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Catheter-Related Thrombosis Can Be Prevented
Onco360 The Changing Role of Oncology Pharmacy nco360 is an oncology pharmaceutical services company dedicated to advancing the continuum of pharmaceutical cancer care for patients. To that end, the company has developed specialized clinical and supportive care oncology pharmacy care programs and services that are managed by boardcertified oncology pharmacists (BCOPs) with the goal of providing quality services and improving outcomes for patients. Burt Zweigenhaft, CEO of Onco360 Onco360 provides services to more than 1800 oncologists; 43 major BlueCross/BlueShield programs; commercial, Medicare, and Medicaid managed care payers; hospital systems; and the National Comprehensive Cancer Network (NCCN) Centers of Excellence through its national network of certified and JCAHO-accredited OncoMed pharmacies. The Oncology Pharmacist spoke with Burt Zweigenhaft, CEO of Onco360, about the company and the future of oncology pharmacy.
What role do you see Onco360 playing in the current healthcare environment? Burt Zweigenhaft (BZ): We don’t believe the market has fully grasped the potential value of oncology pharmacists, outside of some of the better-known hospitals and NCCN centers like MD Anderson or Roswell Park. What keeps us awake at night is the ASCO-projected shortage of 4000 treating oncologists, and the corresponding aging of America fueled by 10,000 new Medicare beneficiaries a day until 2020; this will create a cancer care access crisis. Additionally, delivering cancer care will become exponentially more complex as we move to personalized medicine. Thus, the greater focus on patient care plan personalization, based on the specific tumor diagnosis using predictive sciences and targeted, evidence-based guidelines, will be the norm.
By Caroline Helwick
nticoagulation prophylaxis is effective in preventing both symptomatic and asymptomatic catheter-related deep vein thrombosis in ambulatory cancer patients with locally advanced or metastatic solid tumors, French investigators reported at the European Society for Medical Oncology (ESMO) 2012 Congress, held in Vienna, Austria.1 Among cancer patients who have catheters in place for chemotherapy,
catheter-related deep vein thrombosis causes morbidity and mortality. The incidence of symptomatic events ranges from 0.3% to 28.3%, and the incidence rises to 27% to 66% when asymptomatic episodes are included. Current guidelines from American and European societies do not recommend prophylactic anticoagulation for cancer outpatients, but symptomatic catheterrelated deep vein thrombosis is still a subject of active research, and the value of Continued on page 8
Crizotinib Superior to Chemotherapy in First Head-to-Head Comparison PROFILE 1007 Was a Headliner at ESMO By Audrey Andrews
n a phase 3 head-to-head comparison trial, the anaplastic lymphoma kinase (ALK) inhibitor crizotinib proved more effective than standard chemotherapy with pemetrexed or docetaxel as a second-line treatment for
non–small cell lung cancer (NSCLC) patients with the ALK genetic abnormality. The results of the global PROFILE 1007 trial were reported by Alice Shaw, MD, of Massachusetts General Hospital in Boston, at the European Society for Continued on page 17
Continued on page 28
INSIDE CONFERENCE NEWS
Highlights From ASTRO
Proton Beam Therapy ComPlimentary Ce
By Alice Goodman
he 2012 American Society for Radiation Oncology (ASTRO) Annual Meeting, held in Boston, Massachusetts, coincided with Superstorm Sandy. Despite the havoc wreaked by the storm, Boston was largely spared, although ASTRO can-
celed Monday afternoon’s Plenary Session when public transportation was shut down. Below are some highlights from the meeting, including some news stories from the Plenary Session, which was available online.
Considerations in Multiple Myeloma—Ask the Experts: Retreatment Settings . . . . . . . . . . . . . .18 Considerations in Multiple Myeloma—Ask the Experts: Bone Health . . . . . . . . . . . . . . . . . . . . . . .32
Continued on page 26
©2012 Green Hill Healthcare Communications, LLC
Advances in the Treatment of Pancreatic Neuroendocrine Tumors ConferenCe news: esmo
Who’s Your T.O.P. Pharmacist Nominee? Nominate a pharmacist at www.TheOncologyPharmacist.com/award For more information, see page 7.
