December 2011, Vol 4, No 8 by The Oncology Pharmacist

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DECEMBER 2011

www.TheOncologyPharmacist.com

CANCER CENTER PROFILE

The Cleveland Clinic Taussig Cancer Institute For Oncology Pharmacists, Patient Education Is Key

VOL 4, NO 8

Drug Interactions With Commonly Prescribed Oral Chemotherapeutic and Targeted Agents By Shannon Hough, PharmD; Emily Mackler, PharmD, BCOP University of Michigan Pharmacy Services and College of Pharmacy, Ann Arbor

any malignancies currently have oral medication options for cancer therapy. The use of oral therapy can avoid complex intravenous (IV) regimens that negatively affect patient quality of life.1 According to the literature, cancer patients favor oral medications over IV chemotherapy.2

Many of the newly approved anticancer agents are administered orally, suggesting a paradigm shift from IV administration.3 While oral medications for cancer therapy offer improved quality of life and convenient and flexible administration for patients, many agents have the potential for overlapping drug toxicities and drugContinued on page 31

BREAST CANCER

Emerging Therapies in the Treatment of Breast Cancer By Caroline Helwick One of the outpatient pharmacies at the Cleveland Clinic. The Cleveland Clinic operates 9 outpatient pharmacies in addition to the specialized inpatient pharmacies.

he Cleveland Clinic was founded in 1921 in Cleveland, Ohio, by 4 physicians. At that time, it was one of only a few group practices in the United States. This group practice model was very familiar to 3 of the founders—George Crile Sr, Frank Bunts, William Lower—as they served together in military hospitals near the front lines of World War I. These 3 colleagues were determined to establish a not-for-profit clinic that combined the best of military and civilian medical practices. Joined by a fourth physician—John Phillips—they set about building a

Continued on page 18

romising data on several new breast cancer agents, including one new cytotoxic, were presented at the American Society of Clinical Oncology Breast Cancer Symposium 2011 held September 8-10 in San Francisco, California. The addition of the novel histone deacetylase (HDAC) inhibitor entinostat to exemestane significantly delayed recurrences and showed a trend for a survival benefit in the phase 2 ENCORE 301 (ENtinostat Combinations Overcoming

REsistance) study reported by Denise Yardley, MD, of Sarah Cannon Research Institute and Tennessee Oncology in Nashville. The regimen is based on the concept that HDAC inhibitors can restore estrogen receptor (ER) sensitivity in the tumor, allowing patients to respond again to an endocrine agent. “This combination may allow patients to remain on hormonal therapy longer, delaying the need for chemotherapy,” she suggested. ENCORE 301 randomized 114 postContinued on page 28

CONFERENCE NEWS: ASTRO

Higher Radiation Doses May Not Help Lung Cancer Patients Live Longer By John Schieszer

higher dose of radiation (74 Gy) does not improve overall survival for non–small cell lung cancer (NSCLC) that has spread to the lymph nodes compared with the standard radiation dose (60 Gy), according to a new study presented at the 53rd Annual Meeting of the American Society for Radiation Oncology. “Most radiation oncologists and lung

cancer specialists are surprised by this finding. Although the optimal radiation dose for lung cancer patients has not been tested in a randomized phase 3 trial for over 30 years, most believed that higher doses of radiation cured more patients with lung cancer,” said study investigator Jeffrey Bradley, MD, radiation oncologist at the Wash -

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Positive Data Continue to Accrue for Crizotinib in ALK-Positive NSCLC Side effeCt management

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Continued on page 16

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Thromboembolism After Chemotherapy Raises Healthcare Costs About 30%

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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

ASSOCIATE EDITOR-IN-CHIEF

Beth Faiman, RN, 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

BioPharma Partners LLC New York, 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, RPh, PharmD

The University of Texas M. D. 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&#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

December 2011 I VOL 4, NO 8

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

www.TheOncologyPharmacist.com

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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 Docetaxel Injection safely and effectively. See full prescribing information for Docetaxel.

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.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Topotecan Injection safely and effectively. See full prescribing information for Topotecan Injection.

Docetaxel Injection

Gemcitabine Injection

Topotecan Injection

For intravenous infusion only. Initial U.S. Approval: 1996

For Intravenous Infusion Only. Must Be Diluted Before Use. Initial U.S. Approval: 1996

Must be diluted before intravenous infusion Initial U.S. Approval: 1996

•

• •

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION See full prescribing information for complete boxed warning Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1) Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6) Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4) Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection and administration of appropriate therapy (5.4) Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4) Severe fluid retention may occur despite dexamethasone (5.5)

CONTRAINDICATIONS • Hypersensitivity to docetaxel or polysorbate 80 (4) • Neutrophil counts of <1500 cells/mm3 (4) WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6) • Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7) • Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8) • Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9) • Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection (5.10, 8.1) ADVERSE REACTIONS Most common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

INDICATIONS AND USAGE Gemcitabine is a nucleoside metabolic inhibitor indicated for: • Ovarian cancer in combination with carboplatin (1.1) • Breast cancer in combination with paclitaxel (1.2) • Non-small cell lung cancer in combination with cisplatin (1.3) • Pancreatic cancer as a single-agent (1.4) DOSAGE AND ADMINISTRATION Gemcitabine Injection is for intravenous use only. • Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1) • Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.2) • Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3) • Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4) • Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4) DOSAGE FORMS AND STRENGTHS • 200 mg/5.26 mL injection vial (3) • 1 g/26.3 mL injection vial (3) • 2 g/52.6 mL injection vial (3) 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)

WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Do not give topotecan injection to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marroww suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan injection. (5.1) CONTRAINDICATIONS • History of severe hypersensitivity reactions (e.g. anaphylactoid reactions) to topotecan or any of its ingredients (4) • Severe bone marrow depression (4) WARNINGS AND PRECAUTIONS • Bone marrow suppression. Administer topotecan injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. (5.1) • Topotecan-induced neutropenia can lead to neutropenic colitis. (5.2) • Interstitial lung disease: Topotecan has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Injection if the diagnosis is confirmed. (5.3) • Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1) ADVERSE REACTIONS Small cell lung cancer: • The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). (6.1) • The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• 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. See 17 for PATIENT COUNSELING INFORMATION Revised: 07/2011

Manufactured by: Hospira Australia Pty., Ltd., Mulgrave, Australia Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India Distributed by: Hospira, Inc., Lake Forest, IL 60045 USA GUJ DRUGS/G/28/1267

Manufactured by: Hospira Australia Pty Ltd Mulgrave VIC 3170 Australia Manufactured for: Hospira, Inc. Lake Forest, IL 60045 USA Product of Australia

Manufactured and Distributed by: Hospira, Inc. Lake Forest, IL 60045 USA Made in India

TOP_December 2011_v5_TOP 12/18/11 1:39 PM Page 5

Solutions that can help your patients stay ahead of access barriers What your patients need for access—from benefits investigations through patient assistance options— is available through Genentech BioOncologyTM Access Solutions®. Our Specialists can help you navigate the process.

To find out more, contact our Specialists at (888) 249-4918 or visit BioOncologyAccessSolutions.com/resources

TOP_December 2011_v5_TOP 12/18/11 1:39 PM Page 6

From the Editor PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com

Patrick Medina, PharmD, BCOP Editor-in-Chief

Quality Control Director Barbara Marino Directors, Client Services Joe Chanley joe@greenhillhc.com

s 2011 comes to an end, I have great news for readers of The Oncology Pharmacist (TOP). Steve Stricker, PharmD, MS, BCOP, a member of our editorial board, has agreed to join me as associate editor-inchief. Steve will bring great energy to his new role here at TOP and will help us address the issues that affect us as oncology pharmacists, including the drug shortage situation and how to deal with it at the clinical level, the expanding use of oral oncolytics, and the increasing role of personalized medicine in oncology and the implications for our practices. We at TOP work hard to help keep you up-to-date about what is happening in the world of oncology and to bring you information you can use in your day-to-day pharmacy practice. In this issue, Shannon Hough and Emily Mackler discuss drug interactions that can occur with some commonly prescribed oral chemotherapeutic and targeted agents. We

Jack Iannaccone jack@greenhillhc.com Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-992-1891 Fax: 732-656-7938

241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831

GH Green Hill Healthcare Communications

Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief

also report on some of the therapies on the horizon for treating breast cancer and provide information about how you and your colleagues can help patients manage radiation-induced skin reactions. Take note of the statistics presented in Noteworthy Numbers about overall healthcare literacy and its connection to a patient’s health status—a good reminder that we need to do everything we can to make sure patients understand all of the information we give them. Please be sure to visit our Web site, www.TheOncology Pharmacist.com. Answer this month’s reader question about the drug shortage issue and tell us how your patients are reacting. Submit a question to our column, Your FAQs…Answered! Let us know what you like (or don’t like), and tell us what issues you want to see us cover. We want to hear from you! All of us at TOP wish you the best in the new year. ●

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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: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. BPA Worldwide membership applied for April 2011.

December 2011 I VOL 4, NO 8

Bortezomib Median Overall Survival Update for Previously Untreated Multiple Myeloma The US Food and Drug Administration (FDA) has approved a supplemental new drug application for Velcade (bortezomib) for Injection (Millennium: The Takeda Oncology Company) that updates the label to include additional longterm (median follow-up 60.1 months) overall survival (OS) data from the VISTA trial. The VISTA trial examined the use of bortezomib-based therapy in patients with previously untreated multiple myeloma (MM). The 5-year follow-up data demonstrated that patients treated with bortezomib, melphalan, and prednisone (VcMP) continued to have a statistically significantly longer OS (median OS 56.4 vs 43.1 months, P <.05) than those treated with melphalan and prednisone (MP) alone, a recognized standard of care. These results translated into a 43.9% improvement in OS when patients received the bortezomibcontaining regimen. A complete data set from the trial was presented at the December 2011 meeting of the American Society of Hematology. An earlier analysis (median follow-up of 36.7 months) demonstrated that starting with the bortezomib combination (VcMP) provided a statistically significant OS advantage over MP that was not regained despite the use of subsequent therapies including bortezomib-based regimens. The VISTA trial is the largest phase 3 registration study to

report long-term OS in previously untreated MM patients. This multicenter, international, 682-patient clinical trial compared VcMP to MP in patients with previously untreated MM who were not eligible for stem cell transplantation. The safety profile of bortezomib in combination with MP was consistent with the known safety profiles of both bortezomib and MP. The prescribing information is also being updated to provide the information that the concomitant use of strong CYP3A4 inducers with bortezomib is not recommended. In VISTA, the most commonly reported adverse events for bortezomib in combination with MP versus MP, respectively, included 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%), and edema peripheral (20% vs 10%). Other noted adverse events for both combinations were rash, back pain, pneumonia, dizziness, dyspnea, headache, pain in extremity, abdominal pain, paresthesia, herpes zoster, bronchitis, hypokalemia, hypertension, upper abdominal pain, hypotension, dyspepsia, nasopharyngitis, bone pain, arthralgia, and pruritus. ●

Check out our user-friendly Web site

www.TheOncologyPharmacist.com In addition to Web-only exclusives, news coverage, and journal articles, you’ll have the opportunity to participate in our current reader poll.

www.TheOncologyPharmacist.com

TOP_December 2011_v5_TOP 12/18/11 1:39 PM Page 7

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

Lymphoma1,5

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)

Lung Cancer1,3

Colorectal Cancer1,6,7

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

Ovarian Cancer1,8

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

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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

Noteworthy Numbers atients may not understand the information medical care providers give them for a number of reasons, but significant among them is poor healthcare literacy, which is the ability to understand health information and to use that information to make good decisions about health and medical care. Unfortunately, about 33% of the adult population in the United States has limited healthcare literacy. Yet, the need for this proficiency is greater than ever because medical care has become progressively more complex. Let us take a look at healthcare literacy facts and figures:

In addition to basic literacy skills, healthcare literacy requires understanding of health topics and number skills.1 Healthcare literacy is one of the strongest predictors of health status. In fact, studies of the issue show literacy as a stronger predictor of an individualâ&#x20AC;&#x2122;s health status than income, employment status, education level, and racial or ethnic group.2 Healthcare literacy influences peopleâ&#x20AC;&#x2122;s ability to: â&#x20AC;˘ Participate in the healthcare system (fill out complex forms, locate providers and services, etc) â&#x20AC;˘ Communicate information, such as health history, with providers â&#x20AC;˘ Manage self-care and chronic disease â&#x20AC;˘ Understand mathematical concepts (ie, probability and risk)1 The 2003 National Assessment of Adult Literacy, issued by the US Department of Education, estimated the healthcare literacy skills of adults based on the following categories: Below Basic, Basic, Intermediate, and Proficient. The study findings include: â&#x20AC;˘ Proficient health literacy was present in only 12% of adults www.TheOncologyPharmacist.com

â&#x20AC;˘ Nearly 9 of 10 adults may lack the necessary skills to manage their health and prevent disease â&#x20AC;˘ In the US, 14% of adults (30 million people) have Below Basic health literacy â&#x20AC;˘ Adults with Below Basic health literacy were more likely to report their health as poor (42%) and are more likely to lack health insurance (28%) compared to adults with Proficient health literacy â&#x20AC;˘ Lower average healthcare literacy was found among adults aged 65 and older compared to adults in younger age groups1,3 Strategies for improving patient communication and understanding include: â&#x20AC;˘ Using plain, nonmedical language â&#x20AC;˘ Showing or drawing pictures to enhance understanding â&#x20AC;˘ Encouraging questions2 Sources 1. US Department of Health and Human Services. http://www.health.gov/com munication/literacy/quickguide/factslit eracy.htm. 2. Weiss BD. Health literacy and patient safety: help patients understand. American Medical Association. http:// www.ama-assn.org/ama1/pub/upload/ mm/367/healthlitclinicians.pdf. 3. National Coalition for Literacy. http:// www.ncladvocacy.org/HealthLiteracyFac tst2009/HealthLiteracyFactst2009.pdf.

December 2011 I VOL 4, NO 8

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Hematologic Malignancies

Ruxolitinib Tablets: A New Oral Option for the Treatment of Patients With Intermediate- or High-Risk Myelofibrosis Disorders By Rhonda Williams

yeloproliferative neoplasms (MPNs) are a group of closely related hematologic malignancies that arise from abnormal development and function of the body’s bone marrow cells. Primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) comprise the Philadelphia chromosome (Ph)-negative MPNs.1 Myelofibrosis (MF) can arise on its own, which is called PMF, or it can result from the progression of other MPNs, such as postpolycythemia vera MF (PPV-MF) and postessential thrombocythemia MF (PET-MF).1

The Burden of Disease and Its Impact MF is characterized by cytopenias, splenomegaly, poor quality of life, and shortened survival.1 Because chronic MPNs previously were not classified as hematologic malignancies, limited epidemiologic studies are available to estimate the incidence of MF. Multiple regional studies suggest that an estimated 6328 new cases of chronic myeloproliferative disorders (CMPDs as they were previously known) occurred in the US population in 2004.2 Of these patients, 45% had PV, 24% had ET, and 10% had PMF.2 The average annual age-adjusted incidence in the United States between 2001 and 2003 was 2.1 per 100,000 persons,

with rates ranging among states from a low of 0.8 per 100,000 persons in Delaware to as high as 4.1 per 100,000 persons in Idaho.2 The incidence was significantly higher in males (2.6 per 100,000) than in females (1.8 per 100,000; P <.05).2 In addition, the incidence increased significantly with age, reaching 13.3 per 100,000 persons among individuals aged ≥80 years.2

In November 2011, the FDA approved Jakafi (ruxolitinib) tablets for the treatment of patients with intermediate- or high-risk MF, including PMF, PPVMF, and PET-MF.

