract 3567. 7. Peyrade F, Jardin F, Gisselbrecht C, et al. Rituximab and reduced dose CHOP (R-mini-CHOP) for patients over 80 years with diffuse large B-cell lymphoma (DLBCL) – Groupe d’Etude Des Lymphomes De l’Adulte (GELA) study LNH03-7B. Abstract 853. 8. Rummel MJ, Kaiser U, Balser C, et al. Bendamustine plus rituximab versus fludarabine plus rituximab in patients with relapsed follicular, indolent and mantle cell lymphomas – final results of the randomized phase III study NHL 2-2003 on behalf of the StiL (Study Group Indolent Lymphomas, Germany). Abstract 856. 9. Coiffier B, Osmanov E, Hong X, et al. A phase 3 trial comparing bortezomib plus rituximab with rituximab alone in patients with relapsed, rituximab-naive or -sensitive, follicular lymphoma. Abstract 857. 10. Karmali R, Kassar M, Jimenez AM, et al. Update on a prospective study evaluating the safety and efficacy of combination therapy with fludarabine, mitoxantrone and rituximab followed by yttrium-90 ibritumomab tiuxetan and maintenance rituximab as front line therapy for patients with indolent lymphomas. Abstract 3946. 11. Karmali R, Manson A, Bueschel K, et al. Phase II study of 2-weekly CHOP+rituximab followed by yttrium-90 ibritumomab tiuxetan (Zevalin) in patients with previously untreated diffuse large B cell lymphoma (DLBCL): final analysis. Abstract 3947. 12. Hoang S-S, Gruschkus S, Darragh J, et al. Economic impact of disease progression in follicular non-Hodgkin’s lymphoma. Abstract 1522. 13. Papadakis K, Follows GA, Boyer J, et al. Cost effectiveness analysis of rituximab maintenance in patients with untreated high tumour burden follicular lymphoma after response to immunochemotherapy: a UK national healthcare services perspective. Abstract 3833. 14. Sebban C, Lefranc A, Perrier L, et al. A randomized phase II study evaluating the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after high dose chemotherapy and autologous stem cell transplantation in patients with lymphoma and myeloma (PALM study). Abstract 3479. 15. Taylor DCA, Skorneck M, Hill C, et al. Clinic staff time and labor costs associated with administering pegfilgrastim as compared with filgrastim to patients receiving myelosuppressive chemotherapy: results of a health economic model. Abstract 1515. 16. Abou-Nassar KE, Vanderplas A, Friedberg JW, et al. Patterns of use of FDG-PET for the initial staging of follicular lymphoma (FL) and its impact on initial treatment strategy and outcomes in the National Comprehensive Cancer Network (NCCN) lymphoma database. Abstract 81.
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Advances and Challenges in Non-Hodgkin Lymphoma: A Payer’s Perspective
To Receive cRediT, compleTe The posTTesT aT TheOncologyPharmacist.com
By John Fox, MD Associate Vice President, Medical Affairs, Priority Health, Grand Rapids, Michigan
lthough rituximab was ap proved in 1997 as a single agent for patients with relapsed or refractory low-grade or follicular CD20positive B-cell non-Hodgkin lymphoma (NHL), the number of studies demonstrating its broad potential continues to increase. As discussed in Ms Helwick’s article and presented at the 2010 meeting of the American Society of Hematology, the demonstration that immunoprophylaxis in patients with asymptomatic follicular lymphoma (FL) reduces the risk of progression at 3 years by 79% is yet another example.1 This begs the question whether this should become the new standard of care. From the payer’s perspective, we would advocate a response using the Institute for Healthcare Improvement’s Triple AIM goals, which call for improving patient experience with the healthcare system, improving health outcomes meaningful to the patient, and reducing percapita cost.2 Arguably, such preventive encounters with the health system are likely a better experience for the patient than the treatment of progressive disease. In one study, only 2 patients required treatment for 1 additional person to benefit (ie, number needed to treat, 2.1; absolute risk reduction, 48%).1 Although one could reasonably argue that improving progressionfree survival (PFS) and avoiding chemotherapy would improve quality of life, this measure was not assessed. Most notably, improved overall survival (OS) was not observed.1 And what about cost? This study begs for a formal cost-effectiveness analysis to assess whether the $70,000 plus cost of 25 months of chemoprophylaxis reduces overall costs. Regrettably, an intermediate and potentially more cost-effective regimen— induction without maintenance—was not studied. Findings from the Primary Rituximab and Maintenance (PRIMA) trial also demonstrated PFS benefit, but again no OS benefit, with statistically increased risk of grade 3-4 adverse events and serious infections.3,4 Numerous other studies in this continuing education activity cite the benefits of maintenance therapy in patients with NHL,1,5,6 and rituximab in combination with chemotherapy followed by rituximab maintenance seems to be the optimal option in patients with relapsed disease.7 This, in combination with preliminary statements from the United Kingdom’s National Institute for
Several reviews show that in patients receiving myelosuppressive chemotherapy, pegfilgrastim is cost-effective—but not cost-saving—compared with 6 days of filgrastim.
Health and Clinical Excellence (NICE) on maintenance therapy in FL, will almost certainly lead to private payer coverage, even without demonstrated survival benefit. What about cost? Annual net revenue for rituximab was close to $5.5 billion in 2008, with that amount likely to increase further given the expanded indications.8 Payers would welcome predictive markers identifying patients most likely to benefit from anti-CD20 therapy, yet few potential markers are being studied.9,10 Payers may have to wait until patent expiration in 2015 for biosimilars to become available and make therapy more costeffective or even cost-saving for this patient population. Similar to red-cell colony-stimulating factors (CSFs), payers are increasingly evaluating the health benefits of granulocyte CSFs (G-CSFs). Previous randomized trials have shown that pegfilgrastim is no more effective than filgrastim for primary prophylaxis in this patient population, although a recent meta-analysis shows pegfilgrastim is more effective at preventing episodes of febrile neutropenia.11 Several reviews show that in patients receiving myelosuppressive chemotherapy, pegfilgrastim is cost-effective—but not cost-saving—compared with 6 days of filgrastim.12-14 In contrast, the new study presented at the meeting by Catherine Sébban, MD, showed pegfilgrastim dominating (better outcomes, lower cost) filgrastim post-ASCT (autologous stem cell transplantation) in patients with NHL.15 Given the extraordinary cost difference between these 2 agents, payers will have to weigh whether the long-term potential savings justify the upfront costs of daily versus biweekly injections. New predictive tools to quantify the risk of febrile neutropenia will stratify patients more consistently than current National Comprehensive Cancer
Network guidelines and will further justify expenditures for G-CSFs.16 There is no payer in the United States that is not exploring methods of controlling oncology costs. Pathways programs, as pointed out in the main article, are challenging to construct, especially if the aim is to find a pathway acceptable to all oncologists. More challenging still will be maintaining these guidelines and the principles of choosing the most cost-effective therapy, especially given the plethora of new agents gushing from the pipeline.