The median age of patients in the VISTA† trial was 71 years (range: 48-91).
Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.
▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.
In treating multiple myeloma
What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies
IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1
IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,506 per 3.5-mg vial as of July 2012 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen
▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE on the next page of this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.
Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.
Noteworthy Numbers Billions of dollars are spent each year to fund research as scientists continue to identify the causes of cancer and to develop strategies for prevention, detection, treatments, and cures. The following statistics allow a glimpse into the immense field of cancer research funding. Cancer research is funded by the federal government primarily through the
National Cancer Institute (NCI), part of the National Institutes of Health (NIH).1
Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE 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 (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: 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. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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 8%. 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 Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, 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 of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred 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, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: 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. Interrupt VELCADE for severe symptoms. 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 of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.
More than $30 billion annually is invested into medical research by the NIH.1
Embryo-fetal: Pregnancy Category D. Women of reproductive 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. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) 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 (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. 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, VELCADE 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 bortezomib 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 VELCADEHCP.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 © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA
Greater than 80% of NIH’s funding is awarded through competitive grants to researchers at more than 3000 locations in all 50 states across the country.1 Between fiscal years 2010 and 2012, NIH federal appropriations fluctuated only slightly, with a low of $30,399 million (FY 2011) and a high of $31,010 (FY 2010).1 Over half of NCI’s budget is assigned to more than 6500 research grants funded at more than 150 research facilities located in 49 states.1 NCI federal appropriations also varied only marginally between fiscal years 2010 and 2012, with a low of $5058 million (FY 2011) and a high of $5103 (FY 2010).1 The National Cancer Society annually spends approximately $5.2 billion in its fight against cancer.2 Many times, research funding is appropriated to a specific cancer that has scientific groundwork already established. Therefore, the little known and/or less understood cancers tend to receive less funding than the more understood cancers, such as breast cancer.3 Sources 1. www.aacr.org. 2. www.StatisticBrain.com. 3. www.everydayhealth.com.
DECEMBER 2012 I VOL 5, NO 8
Editorial Board EDITOR-IN-CHIEF
Patrick Medina, PharmD, BCOP
Anjana Elefante, PharmD, BSc, BSc Pharm, RPh
Dwight Kloth, PharmD, FCCP, BCOP
Oklahoma University College of Pharmacy Tulsa, OK
Roswell Park Cancer Institute Buffalo, NY
Fox Chase Cancer Center Philadelphia, PA
Beth Faiman, PhD(c), MSN, APRN-BC, AOCN
Jim Koeller, MS
Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL
University of Texas at Austin San Antonio, TX
Cleveland Clinic Taussig Cancer Institute Cleveland, OH
Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA
John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
Christopher Fausel, PharmD
Christopher J. Lowe, PharmD
Indiana University Simon Cancer Center Indianapolis, IN
Indiana University Hospital Indianapolis, IN
David Baribeault, RPh, BCOP
Rebecca S. Finley, PharmD, MS
Emily Mackler, PharmD, BCOP
Burt Zweigenhaft, BS
Boston Medical Center Boston, MA
Jefferson School of Pharmacy Philadelphia, PA
University of Michigan Health System & College of Pharmacy Ann Arbor, MI
OncoMed Onco360 Great Neck, NY
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
John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT
Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE
Marlo Blazer, PharmD, BCOP
The University of Texas MD Anderson Cancer Center Houston, TX
James Cancer Hospital & Solove Research Institute Columbus, OH
Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN
Steven L. Dâ€™Amato, RPh, BCOP
Lew Iacovelli, BS, PharmD, BCOP, CPP
LeAnn Best Norris, PharmD, BCPS, BCOP
Maine Center for Cancer Medicine Scarborough, ME
Moses H. Cone Health System Greensboro, NC
South Carolina College of Pharmacy Columbia, SC
Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC
DECEMBER 2012 I VOL 5, NO 8
From the Editors PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko firstname.lastname@example.org Publisher John W. Hennessy email@example.com Associate Publisher Joe Chanley firstname.lastname@example.org
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n this month’s issue of The Oncology Pharmacist (TOP), we wrap up the year with highlights of the news from the 2012 American Society for Radiation Oncology Annual Meeting and the European Society for Medical Oncology 2012 Congress. Also, we continue our coverage of the news from the 2012 Annual Meeting of the American Society of Clinical Oncology. The information we present from these professional meetings helps keep you up-to-date with the
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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, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 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®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. 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, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. 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.