Although appropriate treatment of patients with ET and PV is associated with prolonged survival, patients with symptomatic forms of PMF have a median survival of <5 years.1 The prognosis of MF is quite variable; however, those who develop anemia generally have a poorer prognosis. Patients with a good prognosis

Table 1 Baseline Characteristics of Patients in Study 1 and Study 2 Baseline Characteristic

Study 1 (N = 309)

Study 2 (N = 219)

Median age, yrs (range)

68 (40-91)

66 (35-85)

Patients aged >65 yrs, %

Male patients, %

Primary myelofibrosis, %

Postpolycythemia vera myelofibrosis, %

Postessential thrombocythemia myelofibrosis, %

10.5

10.4

251

236

Disease state

Hematologic value Median hemoglobin, g/dL 9

Median platelet count, × 10 /L Median palpable spleen length below the costal margin, cm Median spleen volume, cm3 (range) Source: Reference 10.

December 2011 I VOL 4, NO 8

2595 (478-8881) 2381 (451-7765)

can live for many years without experiencing major symptoms, whereas those with a poor prognosis may have a significantly shorter survival. A small percentage of patients with MF can transform to acute myeloid leukemia, which is often difficult to treat and can be fatal. Few treatment options exist for patients with MF. Until recently, the choice of treatment was often dictated by a patient’s symptoms and specific circumstances. Some patients with MF may remain symptom-free for many years, without undergoing treatment; however, monitoring for any signs or symptoms that may suggest worsening of the disease is required. For patients who require symptomatic treatment, chemotherapeutic agents, immunomodulatory drugs, and biological response modifiers (eg, hydroxyurea, androgen therapies, corticosteroids, thalidomide, lenalidomide, and interferon) are often used. It is important to note that these therapies are not always directed to the biological processes that underlie the origin of disease or lead to progression of PMF. Therefore, these strategies are often primarily palliative in nature, and their effect on survival is uncertain. Finally, surgery or radiation therapy may also be used in those who fail to respond to other treatments. For many patients with MF, however, available treatments may be ineffective and allogeneic stem cell transplantation may be the only potential known cure. A decisive advance in our understanding of the underlying molecular mechanisms of MPNs has been the discovery of a somatic gain-of-function point mutation in the Janus kinase (JAK) 2 gene, which is a common clinical feature in patients with ET, PV, and PMF.3,4 We now know that approximately 50% of patients with MF have a gain-of-function mutation in the JAK2 gene.5,6 Discoveries in the molecular pathogenesis of PV, ET, and PMF enabled the genetic classification and molecular diagnosis of these neoplasms. The World Health Organization diagnostic criteria, which were based largely on clinical and pathologic descriptions, were subsequently revised for PV, ET, and PMF to include the incorporation of testing for JAK2 and other genetic mutations.7 In addition to modifying the criteria for diagnosing, monitoring, and assessing patients with ET, PV, and PMF, the discovery of JAK2 involvement in patients with MF also led to the development of small-molecule inhibitors that specifically

target JAK2. Although JAK2 mutations are responsible for the majority of dysregulated signaling in Ph-negative MPNs, JAK1 and JAK2 may interact, resulting in their transactivation.8,9 Armed with this information and a greater understanding of the cellular and molecular events that lead to the development of PMF, the possibility of more targeted and effective therapies for this disorder has become a reality. In November 2011, the US Food and Drug Administration (FDA) granted marketing approval of oral Jakafi (ruxolitinib; Incyte) tablets for the treatment of patients with intermediate- or high-risk MF, including PMF, PPV-MF, and PET-MF.10

Clinical Pharmacology Mechanism of Action Ruxolitinib, a kinase inhibitor, inhibits the Janus-associated kinases JAK1 and JAK2, which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus, leading to modulation of gene expression.10 MF is known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutated cells in the spleen, and decreased circulating inflammatory cytokines (eg, tumor necrosis factor–alpha and interleukin-6).10 Pharmacodynamics. In healthy persons and in patients with MF, ruxolitinib inhibited cytokine-induced STAT3 phosphorylation in whole blood. The maximal inhibition of STAT3 phosphorylation occurred 2 hours after dosing, returning to near-baseline levels by 10 hours in both groups of people. Pharmacokinetics. Maximal plasma concentration (Cmax) of ruxolitinib occurred 1 to 2 hours after oral administration. Pharmacokinetic studies demonstrated no evident food effect on the absorption of ruxolitinib; when administered with a high-fat meal, the mean Cmax decreased moderately (24%) and the area under the curve remained nearly unchanged (ie, 4% increase). In early clinical trials, the volume of distribution at steady state was between 53 L and 65 L in patients with MF.10

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TOP_December 2011_v5_TOP 12/18/11 1:39 PM Page 11

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TOP_December 2011_v5_TOP 12/19/11 12:13 PM Page 12

Hematologic Malignancies Phase 3 Clinical Trials Jakafi was approved by the FDA based on the results of 2 randomized, phase 3 trials (Study 1 and Study 2) conducted in patients with MF.10 These trials are described in detail in the product prescribing information, with key data highlighted in this article.

The primary end point in both phase 3 trials was the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline at week 24 in Study 1 and at week 48 in Study 2.

Trial Designs Study 1 was a randomized, double-blind trial that compared ruxolitinib with placebo in patients with MF who were refractory to or were not candidates for available therapy. The primary end point was the proportion of patients achieving a reduction in spleen volume of ≥35% from base-

line at week 24, as measured by magnetic resonance imaging (MRI) or computed tomography (CT). Secondary end points included the duration of ≥35% reduction in spleen volume from baseline and the proportion of patients with a ≥50% reduction in Total Symptom Score from

Table 2 Percentage of Patients With ≥35% Reduction in Baseline Spleen Volume Study 1 (24 wks) Ruxolitinib (N = 155)

Placebo (N = 154)

41.9%

0.7%

Study 2 (48 wks)

P Value

Ruxolitinib (N = 146)

Best available Treatment (N = 73)

P Value

<.001

28.5%

<.001

Source: Reference 10.

Adverse Reactions and Laboratory Abnormalities Reported in Study 1: Table 3 Ruxolitinib Versus Placebo Ruxolitinib (N = 155) Reported Outcomes

Placebo (N = 151)

All grades, Grade 3, Grade 4, All grades, Grade 3, % % % % %

Grade 4, %

Adverse reaction Bruisinga

23.2

0.6

14.6

Dizzinessb

18.1

0.6

7.3

Headache

14.8

5.3

Urinary tract infectionc

9.0

5.3

0.7

Weight gaind

7.1

0.6

1.3

0.7

Flatulence

5.2

0.7

Herpes zostere

1.9

0.7

Laboratory abnormalityf Thrombocytopenia

69.7

9.0

3.9

30.5

1.3

Anemia

96.1

34.2

11.0

86.8

15.9

3.3

Neutropenia

18.7

5.2

1.9

4.0

0.7

1.3

Elevated ALT

25.2

1.3

7.3

Elevated AST

17.4

6.0

Includes contusion, ecchymosis, hematoma, injection-site hematoma, periorbital hematoma, vessel puncture-site hematoma, increased tendency to bruise, petechiae, and purpura. b Includes dizziness, postural dizziness, vertigo, balance disorder, Ménière disease, and labyrinthitis. c Includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, and nitrite urine present. d Includes weight increased and abnormal weight gain. e Includes herpes zoster and postherpetic neuralgia. f Worst grade values are presented, regardless of baseline. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase. Source: Reference 10.

December 2011 I VOL 4, NO 8

baseline to week 24. The latter was measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.10 Study 2 was a randomized, open-label trial that compared ruxolitinib with the best available therapy in patients with MF. The study investigators selected the best available therapy on a patient-bypatient basis, with the most frequently used agents, including hydroxyurea (N = 47%) and glucocorticoids (N = 16%). The primary end point of this trial was similar to that in Study 1—the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline, but at week 48 (as measured by MRI or CT). The secondary end point of Study 2 was the proportion of patients achieving a ≥35% reduction in spleen volume from baseline to week 24.10 In both trials, patients were required to have palpable splenomegaly >5 cm below the costal margin, as well as an MF risk category of intermediate-2-risk (2 prognostic factors) or high-risk (>3 prognostic factors).10 Dosing in these trials was based on platelet counts. The starting dose of ruxolitinib was 15 mg administered orally twice daily in patients with baseline platelet counts of 100 to 200 x 109/L and 20 mg administered orally twice daily in patients with baseline platelet counts >200 x 109/L. The doses of ruxolitinib were then adjusted during the course of therapy based on efficacy and tolerability. Maximum doses based on platelet counts were as follows10: • Platelet count 100 to ≤125 x 109/L: 20 mg twice daily • Platelet count 75 to ≤100 x 109/L: 10 mg twice daily • Platelet count 50 to ≤75 x 109/L: 5 mg twice daily.

Patient Populations Baseline characteristics of patients enrolled in Study 1 and Study 2 are shown in Table 1. The 2 patient populations were very similar in terms of demographics and the extent of disease before study treatment.10 Efficacy The primary end point in both phase 3 trials was the proportion of patients achieving a reduction in spleen volume of ≥35% from baseline at week 24 in Study 1 and at week 48 in Study 2 (Table 2). A significantly greater percentage of ruxolitinibtreated patients achieved this magnitude of reduction in baseline spleen volume

compared with either placebo (41.9% vs 0.7%, respectively; P <.001) or best available therapy (28.5% vs 0%, respectively; P <.001).10 In Study 1, a secondary end point was improvement in symptoms, as measured by the MFSAF v2.0. This scale captures MFrelated symptoms, including abdominal discomfort, pain under the left ribs, night sweats, itching, bone or muscle pain, and early satiety. A higher proportion of ruxolitinib-treated patients experienced a ≥50% reduction in Total Symptom Score compared with placebo (45.9% vs 5.3%, respectively; P <.001). The median time to symptom response was <4 weeks.10 Safety Profile Because clinical trials are conducted under widely varying conditions, rates of adverse reactions observed in the clinical trials of a particular drug cannot be compared directly with rates observed in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ruxolitinib was assessed in 617 patients in 6 clinical studies with a median duration of followup of 10.9 months, including 301 patients with MF in 2 phase 3 studies. In these 2 studies, patients had a median duration of exposure to ruxolitinib of 9.5 months (range, 0.5-17 months), with 88.7% of patients treated for >6 months and 24.6% treated for >12 months. A total of 111 patients started treatment at 15 mg orally twice daily and 190 patients started at 20 mg orally twice daily.10 The most often reported adverse events were thrombocytopenia and anemia; the most frequent nonhematologic adverse events were bruising, dizziness, and headache.9 A total of 11.0% of patients receiving ruxolitinib and 10.6% of patients receiving placebo discontinued therapy because of adverse events.9 The rates of adverse reactions and laboratory abnormalities reported in Study 1 are summarized in Table 3. The median time to onset of grade 2 or higher anemia was approximately 6 weeks. Mean decreases in hemoglobin of 1.5 to 2 g/dL below baseline after 8 to 12 weeks of therapy were reported in ruxolitinibtreated patients, recovering gradually to reach a new steady state of approximately 1.0 g/dL below baseline.10 The median time to onset of grade 3 or 4 thrombocytopenia was approximately 8 weeks. Patients with baseline platelet counts of 100 to 200 x 109/L experienced a higher incidence of grade 3 or 4 thrombocytopenia than did those with baseline platelet counts >200 x 109/L.10 Dosing Ruxolitinib is dosed orally and can be administered with or without food. If a dose is missed, the patient should not take an additional dose, but should take the next usual prescribed dose. When discontinuing ruxolitinib therapy for rea-

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Hematologic Malignancies sons other than thrombocytopenia, gradual tapering of the dose may be considered—for example, by 5 mg twice daily each week.10 In patients who are unable to ingest tablets, ruxolitinib can be administered through a nasogastric tube (8 French or greater) by suspending 1 tablet in approximately 40 mL of water and stirring for approximately 10 minutes. Within 6 hours after the tablet has dispersed, the suspension can be administered via a nasogastric tube using an appropriate syringe. After use, the tube should be rinsed with approximately 75 mL of water. The effect of tube-feeding preparations on ruxolitinib exposure during administration through a nasogastric tube has not been evaluated.10 The recommended starting dose of ruxolitinib is based on platelet count (Table 4). A complete blood count (CBC) and platelet count must be performed prior to initiating therapy, every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. Doses may be titrated based on safety and efficacy.10 Treatment with ruxolitinib should be interrupted in patients with platelet counts <50 x 109/L. Once the platelet count recovers to >50 x 109/L, dosing may be restarted or increased following recovery of platelet counts to acceptable levels. Table 5 shows the maximum allowable dose that may be used when restarting ruxolitinib therapy following a previous interruption.10 Patients who develop anemia may require blood transfusions. Dose modifications of ruxolitinib in patients who develop anemia may also be considered.10 Neutropenia (absolute neutrophil count [ANC] <0.5 x 109/L) was generally reversible and was managed by temporarily withholding ruxolitinib. CBCs should be monitored as clinically indicated, with dosing adjusted as required.10 Dose Modification Based on Response If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses may be increased in 5-mg twice-daily increments to a maximum of 25 mg twice daily. Doses should not be increased during the first 4 weeks of therapy and not more often than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement is observed since initiation of ruxolitinib therapy.10 Based on limited clinical data, longterm maintenance with a 5-mg twicedaily dose has not demonstrated responses, and continued use of this dose should be limited to patients in whom the benefits outweigh the potential risks.10 Dose increases may be considered in patients who meet all of the following criteria10: • Failure to achieve a reduction from pretreatment baseline in either palpable

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spleen length of 50% or a 35% reduction in spleen volume, as measured by CT or MRI • Platelet count >125 x 109/L at 4 weeks and platelet count never <100 x 109/L • ANC >0.75 x 109/L. Dose Adjustment, Concomitant Strong CYP3A4 Inhibitors On the basis of pharmacokinetic studies in healthy volunteers, when administering ruxolitinib along with strong cytochrome (CY)P3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole), the recommended starting dose is 10 mg twice daily for patients with platelet counts ≥100 x 109/L. Additional dose modifications should be made with careful monitoring of safety and efficacy. Concurrent administration of ruxolitinib with strong CYP3A4 inhibitors should be avoided in patients with platelet counts <100 x 109/L.10

Table 4 Proposed Ruxolitinib Starting Doses Platelet Count, × 109/L

Starting Oral Dose

>200

20 mg twice daily

100 to 200

15 mg twice daily

Source: Reference 10.