These pathways programs are fundamentally flawed; however, they represent the primary mechanism for payment reform.
These pathways programs are fundamentally flawed; however, they represent the primary mechanism for payment reform. We do not pay orthopedic surgeons differentially based on the type of implant they use, nor should we pay oncologists based on the drugs they choose. Programs such as the Physician Quality Reporting Initiative will continue to evolve, and other payment reforms, such as UnitedHealthcare’s payment of a management fee and acquisitions costs, will bring oncology care into line with other payment mechanisms in the healthcare system. ● References 1. Ardeshna KM, Smith P, Qian W, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2, and 3a). A
preliminary analysis. Abstract presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 6. 2. Institute for Healthcare Improvement. The Triple AIM. www.ihi.org/IHI/Programs/StrategicInitiatives/Triple Aim.htm. Accessed February 2, 2011. 3. Salles G, Seymour JF, Offner F, et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011;377:4-6. 4. Salles GA, Catalano J, Feugier P, et al. Updated results of the PRIMA study confirms the benefit of 2-years rituximab maintenance in follicular lymphoma patients responding to immunochemotherapy. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 1788. 5. Moccia AA, Hoskins P, Klasa R, et al. Front-line therapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) followed by 2 years of rituximab maintenance for follicular lymphoma (FL) is associated with excellent outcomes and improved progression-free survival (PFS) in comparison to no maintenance. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 1803. 6. Taverna CJ, Bassi S, Hitz F, et al. Rituximab maintenance treatment for a maximum of 5 years in follicular lymphoma: safety analysis of the randomized phase III trial SAKK 35/03. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 47, 2010. Abstract 1802. 7. Rummel M. Reassessing the standard of care in indolent lymphoma: a clinical update to improve clinical practice. J Natl Compr Canc Netw. 2010;8(suppl 6):S1-S14. 8. Thomson Reuters. News & Highlights from week 47. November 20, 2009. Current Patents Gazette. 2009;12. http://thomsonreuters.com/content/science/pdf/news 2009_CPG.pdf. Accessed February 2, 2011. 9. Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003;21:3940-3947. 10. Horvat M, Kloboves Prevodnik V, Lavrencak J, et al. Predictive significance of the cut-off value of CD20 expression in patients with B-cell lymphoma. Oncol Rep. 2010;24:1101-1107. 11. Pinto L, Liu Z, Doan Q, et al. Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials. Curr Med Res Opin. 2007;23:2283-2295. 12. Lyman GH, Lalla A, Barron RL, Dubois RW. Costeffectiveness of pegfilgrastim versus filgrastim primary prophylaxis in women with early-stage breast cancer receiving chemotherapy in the United States. Clin Ther. 2009;31: 1092-1104. 13. Liu Z, Doan QV, Malin J, Leonard R. The economic value of primary prophylaxis using pegfilgrastim compared with filgrastim in patients with breast cancer in the UK. Appl Health Econ Health Policy. 2009;7:193-205. 14. Lyman G, Lalla A, Barron R, Dubois RW. Cost-effectiveness of pegfilgrastim versus 6-day filgrastim primary prophylaxis in patients with non-Hodgkin’s lymphoma receiving CHOP-21 in United States. Curr Med Res Opin. 2009;25:401-411. 15. Sébban C, Lefranc A, Perrier L, et al. A randomized phase II study evaluating the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after high dose chemotherapy and autologous stem cell transplantation in patients with lymphoma and myeloma (PALM Study). Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 3479. 16. Lyman GH, Kuderer NM, Crawford J, et al. Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy. Cancer. 2010 Nov 29. [Epub ahead of print].
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Balancing Cost and Efficacy in Non-Hodgkin Lymphoma: A Pharmacist’s Perspective By James T. Kenney, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, Massachusetts
n general, US health plans look for opportunities to guide treatments that balance efficacy and cost-effectiveness in an effort to manage the application of limited financial resources to reimburse providers for their services. The management of patients with cancer in the managed care setting has primarily been left to the discretion of oncologists, regardless of the type and stage of a particular cancer. The potential for new applications of existing treatments and the development of new therapies provide hope for better outcomes and improved survival for patients with different types of cancer. The availability of new therapies also expands the population of patients who will be candidates for these treatments, including patients who were refractory to current options or who previously were not treated because of clinical practice approaches that supported a deferred treatment strategy for the asymptomatic population. The advent of biotechnology has brought a host of new biologic therapies for the treatment of complex diseases that have led to changes in the therapeutic approaches for a number of diseases. The option to treat patients with non-Hodgkin lymphoma (NHL) earlier in the disease process rather
than withhold treatment until symptoms arise affords physicians the opportunity to offer patients a new option and extend the time before using more traditional and potentially toxic chemotherapeutic alternatives. The efficacy of rituximab in the early treatment of follicular lymphoma (FL) with subsequent deferment of chemotherapy for 3 years can offer clinical benefits to the patients, as well as delay medical and pharmaceutical expenses for the health plan.1 In Ms Helwick’s article, Dr Kirit M. Ardeshna discusses his study that concerns the impact of early treatment on patients with NHL and its effect on future tumor response as an issue for the oncologist who selects a treatment approach for these patients.1 Dr Ardeshna also suggests that patients may be more appropriate candidates for future treatments when treated earlier in the disease process. These concerns are of interest to health plans from a clinical perspective; however, plans would not attempt to engage in this discussion and would typically opt to allow the treating physician the professional latitude to select the desired treatment pathway for his or her patient. Dr Ardeshna’s comment that does concern managed care health plans is
that 1 of 5 patients who are not exhibiting symptoms of FL will not develop fullblown disease, and the early treatment with rituximab could be a waste of resources.1 In addition to the cost of therapy, the cost of treating any side effects directly related to the drug therapy must also be covered by the health plans. This gets to a core issue from the payer perspective, which is the desire to identify patients who are appropriate candidates for a particular therapy and in effect more likely to respond to treatment. Supportive care options with growth factor treatment in the population of patients with NHL are also discussed in this publication. This is an area for which managed care plans actively engage the oncologist in an attempt to best manage this therapeutic area. Plans routinely utilize specialty pharmacies to distribute and often manage these agents. The discussion in the main article also suggests potential savings with these agents, without factoring in the cost of the medication, which is the key focus from the health plan perspective. Plans need to confirm the savings when the cost of the medication is also factored into the analysis, including any discounts, rebates, or other cost offsets pro-
vided from the specialty pharmacy distribution option. Health plans can often achieve additional savings by simple dose-management approaches or by implementing treatment guidelines with network physicians. The ideal approach incorporates input from the clinical experts in the field that balances patient, provider, and the health plan needs to achieve optimal patient outcomes, utilizing appropriate resources in the most cost-effective way. Clearly, many challenges exist for a managed care plan to actively and effectively participate in the oncology management area. A robust development pipeline of medications and diagnostics, patients living longer with cancer, and limited financial resources to cover the cost of care are examples of challenges that must be addressed. A collaborative approach to care will serve our patient populations well in an attempt to achieve an ideal clinical response in our patients. ● Reference 1. Ardeshna KM, Smith P, Qian W, et al. An intergroup randomised trial of rituximab versus a watch and wait strategy in patients with stage II, III, IV, asymptomatic, non-bulky follicular lymphoma (grades 1, 2, and 3a). A preliminary analysis. Abstract presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 6.