DECEMBER 2012 I VOL 5, NO 8
latest research and may affect your daily practice as an oncology pharmacist. Our new TOP reader poll asks, “What inspired you to enter the oncology field?” Please go to our website, www.The OncologyPharmacist.com, and tell us what motivated you to become an oncology pharmacist. We’ll publish some of your responses in the first issue of the new year. All of us at TOP wish you the best for 2013. l
Recent FDA News
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Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief
Omacetaxine mepesuccinate Approved to Treat Cml The US Food and Drug Administration (FDA) has approved omacetaxine mepesuccinate subcutaneous injection (Synribo, Teva Pharmaceutical Industries) for the treatment of adult patients with chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). Approval for omacetaxine mepesuccinate was granted on October 26, 2012. The FDA approval was based on the combined results of 2 open-label, single-arm trials that enrolled patients with CML in chronic phase or accelerated phase. Patients in the trials had received 2 or more prior TKIs, including imatinib. The end points for the studies were major cytogenetic response for chronic-phase CML and major hematologic response for accelerated-phase CML. For those with chronic-phase CML, major cytogenetic response was achieved in 18.4% of patients (median response duration of 12.5 months). For patients with accelerated-phase CML, 14.3% achieved major hematologic response (median response duration of 4.7 months). Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection-site reaction, pyrexia, infection, and lymphopenia were the most common (≥20%) grades 1 to 4 adverse drug reactions. Thrombocytopenia, anemia, neutropenia, febrile neutropenia, asthenia/fatigue, pyrexia, and diarrhea were the most common (≥5%) grades 3 to 4 adverse drug reactions. Among the patients in the trials, 10 died within 30 days of the last omacetaxine mepesuccinate dose: 4 deaths were attributed to progressive disease, 4 to cerebral hemorrhage, 1 to multiorgan failure, and 1 to unknown causes. Omacetaxine mepesuccinate was reviewed under the FDA’s accelerated approval review program that provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists. In addition, the FDA designated omacetaxine mepesuccinate as an orphan product because it is intended to treat a rare disease or condition. Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, stated that the approval of omacetaxine mepesuccinate “provides a new treatment option for patients who are resistant to or cannot tolerate other FDA-approved drugs for chronic or accelerated phases of CML.” He also noted that it “is the second drug approved to treat CML in the past two months.”