Table 5 Maximum Restarting Doses for Ruxolitinib After Safety Interruption Current Platelet Count, × 109/L

Maximum Restarting Dosea

≥125

20 mg twice daily

100 to <125

15 mg twice daily

75 to <100

10 mg twice daily for at least 2 wks; if patient is stable, may increase to 15 mg twice daily

50 to <75

5 mg twice daily for at least 2 wks; if patient is stable, may increase to 10 mg twice daily

<50

Continue hold

When restarting therapy, begin with a dose at least 5 mg twice daily below the dose at interruption. Source: Reference 10.

Table 6 Dosing Recommendations for Thrombocytopenia Dose at Time of Platelet Decline

The most often reported adverse events were thrombocytopenia and anemia; the most frequent nonhematologic adverse events were bruising, dizziness, and headache.

Platelet Count, × 109/L

25 mg twice 20 mg twice 15 mg twice 10 mg twice 5 mg twice daily daily daily daily daily New Dose

100 to <125

20 mg twice 15 mg twice No change daily daily

No change

75 to <100

10 mg twice 10 mg twice 10 mg twice No change daily daily daily

No change

50 to <75

5 mg twice daily

No change

Hold

<50

Source: Reference 10.

Contraindications, General Warnings, and Precautions There are no black box warnings or contraindications associated with the use of ruxolitinib. Warnings and precautions associated with use of the agent include such hematologic adverse reactions as thrombocytopenia, anemia, and neutropenia. As indicated earlier, a CBC and platelet count must be performed prior to initiating therapy with ruxolitinib. In clinical trials, patients with platelet counts <200 x 109/L at the start of therapy were more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible, however, and was usually managed by modifying or interrupting the dose of ruxolitinib in clinical trials. Patients may also require a platelet transfusion, if clinically indicated. Dose reductions should be considered if platelet counts decrease, with the goal being to avoid dose interruptions for thrombocytopenia (Table 6).10 Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal, and viral infections. Active

serious infections should have resolved prior to initiating ruxolitinib therapy. Physicians should carefully observe patients receiving ruxolitinib for signs and symptoms of infection, and should initiate appropriate treatment promptly. Physicians should inform patients about early signs and symptoms of herpes zoster, and should advise patients to seek treatment as early as possible. ●

References 1. Verstovsek S, Kantarjian H, Mesa R, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med. 2010;363:1117-1127. 2. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 20012004, using data from the NAACCR and SEER programs. Blood. 2008;112:45-52. 3. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-397. 4. Kralovics R, Passamonti F, Buser AS, et al. A gain-offunction mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005;352:1779-1790. 5. Santos FPS, Kantarjian HM, Jain N, et al. Phase 2 study of CEP-701, an orally available JAK2 inhibitor, in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Blood. 2010;115:1131-1136.

6. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061. 7. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009; 113:2895-2901. 8. Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signaling. Cell. 2007;131:612.e1. 9. Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: approaches for targeted therapies. Genes Cancer. 2010;1:979-993. 10. Jakafi [prescribing information]. Wilmington, DE: Incyte Corporation; 2011.

Did You Know?

Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, expressed cautious hope for the future of personalized drug therapy, acknowledging that “we’re now out of the general skepticism phase [and] into the long slog phase.” Woodcock spoke at a conference hosted by the FDA and the Drug Information Association in October. —American Society of Health-System Pharmacists

December 2011 I VOL 4, NO 8

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New Data: 5-Year Median Follow-up

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

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.

i dd

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UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival:

56.4 vs 43.1 months

Patients Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 70 60 50 40 30 20

VELCADE+MP (n=344)

MP (n=338)

0 0

Kaplan-Meier estimate.

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

9:26 AM

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Conference News The following articles are based on presentations at the 53rd Annual Meeting of the American Society for Radiation Oncology held October 2-6, 2011, in Miami Beach, Florida.

Higher Radiation Doses May Not Help Lung Cancer... Continued from cover ington University School of Medicine in St. Louis. The goals of the current phase 3 trial were to find out if high doses of radiation improved survival and also if the

chemotherapy drug cetuximab increased survival among patients with stage III NSCLC. Investigators randomized 423 patients to different doses of radiation therapy and concurrent

chemotherapy of paclitaxel and carboplatin with or without cetuximab. Patients received 1 of 4 treatments: standard-dose (60 Gy) or high-dose (74 Gy) radiation therapy and to chemotherapy

with or without cetuximab. Two types of external beam radiation therapy were used during the trial: three-dimensional conformal radiation therapy (3D-CRT), and intensitymodulated radiation therapy (IMRT), a newer, specialized form of 3D-CRT that further limits the radiation dose to the healthy tissues.

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

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.

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.

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. 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.

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%). 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. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. 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) m 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, 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 VELCADE.com.

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. 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. Use in Pregnancy: 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.

December 2011 I VOL 4, NO 8

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. All rights reserved. Printed in USA

V-11-0264

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Bradley noted that these findings are important because this is an area that had not been carefully studied in more than 20 years.

The researchers found that the patients who received the higher dose of radiation (74 Gy) did not have better survival rates than those receiving the standard dose (60 Gy). Subsequently, the 2 arms of the trial that used highdose radiation therapy were closed to patient accrual. Bradley said the trial provides pivotal evidence that the standard dose of radiation therapy for stage III lung cancer should remain at 60 Gy, as doses as high as 74 Gy do not achieve better outcomes in stage III lung cancer. He said it is uncertain why this is the case. The data are still being carefully reviewed. Bradley noted that these findings are important because this is an area that had not been carefully studied in more than 20 years. He noted that it has been 30 years since the radiation dose of 60 Gy was established. However, the techniques of radiation therapy have improved a great deal. “This is the largest study to look at this question, and it is a definitive study for stage III lung cancer,” said Bradley. ●

Did You Know? The National Cancer Institute currently designates 66 research institutions as Cancer Centers. These centers are engaged in transdisciplinary research to reduce cancer incidence, morbidity, and mortality. —National Cancer Institute Office of Cancer Centers

www.TheOncologyPharmacist.com

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Conference News

Chemo Plus Radiation Prior to Surgery May Increase Tumor Response for Rectal Cancer By John Schieszer

atients with rectal cancer who receive a combination of chemotherapy (capecitabine) and 5 weeks of radiation (50 Gy) prior to surgery may have an 88% chance of surviving the cancer 3 years after treatment. â&#x20AC;&#x153;The results of the trial allow us to recommend a new preoperative treatment, the Cap50 regimen, in locally advanced rectal cancer. Itâ&#x20AC;&#x2122;s safe and reduces the risk of the cancer coming back to less than 5%,â&#x20AC;? said study investigator Jean-Pierre GĂŠrard, MD, radiation oncologist at Centre AntoineLacassagne in Nice, France. Currently, the primary treatment for cancer of the rectum (the lower 15 cm of the bowel) is surgery. However, there is a risk of cancer recurrence within the bowel and the surrounding tissue. In the majority of cases, this recurrence is incurable. Depending on the location and stage of the cancer, physicians usually recommend radiation therapy and chemotherapy before surgery. However, the optimal regimen is still unknown. This current study involved 598 patients with locally advanced rectal cancer who were diagnosed and treated in 50 hospitals in France between 2005 and 2008. Researchers wanted to find the most effective and safe preoperative treatment for rectal cancer by comparing a combination of 2 different chemotherapies and 2 different radiation doses. Patients were randomized to receive either Cap45 (capecitabine and radiation treatment to 45 Gy) or Capox50 (capecitabine plus oxaliplatin and radiation to 50 Gy). At 3 years after treatment, the researchers found that the Capox50 regimen did not have a significantly lower rate of local recurrence compared with the Cap45 treatment. Oxaliplatin, given as part of the Capox50 treatment, was shown to immediately increase side effects, including severe diarrhea, and was not effective in increasing the chance of local tumor sterilization. However, the increase of the radiation dose from 45 to 50 Gy over 5 weeks was effective, well tolerated, and did not extend the duration of treatment. GĂŠrard said the Cap50 regimen should be the standard treatment for locally advanced rectal cancer. He noted that using capecitabine avoids the intravenous injection of fluorouracil, while a radiation dose to 50 Gy in 25 fractions over 5 weeks increases the chance of tumor sterilization and limits the risk of local recurrence to 5% or less. â&#x20AC;&#x153;We know now that if we add chemothera-

www.TheOncologyPharmacist.com

py before surgery, you can improve survival,â&#x20AC;? said GĂŠrard. He and his colleagues are now devis-

AY D TO 0 R 0 E ISTVE $1 G R E SA

ing new guidelines for the management of rectal cancer patients. GĂŠrard said that currently there is a wide vari-

ety in practice patterns in the treatment of these patients. â&#x20AC;&#x153;Many patients are getting neoadjuvant therapy in the United States, but it is not considered the standard care of yet. This study may change that,â&#x20AC;? said Tim Williams, MD, medical director of radiation oncology at Boca Raton Regional Hospital in Florida. â&#x2014;?

The One Conference You Canâ&#x20AC;&#x2122;t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care Conference Strategies for Optimizing Value in Cancer Care Delivery March 29-31, 2012 â&#x20AC;˘ JW Marriott â&#x20AC;˘ Houston, Texas

REGISTER TODAY at www.regonline.com/avbcc2012 TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

CONFERENCE GOAL The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

CONFERENCE CO-CHAIRS Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University

EDUCATIONAL OBJECTIVES â&#x20AC;˘ Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery â&#x20AC;˘ Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered â&#x20AC;˘ Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively â&#x20AC;˘ Examine the current trends in personalized care and companion diagnostics â&#x20AC;˘ Analyze the patient issues around cost, quality, and access to care

Gary Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS

DESIGNATION OF CREDIT STATEMENTS

President, CEO OncoMed

Physician Accreditation â&#x20AC;&#x201C; Joint Sponsor The Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical Learning Institute, Inc. and the Association for Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5 contact hours.

Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit.

CONFERENCE REGISTRATION

SAVE $100 off full Conference Tuition REGISTER TODAY FOR ONLY $275 at www.regonline.com/avbcc2012 For more information, please visit www.avbcconline.org/2012 or e-mail association@avbcconline.org.

This activity is jointly sponsored by Medical Learning Institute, Inc., and the Association for Value-Based Cancer Care

December 2011 I VOL 4, NO 8

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Cancer Center Profile The Cleveland Clinic Taussig Cancer Institute Continued from cover practice where medical specialists worked together to achieve the best outcomes in

patient care while furthering the goals of research and education. From the very beginning, the mission of the Cleveland Clinic has been to provide “better care of the sick, investigation into their problems, and further education of those who serve.” To help ensure the success of their mission, the founders decided to commit 25% of their net income to an endowment that supported medical research, education, and care of the indigent. Today, the Cleveland Clinic has facilities throughout Ohio, as well as in Florida, Nevada, Canada, and Abu Dhabi. In the field of oncology, the Cleveland Clinic has a distinguished history. George Crile Jr, MD, the son of one of the founders, was a pioneer in establishing alternatives to radical mastectomy to treat breast cancer. His book, Cancer and Common Sense, was written for the public and endorsed conservative treatment for cancer while railing against what Dr Crile called “the unnecessarily mutilating results of the surgery being done at some of the socalled cancer centers.” These were controversial ideas in 1955, and Life magazine published excerpts from his book. Today, the Cleveland Clinic Taussig Cancer Institute is internationally recognized for its clinical, translational, and basic cancer research and is a National Cancer Institute–designated cancer center, as part of the Case Comprehensive Cancer Center. The Cleveland Clinic’s Department of Pharmacy is at the forefront of using technology and automation to let pharmacists focus on patient care and physician support—ensuring that all members of the oncology team are able to offer high-level care to their patients. Marc Earl, PharmD, BCOP, a hematology/ oncology clinical specialist, answered our questions about the Cleveland Clinic and how oncology pharmacists are working with patients to educate and counsel them about their medication therapy.

Hematology/oncology clinical specialists at the Cleveland Clinic’s Department of Pharmacy provide inpatient and outpatient care services to patients.

How does that translate to better outcomes for your patients? ME: It helps us meet our goal in that every cancer patient at the Cleveland Clinic has his or her own pharmacist. This technology will be safer and more efficient, allowing our pharmacists to interact with patients in a one-on-one manner. We will be able to work through issues in supportive care and medication discharge counseling that will translate to improved care for our patients.

The founders decided to commit 25% of their net income to an endowment that supported medical research, education, and care of the indigent.

What is your hospital doing that is different from other cancer centers? Marc Earl (ME): We are using technology to increase the amount of time pharmacists spend with patients. We have recently instituted physician order entry for chemotherapy as well as robotic technology for chemotherapy compounding. Over time, these things will allow our pharmacists to interact with more of our oncology patients.

December 2011 I VOL 4, NO 8

The Cleveland Clinic believes in educating the patient and his/her family about cancer as a means of increasing the chance for a better outcome of therapy. Can you share a patient success story illustrating this belief?

ME: My biggest impact has been with What is in the future for the adult patients who have recently been Cleveland Clinic? diagnosed with acute myeloid leukemia. ME: I am excited about the future of It is an overwhelming time for the pharmacy at the Cleveland Clinic. We have grown significantly in entire family. I am able to the past few years, and this work with these patients and will allow us to become more their families on a daily basis involved with our patients. to answer any medicationWe are also going to be incorrelated questions while they porating more pharmacy stuare in the hospital. I also dents and residents into these look for a variety of medicaprograms so that we can reach tion-related problems during more patients. I think there their 4- to 6-week stay in the are opportunities in supportive hospital. I meet with them Marc Earl, care and discharge education before they are discharged to PharmD, BCOP our pharmacists can assist go through any new medicawith. Our goal is that one day tions. Many of these patients are not on any medications when diag- every patient will personally interact nosed but must go home on 5 to 10 new with a pharmacist on each visit to the medications. This is overwhelming for Cleveland Clinic. ● the patient and his/her family and provides an opportunity to answer questions and improve patient safety.

How has the oncology pharmacist’s role changed in the past 5 years? ME: The majority of the changes have been related to patient safety. We are actively involved in developing preprinted and electronic chemotherapy orders, which help decrease errors. It helps standardize the treatment approach for many malignancies. This ensures that every cancer patient receives a similar treatment with the exact same supportive care management.

Did You Know?

For fiscal year 2010, the National Cancer Institute had $5.098 billion in available funds, representing a 2.6% increase over fiscal year 2009. Of the total fiscal year 2010 budget, 43% of the funds were allocated for research project grants. A total of 5079 of these grants were awarded. —National Cancer Institute Office of Budget and Finance

www.TheOncologyPharmacist.com

TOP_December 2011_v5_TOP 12/18/11 1:40 PM Page 19

NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • It has been observed that patients with platelet counts <200 X 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother Please see Brief Summary of Full Prescribing Information on the following page.