Cancer Center Profile Hallmark Health Hematology and Oncology Center Continued from cover The center also houses an onsite oncology pharmacy. Being positioned on the same floor as the treatment area places the pharmacists right where they need to be. “As in any oncology practice, we are fully available for any kind of consults,” Michelle Corrado, PharmD, System Director of Pharmacy Services, told The Oncology Pharmacist. “We are regularly requested by patients…if they have any questions about their regimen or side effects, the pharmacist will typically go out to the infusion room and sit and talk with patients and their families, answering any questions they might have.” This ease of communication extends beyond patient consults. Proximity to team members increases the frequency of face-to-face conversations and enhances personalization of cancer care, according to Corrado. “Many interdependencies are needed among physicians, nurses, and pharmacists to get the
OctOber 2011 I VOL 4, NO 7
right treatment for the right patient; and you really need to know that patient. You need to know that he or she was hospitalized last week. You need to know how his or her labs are trending. You need to know that he or she vomited for 3 days the last time.” This degree of information is not always available when pharmacists work remotely. “Sometimes it is just a casual conversation. I really have seen that the level of information you get about the patient increases exponentially by being integrated into the practice,” she said. And this dedication has its rewards. Patients regularly compliment the center, specifically the pharmacy. Behind the Scenes What many patients don’t know is that their high-quality care stems from a lot of hard work. As in many oncology pharmacies, pharmacists at Hallmark Health head up the Risk Evaluation and
Mitigation Strategies (REMS), including oncology and nononcology REMS programs. For the center, that represents between 6 and 12 programs for such agents as epoetin alfa, darbepoetin alfa, natalizumab, and denosumab, each requiring the verification of lab values and documentation. Pharmacists also are the point people for the center’s computer-based orderentry system (IntelliDose, IntrinsiQ), building any new protocols instituted by the center, including supporting literature, into the system. Add in their use of the existing pharmacy information system (MT Software, MediTech) and the just-implemented electronic health record system (Centricity, GE Health care), and the center’s pharmacists are coordinating a good amount of hightech. Plus, they currently are implementing a bar-coding system as an additional source of quality assurance. Pharmacy also handles pharmaceuti-
cal purchasing and contracting. As the system director, Corrado is responsible for contracting, and Hallmark Health has a buyer. However, “the oncology pharmacy coordinator is responsible for all the inventory [at the center].” The center keeps a very tight inventory margin, which requires close communication with the team. “What patients are coming in. What treatments we need to handle,” she explained. In addition, there is the business plan for the upcoming year. Corrado and the center’s oncology pharmacy coordinator will work with the director and the health system’s finance and compliance officers to “make sure that we are offering the right therapies for our community, and that goes into the expansion of the nononcology infusions,” as the center currently acts as an infusion center for multiple sclerosis treatments, osteoporosis, as well as various neurologic conditions, she said. ●
TOP_October 2011_v6_TOP 10/20/11 10:26 AM Page 27
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TOP_October 2011_v6_TOP 10/20/11 11:49 AM Page 28
Oral Oncolytics Oral Chemotherapeutic Agents... Continued from cover agents in patients with renal tic effects by binding to the side is cell-cycle-phase–specific, activity dysfunction are limited. N7 position of guanine to cre- is best achieved when administered in ate intra- and interstrand divided doses over multiple days rather Renal dysfunction repreDNA cross-linkages.8 Cyclo - than in large single doses.13 Oral bioavailsents one of the most imporphosphamide has been used ability of etoposide capsules appears to be tant contributors to drug to treat a wide variety of linear and ranges from 25% to 75%, with accumulation, which may oncologic diseases, such as mean bioavailability of 50%.14 Etoposide manifest as mild to severe Hodgkin and non-Hodgkin and its metabolites are primarily elimiadverse effects. Dose reduclymphomas, acute and chronic nated via renal clearance, which actions are often necessary to Melinda Tran, PharmD leukemias, as well as breast, counts for 44% to 60% of plasma clearprevent the accumulation of renally metabolized and/or eliminated ovarian, and testicular cancers.3 In addi- ance (67% as unchanged drug).15 Multiple studies have correlated dedrugs to prevent toxicities, such as pro- tion, cyclophosphamide possesses potent longed myelosuppression, mucositis, immunosuppressive activity and may be creased renal function with decreased peripheral neuropathies, or central used to treat various nonneoplastic etoposide systemic clearance, which sugneurotoxicities.1,2 Treatment goals autoimmune disorders where disease- gests that doses should be reduced in eldshould be considered carefully, because modifying antiinflammatory drugs have erly patients and/or patients with imthey may influence the clinical deci- been ineffective, such as refractory paired renal function.16-19 Pflüger and colleagues evaluated the sion of proceeding with a more aggres- nephritic syndrome in children. pharmacokinetic parameters sive dose or pursuing a reduced dose for Oral cyclophosphamide is well of etoposide in 35 patients, palliative purposes. absorbed, usually nearing comwhich demonstrated that The following review presents the plete absorption.8,9 As a prodrug, cyclophosrenal impairment resulted in available data to help guide the manincreased terminal eliminaagement of oral chemotherapeutic phamide requires hepatic actition half-life and area under agents in patients with renal dysfunc- vation via CYP2B6, CYP2C9, the curve (AUC) as well as tion. Based on the information provid- and CYP3A4 to generate