expanded labeling for Pemetrexed The FDA expanded the labeling of pemetrexed (Alimta, Eli Lilly and Company) to include the results of an additional trial evaluating its safety and efficacy for the initial treatment of patients with locally advanced or metastatic, nonsquamous, non‒small cell lung cancer followed by pemetrexed maintenance in patients with disease that has not progressed after 4 cycles of platinum and pemetrexed as first-line chemotherapy. The approval for expanded labeling was granted on October 17, 2012. The expanded labeling describes the results of a multicenter, randomized (2:1), double-blind, placebo-controlled trial that evaluated pemetrexed maintenance in patients with stage IIIB/IV nonsquamous, non‒small cell lung cancer whose initial treatment was 4 cycles of pemetrexed plus cisplatin. There were 539 patients randomized to receive 500 mg/m2 pemetrexed intravenously on day 1 of each 21-day cycle (359 patients) or matching placebo (180 patients). All patients had an ECOG performance status of 0 or 1 and had completed 4 cycles of pemetrexed plus cisplatin with a best response of stable disease, partial response, or complete response. Investigator-assessed progression-free survival (PFS) was significantly improved in patients randomized to receive pemetrexed maintenance, compared with those who received placebo. Median PFS was 4.1 months for patients in the pemetrexed arm and 2.8 months for patients receiving placebo. Overall survival, a secondary end point, also was significantly improved for patients receiving pemetrexed maintenance, with median survival time of 13.9 months, compared with 11.0 months for patients receiving placebo. Neutropenia, anemia, fatigue, nausea, vomiting, stomatitis, and edema were the most common (>5%) adverse events for patients in the pemetrexed arm. Anemia and neutropenia were the most common severe adverse reactions. Approximately 25% of patients receiving pemetrexed maintenance had treatment reduced or delayed because of toxicity. l
Sources http://www.fda.gov/Drugs/InformationOnDrugs/Approv edDrugs/ucm325990.htm http://www.fda.gov/NewsEvents/Newsroom/PressAnnou ncements/ucm325895.htm http://www.fda.gov/Drugs/InformationOnDrugs/Approved Drugs/ucm324239.htm
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Supportive Care Catheter-Related Thrombosis Can Be Prevented Continued from cover prophylaxis in this population is controversial, said Sandrine Lavau-Denes, MD, of the University Hospital at Limoges in France. Lavau-Denes reported the results of a phase 3 single-center prospective, randomized, open-label trial, conducted over a 10-year period (1999-2010), that compared a prophylactic strategy to no prophylaxis over 3 months of chemotherapy among 420 patients with advanced solid tumors. “We found that prophylaxis with either warfarin or low-molecular-weight heparin was effective in preventing thrombotic events, and there was no increase in bleeding with prophylaxis,” said Lavau-Denes. The study was initiated prior to the publication of the current guidelines. The primary end point was the rate of symptomatic and asymptomatic catheter-related deep vein thromboses of the ipsilateral upper limbs and cervical veins of patients who received, versus those who did not receive, thromboprophylaxis. It excluded intraluminal thrombosis. Investigators randomized 142 patients starting a first line of treatment to lowmolecular-weight heparin (at the recom-
mended dose), 138 to warfarin (1 mg/day), and 140 to a control arm. Patients were evaluated at baseline and on day 90 (sooner, in the case of symptoms), using Doppler ultrasound of the upper limbs and cervical veins, and venography.
Adverse events were not significantly increased with thromboprophylaxis.
effectiveness of Prophylaxis In 407 evaluable patients, 42 catheterrelated deep vein thromboses occurred (10.3%), 30 (15.1%) of which were asymptomatic. This included 20 of 135 (14.8%) patients in the control arm and 22 of 272 (8.1%) patients receiving either warfarin or low-molecular-weight heparin. The effect of prophylaxis amounted to a 45% reduction in risk that was statistically significant (P = .0357). Warfarin and low-molecular-weight
heparin were equally effective, LavauDenes noted. Rates of symptomatic events were 6.7% in controls, versus 1.1% after prophylaxis; asymptomatic events occurred in 8.1% and 7.0%, respectively. Unrelated deep vein thromboses also were prevented. Adverse events were not significantly increased with thromboprophylaxis. Bleeding occurred in 0.7% of controls, 2.2% of the low-molecular-weight heparin arm, and 4.5% of the warfarin arm (P = .1361). However, there was an increase in thrombopenia in patients receiving thromboprophylaxis (P <.0001), particularly with low-molecular-weight heparin. However, this was grade 3/4 in only 12 (8.8%), 4 (3.0%), and 7 (5.0%) patients, respectively, with no difference among the arms (P = .1039), she said. Prophylaxis was discontinued by 25% in the control arm, 27% in the warfarin arm, and 33% in the low-molecular-weight heparin arm. For 12.5% of patients in the control arm the reason was the occurrence of a thrombotic event, compared with 2.2% in the warfarin arm and 2.2% in the low-molecular-weight heparin arm.