RUX-1004C

11/11

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Prostate Cancer

New Bone-Targeting Compound Improves Survival in Metastatic Prostate Cancer By Caroline Helwick

alpha-phar n investigational maceutical not only prevented skeletal-related events (SREs)

in patients with prostate cancer with bone metastases in a phase 3 study presented at the 2011 European

Multidisciplinary Cancer Congress, but it also improved overall survival. “This is the first drug targeted to

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its Reactions Gradesa metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d Urinary Tract Infections 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

December 2011 I VOL 4, NO 8

bone metastases in prostate cancer to improve survival,” said lead investigator Chris Parker, MD, Royal Marsden Hospital, London. “There are other bone drugs used in prostate cancer, but they help to minimize symptoms; they don’t improve survival. In my opinion, radium-223 is likely to become a new standard of treatment for advanced prostate cancer,” Dr Parker told journalists at a press briefing. Jean-Charles Soria, MD, Institut Gustave Roussy, Villejuif, France, who cochaired the meeting’s scientific program, agreed. “This is really practice changing, and after regulatory approval, I think this is going to be a major player in advanced prostate cancer.” A US coinvestigator of the trial, Oliver Sartor, MD, Tulane University, New Orleans, Louisiana, said the radiopharmaceutical is far superior to prior compounds of the sort, and the study results were highly impressive. Radium-223 chloride (Alpharadin; Algeta/Bayer) was recently granted a fast-track designation by the US Food and Drug Administration. The company plans to file a New Drug Application in mid-2012. The Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial was a phase 3, randomized, doubleblind, placebo-controlled, international study that compared radium-223 chloride plus current standard of care with placebo plus current standard of care in 922 men with symptomatic castration-resistant prostate cancer that had spread to the bone. Patients had multiple skeletal metastases on bone scan and were taking regular analgesics for bone pain. At a planned interim analysis, patients who received radium-223 had the following positive outcomes: • Median overall survival: 14 months compared with 11.2 months for the placebo group, a 30% reduction in mortality (P = .00185) • Time to first SREs: 13.6 months versus 8.4 months, a 64% improvement (P = .00046) • Total alkaline phosphatase (bone marker) normalization: 33% versus 1% (P <.001) • Time to prostate-specific antigen progression: 49% improvement (P = .00015). Nonhematologic adverse events were not significantly worse with radium-223 versus placebo; the most common grade 3/4 adverse events were bone pain (18% vs 23%, respectively). Other serious toxicities were uncommon. Based on the interim analysis, the data monitoring committee recommended the study be stopped and patients in the placebo arm be offered radium-223. ●

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drug

shortages

genetic testing

medicine and

personalized

Emergence of

Increased need for

Patient Financial

Assistance

Co-payments shift from dollars to thousands

channel

Emerging clinical standards and pathways

Keeping patients in community versus in-patient care

Supply

Cutbacks in Government programs

with REMS regulatory processes

Compliance and Adherence to therapy and protocols

of FDA reach

Higher drug oversight and Prior Authorization processes

Growing billing and collection risks Expansion 500% increase in drug inventory carrying costs

Reduction in drug margins

Oncology providers face a multitude of disruptive changes...

Complex insurance verification

Additional staff burdens

What to do?

REACT TO CHANGE SEEK PROVEN SOLUTIONS Pharmacy / 877.662.6633

Fax / 877.662.6355

Website / OncoMed.net

TOP_December 2011_v5_TOP 12/18/11 1:40 PM Page 22

CONTINUING EDUCATION EXPIRATION DATE: FEBRUARY 4, 2012 • ESTIMATED TIME TO COMPLETE: 1.0 HOUR COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

Metastatic Breast Cancer: Advances in Treatment and Management TARGET AUDIENCE This activity was developed for oncology nurses and pharmacists who wish to enhance their competence concerning the treatment of patients with metastatic breast cancer. LEARNING OBJECTIVES After completing this activity, the reader should be able to: • Discuss the impact of metastatic breast cancer and key parameters for disease stratification • Describe the role of prognostic/genetic markers and tumor histology in classifying breast cancer subtypes and predicting treatment response • Review advances in the treatment of metastatic breast cancer, including the role of endocrine therapy, chemotherapy, targeted therapy, and bisphosphonates, with emphasis on targeted therapies • Examine effective patient-tailored treatment approaches, based on recent data and clinical practice guidelines SPONSOR

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

lthough an estimated 207,090 cases of breast cancer will be diagnosed in the United States in 2010,1 mortality rates from the disease have been on the decline since 1990, especially in women younger than 50 years of age.2 This decrease is likely attributable to early detection through screening, increased general awareness, and improved therapies.2 Nevertheless, breast cancer remains the second leading cause of cancer-related death in women, and is responsible for more than 40,000 deaths a year in the United States alone.1,2 The majority of breast cancer–related deaths are a result of complications from recurrent or metastatic disease. Metastatic breast cancer (MBC) is uncommon at initial presentation, occurring in only about 6% of newly diagnosed cases.2,3 However, approximately 30% of women initially diagnosed with earlier stages of breast cancer eventually develop recurrent advanced or metastatic disease.3,4 The 5-year relative survival rate for patients with MBC is only 23%.1 Given this poor prognosis, researchers continue to focus their efforts on the development of more effective and tolerable treatments that may provide prolonged survival and improved quality of life. Investigators are also striving to more clearly identify biomarkers in breast cancer that can be used to assess prognosis and guide the selection of therapies, in the hopes of offering more indi-

December 2011 I VOL 4, NO 8

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 at (609) 333-1693 or cgusack@mlicme.org. PhARmACIST DESIGNATION

Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.5 contact hours (0.15 CEUs) of continuing education credit. The universal program number for this activity is 0468-9999-11-001-H01-P.

vidualized treatment. As integral members of the oncology team, it is essential that nurses and pharmacists are aware of the latest advances in the treatment and management of MBC, including safety and efficacy data from clinical trials evaluating novel biologic and cytotoxic agents, as well as administration guidelines and side-effect management strategies pertaining to these therapies. Breast Cancer Disease Stratification: Predictive and Prognostic Markers Advances have recently been made in the area of molecular profiling, which may help clinicians more accurately classify subtypes of breast cancer, as well as predict risk of recurrence and response to therapy.5 A number of genes have been identified as important predictive markers of chemotherapeutic and targeted therapy efficacy, and may be used to guide more patient-specific treatment. The technology of DNA microarray gene expression profiling has led to a system of classifying breast cancer into the following major subtypes: estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative (luminal A and B subtypes); ER-negative/HER2-negative (basal subtype); HER2-positive; and tumors that are similar to normal breast tissue (normal breast-like).6 Retro spective analyses have shown that characteristic relapse-free survival and overall survival (OS) are associated with

fACULTy DISCLOSURES

Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial products(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. 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. Peer reviewers—Jayshree Shah, RN, APN-C, MSN, BSN, BS, is on the speakers’ bureau for BristolMyers Squibb, Celgene, Merck, and Novartis, and is on the advisory board for Bristol-Myers Squibb and Novartis. Nancy Nesser, JD, PharmD, has nothing to disclose. • Joanna Schwartz, PharmD, BCOP, has nothing to disclose.

these gene expression subtypes.6 Key tumor markers and their role in the management of breast cancer are shown in Table 1.7 Additional gene-based approaches have been developed for prognostic and predictive purposes. OncotypeDX is a 21-gene assay used to estimate the risk of recurrence in patients with earlystage, ER-positive, node-negative breast cancer, and to identify patients who may be successfully treated with tamoxifen alone (without chemotherapy).6,7 This test uses reverse transcription polymerase chain reaction on RNA isolated from paraffin-embedded breast cancer tissue. MammaPrint is an assay that uses microarray technology to analyze a 70gene expression profile from frozen breast tumor tissue of patients with early-stage, node-negative disease to determine their risk of developing distant metastases.6,8 Both of these multigene expression tests are commercially available and have been incorporated into several diagnostic protocols. It is important to note, however, that results from prospective trials evaluating the clinical value of these assays have yet to be reported, although 2 such trials (TAILORx and MINDACT) are currently under way. Current Management Strategies for Patients With MBC Although survival rates for MBC have improved over the past 20 years, the primary goal of treatment is still palliation.

• Georgia Litsas, MSN, ANP-BC, AOCNP, is on the speakers’ bureau for Genentech, Novartis, and Pfizer. 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. Trade names used in this article are for the learner’s reference only. No promotion of or bias toward any product should be inferred. COmmERCIAL SUPPORT ACkNOwLEDGmENT This activity is supported by an educational grant from Eisai, Inc.

The decision-making process regarding the choice of agents and the sequencing and duration of therapy for metastatic disease is complex, and requires consideration of numerous key factors, including the pathology, histology, and clinical characteristics of the tumor(s), axillary node status, hormone receptor (HR) and HER2 status, and patientrelated factors (eg, age, menopausal status, and comorbid conditions).6

HR-Positive MBC The goals of systemic therapy for recurrent or metastatic disease are prolonging survival and improving quality of life. Therefore, treatments with minimal toxicity are usually preferred and often include endocrine therapies (as opposed to cytotoxic therapies). Patients with HR-positive MBC (ie, those with tumors that are ER- and/or progesterone receptor [PR]-positive) may benefit from initial endocrine therapy. Recent data support treatment with a selective aromatase inhibitor (AI) for postmenopausal women with previous antiestrogen therapy who are within 1 year of antiestrogen exposure.6 For postmenopausal women who are antiestrogen naïve or more than 1 year from previous treatment with an antiestrogen, tamoxifen or an AI is an appropriate therapeutic option.6 In this setting, AIs have shown a modestly superior outcome compared with tamoxifen.6 Sequential treatment with endocrine therapy may be beneficial at the time of

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disease progression.6 Subsequent endocrine therapy may include nonsteroidal AIs (anastrozole or letrozole); a steroidal AI (exemestane); fulvestrant; tamoxifen or toremifene; megestrol acetate; fluoxymesterone; or ethinyl estradiol.6 For women with HR-positive metastatic disease who have been previously treated with an AI or antiestrogen, fulvestrant is an option that appears to be well tolerated as a monthly injection, with an efficacy profile similar to anastrozole and a longer duration of response.6

ER-Negative MBC Both the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) guidelines indicate an absence of benefit with endocrine therapy in women with ER-negative, invasive breast cancer, based on large, randomized, clinical trials.6,9 Chemotherapy has been shown to be more effective in the treatment of patients with this type of breast cancer (compared with adjuvant endocrine therapy),6,10 with a dosedense regimen of doxorubicin, cyclophosphamide, and paclitaxel showing the greatest benefit in terms of reducing the risk for recurrence and death.11 HER2-Positive MBC HER2 protein overexpression occurs in 20% to 25% of breast tumors, often leading to aggressive disease and poor outcomes.12 Consequently, successful targeting of HER2-positive tumors is an important therapeutic goal. Patients with this type of MBC may benefit from treatment with trastuzumab as monotherapy or in combination with select chemotherapy agents; or with a combination of capecitabine plus lapatinib for patients who are refractory to treatment with an anthracycline, a taxane, and trastuzumab. The preferred first-line agents for treating HER2-positive disease are listed in Table 2.6 Trastuzumab, a recombinant human anti-HER2 monoclonal antibody, specifically targets signaling mechanisms of HER2, which inhibits the growth of tumor cells that overexpress the receptor. The addition of trastuzumab to anthracycline or taxane chemotherapy in patients with HER2-positive breast cancer has been shown to significantly improve time to progression, rate of objective response, and median survival.13 Trastuzumab combined with other chemotherapeutic agents is also a viable option, and a number of combinations are available.6 Clinical trials evaluating trastuzumab combined with other targeted agents, including pertuzumab and lapatinib, are currently under way.12 Cardiac toxicity is a concern with trastuzumab treatment, particularly when this agent is combined with an anthracycline.6,14 According to NCCN

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Table 1 Key Tumor Markers in Breast Cancer7 Tumor Marker

Role

Estrogen receptor (ER)

Determine whether the cancer is likely to be successfully treated with hormone therapy, such as tamoxifen.

Progesterone receptor (PR) Human epidermal growth factor receptor 2 (HER2)

Cancer antigen 15-3 (CA 15-3) Cancer antigen 27.29 (CA 27.29) Carcinoembryonic antigen (CEA) Urokinase plasminogen activator (uPA) Plasminogen activator inhibitor (PAI-1)

guidelines, trastuzumab should not be administered concurrently with an anthracycline because of the risk of cardiac toxicity, except as part of the neoadjuvant regimen of trastuzumab plus paclitaxel followed by cyclophosphamide/epirubicin/fluorouracil.6 Close monitoring of cardiac function is advised for patients receiving trastuzumab therapy.6 Less serious side effects associated with this agent include nausea, vomiting, hot flashes, and joint pain.14,15

The goals of systemic therapy for recurrent or metastatic disease are prolonging survival and improving quality of life.