a 4decreased volume of distribued, dose adjustment recommendations hydroxycyclophosphamide intion at steady state and sysin renally compromised patients have termediate that exists in equiEmily Mackler, librium with aldophosphamide. temic clearance of etopobeen summarized in the Table. PharmD, BCOP The spontaneous cleavage of side.16 Kintzel and Dorr Capecitabine aldophosphamide generates the cytotox- recommend a 15% dose reduction for 5-Fluorouracil (5-FU) is a pyrimidine ic component phosphoramide mustard CrCl 46 mL/min to 60 mL/min, 20% for analog with antitumor activity against a and the urotoxic metabolite, acrolein.8 CrCl 31 mL/min to 45 mL/min, and 25% wide variety of solid tumors, such as col- Although cyclophosphamide and its for CrCl ≤30 mL/min.20 Interestingly, orectal, esophageal, gastric, bladder, and metabolites are eliminated in the urine etoposide also is cleared via nonrenal breast.3 Capecitabine, an oral prodrug of (5%-25% as unchanged drug), no processes, such as metabolism and bil5-FU, exhibits nearly 100% bioavailabil- consistent evidence indicate dose mod- iary excretion; thus, there is a potential ity and is activated preferentially in ifications in renally compromised for compensatory elimination in tumor cells. After absorption through patients.8,10,11 Aronoff and colleagues rec- patients with impaired hepatic and/or the gastrointestinal tract, capecitabine ommend a 25% dose reduction in renal function.14,18 undergoes hepatic metabolism to gen- patients with a glomerular filtration rate Hydroxyurea erate 5′-deoxy-5-fluorocytidine and <10 mL/min.12 Hydroxyurea produces antineoplastic 5′-deoxy-5-fluorouridine (5′-DFUR). effects by interfering with ribonuUltimately, 5′-DFUR is converted to cleotide reductase to cause “immediate 5-FU by the enzyme thymidine phospho- Renal clearance of inhibition of DNA synthesis.”21 In rylase, which is found in both normal and hydroxyurea is doing so, significant tumor response to tumor tissues. Thymidine phosphorylase approximately 75% of the hydroxyurea has been demonstrated in concentrations, however, are 3 to 10 melanoma; refractory chronic myelogetimes higher in solid tumors than in nor- glomerular filtration rate, nous leukemia; recurrent, metastatic, or mal tissues, which theoretically allows for which suggests that inoperable ovarian cancer; and squapreferential activation and fewer systemic hydroxyurea should be mous cell head and neck cancer.3 In toxicities, such as diarrhea, hand–foot reduced when used in 4 addition, hydroxyurea concentrates in syndrome, and neutropenia. Capecitabine and its metabolites are patients with renal erythrocytes and leukocytes and is used eliminated in the urine, with mean uri- impairment. widely for adjunctive management of nary recovery between 71% and 87%.5 sickle cell disease, rapid reduction of Renal impairment, therefore, may lead white blood cell count in patients with to an increase in the systemic exposure Etoposide elevated blast counts or leukostasis, and to certain metabolites; dosing at 75% of Since its introduction in 1971, etoposide supportive care induction therapy in the standard dose is recommended in has been used to treat a variety of cancers, acute myeloid leukemia patients aged 60 patients with moderate renal impair- such as lung, testicular, breast, bone years or older with poor performance ment (baseline creatinine clearance (Ewing sarcoma, osteosarcoma), ovarian, status or significant comorbidities.3,21 Hydroxyurea was found to be 79% [CrCl] 30-50 mL/min).6 In addition, esophageal, and gastric, as well as capecitabine is contraindicated in leukemias and lymphomas.3 Although bioavailable in cancer patients followpatients with severe renal impairment etoposide is a semisynthetic podophyllo- ing oral administration and eliminated toxin derivative, it exerts its antineoplas- via renal and nonrenal mechanisms (CrCl <30 mL/min).7 tic effects as a topoisomerase II inhibitor as unchanged drug, urea, and other Cyclophosphamide by forming a ternary complex with DNA metabolites.21-23 Renal clearance of Cyclophosphamide, a nitrogen mustard and topoisomerase II to prevent the reli- hydroxyurea is approximately 75% of alkylating agent, exerts its antineoplas- gation of DNA strands.13 Because etopo- the glomerular filtration rate, which
OctOber 2011 I VOL 4, NO 7
suggests that hydroxyurea should be reduced when used in patients with renal impairment. In their summary, Kintzel and Dorr provided dose reduction recommendations for hydroxyurea: 15% for CrCl 46 mL/min to 60 mL/min, 20% for CrCl 31 mL/min to 45 mL/min, and 25% for CrCl ≤30 mL/min.20 Aronoff and colleagues recommended an 80% dose reduction for CrCl <10 mL/min.12 In general, the use of hydroxyurea requires close supervision and doses should be titrated based on the patient’s response and white blood cell count. Imatinib Imatinib and related tyrosine kinase inhibitors (TKIs) target the BCR-ABL oncogene, a constitutively activated protein kinase that resulted from the fusion of the Abelson proto-oncogene on chromosome 9 with the breakpoint cluster region on chromosome 22.24 In addition, imatinib inhibits tyrosine kinase receptors for c-KIT, which is often associated with gastrointestinal stromal tumors (GISTs), as well as platelet-derived growth factor, which is often associated with hypereosinophilic syndrome.3,24-26 All TKIs are predominantly metabolized by CYP3A4, with minor assistance from other pathways and eliminated in the feces.25 Although renal elimination plays a minor role in the elimination of imatinib, renal impairment can have a noticeable effect on imatinib pharmacokinetics, increasing the mean AUC by 1.5- to 2-fold compared with pa tients with normal renal function.27,28 The manufacturer recommends maximum doses of 600 mg and 400 mg in patients with CrCl 40 mL/min to 59 mL/min and CrCl 20 mL/min to 39 mL/min, respectively.28 In a phase 1 study conducted in 60 adult patients with varying renal function, imatinib exposure was significantly greater and serious adverse events were significantly more common in the mild-to-severe renal dysfunction groups than in the normal group. Despite having increased imatinib exposure, daily imatinib doses up to 800 mg were generally well tolerated in the mild-to-moderate group.27 Lenalidomide Lenalidomide is an immunomodulatory analog of thalidomide with antiangiogenic and antineoplastic properties.13 It is indicated for the treatment of patients with transfusion-dependent myelodysplastic syndrome (MDS) with or without deletion 5q cytogenetic abnormality and in combination with dexamethasone for multiple myeloma.29 Lenalidomide is absorbed rapidly from the gastrointestinal tract and approxi-