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Who Should Receive Prophylaxis? Fausto Roila, MD, of Terni, Italy, who chairs ESMO’s Supportive Care Track, reiterated that routine prophylaxis for ambulatory patients with solid tumors is not recommended by any society, except when patients are considered at high risk. However, he noted, “Thrombosis is a potentially deadly complication, and it is not rare.” Therefore, Roila suggested that primary prophylaxis be considered under the following circumstances: • The incidence within one’s institution is 8% to 10% • The tip of the central venous catheter is not positioned at the junction between the atrium and the vena cava • The patient has factor V Leiden mutation or a previous venous thromboembolism • The patient has mediastinal syndrome l Reference 1. Tubiana-Mathieu N, Lavau-Denes S, Lacroix P, et al. Prophylaxis of catheter-related deep vein thrombosis in cancer patients with low-dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study. Presented at: European Society for Medical Oncology 2012 Congress; October 1, 2012; Vienna, Austria. Abstract 1546O PR.
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For appropriate patients receiving highly emetogenic chemotherapy who are at risk of chemotherapy-induced nausea and vomiting (CINV)
PREVENTION BEGINS WHERE TRIPLE THERAPY STARTS
On Cycle 1, Day 1, start with Triple Therapy—EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid—for first-line prevention of CINV. EMEND for Injection, 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. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.
Selected Important Safety Information tEMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. tAprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. tEMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant. tChemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) 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 did not influence the pharmacokinetics of docetaxel or vinorelbine. tBecause 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.
Selected Important Safety Information (continued) tThere have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. tCoadministration of EMEND for Injection 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 for Injection with each chemotherapy cycle. tThe efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. tChronic continuous use of EMEND for Injection 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. tIn clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). tIn a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. Please see the adjacent Brief Summary of the Prescribing Information.
An antiemetic regimen including
Merck Oncology Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1029338-0014 09/12 emendforinjection.com
Brief Summary of the Prescribing Information for
INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.
Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting. Chronic continuous administration is not recommended [see Warnings and Precautions]. CONTRAINDICATIONS Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. Concomitant Use With Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide 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: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [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, the oral aprepitant 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 the oral aprepitant 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]. Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant 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 fosaprepitant with each chemotherapy cycle [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. Chronic Continuous Use: Chronic continuous use of EMEND for Injection 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 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adversereaction 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. Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection. The overall safety of fosaprepitant was evaluated in approximately 1,100 individuals and the overall safety of aprepitant was evaluated in approximately 6,500 individuals. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): 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. Oral aprepitant was given in combination with ondansetron and dexamethasone. In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy. The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence of >1% and greater than with standard therapy (n=550), respectively, are listed below: Respiratory system: hiccups 4.6 vs 2.9 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9 Nervous system: headache 2.2 vs 1.8 Metabolism and nutrition: anorexia 2.0 vs 0.5 A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than with standard therapy are presented in the Less Common Adverse Reactions subsection below. In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverseexperience profile was generally similar to that seen in the other HEC studies with aprepitant. Less Common Adverse Reactions: Adverse reactions reported in either HEC or moderately emetogenic chemotherapy (MEC) studies in patients treated with the aprepitant regimen with an incidence of <1% and greater than with standard therapy are listed below. Infection and infestations: candidiasis, staphylococcal infection Blood and lymphatic system disorders: anemia, febrile neutropenia Metabolism and nutrition disorders: weight gain, polydipsia Psychiatric disorders: disorientation, euphoria, anxiety Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders: conjunctivitis Ear and labyrinth disorders: tinnitus Cardiac disorders: bradycardia, cardiovascular disorder, palpitations
EMENDÂŽ (fosaprepitant dimeglumine) for Injection Vascular disorders: hot flush, flushing Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, hard feces, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness Renal and urinary disorders: polyuria, dysuria, pollakiuria General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, decreased weight, decreased neutrophil count In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1. Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared with 1,169 patients receiving the 3-day regimen of EMEND. The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared with those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above: General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain Investigations: increased blood pressure Skin and subcutaneous tissue disorders: erythema Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis) Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4 and does not induce CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs that are substrates for the P-glycoprotein transporter. The following information was derived from data with oral aprepitant, 2 studies conducted with fosaprepitant and oral midazolam, and 1 study conducted with fosaprepitant and dexamethasone. Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 Substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications]. 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: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0â€“24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg I.V. on Day 1. An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone 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 intravenous methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions]. Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions]. Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks posttreatment. The coadministration of fosaprepitant or aprepitant 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 fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as K, decrease as L, no change as ): Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC K 1.8-fold on Day 1 and AUC on Day 4 Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC K 1.6-fold Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC K 2.3-fold on Day 1 and K 3.3-fold on Day 5 Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day
EMEND® (fosaprepitant dimeglumine) for Injection regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC K 25% on Day 4, AUC L 19% on Day 8, and AUC L 4% on Day 15 Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC K 1.5-fold
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. Carcinogenicity studies were not conducted with fosaprepitant.