Resistance to trastuzumab often develops over time.16 One strategy for overcoming this resistance involves switching patients to lapatinib, a dual tyrosine kinase inhibitor that blocks HER2 signaling through an alternative mechanism.16 Lapatinib was approved by the US Food and Drug Administration (FDA) in 2007 for use in combination with capecitabine for the treatment of patients with advanced or metastatic disease whose tumors overexpress HER2 and who have received prior therapy, including an anthracycline, a taxane, and trastuzumab.17,18 In February 2010, lapatinib received approval for an expanded indication in combination with letrozole for the treatment of postmenopausal women with HR-positive/HER2-positive MBC for whom hormonal therapy is indicat-

Determines whether the cancer can be treated with an anti-HER2 treatment, such as trastuzumab; in some cases, may indicate whether additional treatment with chemotherapy may be beneficial. Found in 50% to 90% of patients with metastatic disease, these tumor markers may point to early recurrence or indicate whether the cancer is responding to treatment. High levels of these markers may indicate that the cancer is aggressive; these markers may guide the use of chemotherapy after surgery for patients with node-negative disease. ed.17,18 The approved labeling includes a caution stating that hepatotoxicity is a potentially serious adverse effect associated with lapatinib.18

HR-Negative MBC and HR-Positive, Endocrine-Refractory MBC Cytotoxic chemotherapy is recommended for patients with HR-negative MBC as well as HR-positive disease refractory to endocrine treatment. The NCCN guidelines recommend first-line singleagent chemotherapy until progression of disease.6 However, the adverse events associated with this therapy may necessitate dose reductions or treatment cessation.6 Preferred single-agent and combination chemotherapy regimens for HR-negative and HR-positive, endocrine-refractory breast cancer, as outlined in these guidelines, are shown in Table 3.6 Recent Advances in the Treatment of MBC Treatment options for patients with MBC continue to expand as investigators learn more about the biology of the disease and the process of metastasis. Recent advances in treatment include the development of novel targeted agents, new formulations of existing drugs, and more effective combination regimens. Microtubule-Targeting Agents

Eribulin Mesylate Eribulin mesylate, a nontaxane microtubulin, was highlighted as a “notable advance” in the treatment of breast cancer in ASCO’s annual report titled Clinical Cancer Advances 2010.19 Representing a new class of agents, eribulin is an analog of a chemical derived from a marine sponge. This drug was approved by the FDA in November 2010 for the treatment of patients with MBC who previously received at least 2

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chemotherapy regimens. This decision was based on preliminary results of the pivotal phase 3 EMBRACE trial (N = 762), in which a significant improvement in OS (median of 2.47 months) was seen with eribulin compared with treatment of physician’s choice (TPC).20 Results from an updated analysis of this trial, presented at the 2010 San Antonio Breast Cancer Symposium, were consistent with these earlier findings, with a median OS of 13.2 months for eribulin versus 10.5 months for TPC.21 The most recently updated NCCN practice guidelines list eribulin as a preferred single agent for recurrent or metastatic disease.6 The most common adverse events (incidence ≥25%) associated with this agent include neutropenia, asthenia/ fatigue, anemia, peripheral neuropathy, nausea, and constipation.22

Ixabepilone Ixabepilone, a semisynthetic analog of epothilone B, received FDA approval in 2007 as both a single agent and in combination with capecitabine for the treatment of locally advanced and metastatic disease.6 Phase 2 clinical trials evaluating ixabepilone monotherapy in the first-line setting have reported significant activity in patients who have received prior therapy with anthracyclines and taxanes.23 In a pivotal phase 3 trial comparing ixabepilone plus capecitabine versus Table 2 NCCN Guidelines: Preferred First-Line Therapies for HER2-Positive Breast Cancer6 Preferred First-Line Agents Trastuzumab with: • Paclitaxel + carboplatin • Docetaxel • Vinorelbine • Capecitabine Preferred Chemotherapy Agents for Trastuzumab-Exposed HER2Positive Breast Cancer Lapatinib plus capecitabine • Trastuzumab plus other first-line agents • Trastuzumab plus capecitabine • Trastuzumab plus lapatinib (without cytotoxic therapy) HER2 indicates human epidermal growth factor receptor 2; NCCN, National Comprehensive Cancer Network.

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CONTINUING EDUCATION capecitabine alone in patients with resistance to previous anthracycline and taxane therapy, a significant improvement in progression-free survival (PFS) was seen with the combination regimen (6.2 months vs 4.4 months, respectively; P = .0005).24 The most common adverse events (≥20% incidence) associated with ixabepilone include peripheral neuropathy, fatigue/asthenia, myalgia/ arthralgia, alopecia, nausea, vomiting, stomatitis/mucositis, diarrhea, and musculoskeletal pain.24

Nab-paclitaxel Nanoparticle albumin-bound (nab)paclitaxel is a solvent-free, albuminbound 130-nm particle form of paclitaxel that was developed to avoid toxicities associated with the cremophor vehicle used in solvent-based paclitaxel. This agent was approved by the FDA in January 2005 for the treatment of breast cancer after failure of combination therapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy.25 A phase 3 trial (N = 454) compared nab-paclitaxel with a conventional formulation of the drug in MBC, showing a higher target-lesion response and objective response rates with nabpaclitaxel.25 In a separate phase 2 trial (N = 302) in previously untreated MBC, nab-paclitaxel demonstrated significantly longer PFS than docetaxel by both independent radiologist assessment (12.9 vs 7.5 months, respectively; P = .0065) and investigator assessment (14.6 vs 7.8 months, respectively; P = .012).26 Novel Combinations for HER2Positive MBC In a recent phase 3 trial, dual HER2targeted therapy with lapatinib and trastuzumab showed an increase in PFS compared with lapatinib alone (12 weeks vs 8.1 weeks; P = .008) in

Table 3 NCCN Guidelines: Preferred First-Line Chemotherapies for Patients With HR-Negative or HRPositive, Endocrine-Refractory Breast Cancer6 Single Agents Anthracyclines • Doxorubicin • Epirubicin • Pegylated liposomal doxorubicin Taxanes • Paclitaxel • Docetaxel • Albumin-bound paclitaxel Antimetabolites • Capecitabine • Gemcitabine Nontaxane Microtubule Inhibitors • Eribulin • Vinorelbine

ment in tumor response rate compared with individual agents in patients with HER2-positive disease.28 According to preliminary findings from a phase 1b/2 trial, trastuzumabDM1 (T-DM1) plus pertuzumab demonstrated encouraging safety and efficacy in women with HER2-positive, locally advanced or metastatic disease who were previously treated with trastuzumab.29 T-DM1, an HER2-targeted antibody-drug conjugate, is composed of the cytotoxic agent DM1, an antimicrotubule agent, conjugated to the monoclonal antibody trastuzumab.29,30 Pertuzumab, a humanized monoclonal antibody, is the first HER2-directed dimerization inhibitor for the treatment of HER2-positive breast cancer. T-DM1 and pertuzumab bind to different HER2 receptors; combining these agents has shown synergistic antitumor activity in HER2-positive xenograft models.29,30

Combination Regimens Cyclophosphamide, doxorubicin, and fluorouracil (FAC/CAF) Fluorouracil, epirubicin, cyclophosphamide (FEC) Doxorubicin, cyclophosphamide (AC) Epirubicin, cyclophosphamide (EC) Doxorubicin in combination with either docetaxel or paclitaxel (AT) Cyclophosphamide, methotrexate, fluorouracil (CMF)

Emerging Therapies for TripleNegative Disease Triple-negative breast cancer (TNBC) is a term used to describe tumors that lack expression of ER, PR, and HER2. This type of breast cancer is associated with rapid disease progression and poor prognosis. Therefore, advances in treatment for this subtype of disease are particularly noteworthy. A recent study found that TNBC patients with BRCA1/BRCA2 mutations appear to have better survival than patients without these mutations.31

Docetaxel, capecitabine Gemcitabine, paclitaxel HR indicates hormone receptor; NCCN, National Comprehensive Cancer Network.

patients with heavily pretreated MBC and disease progression on trastuzumab therapy.27 In addition, according to recent data, the combination of lapatinib, trastuzumab, and paclitaxel was associated with a significant improve-

PARP Inhibitors Poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors appear to have clinical activity in BRCA1-/ BRCA2-associated cancer. Results from a phase 2 study (N = 123) showed that the PARP inhibitor, iniparib, plus chemotherapy was associated with significantly prolonged OS in TNBC, compared with chemotherapy alone

(12.3 months vs 7.7 months, respectively; hazard ratio for death, 0.57; P = .01).32 In addition, another PARP inhibitor, olaparib, is being investigated for its potential activity when combined with paclitaxel.33 In a small study (N = 10), 4 patients achieved a partial response with this combination; however, acceptable dose intensity was delayed or not achieved because neutropenia was reported in a number of patients.34 In another small study (N = 24), no responses were observed in patients with TNBC treated with olaparib plus paclitaxel.33

Cetuximab Cetuximab, an antibody that targets epithelial growth factor receptor, is being studied for its potential role in treating TNBC. Based on results of a recent phase 2 trial (N = 173), adding cetuximab to cisplatin chemotherapy in heavily pretreated patients with TNBC resulted in twice the response rate and twice the time to progression compared with patients who received cisplatin alone.35 Bone Disease in Patients With MBC Bone metastasis, which occurs in approximately 70% of patients with advanced breast cancer,36 can lead to significant skeletal morbidity, including bone pain, pathologic fracture, hypercalcemia of malignancy, and spinal cord compression.36 Patients with breast cancer who are treated with AIs (eg, anastrozole, letrozole, exemestane) are at increased risk for bone loss and fractures.37 Bisphosphonates have demonstrated efficacy in delaying the onset and reducing the incidence of skeletal-related events (SREs) associated with bone metastasis.38 The recently approved agent, denosumab, has also been shown to be effective in preventing these events in patients with bone metastases from solid tumors.39

Update on Bevacizumab Use in Breast Cancer

n February 2008, the FDA granted accelerated approval of bevacizumab in combination with paclitaxel for the first-line treatment of HER2negative MBC. This approval was based on results of E2100, a phase 3 trial in which initial treatment with this combination almost doubled PFS compared with paclitaxel alone in women with recurrent or metastatic disease (11.8 months vs 5.9 months, respectively; P <.001).1 Subsequent phase 3 trials also demonstrated longer PFS when bevacizumab was added to various first-line chemotherapeutic regimens for MBC, but these gains were not as clinically significant as those seen in the E2100 trial.2,3 A recent meta-analysis of these trials failed to show an improvement in OS with the addition of bevacizumab.4 Given the fact that bevacizumab use has been associated with serious adverse events, including

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hypertension, bleeding, and febrile neutropenia,2,3,5 the FDA is now questioning whether the benefits of this drug outweigh the risks for women with MBC.6 After consideration of the data, the agency’s review panel announced that it was revoking this indication.6 The manufacturer of bevacizumab has requested a hearing to maintain their drug as a treatment option for HER2-negative MBC.7 It should be noted, however, that the European Medicines Agency and the National Comprehensive Cancer Network have both indicated that bevacizumab plus paclitaxel should remain a therapeutic option for women with this type of breast cancer.8 References 1. 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.

2. 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. 3. Robert NH, Dieras V, Glaspy J, et al. RIBBON-1: randomized, doubleblind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(15 suppl). Abstract 1005. 4. O’Shaughnessy J, Miles D, Gray RJ, et al. A meta-analysis of overall survival data from three randomized trials of bevacizumab (BV) and first-line chemotherapy as treatment for patients with metastatic breast cancer (MBC). J Clin Oncol. 2010;28(15 suppl). Abstract 1005. 5. Avastin [package insert]. South San Francisco, CA: Genentech, Inc; December 2010. 6. U.S. Food and Drug Administration. FDA begins process to remove breast cancer indication from Avastin label. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm237172.htm? Accessed January 3, 2011. 7. Rohrer MH. Request for hearing (letter). www.gene.com/gene/news/ news-events/avastin/documents/avastin_use.pdf. Accessed January 3, 2011. 8. FDA revokes bevacizumab’s breast cancer indication. http://ascopost. com/articles/january-15-2011/fda-recommends-removal-of-bevacizum ab’s-breast-cancer-indication. Accessed January 13, 2011.

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Bisphosphonate Therapy The use of bisphosphonates is considered a palliative care measure in patients with MBC; these agents may also play a role in preventing skeletal complications associated with bone loss.6 The 2 intravenous (IV) bisphosphonates approved by the FDA for the treatment of bone metastases are zoledronic acid and pamidronate. Both of these agents have been studied in numerous clinical trials, and zoledronic acid appears to be superior to pamidronate in patients with lytic breast metastasis.6 Recent data also suggest that zoledronic acid may have antitumor properties.40 Zoledronic acid and pamidronate may help to decrease the pain related to bone metastasis, thereby reducing the need for supplemental analgesics in some patients.41 Generally, IV bisphosphonates are well tolerated. However, osteonecrosis of the jaw (ONJ), a rare but serious complication, may occur.6 Most reported cases of ONJ during bisphosphonate therapy have been associated with dental procedures such as tooth extractions. A dental examination is recommended prior to treatment, and invasive procedures during therapy should be avoided whenever possible.6 In addition, serum creatinine should be monitored prior to each dose of zoledronic acid or pamidronate. According to recent data, short-term use (≤12 months) of these agents is associated with a low risk of renal dysfunction.41 However, the effects of extended therapy have not been studied extensively.41 Denosumab Denosumab, a fully human monoclonal antibody, was approved by the FDA in November 2010 for the prevention of SREs in patients with bone metastases from solid tumors.39 This novel agent inhibits bone resorption by specifically targeting the receptor activator of nuclear-factor kappa beta ligand (RANKL) and its receptor, RANK, key mediators of osteoclast formation and function.42 Phase 3 data presented at the 2010 San Antonio Breast Cancer Symposium showed that denosumab was superior to zoledronic acid in delaying the time to first on-study SREs by 18%, and denosumab delayed the time to firstand-subsequent on-study event by 22%.43 Moreover, in patients with advanced breast cancer and bone metastases who were at risk, the median time to first on-study SRE was 5 months longer in the denosumab group compared with the zoledronic acid group. Denosumab was also associated with less pain, less interference with daily functioning, and improved health-related quality of life, based on other data presented at this meeting.43 In general, the rate of adverse events

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associated with denosumab was similar to the rate observed with zoledronic acid; cases of ONJ were rare, and hypocalcemia was more frequent in the denosumab arm.39 Calcium levels must be monitored in patients receiving denosumab, and administration of calcium, magnesium, and vitamin D may be required.39 The most common adverse events associated with denosumab were fatigue/asthenia, hypophosphatemia, and nausea; dyspnea was the most common serious adverse event.39

HER2 protein overexpression occurs in 20% to 25% of breast tumors, often leading to aggressive disease and poor outcomes.