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YOUR QUESTIONS ANSWERED
Editor in Chief
Editor in Chief
Sagar Lonial, MD
Stephanie A. Gregory, MD
Associate Professor of Hematology and Oncology Emory University School of Medicine
The Elodia Kehm Chair of Hematology Professor of Medicine Director, Section of Hematology Rush University Medical Center/Rush University
Topics include: â&#x20AC;˘ Newly Diagnosed Patients â&#x20AC;˘ Maintenance Therapy â&#x20AC;˘ Transplant-Eligible Patients â&#x20AC;˘ Retreatment â&#x20AC;˘ Transplant-Ineligible Patients â&#x20AC;˘ Cytogenetics â&#x20AC;˘ Side-Effect Management â&#x20AC;˘ Bone Health
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TOP_October 2011_v6_TOP 10/20/11 12:46 PM Page 30
Oral Oncolytics Table Oral Chemotherapy and Recommended Dose Adjustments Major Route of Agent Metabolism Elimination Capecitabine
Renal Dose Adjustment CrCl 30-50 mL/min: 25% dose reduction7 CrCl <30 mL/min: contraindicated7 No adjustments required2,20 CrCl 10-50 mL/min: 25% dose reduction12 CrCl <10 mL/min: 50% dose reduction12
Cyclophosphamide Dasatinib Erlotinib Etoposide
Hepatic Hepatic Hepatic Hepatic
Renal Fecal Fecal Renal, fecalb
CrCl <10 mL/min: 25% dose reduction12 --CrCl 15-50 mL/min: 25% dose reduction14 CrCl <15 mL/min: further dose reduction14 SCr >1.4 mg/dL: up to 30% dose reduction18 CrCl 46-60 mL/min: 15% dose reduction20 CrCl 31-45 mL/min: 20% dose reduction20 CrCl â&#x2030;¤30 mL/min: 25% reduction20 CrCl 10-50 mL/min: 25% dose reduction12 CrCl <10 mL/min: further dose reduction12
Everolimus Gefitinib Hydroxyurea
Hepatic Hepatic Hepatic
Fecal Fecal Renal
--CrCl 46-60 mL/min: 15% dose reduction20 CrCl 31-45 mL/min: 20% dose reduction20 CrCl â&#x2030;¤30 mL/min: 25% dose reduction20 CrCl 10-50 mL/min: 50% dose reduction12 CrCl <10 mL/min: 80% dose reduction12
Undetermined in humans
CrCl 40-59 mL/min: maximum 600 mg/day29 CrCl 20-39 mL/min: 50% dose reduction; maximum 400 mg/day29 -29,31
Multiple myeloma : CrCl 30-60 mL/min: 10 mg/day CrCl <30 mL/min (nondialysis): 15 mg every 48 hours CrCl <30 mL/min (dialysis): 5 mg/day or 15 mg 3 times weekly (after dialysis on dialysis days) Myelodysplastic syndrome29,31: CrCl 30-60 mL/min: 5 mg/day CrCl <30 mL/min (nondialysis): 5 mg every other day CrCl <30 mL/min (dialysis): 5 mg 3 times weekly after dialysis
Oral bioavailability is highly variable and incomplete Reduce starting dose in patients with moderate-severe renal insufficiency32
No clear recommendations47
CrCl 10-50 mL/min: 50% dose reduction12,36 CrCl <10 mL/min: avoid use12,36 CrCl 46-60 mL/min: 35% dose reduction20 CrCl 31-45 mL/min: 50% dose reduction20
Undetermined in Other humans; likely hepatic
No clear recommendations May result in increased toxicity39 Recommended starting doses46: CrCl >60 mL/min: 400 mg twice daily CrCl 40-59 mL/min: 400 mg twice daily CrCl 20-39 mL/min: 200 mg twice daily CrCl <20 mL/min: undefined Hemodialysis: 200 mg daily -Patients with severe renal failure should be monitored closely and consideration given to dose modification2
<1% contribution. b <20% contribution. CrCl indicates creatinine clearance; SCr, serum creatinine.
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Oral Oncolytics mately 67% is eliminated in the urine as unchanged drug. In patients with moderate-to-severe renal function, the drug has an increased half-life, increased AUC, and decreased clearance.29 Thus, dose adjustments are required in patients with abnormal renal function to prevent unnecessary toxicities. In a retrospective analysis to assess the impact on safety and efficacy of lenalidomide in patients with varying degrees of renal dysfunction, Dimopoulos and colleagues found that patients with renal insufficiency experienced an increased incidence of thrombocytopenia and more often required lenalidomide dose reduction or interruptions.30 In a separate, prospective analysis of 50 patients treated with lenalidomide, Dimopoulos and colleagues concluded that lenalidomide could be administered without excessive toxicities at doses adjusted according to renal function.31 The following dose adjustments are recommended for patients with multiple myeloma: 10 mg daily for CrCl 30 mL/min to 60 mL/min, 15 mg every other day for CrCl <30 mL/min (nondialysis patients), 5 mg daily or 15 mg 3 times per week for CrCl <30 mL/min (following dialysis on dialysis days).29,31 In addition, the following dose adjustments are recommended for patients using lenalidomide for treatment of MDS: 5 mg daily for CrCl 30 mL/min to 60 mL/min, 5 mg every other day for CrCl <30 mL/min (nondialysis patients), and 5 mg 3 times weekly for CrCl <30 mL/min (following dialysis).29 Melphalan Like other nitrogen mustard alkylating agents, melphalan exerts its cytotoxic activity by binding to the N7 position of guanine to create intra- and interstrand DNA cross-linkages.13,32 Melphalan tablets are indicated for the palliative treatment of multiple myeloma as well as nonresectable epithelial carcinoma of the ovary.3 Melphalan is generally reserved for nontransplant candidates because long-term treatment with alkylating agents damages the bone marrow and may make stem cell harvest and autologous transplant difficult.33 Oral absorption of melphalan is highly variable and incomplete, with average absolute bioavailability ranging from 56% to 93%.9,32 Melphalan is primarily eliminated from the plasma via chemical hydrolysis but also is partially eliminated in the urine (~10%).9,32 Multiple pharmacokinetic studies have demonstrated the effects of impaired renal function on plasma melphalan elimination, AUC, and mean residence time, all which suggest the need for dose adjustments in patients with impaired renal function.20,34 However, because oral absorption of melphalan is incomplete and highly
Oral absorption of melphalan is highly variable and incomplete, with average absolute bioavailability ranging from 56% to 93%.