A difference of less than 2-fold increase of midazolam AUC was not considered clinically important. 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 fosaprepitant or aprepitant.
Aprepitant and fosaprepitant were 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.
CYP2C9 Substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant 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 oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as INR) 5 days after completion of dosing with oral aprepitant. 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 fosaprepitant with each chemotherapy cycle. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide 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 oral aprepitant and on Days 4, 8, and 15. Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant 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 fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy. Ketoconazole: When a single 125-mg dose of oral aprepitant 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 fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of oral aprepitant 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 fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy. Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs 15.6 [±4.1] mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood pressure (mean [SD] of 29.5 [±7.9] mmHg with fosaprepitant vs 23.8 [±4.8] mmHg without fosaprepitant), which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval beyond those changes induced by diltiazem alone. In the same study, 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 Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant of up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcgshr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcgshr/mL, about 1.4 times the human exposure at the recommended dose) 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 for Injection in pediatric patients have not been established. Geriatric Use: In 2 well-controlled CINV clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% 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. 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 fosaprepitant or aprepitant is administered in these patients. OVERDOSAGE There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population. 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 AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcgshr/mL) 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
Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral 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]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Patients should follow the physician’s instructions for the regimen of EMEND for Injection. Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation. EMEND for Injection 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 fosaprepitant with each chemotherapy cycle. Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. For detailed information, please read the Prescribing Information. Rx only
Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1029338-0014
Proton Beam Therapy: Similar Toxicity to Standard Radiation, at much Higher Cost By Phoebe Starr
he use of proton beam radiation therapy (PBRT) for the treatment of prostate cancer is in-
creasing across the United States, but there is no evidence from randomized controlled trials to suggest that PBRT is
more effective than intensity modulated radiation therapy (IMRT), which is the current standard of care. A study pre-
YOUR QUESTIONS ANSWERED
Editor in Chief
Editor in Chief
Sagar Lonial, MD
Stephanie A. Gregory, MD
Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine
Topics include: • Newly Diagnosed Patients • Maintenance Settings • Transplant-Eligible and -Ineligible Patients • Retreatment Settings • Bone Health
The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University
sented at the 2012 American Society for Radiation Oncology Annual Meeting found few differences in toxicity between the 2 techniques, but demonstrated that PBRT was associated with a 57% increase in median cost per patient. Similar efficacy, Double the Cost “PBRT is an emerging treatment for men with prostate cancer, yet it is much more expensive than IMRT,” said James B. Yu, MD, Assistant Professor of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut. “We need a prospective large study comparing radiation techniques to justify widespread use of PBRT for prostate cancer,” he explained. The population-based, retrospective, observational study was based on 22,647 Medicare beneficiaries between the ages of 66 and 94 years who received PBRT or IMRT for prostate cancer in 2008 and 2009; 421 patients (2%) received PBRT and 27,226 patients (98%) received IMRT.
Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma
These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.
These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.
ALL NEW CONTENT FOR 2012
A study presented at the 2012 American Society for Radiation Oncology Annual Meeting found few differences in toxicity between the 2 techniques, but demonstrated that PBRT was associated with a 57% increase in median cost per patient.