Conclusion Extended survival and improved quality of life are of paramount importance in patients with MBC. Advances in systemic, hormonal, and targeted therapies are yielding novel approaches and protocols that hold promise for improving clinical outcomes. Addressing pain and other disease-related comorbidities and preventing SREs are also key aspects of managing patients with MBC. The approach to treatment continues along the path of personalized care plans that are based on tumor/disease profile, patient-specific factors, and patient and physician preferences. Increasing attention is being directed toward the use of genetic markers and other tools that help clinicians stratify patients who will receive maximal benefit from a specific therapy while sparing those patients who may not benefit from such regimens. Research continues to focus on the development of novel therapies that increase response and survival time for patients with MBC, while minimizing toxicity and other adverse events. ● References 1. Surveillance, Epidemiology, and End Results (SEER) Stat Fact Sheets—Cancer Statistics: Breast. http://seer.cancer.gov/statfacts/html/breast.html. Accessed December 28, 2010. 2. American Cancer Society. Breast cancer—what are the key statistics about breast cancer? Reviewed September 17, 2010. http://www.cancer.org/cancer/breastcancer/ detailedguide/breast-cancer-key-statistics. Accessed December 28, 2010. 3. O’Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. Oncologist. 2005; 10(suppl 3):20-29. 4. MBC Advocacy Working Group. Metastatic breast cancer patients: addressing their unmet needs-Special Report. Commun Oncol. 2008;5:645-647. 5. Moulder S, Hortobagyi GN. Advances in the treatment of breast cancer. Clin Pharmacol Ther. 2008;83:26-36. 6. National Comprehensive Cancer Network. NCCN

Clinical Practice Guidelines in Oncology™. Breast Cancer, V.2.2011. December 16, 2010. http://www.nccn. org/professionals/physician_gls/PDF/breast.pdf. Accessed December 29, 2010. 7. American Society of Clinical Oncology. What to know: ASCO’s guideline on tumor markers for breast cancer. Updated October 6, 2010. http://www.cancer. net/patient/Publications+and+Resources/What+to+Kn ow%3A+ASCO%27s+Guidelines/What+to+Know%3 A+ASCO%27s+Guideline+on+Tumor+Markers+for+ Breast+Cancer?sectionTitle=Introduction&sectionId=1 02827&vgnextrefresh=1. Accessed December 29, 2010. 8. Knauer M, Rutgers EJ, Mook S, et al. Evaluation of the 70-gene prognosis MammaPrint signature for the prediction of prognosis of breast cancer independently from histologic grade. J Clin Oncol. 2010;28:15(suppl). Abstract 561. 9. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology—College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784-2795. 10. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365:1687-1717. 11. Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA. 2006;295:1658-1667. 12. Brufsky A. Trastuzumab-based therapy for patients with HER2-positive breast cancer: from early scientific development to foundation of care [abstract]. Am J Clin Oncol. Epub August 11, 2009 [ahead of print]. 13. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17:2639-2648. 14. Herceptin (trastuzumab) [package insert]. San Francisco, CA: Genentech, Inc; 2010. 15. National Cancer Institute. US National Institutes of Health. Adjuvant and neoadjuvant therapy for breast cancer. Rev June 16, 2009. http://www.cancer.gov/ cancertopics/fact sheet/Therapy/adjuvant-breast. Accessed December 29, 2010. 16. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743. 17. Tykerb (lapatinib). Rxlist. http://www.rxlist.com/ tykerb-drug.htm. Accessed December 29, 2010. 18. Tykerb (lapatinib) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010. 19. Clinical cancer advances 2010—ASCO’s annual report on progress against cancer. J Clin Oncol. Epub ahead of print. November 8, 2010. http://www.can cer.net/patient/Publications%20and%20Resources/ Clinical%20Cancer%20Advances/CCA_2010.pdf. Accessed December 10, 2010. 20. Twelves C, Loesch D, Blum JL, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract CRA 1004. 21. Twelves C, Loesch D, Blum J, et al. Updated survival analysis of a phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in subjects with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. Presented at the 33rd annual San Antonio Breast Cancer Symposium. December 8-12, 2010. San Antonio, TX. Poster P6-14-18. 22. Halaven (eribulin mesylate) [package insert]. Woodcliff Lake, NJ: Eisai Inc; and Nerviano, Italy: NerPharMa; 2010. 23. Vahdat L. Ixabepilone: a novel antineoplastic agent with low susceptibility to multiple tumor resistance mechanisms. Oncologist. 2008;13:214-221. 24. Sparano JA, Vrdolja E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28:3256-3263. 25. Robinson DM, Keating GM. Albumin-bound paclitaxel: in metastatic breast cancer. Drugs. 2006;66:941-948. 26. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line

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therapy for metastatic breast cancer. J Clin Oncol. 2009;27:3611-3619. 27. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124-1130. 28. Combination therapy reduced HER2-positive breast cancers. Medical News Today. December 11, 2010. http://www.medicalnewstoday.com/articles/211172.php. Accessed December 29, 2010. 29. Miller K, Gianni L, Andre F, et al. A phase Ib/II trial of trastuzumab-DM1 (T-DM1) with pertuzumab (P) for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treated with trastuzumab (T). J Clin Oncol. 2010;28(suppl). Abstract 1012. 30. Susman E. ASCO: new agents show promise in HER2-positive breast cancer [press release]. Medpage Today. Released June 8, 2010. http://www.medpageto day.com/tbprint.cfm?tbid+20550. Article 20550. 31. University of Florida—Shands Cancer Center. BRCA1/2 mutations linked with better outcome in triple-negative breast cancer. Breast cancer news. http://cancer.ufl.edu/2010/10/13/brca12-mutationslinked-with-better-outcome-in-triple-negative-breastcancer/. Accessed December 30, 2010. 32. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. Epub ahead of print. January 5, 2011. 33. Susman E. Olaparib may have promise in breast cancer. Medpage Today. June 8, 2010. http://www.medpage today.com/MeetingCoverage/ASCO/ 20546. Accessed December 30, 2010. 34. Dent RA, Lindeman GJ, Clemons M, et al. Safety and efficacy of the oral PARP inhibitor olaparib (AZD2281) in combination with paclitaxel for the firstor second-line treatment of patients with metastatic triple-negative breast cancer: results from the safety cohort of a phase I/II multicenter trial. J Clin Oncol. 2010;28:15s(suppl). Abstract 1018. 35. Triple-negative breast cancer responds well to cetuximab addition to chemotherapy [press release]. Medical News Today. October 12, 2010. http://www.medicalnew stoday.com/articles/204334.php. Accessed December 30, 2010. 36. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664. 37. Cancer treatment may result in bone loss [press release]. Medical News Today. November 16, 2008. http://www.medicalnewstoday.com/articles/129429.php. Accessed December 8, 2010. 38. Coleman R. On the horizon: can bisphosphonates prevent bone metastases? Breast. 2007;(3)Suppl;S21-7. Epub November 7, 2007. Review. 39. FDA approves Amgen’s Xgeva (denosumab) for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Medical News Today. November 19, 2010. http://www.medicalnewstoday. com/articles/208585.php. Accessed December 29, 2010. 40. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009; 360:679-691. 41. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003. Update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21:4042-4057. 42. Lipton A, Jun S. RANKL inhibition in the treatment of bone metastases. Curr Opin Support Palliat Care. 2008;2:197-203. 43. Amgen presents new XGEVA (denosumab) breast cancer skeletal-related event prevention data at SABCS. December 11, 2010. Medical News Today. http://www.medicalnewstoday.com/articles/211175.php. Accessed December 14, 2010.

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CONTINUING EDUCATION

Novel Targeted Agents for the Treatment of Metastatic Breast Cancer By Joanna Schwartz, PharmD, BCOP Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Colchester, VT

reast cancer is the most common female malignancy worldwide, with an annual global incidence of over 1 million and a resulting 450,000 deaths.1 Although the diagnosis of localized breast cancer is more common since the advent of screening mammogram guidelines, the number of women diagnosed with metastatic disease is still significant.2 The prognosis for advanced metastatic breast cancer (MBC) is very poor, with only 1 in 5 women surviving for 5 years.2 Anthracyclines and taxanes are among the most active drugs used to treat breast cancer; however, a significant number of patients become resistant to these therapies over time, resulting in low response rates.3,4 In some cases, resistance is due to the expression of multidrug-resistant (MDR) protein products of the MDR gene, such as Pglycoprotein. This results in the production of drug efflux pumps, which actively transport many chemotherapy agents, such as taxanes, out of cancer cells.5 Drug resistance is especially problematic for patients with triple-negative breast cancer (TNBC) and/or breast cancer with the BRCA mutation (deficiency), as these types of malignancies are inherently resistant to most cytotoxic therapies.6 In the case of TNBC, patients who develop resistance are left with very limited treatment options, as they are not candidates for hormonal or targeted agents, due to a lack of tumor receptors. Furthermore, TNBC is the most aggressive type of breast cancer and is associated with the poorest prognosis.7 There is an important need for novel agents to address these challenges in the treatment of breast cancer. Two new cytotoxic drug classes, epothilones and halichondrins, and 1 new targeted drug class, poly(adenosine diphosphateâ&#x20AC;&#x201C;ribose) polymerase (PARP) inhibitors, have been developed to meet this need. Novel Microtubule-Targeting Agents

Ixabepilone Ixabepilone was the first agent from the epothilone class to be approved by the US Food and Drug Administration (FDA) for the treatment of metastatic or locally advanced breast cancer. Epothilones are naturally occurring macrolide antibiotics, produced by the myxobacterium Sorangium cellulosum, and are nontaxane microtubule inhibitors. The taxanes exert their cytotoxic

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Table Phase 3 Trial of Ixabepilone Plus Capecitabine Versus Capecitabine Alone in MBC Resistant to Anthracyclines and Taxanes9 Ixabepilone + Capecitabine

Capecitabine

P Value

Median PFS, months

6.2

4.2

.0005

ORR, %

.0001

Best response, N (%) CR PR SD PD

16 (3) 184 (40) 170 (37) 57 (12)

11 (2) 122 (26) 182 (39) 111 (24)

CR indicates complete response; MBC, metastatic breast cancer; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; SD, stable disease.

effect by binding tubulin, and stabilizing the microtubule and inhibiting its disassembly, ultimately leading to cell death by apoptosis. Although epothilones have a similar mechanism of action, these novel agents bind to tubulin at a different site. Importantly, epothilones appear to retain activity in cell lines expressing the P-glycoprotein pump, which, as mentioned earlier, is a known cause of resistance to agents such as taxanes.8

In the case of TNBC, patients who develop resistance are left with very limited treatment options.

The combination of ixabepilone plus capecitabine was evaluated in a phase 3 randomized double-blind clinical trial of patients with MBC resistant to treatment with anthracyclines and taxanes. As shown in the Table, this combination was associated with significantly longer median progression-free survival (PFS) than capecitabine alone (6.2 vs 4.2 months; P = .0005), as well as a higher response rate (43% vs 29%; P <.0001).9 Ixabepilone monotherapy has also demonstrated clinical activity in patients with MBC after failure of capecitabine in several phase 2 trials, with objective response rates ranging from 12% to 18%.10-12 The main toxicities observed in clin-

ical trials of ixabepilone have included peripheral neuropathy, fatigue, myalgia/arthralgia, diarrhea, neutropenia, and less commonly, hypersensitivity infusion reactions. Ixabepilone is reconstituted with a supplied diluent containing polyethoxylated castor oil, which is a known cause of reactions with other agents, such as paclitaxel.13 Based on data from the above-mentioned trials, ixabepilone was approved by the FDA in 2007 for the following indications: (1) in combination with capecitabine for treatment of patients with metastatic or locally advanced breast cancer resistant to treatment with an anthracycline and a taxane or whose cancer is taxane resistant and for whom further anthracycline therapy is contraindicated, and (2) as single-agent therapy for the treatment of metastatic or locally advanced breast cancer in patients whose tumors are resistant or refractory to anthracyclines, taxanes, and capecitabine.14 According to the approved package labeling, ixabepilone should be administered intravenously (IV) over 3 hours at a dose of 40 mg/m2 (to a maximum of 88 mg for patients with a body surface area >2.2 m2) every 3 weeks. Patients should be premedicated with a histamine-1 antagonist such as diphenhydramine and a histamine-2 antagonist such as ranitidine 1 hour before ixabepilone and should be closely monitored for hypersensitivity reactions prior to the first 2 infusions. Ixabepilone is extensively metabolized by the liver, and the package labeling contains specific dosing recommendations for patients with hepatic impairment.14 In fact, the combination of ixabepilone and capecitabine is contraindicated

when the total bilirubin rises over the upper limit of normal. This prescribing information should be consulted for specific dose adjustments for patients with elevated liver function tests or significant toxicities, such as neutropenia or neuropathy. Complete blood counts, examination for neurologic symptoms, and liver function tests should be performed prior to every dose, and the use of strong cytochrome P-450 3A4 inhibitors (including grapefruit juice) should be avoided.14

Eribulin Mesylate Eribulin mesylate is a novel microtubule inhibitor with a distinct mechanism of action. Other microtubule inhibitors, such as taxanes, vinca alkaloids, and epothilones, inhibit both growth and shortening of microtubules. In contrast, eribulin suppresses microtubule growth with no effect on microtubule shortening, and also sequesters tubulin into nonfunctional aggregates. It is a synthetic analog of the marine natural macrolide halichondrin B, which was first isolated from the Japanese sponge Halichondria okadai, and is the first in class of the halichondrins.15 Eribulin was FDA approved in November 2010 for the treatment of patients with MBC who have previously received anthracyclines and taxanes, based on the results of the pivotal phase 3 EMBRACE trial. This study was designed to represent common practice situations in that the 762 enrolled patients with metastatic or locally recurrent breast cancer had been heavily pretreated with 2 to 5 previous chemotherapy regimens that included an anthracycline and a taxane.16 Furthermore, patients were randomized to eribulin or a treatment of physicianâ&#x20AC;&#x2122;s choice (TPC), which could be any monotherapy (cytotoxic, hormonal, biologic) or supportive care only. This choice was considered representative of actual practice scenarios, since there is no current standard of care for breast cancer patients after failure of anthracyclines and taxanes. The primary end point of this trial was overall survival (OS); secondary end points were objective response rate, PFS, and duration of response. Median OS was significantly prolonged with eribulin compared with TPC (13.12 vs 10.65 months, a difference of 2.47 months; P = .041). The 1year survival was 53.9% with eribulin and 43.7% with TPC (Figure 1).16 Although the trial did not show a statis-

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tically significant improvement in PFS (albeit a strong trend in favor of eribulin), the results are still significant in that eribulin is the first agent to demonstrate an OS advantage for MBC since docetaxel was approved more than 10 years ago. The main toxicities observed in the eribulin arm of the trial were neutropenia, anemia, peripheral neuropathy, alopecia, nausea (mostly mild), myalgia/arthralgia, fatigue, constipation, and QT prolongation (rare).16 According to the package labeling, eribulin should be avoided in those with congenital long QT syndrome, and electrolytes should be corrected prior to initiating therapy, and monitored periodically during treatment.17 Eribulin should be administered IV over 2 to 5 minutes at a dose of 1.4 mg/m2 on days 1 and 8 of a 21-day cycle. Because eribulin is extensively hepatically cleared with some metabolites being renally cleared, the package labeling should be consulted for suggested dosing modifications for mild-tomoderate hepatic impairment and/or a creatinine clearance <50 mL/min. There is no safety data or dosing recommendations for those with a creatinine clearance <30 mL/min. Patients should be assessed for peripheral neuropathy and with complete blood counts prior to each dose, and therapy should be delayed for significant neuropathy or an absolute neutrophil count <1000/mm3 and/or platelets <75,000/mm3. The package labeling should also be consulted for suggested dosage reductions in the event of very low blood counts, febrile neutropenia, or toxicities that do not resolve within 7 days.17 PARP Inhibitors for MBC PARP inhibitors appear to be among the most promising agents being studied for the treatment of BRCA-mutated breast cancer and TNBC. Both BRCA1 and BRCA2 are involved in the repair of DNA damage (in particular, doublestrand DNA breaks), which arises from exposure to chemotherapy. This process is known as homologous recombination. DNA damage is essential in the treatment of cancer, as it triggers cell cycle arrest and cell death.18 In women with BRCA-mutated breast cancer, the tumor loses the wild-type allele of BRCA1 or 2 and is left with a nonfunctioning BRCA1 or 2 protein.19-21 When this occurs, another pathway of DNA repair, known as base excision repair, allows the cancer cell to recover from DNA damage. This pathway is dependent on the function of enzymes called PARPs, which repair single-strand DNA breaks. Investigators have hypothesized that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mecha-

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To Receive cRediT, compleTe The posTTesT aT TheOncologyPharmacist.com Two new agents, ixabepilone and eribulin, are novel microtubule agents that have been FDA approved and provide options for patients who are resistant or intolerant to other therapies.

nisms, may result in synergistic tumor cell death (Figure 2).22 Triple-negative tumors, while not all stemming from BRCA mutation, share characteristics with BRCA1-associated breast tumors and may harbor other genetic lesions that impair double-strand repair.21 Currently, there are 8 PARP inhibitors in clinical trial development worldwide, but only 3 agents are being evaluated in late-stage clinical trials: olaparib, veliparib, and iniparib. To date, the largest and most promising trials of PARP inhibitors in breast cancer include a phase 2 multicenter, singlearm trial of olaparib in patients with refractory, advanced BRCA-mutated breast cancer,23 and a randomized, phase

2 trial investigating iniparib in combination with gemcitabine and carboplatin in patients with TNBC.24 Additionally, results of a small phase 2 trial of veliparib in combination with temozolomide in patients with advanced refractory breast cancer (not restricted to BRCA or triple-negative status) were recently presented at the 2010 American Society of Clinical Oncology annual meeting. Although these were only preliminary findings, several excellent clinical responses were reported, including 1 complete response and 2 partial responses in 24 evaluable patients.25 In the phase 2 single-agent study,23 54 women with recurrent MBC and con-

CI indicates confidence interval; HR, hazard ratio; MBC, metastatic breast cancer; TPC, treatment of physician’s choice.