unpredictable, limited data regarding recommendations for dose adjustments currently exist for oral melphalan.32 In a retrospective analysis in multiple myeloma patients with renal failure, Carlson and colleagues suggest a 25% dose reduction for CrCl <30 mL/min. Unfortunately, less than 2% of their study patients had CrCl ≤10 mL/min; therefore, no further recommendations could be provided.35 Methotrexate Methotrexate inhibits DNA synthesis, repair, and cellular replication by binding to the active catalytic site of dihydrofolate reductase (DHFR).36 DHFR is needed to convert dihydrofolate to tetrahydrofolate, the active form of folic acid needed in the synthesis of purine nucleotides and thymidylate.13,26 Patients may be at risk of developing methotrexate toxicity for a variety of reasons, some of which include impaired renal function (which in turn can delay methotrexate clearance); presence of pleural or peritoneal effusions or other third spacing (which in turn acts as a reservoir for methotrexate); and concomitant administration with interacting medications, such as penicillin, trimethoprim-sulfamethoxazole, proton pump inhibitors, nonsteroidal antiinflammatory drugs, and organic acids. Delayed methotrexate elimination may lead to serious adverse effects, such as myelosuppression, nephrotoxicity, hepatotoxicity, mucositis, sepsis, and death.36 Approximately 80% of methotrexate is eliminated in the urine as active or toxic moiety (range, 51%-89%).20,37,38 Thus, methotrexate doses should be reduced in patients with severe renal impairment to avoid potential toxicities. Kintzel and Dorr recommended a 35% dose reduction in patients with CrCl 46 mL/min to 60 mL/min and a 50% dose reduction in patients with CrCl 31 mL/min to 45 mL/min.20 In addition, use should be avoided in patients with CrCl <10 mL/min. Procarbazine The exact mechanism of procarbazine is largely undefined but is thought to involve the methylation of the N7 position of guanine of transfer RNA (tRNA).39 By inhibiting the synthesis of tRNA, procarbazine ultimately interferes with proper protein, DNA, and RNA syntheses.26,40 Procarbazine originally was indicated for stage III
and IV Hodgkin lymphoma as part of the mechlorethamine/vincristine/procarbazine/prednisone (MOPP) regimen.39 However, because of significant and undue long-term toxicities, MOPP largely has been replaced with alternative regimens. Procarbazine also may be used in combination with other antineoplastic agents to treat non-Hodgkin lymphoma and central nervous system malignancies.3
Renal dysfunction is an important contributor to the accumulation of antineoplastic agents and may lead to severe adverse effects, such as bone marrow suppression, mucositis, end-organ damage, and death.
sorafenib has been demonstrated in unresectable liver carcinoma, advanced renal cell carcinoma, angiosarcoma, GIST, and thyroid carcinomas.3 Oral bioavailability of sorafenib is 38% to 49% and achieves peak plasma levels approximately 3 hours after administration.45 Sorafenib undergoes significant hepatic metabolism by CYP3A4 and is also glucuronidated by uridine diphosphate glucuronosyltransferase (UGT) 1A9.25,45 In a prospective study of 138 treated patients, sorafenib pharmacokinetics were characterized to determine tolerable starting doses in patients with hepatic and/or renal impairment: 400 mg twice daily for CrCl ≥40 mL/min, 200 mg twice daily for CrCl 20 mL/min to 39 mL/min, and 200 mg daily in patients on hemodialysis.46 Conclusion Renal dysfunction is an important contributor to the accumulation of antineoplastic agents and may lead to severe adverse effects, such as bone marrow suppression, mucositis, end-organ damage, and death. Dose reductions are often necessary to prevent such adverse effects but may be complicated by the balance between “sufficient efficacy and acceptable toxicity.”1 In most cases, dose escalations may be made after it is determined that the patient was able to tolerate the previous dose. ● References
Oral absorption of procarbazine is rapid, complete, and largely comparable with intravenous administration.26,39,40 Procarbazine, however, requires activation via hepatic and mitochrondrial activity, most of which occurs during first-pass metabolism following absorption from the gastrointestinal tract, to form azoprocarbazine, the major circulating metabolite, and benzylazoxy and methylazoxy intermediates.26,39,41-43 These 2 intermediates are metabolized further to produce N-isopropylterepthalamic acid, an inactive metabolite that is excreted in the urine; and methyldiazonium, the major cytotoxic metabolite, respectively.26,39,41-43 Following a radiolabeled dose of procarbazine, approximately 70% of radioactivity was recovered in the urine as N-isopropylterepthalamic acid.39,44 Although procarbazine largely is eliminated in the urine as inactive metabolites, caution should be exercised in patients with impaired renal and/or hepatic function.39 No dosing recommendations are currently available. Sorafenib Similar to other members of the TKI class, sorafenib inhibits multiple intracellular and cell surface kinases to inhibit tumor growth and angiogenesis.45 Significant tumor response to
1. Niscola P, Vischini G, Tendas A, et al. Management of hematological malignancies in patients affected by renal failure. Expert Rev Anticancer Ther. 2011;11:415-432. 2. Lichtman SM, Wildiers H, Launay-Vacher V, et al. International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer. 2007;43:14-34. 3. NCCN Drugs & Biologics Compendium (NCCN Compendium). Fort Washington, PA: National Comprehensive Cancer Network; 2011. 4. Walko CM, Lindley C. Capecitabine: a review. Clin Ther. 2005;27:23-44. 5. Reigner B, Blesch K, Weidekamm E. Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet. 2001;40:85-104. 6. Poole C, Gardiner J, Twelves C, et al. Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients. Cancer Chemother Pharmacol. 2002;49:225-234. 7. Capecitabine (Xeloda) [package insert]. South San Francisco, CA: Genentech USA, Inc; 2011. 8. Cyclophosphamide (Cytoxan) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2005. 9. Wildiers H, Highley MS, de Bruijn EA, van Oosterom AT. Pharmacology of anticancer drugs in the elderly population. Clin Pharmacokinet. 2003;42:1213-1242. 10. Fox DA, McCune WJ. Immunosuppressive drug therapy of systemic lupus erythematosus. Rheum Dis Clin North Am. 1994;20:265-299. 11. van den Bongard HJ, Mathôt RA, Beijnen JH, Schellens JH. Pharmacokinetically guided administration of chemotherapeutic agents. Clin Pharmacokinet. 2000;39:345-367. 12. Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of Physicians; 2007. 13. Medina PJ, Shord SS. Cancer treatment and chemotherapy (chapter 135). In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill Medical; 2011. 14. Etoposide (VePesid) [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2011. 15. Sinkule JA, Hutson P, Hayes FA, et al. Pharmacokinetics of etoposide (VP16) in children and adolescents with refractory solid tumors. Cancer Res. 1984;44:3109-3113.