Accreditation These activities will be accredited for physicians, nurses, and pharmacists. For complete accreditation information, please refer to each activity. This activity is jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC.
DECEMBER 2012 I VOL 5, NO 8
The median Medicare reimbursement per patient is $32,428 for PBRT and $18,575 for IMRT, which represents a 57% difference. PBRT was associated with a significant reduction in urinary toxicity at 6 months versus IMRT (6.1% vs 12%, respectively); however, by 1 year, there was no difference between groups for urinary toxicity (18.9% for PBRT vs 21.9% for IMRT). No signif-
Prostate Cancer icant differences were observed at 6 months and at 1 year between the 2 groups in gastrointestinal (GI) or other toxicities. “The longer-term effects, costs, and other clinical and patient-reported outcomes are needed to inform the adoption of PBRT for prostate cancer,” Yu stated. The study had several limitations, he continued. It is a retrospective study that is a claims-based analysis with no staging information and with no data on the extent or field of radiation. Potential Differences in Side effects A second study found minimal differences between PBRT, IMRT, and the older 3-dimensional conformal radiation therapy (3D-CRT). The study included 153 patients treated with IMRT, 123 patients treated with 3D-CRT, and 94 patients treated with PBRT. Quality of life (QOL) was assessed by the Expanded Prostate Cancer Index Composite in the IMRT cohort and by the Prostate Cancer Symptom Index in the PBRT and 3DCRT cohorts. The main difference in QOL scores in the GI domain was found 2 to 3 months posttreatment, when 3D-CRT and IMRT—but not PBRT—were associated with a clinically meaningful decrement in QOL scores. Over 12 months, the 3 cohorts had similar QOL scores for GI effects. For urinary irritation, all 3 groups
“PBRT is an emerging treatment for men with prostate cancer, yet it is much more expensive than IMRT. The longer-term effects, costs, and other clinical and patient-reported outcomes are needed to inform the adoption of PBRT for prostate cancer.” —James B. Yu, MD
had lower QOL scores at 2 to 3 months of follow-up, but this was clinically meaningful only for IMRT. Sexual
function QOL scores were lower in all 3 groups at 24 months, but this was not clinically meaningful (defined in
this study as scores exceeding half of the standard deviation of the baseline mean score). “These findings are a unique addition to existing research in the field, and suggest that PBRT may lead to fewer immediate side effects in prostate cancer patients,” noted Phillip Gray, MD, a resident at Harvard Radiation Oncology Pro gram, Boston, Massachusetts. He suggested that a prospective, randomized controlled trial is needed to compare these technologies. l
Have you had experience in determining the appropriate chemotherapy dose for patients who are obese? In the October issue, we published an article about the results of a meta-analysis reported at ASCO 2012 that supported the new guidelines that recommend weight-based chemotherapy dosing for obese cancer patients. We asked our online reading community if they had experience with dosing for obese patients. • 89% have dealt with weight-based dosing, with 1 reader commenting “every day” • 11% have not had experience with dosing for obese patients
Our sincere thanks to all who participated in this survey. If you want to participate in the new survey, see page 8 for details.
THIRD ANNUAL CONFERENCE
Influencing the Patient-Impact Factor
May 2-5, 2013 Westin Diplomat • Hollywood, Florida
REGISTER TODAY AT www.AVBCConline.org www.TheOncologyPharmacist.com
DECEMBER 2012 I VOL 5, NO 8
TREANDA速 (bendamustine HCI) for Injection is his chemo.
This is his therapy.
Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). EfďŹ cacy relative to ďŹ rst-line therapies other than chlorambucil has not been established. PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Survival distribution function
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1
18 months median PFS
6 months median PFS
P<.0001 HRâ€ =0.27 (95% CIâ€Ą: 0.17, 0.43)
Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â€ HR=hazard ratio. â€Ą CI=confidence interval.
s 42%!.$! WAS COMPARED WITH CHLORAMBUCIL IN A RANDOMIZED OPEN LABEL PHASE TRIAL IN TREATMENT NAĂ•VE PATIENTS WITH "INET STAGE "