Figure 1. Survival data from a phase 3 trial of eribulin versus treatment of physician’s choice in previously treated patients with MBC.16

Figure 2. Mechanism of cell death from synthetic lethality, as induced by inhibition of poly(adenosine diphosphate-ribose) polymerase 1 (PARP1).22

firmed BRCA mutations were administered olaparib 100 or 400 mg orally twice daily. The overall response rate was 22% in the 100-mg group and 41% in the 400-mg group. In the phase 2 combination study,24 123 women with metastatic TNBC were randomized to either gemcitabine and carboplatin alone, or the same agents in combination with IV iniparib on days 1, 4, 8, and 11 of a 21-day cycle. Updated results of this trial showed that the combination with iniparib extended OS by approximately 4 months compared with gemcitabine/carboplatin alone (12.3 vs 7.7 months, P = .01). Results of these studies indicate the potential of PARP inhibition as a tumor-specific target in specific patient populations, considering most of the participants had been refractory to several prior therapies. As a class, the PARP inhibitors are well tolerated, and the most common toxicities seen in clinical trials have included lowgrade fatigue and nausea.23-25 Before PARP inhibitors can be considered for possible wider use outside of clinical trials, it will be necessary to identify the best candidates for this therapy and to determine which agents will be most effective when used in combination with specific PARP inhibitors. In addition, the clinical activity of these agents needs to be assessed in ongoing randomized, comparative, phase 3 trials. Conclusions Limited options make the successful treatment of MBC difficult. Current treatment options include anthracyclines, taxanes, and capecitabine. Resistance to these classes of drugs is often acquired, thus highlighting the need for newer agents capable of managing treatment-resistant disease. Two new agents, ixabepilone and eribulin, are novel microtubule agents that have been FDA approved and provide options for patients who are resistant or intolerant to other therapies. The addition of these therapies into the breast cancer armamentarium has expanded treatment options for patients with MBC. Several PARP inhibitors are in latephase development and in the future may provide promising treatment options to specific patients, especially women with BRCA mutations or TNBC. Continued research into these agents will be necessary to further

decembeR 2011 I vol 4, No 8

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CONTINUING EDUCATION define their place in therapy. Further results of ongoing studies with all of these agents are keenly awaited. ● References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. Cancer J Clin. 2008;58:71-96. 2. Coughlin SS, Ekwueme DU. Breast cancer as a global health concern. Cancer Epidemiol. 2009;33:315-318. 3. Hortobagyi GN. Treatment of breast cancer. N Engl J Med. 1998;339:974-984. 4. O’Shaughnessy J, Twelves C, Aapro M. Treatment for anthracycline-pretreated metastatic breast cancer. Oncologist. 2002;7(suppl 6):4-12. 5. Kruh GD. Introduction to resistance to anticancer agents. Oncogene. 2003;22:7262-7264. 6. Greenberg S, Rugo HS. Challenging clinical scenarios: treatment of patients with triple-negative or basallike metastatic breast cancer. Clin Breast Cancer. 2010;10(suppl 2):S20-S29. 7. Foulkes WD, Smith IE, Jorge RS. Triple negative breast cancer. N Engl J Med. 2010;363:1938-1944. 8. Halterman PA. Lapatinib and ixabepilone for the

treatment of metastatic breast cancer. Pharmacotherapy. 2008;28:1255-1266. 9. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28:3256-3263. 10. Perez EA, Lerzo G, Pivot X, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007;25:3407-3414. 11. Thomas E, Tabernero J, Fornier M, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol. 2007;25:33993406. 12. Low JA, Wedam SB, Lee JJ, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in metastatic and locally advanced breast cancer. J Clin Oncol. 2005;23:2726-2734. 13.Taxol [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; August 2010. 14. Ixempra [package insert]. Princeton, NJ: Bristol-

Myers Squibb Company; May 2010. 15. Jordan MA, Kamath K, Manna T, et al. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005;4:1086-1095. 16. Twelves C, Loesch D, Blum J, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane. Presented at the 2010 annual meeting of the American Society of Clinical Oncology. June 4-8, 2010. Chicago, IL. Abstract CRA 1004. 17. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; November 2010. 18. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134. 19. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007; 25:1329-1333. 20. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869-10874.

21. Tommiska J, Bartkova J, Heinonen M, et al. The DNA damage signaling kinase ATM is aberrantly reduced or lost in BRCA1/BRCA2-deficient and ER/PR/ERBB2-triple-negative breast cancer. Oncogene. 2008;27:2501-2506. 22. Iglehart JD, Silver DP. Synthetic lethality—a new direction in cancer-drug development. N Engl J Med. 2009;361:189-191. Editorial. 23. Tutt A, Robson J, Garber J, et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235. 24. O'Shaughnessy J, Osborne C, Pippen J, et al. Updated results of a randomized phase II study demonstrating efficacy and safety of BSI-201, a PARPinhibitor, in combination with gemcitabine/carboplatin in metastatic triple negative breast cancer (abstract 3122). Presented at the 2009 San Antonio Breast Cancer Symposium, December 9-12, 2009, San Antonio, TX. 25. Isakof SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib (ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol. 2010;28:15s(suppl; abstract 1019).

Emerging Therapies in the Treatment of Breast Cancer Continued from cover menopausal patients with ER-positive advanced breast cancer progressing on a nonsteroidal aromatase inhibitor to exemestane alone or exemestane plus weekly entinostat. Median progressionfree survival (PFS) was 4.28 months with entinostat/exemestane versus 2.27 months with exemestane alone, a 27% statistically significant reduction in risk.

Median overall survival (OS) was 26.9 months and 20.3 months, respectively, a 54% reduction in risk that trended toward significance. HDAC inhibitors induce hyperacetylation of lysines on histones and a number of other proteins. In a biomarker analysis of 49 patients, protein lysine acetylation measured in blood samples

Readers Survey

Have patients asked you about the situation with bevacizumab and the FDA?

n the October issue, we published an article about the FDA review of bevacizumab for use in metastatic breast cancer. We asked our online reading community if this is something they have discussed with patients. • 31% indicated patients have asked them about the situation

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• 65% said patients have not asked about it • 4% only discuss it if the patient brings it up

Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 35 for details.

www.TheOncologyPharmacist.com 28

December 2011 I VOL 4, NO 8

found that subjects who hyperacetylated experienced a 77% reduction in risk with the combination; median PFS was 8.54 months on the combination versus 1.92 months with exemestane alone. The finding suggests that hyperacetylation “may be a potential marker of benefit,” Yardley said. Symposium session moderator Joyce O’Shaughnessy, MD, of Baylor Sammons Cancer Center in Dallas, called the use of entinostat in advanced ER-positive breast cancer “very, very promising,” and added, “It’s time for a phase 3 trial of this agent.” Topoisomerase Inhibitor Shows Significant Activity NKTR-102, an intravenous topoisomerase-1 inhibitor-polymer conjugate, showed significant antitumor activity in metastatic breast cancer, including poor-prognosis patients with triplenegative disease having received prior anthracycline/taxane therapy. The phase 2 study evaluated the drug in 70 patients, most with visceral metastases. The response rate was 29%, and the clinical benefit rate (response + stable disease) was 46%, including 2 complete and 4 near-complete responses. Fully 39% of the triple-negative subset responded, reported Agustin Garcia, MD, of the University of Southern California Norris Comprehensive Cancer Center, Los Angeles. Median PFS was 4.6 months, and median OS was 10.3 months. The most common grade 3/4 side effect was diarrhea (20%-23%), typically occurring after 3 months of treatment. NKTR-102, given every 21 days, is being evaluated in multiple cancer indications, and phase 3 planning is under way in advanced breast cancer and platinum-resistant ovarian cancer. William Gradishar, MD, director of the Maggie Daley Center for Women’s

Cancer Care at Northwestern University, Chicago, said the key questions are how NKTR-102 will compare with other salvage cytotoxics (eribulin, ixabepilone) and whether there is an optimal sequence into which to incorporate the new cytotoxic. Insulin Growth Factor Inhibitor Intriguing The list of agents targeting the insulin growth factor (IGF) is steadily growing, with almost 20 tyrosine kinase inhibitors and monoclonal antibodies in preclinical and clinical trials. Joining this list is a neutralizing antibody, MEDI-573. The drug neutralizes IGF-I and IGF-II ligands and inhibits IGF receptor signaling pathways. The first-in-human safety and pharmacokinetic profiles were described at the symposium by Paul Haluska, MD, of the Mayo Clinic, Rochester. In a phase 1 study in 37 patients who received various doses and schedules of the intravenous agent, IGF-I and IGFII levels were fully suppressed, and no clinically significant changes in glucose, insulin, or somatotropin levels were observed. A phase 2 study of MEDI-573 plus an aromatase inhibitor is ongoing. Everolimus Shows Promise in Triple-Negative Breast Cancer Clinical benefit was observed in 8 of 12 evaluable patients (56%) in a phase 2 study of 14 heavily pretreated metastatic patients receiving everolimus plus carboplatin. The average responder has been stable for 22 weeks, and response approaches 1 year in several patients. Dose-limiting thrombocytopenia was an unexpected side effect that required protocol amendment, but the results are impressive, according to J. C. Singh, MD, and colleagues at New York University School of Medicine. ●

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BD Welcomes BD PhaSeal®

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Lung Cancer

Positive Data Continue to Accrue for Crizotinib in ALK-Positive NSCLC By Caroline Helwick

n patients with advanced nonâ&#x20AC;&#x201C;small cell lung cancer with ALK gene rearrangements, treatment with crizotinib provided clinically meaningful antitumor activity, producing responses in 51% of patients, in a multicenter phase 2 study reported at the 2011 European

Multidisciplinary Cancer Congress. Rearrangements in ALK are seen in up to 5% of patients, and crizotinibâ&#x20AC;&#x201D;a firstin-class, oral, potent, and selective small molecularâ&#x20AC;&#x201D;competitively inhibits ALK. The report was based on data from the first 133 evaluable patients who

received crizotinib 250 mg twice daily on a continuous basis until progression in an ongoing open-label phase 2 study. Objective responses were observed in 50.4% of patients, one being a complete response. Stable disease was observed in another 33.8%, reported

# ! #

PROGRAM OVERVIEW This is the first global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

CO-CHAIRS

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of tumor biomarkers, their impact on the treatment of patients with solid tumors and hematologic malignancies, and how to integrate key findings into clinical practice. â&#x20AC;˘ Discuss the role of tumor biomarkers in designing personalized therapy for patients with cancer, including management of treatment-related adverse events.

TARGET AUDIENCE This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians. CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should only claim the credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.0 contact hours.

RĂźdiger Hehlmann, MD Chief and Professor of Medicine University of Heidelberg Mannheim, Germany

REGISTERED PHARMACY DESIGNATION Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.0 contact hours (0.12 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-11-088-L01-P.

Early registration of $425 ends January 13, 2012!

COMMERCIAL SUPPORT ACKNOWLEDGMENT This activity is supported by educational grants from Genentech, Inc. and Millennium Pharmaceuticals, Inc.

December 2011 I VOL 4, NO 8

Dong-Wan Kim, MD, Clinical Researcher at Seoul National University Hospital in South Korea. Among the responders, 79.4% demonstrated a response within the first 8 weeks of treatment and maintained the response for an average of 42 weeks. Although 32% of patients discontinued the study, only 4.4% did so as a result of adverse events. Treatment-related grade 3/4 adverse events, mainly elevated liver enzymes and neutropenia, were reported in 26% of patients. About half the patients completed patient-reported outcomes for key symptoms and global quality of life. Clinically meaningful improvements (â&#x2030;Ľ10-point change) were reported for pain, dyspnea, and cough from as early as cycle 2, and for fatigue, cycle 5; these positive changes were maintained through subsequent cycles. Global quality of life was also maintained over treatment, with clinically meaningful improvement seen by cycle 7, Dr Kim reported. One of the most commonly reported side effects of treatment with crizotinib is visual events. These are described as image carryover, flashing/trailing lights and floaters, and/or blurry vision, often occurring during light adaptation. A patient-reported questionnaire (Visual Symptom Assessment Questionnaire [VSAQ]) was developed to further characterize these symptoms and their effect on activities of daily living. At the meeting, Ben Solomon, MD, of Peter MacCallum Cancer Centre in Melbourne, Australia, reported a preliminary analysis of VSAQ findings in 57 patients, showing that the visual effects associated with crizotinib had no or only minimal impact on patientsâ&#x20AC;&#x2122; activities of daily living in the ongoing PROFILE 1005 study of the drug. â&#x20AC;&#x153;The majority of patients reported that each visual effects event was transient, lasting either 30 seconds or less or between 30 and 60 seconds,â&#x20AC;? Dr Solomon noted. Approximately 56% of patients at cycle 2 and 50% at cycle 3 and cycle 4 reported visual effects, but these did not require dose alterations, he said. The frequency of visual effects varied during cycles 2 to 4. In cycle 2, most patients reported visual effects on multiple days per week, whereas during cycles 3 and 4 most patients reported visual effects no more than once a week. Most patients experienced these events in the morning or evening, rather than midday. Most patients said they were not bothered by the visual effects events or found them â&#x20AC;&#x153;only a little bothersome,â&#x20AC;? Dr Solomon said. Patients did not have regular difficulty seeing at night or adapting to changes in lighting. No clinically meaningful changes were noted on ophthalmic examinations. â&#x2014;?