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Oral Oncolytics 16. Pflüger KH, Hahn M, Holz JB, et al. Pharmacokinetics of etoposide: correlation of pharmacokinetic parameters with clinical conditions. Cancer Chemother Pharmacol. 1993;31:350-356. 17. Arbuck SG, Douglass HO, Crom WR, et al. Etoposide pharmacokinetics in patients with normal and abnormal organ function. J Clin Oncol. 1986; 4:1690-1695. 18. Superfin D, Iannucci AA, Davies AM. Commentary: Oncologic drugs in patients with organ dysfunction: a summary. Oncologist. 2007;12:1070-1083. 19. D’Incalci M, Rossi C, Zucchetti M, et al. Pharmacokinetics of etoposide in patients with abnormal renal and hepatic function. Cancer Res. 1986; 46:2566-2571. 20. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev. 1995;21:33-64. 21. Hydroxyurea (Hydrea) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2011. 22. Tracewell WG, Trump DL, Vaughan WP, et al. Population pharmacokinetics of hydroxyurea in cancer patients. Cancer Chemother Pharmacol. 1995;35:417-422. 23. Gwilt PR, Tracewell WG. Pharmacokinetics and pharmacodynamics of hydroxyurea. Clin Pharmacokinet. 1998;34:347-358. 24. Chabner BA, Barnes J, Neal J, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies,
and cytokines. In: Brunton L, Chabner B, Knollmann B, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2010. 25. van Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009;35:692-706. 26. Chabner BA, Bertino J, Cleary J, et al. Cytotoxic agents. In: Brunton L, Chabner B, Knollmann B, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2010. 27. Gibbons J, Egorin MJ, Ramanathan RK, et al. Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of renal dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group. J Clin Oncol. 2008;26:570-576. 28. Imatinib (Gleevec) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011. 29. Lenalidomide (Revlimid) [package insert]. Summit, NJ: Celgene Corporation; 2010. 30. Dimopoulos M, Alegre A, Stadtmauer EA, et al. The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer. 2010; 116:3807-3814. 31. Dimopoulos MA, Christoulas D, Roussou M, et al. Lenalidomide and dexamethasone for the treatment of
refractory/relapsed multiple myeloma: dosing of lenalidomide according to renal function and effect on renal impairment. Eur J Haematol. 2010;85:1-5. 32. Melphalan (Alkeran) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008. 33. Govindan R. The Washington Manual of Oncology. 2nd ed. Philadelphia, PA: Wolters Kluwer Health/ Lippincott Williams & Wilkins; 2007. 34. Osterborg A, Ehrsson H, Eksborg S, et al. Pharmacokinetics of oral melphalan in relation to renal function in multiple myeloma patients. Eur J Cancer Clin Oncol. 1989;25:899-903. 35. Carlson K, Hjorth M, Knudsen LM; for the Nordic Melanoma Study Group. Toxicity in standard melphalanprednisone therapy among myeloma patients with renal failure—a retrospective analysis and recommendations for dose adjustment. Br J Haematol. 2005;128:631-635. 36. Methotrexate (Trexall) [package insert]. Pomona, NY: Duramed Pharmaceuticals Inc; 2005. 37. Breithaupt H, Küenzlen E. Pharmacokinetics of methotrexate and 7-hydroxymethotrexate following infusions of high-dose methotrexate. Cancer Treat Rep. 1982;66:1733-1741. 38. Winograd B, Lippens RJ, Oosterbaan MJ, et al. Renal excretion and pharmacokinetics of methotrexate and 7hydroxy-methotrexate following a 24-h high dose infusion
of methotrexate in children. Eur J Clin Pharmacol. 1986;30:231-238. 39. Procarbazine (Matulane) [package insert]. Gaithersburg, MD: Sigma-Tau Pharmaceuticals; 2004. 40. Spivack SD. Drugs 5 years later: procarbazine. Ann Intern Med. 1974;81:795-800. 41. Preiss R, Baumann F, Regenthal R, Matthias M. Plasma kinetics of procarbazine and azo-procarbazine in humans. Anticancer Drugs. 2006;17:75-80. 42. Pratt WB, Ruddon RW, Ensminger WD, Maybaum J. The Anticancer Drugs. 2nd ed. New York, NY: Oxford University Press Inc; 1994. 43. Avendaño C, Menéndez JC. Medicinal Chemistry of Anticancer Drugs. Amsterdam, the Netherlands: Elsevier; 2008. 44. Oliverio VT. Pharmacologic disposition of procarbazine. In: Carter SK, ed. Proceedings on the Chemotherapy Conference on Procarbazine (Matulane: NSC-77213): Development and Application. Bethesda, MD: National Cancer Institute; 1970:19-56. 45. Sorafenib (Nexavar) [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2011. 46. Miller AA, Murry DJ, Owzar K, et al. Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301. J Clin Oncol. 2009;27:1800-1805. 47. Mercaptopurine (Purinethol) [package insert]. Sellersville, PA: Teva Pharmaceuticals; 2011.
Effects of Chemotherapy on Fertility May Be Underestimated Significantly By John Schieszer
any cancer survivors who thought they were fertile now may be finding that is not the case. New research is suggesting that current estimates of the impact of chemotherapy on women’s reproductive health are too low. Researchers at the University of California San Francisco (UCSF) say their analysis of the age-specific, longterm effects of chemotherapy provides new insights that will help patients and clinicians make more informed decisions about future reproductive options, such as egg harvesting (Cancer. September 1, 2011. Epub ahead of print). The investigators adopted a more tailored investigation into chemotherapy-related infertility and found estimates may have been far too low. They say these findings will now change how oncology nurses counsel their patients. “The nurses play a pivotal role here,” said study investigator Mitchell Rosen, MD, assistant professor in the UCSF Department of Obstetrics, Gynecology and Reproductive Sciences. “Nurses are the most important. Most of the time, referrals are generated and initiated by the nurse.” He said that oncology nurses need to be aware of the new study findings and consider them when educating patients. Rosen said even though an oncologist mentions that fertility may be affected, many patients simply don’t comprehend fully what that means because they are focused more on their current treatment options to enhance survival. “They forget
OctOber 2011 I VOL 4, NO 7
The researchers used the California Cancer Registry (a statewide population-based cancer surveillance system) “We found chemotherapy essentially narrows a to ask women about their reproductive woman’s reproductive window by causing a range of history before and after cancer treatment. Survey questions addressed acute damage to the ovaries, even if her menses resume ovarian failure (cessation of menses after chemotherapy.” —Mitchell Rosen, MD after treatment), early menopause (menopause before 45 years of age), and infertility (failed conception). A total of 1041 women diagnosed about the one sentence from the oncolo- mary reproductive side effect of with 1 of 5 targeted cancers (leukemia, gist,” said Rosen in an interview with The chemotherapy. Analyzing retrospective Hodgkin disease, non-Hodgkin lymOncology Pharmacist. “I think everyone survey responses from women who phoma, breast cancer, and gastroinwho is taking care of patients diagnosed were diagnosed between 18 and 40 testinal cancers) between the ages of 18 with cancer needs to be educated about years, the researchers focused on and 40 years responded, and 620 it. There are still not enough referrals longer-term, age-specific outcomes as- reported having been treated with only going to the fertility specialists. The more sociated with chemotherapy, including chemotherapy. awareness we can do, and the more peo- infertility and early menopause. Their The researchers found the percentage ple that are involved, the better.” analysis suggests that the younger a of women reporting acute ovarian failure He said many men and women woman is when diagnosed with cancer, was 8% (Hodgkin disease), 10% (nonundergoing chemotherapy are not get- the more likely she will experience Hodgkin lymphoma), 9% (breast canting enough information about how early menopause. “We found chemo - cer), and 5% (gastrointestinal cancers). their future fertility may be affected by therapy essentially narrows a woman’s In women without acute ovarian failure, the various treatments they may be reproductive window by causing a the incidence of infertility increased sigreceiving. “At every center there is a range of damage to the ovaries, even if nificantly with age at diagnosis. difference in who is involved when a her menses resume after chemotheraIn addition, the estimated probabilipatient is getting treated, so the more py,” said Rosen. ty of early menopause increased signifi[nurses] are involved the better. It Many of the women who responded cantly with younger age at diagnosis. needs to be standard of care for both to the survey had been told that as long When counseling patients, focusing men and women. Only 10% to 30% of as their periods returned, they would solely on short-term outcomes like loss men bank sperm, and that is easy. It is have no negative impact from treat- of menses may give women unrealistimuch more complicated with women. ment, he said. Making recommenda- cally low assessments of their risks, Yet 10% to 30% do it, and the main tions on preserving fertility currently is because they could experience infertilireason for [the low numbers] is a lack of based on rather limited data. These ty or early menopause years to decades education and awareness,” said Rosen. new findings, which also take into after treatment. Rosen noted that more Previous studies largely have focused account cancer type and age, hopefully research is needed because this study on amenorrhea, the lack of menstrua- will enable clinicians to offer more did not include genetics or variations tion shortly after treatment, as the pri- strategic and personalized counseling. in individual cancer treatments. ●
TOP_October 2011_v6_TOP 10/20/11 10:26 AM Page 33
Pushing Your Limits
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Koeller’s Corner Shooting from the Hip
Will Anybody Be Making Cancer Drugs in the Future? I will admit that I am knowingly and willingly walking into a hornet’s nest by discussing the current drug shortage, but I feel I must. In addition to our (oncology pharmacists’) ruminations about the current drug shortage, the issue has garnered national media attention. Major newspapers, national TV networks, magazines, and numerous websites have jumped on the drug shortage story. Yes, as patient advocates, getting “life-saving” drugs to our patients is our job, but we also must understand all the issues in the very complex generic oncolytic drug-supply chain (compassionate patient advocates we may be, business people not so much). The list of issues that have driven the drug shortage include, but are not limited to, raw material shortages (ie, active pharmaceutical ingredient), industry consolidation, importation and customs, federal regulations for new businesses, US Food and Drug Administration (FDA) regulations for generic approval, the backlog of FDA generic applications, manufacturing plant problems/changes/ inspections, drug reformulation, voluntary or FDA-mandated recalls, natural disasters, federally controlled reimbursement rates, buy-and-bill pricing/payment, industry and marketing changes, just-in-time inventory control, restricted distribution, limited drug use, and unexpected demand. There have always been drug shortages, but not to the degree and magnitude that we have seen in recent years. How many of you have seen the movie The Perfect Storm? Because George Clooney was in it, I imagine most people have. Our current drug shortage has been produced by what I will call “the perfect storm of circumstances.”
The primary issue is money. As with most issues related to business, the free market, and capitalism, everything comes
down to money; and the current drug shortage is no exception. The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) is a key component of the debacle. Buy-andbill drug payments are regulated based on average sales price plus a small percent. For example, 5% or 6% of a $4.00 generic cancer drug (eg, 5-fluorouracil) is just a couple cents. And there lies the problem. If payment for a cheap generic is controlled, market forces (ie, supply and demand) cannot work. Usually, demand would cause the price to rise and subsequently payment, making it attractive for other manufacturers to produce a drug. Unfortunately, that does not occur with generic cancer drugs because payment is set by MMA. Trying to raise the price, therefore, is problematic: You would lose money for a period of time with the Medicare payment.
Why can’t manufacturers just make more drug if there is a shortage? Drugs are not simple widgets that can be run off an assembly line at a minute’s notice when demand increases. And delays are unavoidable. Most companies do not want to invest millions of dollars with a multiyear return on investment for a limited-distribution product that has a set payment not based on the market or production costs. In addition, getting a generic injectable oncolytic to market can take 3 or more years. This has left us, mainly because of consolidation in the market, with just 4 major companies (Teva Pharmaceuticals, Hospira, Mylan, and Bedford Laboratories) making most of our generic oncolytics. Plus, bulk product production is outsourced to foreign countries, such as India, Russia, and China (with the extremely low profit margins, high production costs in the United States force business to be done in lower cost countries), which means delays can be expected. Even after bulk
With total payments for generic oncolytics being roughly $400 million (just 2% of all cancer drug costs), paying a little more for a stable supply of agents would seem reasonable.
too. In fact, 3 companies (Bedford Laboratories, APP Pharmaceuticals, and Hospira) were producing the generic drug. All 3 experienced a manufacturing problem at the same time, again causing shortages that could not just be fixed in a week. APP Pharmaceuticals and Hospira decided to shut down their lines and to no longer manufacture cytarabine (too expensive to fix for the small return on investment), exasperating the supply problem. When a production line is shut down for a problem, such as contamination, finding particulate matter, or other issue, it can take months to find and repair the problem, have the line reinspected, and then reactivate the line. Making matters worse, if one company has a production problem, it doesn’t mean the other companies can increase production. In this case, even though Bedford Laboratories’ market share of cytarabine has jumped from 50% in 2010 to more than 80% this year, the company still will not be able to meet all product needs in the short term.
How about for generic cancer drugs already being produced—why the shortages? Again, it has been a perfect storm scenario. For a drug like Janssen’s Doxil, the supply problem was the result of outsourced contract manufacturing. Ben Venue Laboratories decided to get out of the contract manufacturing business, leaving Janssen without a source of product and with months of delays expected. So for now, Ben Venue Laboratories is trying to increase production in the short term to meet market demands, and Janssen awaits a new manufacturer. Thus, the DOXIL C.A.R.E.S. Physician Access Program was set up basically to ration the limited supply of drug and will be the only way to acquire the drug until a new production line is operational. Cytarabine has had its problems,
There’s enough blame to go around, so how do we fix it? That’s the milliondollar question. I don’t think asking for more government intervention is the solution. I consider the government a big part of the problem. Letting the freemarket supply-and-demand system work would be the more prudent solution, but that would take an act of Congress. Laws would need to be changed to allow payment changes for generics. With total payments for generic oncolytics being roughly $400 million (just 2% of all cancer drug costs), paying a little more for a stable supply of agents would seem reasonable. Fix the money and you will fix the supply. Everything else we do (additional legislative action, real-time drug tracking for shortages, better notification and communication from industry and the FDA, national depots, etc) will just be window dressing. ●
drug is approved and provided, the final product must be manufactured, and FDA good manufacturing practice requirements for sterile injectable drugs are daunting to say the least. Added to that, cancer agents are considered hazardous materials, which means that production lines are even more tightly controlled. All these steps take time, and problems and delays can occur at any point of the process. If that isn’t bad enough, inspecting production plants overseas adds another level of complexity and delay.
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