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Drug Interactions Drug Interactions With Commonly... Continued from cover drug interactions (DDIs). In addition, oncology patients may be at an increased risk for DDIs due to malabsorption, malnutrition, and other disease states, as well as complex medication regimens.4 Many of the more commonly used oral cancer therapy agents include the newer tyrosine kinase inhibitors (TKIs), including but not limited to dasatinib, erlotinib, imatinib, lapatinib, nilotinib, sorafenib, and sunitinib. Capecitabine is also a commonly used oral chemotherapy agent and is included in this review. Each of these agents exhibits clinically significant DDIs as reported in the literature. The interactions of imatinib, nilotinib, and dasatinib were recently reviewed and published in a number of comprehensive tables.5 It is important to consider the pharmacokinetic and pharmacodynamic properties of the chemotherapeutic or targeted agent and any concomitant medications to explore the potential for DDIs not yet reported in the literature, as many of these medications have been available for only a short time.

formin, although in vivo data are not available.13

Shannon Hough, PharmD

Emily Mackler, PharmD, BCOP

Distribution All of the TKIs included in this review have reported protein binding greater than 90%, mainly to albumin.6 While displacement DDIs with other agents have not been reported, TKIs are potentially implicated in DDIs with other agents with high protein binding, such as phenytoin and warfarin. In a case report of phenytoin toxicity, the protein-binding interaction between phenytoin and erlotinib was reasonably postulated as a potential contributor of the toxicity.14

Methods A systematic search of MEDLINE was performed using the following MeSH terms: drug interactions, cytochrome p450, P-glycoprotein, ABCB1, organic cation transporter 1, protein binding, glucuronidation, UGT, and warfarin, along with the aforementioned drug names. The official drug monographs were also used.6 This review is organized by characterizing drug interactions as either pharmacokinetic or pharmacodynamic.7 Pharmacokinetic interactions include changes in the absorption, distribution, or metabolism of a drug due to another drug. Pharmacodynamic changes include changes to the patientâ&#x20AC;&#x2122;s response to a drug, without pharmacokinetic changes.

decrease absorption more than histamine receptor antagonists. Antacids may be used, but their dosing should be separated from administration of the aforementioned TKIs by several hours. In these cases, the indication for acidlowering medications should be thoughtfully considered. Drug transporters such as ATP-binding cassette proteins (ABCB1) or P-glycoprotein (P-gp) and organic cation transporters (OCT1) also play a role in drug interactions with oral chemotherapeutic and targeted agents. As an efflux transporter on endothelial cells of the brain capillaries, P-gp can modulate drug concentrations within the brain; as a transporter on hepatocytes, and on epithelial cells in the small intestine, P-gp can also modulate systemic and intracellular drug concentrations.9 Dasatinib,5 erlotinib,10 imatinib,5 lapatinib,6 nilotinib,6 and sunitinib11 are substrates of P-gp. Brain and intracellular concentrations of these agents can be increased with P-gp inhibitors such as atorvastatin, diltiazem, fluconazole, hydrocortisone, propranolol, tacrolimus, tamoxifen, and verapamil.6,7 Inducers of P-gp (rifampin, St. Johnâ&#x20AC;&#x2122;s wort) may

decrease concentrations of these agents by increasing efflux.6,7 Lapatinib and nilotinib also inhibit P-gp, increasing drug concentrations of other P-gp substrates. This interaction should be monitored carefully in patients also receiving agents with a narrow therapeutic window, such as digoxin, cyclosporine, and tacrolimus. For example, digoxin and lapatinib coadministration has been reported to increase digoxin levels by 2.8-fold, suggesting the need for close monitoring.6 OCT1 is another drug transporter that has been shown to modulate drug interactions among TKIs in vitro. This influx transporter is predominantly located on the membrane between the portal vein and hepatocytes,9 where drugs are metabolized and enter systemic circulation. Imatinib is a substrate for OCT1, and intracellular concentrations can be decreased by inhibitors such as prazosin.12 Imatinib and erlotinib have also been shown to be inhibitors of OCT1. Metformin influx into hepatocytes, a major site of action, has been shown to be OCT1 dependent, and inhibition of OCT1 by imatinib and erlotinib may decrease efficacy of met-

Metabolism Phase 1 Reactions Phase 1 hepatic metabolism reactions include oxidation, demethylation, and hydrolysis of drugs by hepatic microsomal enzymes, which include the cytochrome (CYP) P450 isoenzymes.7 The CYP isoenzymes are often implicated in DDIs, and oral chemotherapeutic and targeted agents are no exception. Many of these drug interactions require dosage adjustments, and all warrant increased monitoring for adverse effects. Capecitabine is a prodrug, activated and metabolized by tissue enzymes. However, capecitabine is an inhibitor of CYP2C9 and therefore potentially increases concentrations of CYP2C9 substrates. Case reports of phenytoin toxicity with capecitabine use have been published.15 A case report of warfarin and capecitabine coadministration resulting in a supratherapeutic international normalized ratio (INR) has also been published.16 Therefore, patients receiving phenytoin and warfarin with capecitabine should be closely monitored for potential toxicity. Dasatinib is metabolized by CYP3A4. Inducers of CYP3A4 should be avoided

Pharmacokinetic Interactions

Table 1 Drug Interactions With Capecitabine

Absorption A number of mechanisms are involved in the absorption of drugs, including disruption of gastrointestinal (GI) microflora required for absorption, changes in the gut pH, and interactions mediated by drug transporters. Sorafenib absorption is dependent on GI microflora. Oral neomycin has been implicated in alterations of the GI microflora, leading to decreased sorafenib absorption.6 Oral antimicrobials expected to alter the GI microflora should therefore be used with caution. Dasatinib,6 erlotinib,6,8 and nilotinib6 display pH-dependent solubility, and an increase in stomach pH by acid-lowering medications decreases their absorption. For example, proton pump inhibitors have been shown to

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Interacting Agent Leucovorin31

Description of Interaction Enhanced 5-fluorouracil toxicity via intracellular mechanisms

Management of Interaction Monitoring/supportive care for diarrhea, dehydration, other capecitabine toxicities.

Phenytoin15

Inhibition of CYP2C9 metabolism of phenytoin by capecitabine, leading to increased phenytoin levels

Frequent monitoring of phenytoin levels. Dose decreases may be necessary.

Vorinostat32

Increased antitumor effects of capecitabine by downregulation of thymidine synthase and upregulation of thymidine phosphorylase

Monitor efficacy of therapy and toxicity.

Warfarin16

Inhibition of CYP2C9 metabolism of warfarin by capecitabine, leading to increased effects of anticoagulation

Increased INR monitoring. Decrease warfarin dose by 40%. Consider alternate anticoagulation agents.

Other CYP2C9 substrates: See Table 4

Potential for inhibition of metabolism, increased drug effects

Frequent monitoring for adverse effects, increased drug effect.

December 2011 I VOL 4, NO 8

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Drug Interactions Table 2 Drug Interactions With Selected Tyrosine Kinase Inhibitors Tyrosine Kinase Inhibitor Interacting Agent

Description of Interaction

Management of Interaction

Sorafenib6

Neomycin, other antimicrobials

↓ Sorafenib absorption due to loss of GI microflora

Carefully consider use of broad-spectrum antibiotics.

Dasatinib6 Erlotinib6,8 Nilotinib6

Acid-lowering medications: proton pump inhibitors, histamine receptor antagonists, antacids

↓ TKI absorption due to pH-dependent solubility

Consider indication for acid-lowering, avoid if possible. Use antacids, separated by several hours if possible.

Dasatinib5 Erlotinib10 Imatinib5 Lapatinib6 Nilotinib6 Sunitinib11

P-glycoprotein inhibitors

↑ TKIs due to inhibition of efflux pump

Monitor for excess toxicity of TKI agents.

P-glycoprotein inducers

↓ TKIs due to inhibition of efflux pump

Avoid inducer use, which can compromise efficacy of TKI.

Nilotinib6 Lapatinib6

P-glycoprotein substrates

↑ P-gp substrates due to inhibition of efflux pump

Imatinib12 Erlotinib13 Imatinib13

OCT1 inhibitor: prazosin OCT1 substrate: metformin

↓ Intracellular imatinib ↓ Effects of metformin due to ↓ hepatocellular concentrations

Monitor for excess toxicity of substrates. Utilize therapeutic drug levels for monitoring when able. Avoid inhibitor, which can compromise efficacy. Monitor blood glucose for efficacy. Consider increased metformin dose or alternative agents.

Dasatinib6 Lapatinib6 Nilotinib6 Sunitinib6,11

Medications that prolong QTc interval5: quinolones, digoxin, antipsychotics, methadone

Additive QTc prolongation

Increase EKG monitoring.

Dasatinib6 Lapatinib6 Sunitinib6

CYP3A4 inducers

↓ Dasatinib/lapatinib/sunitinib concentrations ↑ Dasatinib/lapatinib/sunitinib concentrations ↑ Substrate concentrations via inhibition of CYP3A4 ↓ Erlotinib concentrations ↑ Erlotinib concentrations

Consider dose increase.

CYP3A4 inhibitors CYP3A4 substrates

Consider dose decrease. Monitor for excess toxicity of substrates. Utilize therapeutic drug levels for monitoring when able.

Erlotinib6

CYP1A2/3A4 inducers CYP1A2/3A4 inhibitors

Imatinib6 Nilotinib6

CYP3A4 inducers CYP3A4 inhibitors CYP3A4/2C9 substrates

↓ Imatinib/nilotinib concentrations ↑ Imatinib/nilotinib concentrations ↑ Substrate concentrations via inhibition of CYP3A4/2C9

Consider dose increase. Consider dose decrease. Monitor for excess toxicity of substrates. Utilize therapeutic drug levels for monitoring when able.

Sorafenib6 Sunitinib6

CYP3A4 inducers

↓ Sorafenib/sunitinib concentrations

Consider dose increase.

Sunitinib6

CYP3A4 inhibitors

↑ Sunitinib concentrations

Consider dose decreases. Increase monitoring.

due to decreased concentrations of dasatinib. When coadministered, rifampin decreased both Cmax and AUC of dasatinib by approximately 80%.6 Inhibitors of CYP3A4 should also be avoided due to increased concentrations of dasatinib.6 Dasatinib also inhibits the metabolism of CYP3A4 and should be used cautiously with other CYP3A4 substrates. Patients should be monitored closely for adverse effects of these agents. Erlotinib is metabolized by CYP1A2 and CYP3A4. Erlotinib concentrations can be decreased by inducers of CYP1A2 or CYP3A4. Decreased erlotinib concentrations have been reported in current cigarette smokers, suggesting higher doses may be required for these patients. A phase 1 study determined that a higher dose of erlotinib (300 mg daily) can be tolerated in smokers for 14 days.17 Erlotinib concentrations can be in creased by inhibitors of CYP1A2 and

December 2011 I VOL 4, NO 8

CYP3A4, such as ciprofloxacin, which may increase erlotinib concentrations more than other agents.6 Interactions with erlotinib are also possible with other CYP3A4 substrates, as both agents can compete for sites on the enzyme for metabolism. For example, simvastatin and phenytoin have been implicated in interactions through this mechanism.14 A case report of rhabdomyolysis with the use of erlotinib and simvastatin was published, implicating the decreased clearance of simvastatin due to competition for metabolism by CYP3A4 as the precipitating factor.18 Imatinib is metabolized by CYP3A4, CYP1A2 (minor), CYP2C9 (minor), and CYP2C19 (minor). Imatinib concentrations can be decreased by inducers of CYP3A4.6 Inhibitors of CYP3A4 should also be used with caution due to increased concentrations of imatinib.6 As previously discussed, imatinib is also

Consider dose increase. Consider dose decrease.

a P-gp substrate. Agents that are dual inhibitors of P-gp and CYP3A4 (verapamil, clarithromycin, erythromycin, cyclosporine, ketoconazole, and fluconazole) may increase both systemic and intracellular concentrations of imatinib. Imatinib also inhibits CYP2C9, and CYP3A4 should be used with caution with other CYP3A4 or CYP2C9 substrates. Patients receiving concomitant warfarin therapy should also be monitored closely for increases in INR, as the metabolic pathway for warfarin includes both CYP2C9 and CYP3A4. Although a report of 8 patients receiving concomitant warfarin and imatinib included no INR deviations or bleeding events, patients should still be monitored closely for the effects of this interaction.19 Lapatinib is metabolized by CYP3A4. Studies in healthy subjects indicate that concentrations of lapatinib are increased 2-fold by the CYP3A4 inhibitor

ketoconazole and decreased more than 50% by the CYP3A4 inducer carbamazepine.20 Lapatinib doses may need to be adjusted for other CYP3A4 inhibitors and inducers. Lapatinib also inhibits CYP3A4 and should be used cautiously with other CYP3A4 substrates.6 Nilotinib is another agent metabolized by CYP3A4. Inhibitors of CYP3A4 may increase nilotinib concentrations, while inducers of CYP3A4 may decrease nilotinib concentrations. Nilotinib inhibits the metabolism of CYP3A4 and CYP2C9. The CYP3A4 inhibition is evidenced by increased midazolam concentrations in the presence of nilotinib. Substrates of CYP2C9 can also be increased due to concomitant nilotinib administration.6 The potential interaction between nilotinib and warfarin should be monitored closely in patients receiving both agents. Much of the data regarding the

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Drug Interactions metabolism of sorafenib is in vitro data. In vitro, sorafenib is metabolized by CYP3A4 and inhibits CYP2C9, CYP2C19, CYP3A4, and CYP2D6.6 However, in vivo, sorafenib concentrations were unchanged in the presence of ketoconazole, a CYP3A4 inhibitor.6 Similar studies found no differences in the concentrations of midazolam, a CYP3A4 substrate; omeprazole, a CYP2C19 substrate; or dextromethorphan, a CYP2D6 substrate.21 A single report implicates the calcium channel blocker felodipine (a CYP3A4 substrate) as the precipitating agent in a patient with sorafenib levels increased 3-fold, suggesting competition for the CYP3A4 enzyme.22 Reports indicating increased effects of warfarin, most likely mediated by CYP2C9 inhibition by sorafenib, have also been published.23,24 While inhibition of CYP2C19, CYP3A4, and CYP2D6 has been reported in vitro, it may not be seen clinically. However, concomitant CYP3A4 inhibitors/inducers and substrates of CYP2C19, CYP3A4, and CYP2D6 with a narrow therapeutic window should be used with caution with sorafenib, as individual variability may play a role. Finally, sunitinib and an active metabolite SU12662 are also metabolized by CYP3A4, but these agents do not induce or inhibit the metabolism of any other CYP enzymes. In the presence of the CYP3A4 inhibitor ketoconazole, sunitinib AUC was increased by 50%.6 SU12662 concentrations were also increased in the presence of ifosfamide, another CYP3A4 inhibitor.25 When using sunitinib with other CYP3A4 inhibitors, including grapefruit juice,26 dose reductions should be considered. In the presence of rifampin, sunitinib concentrations were decreased.6 St. John’s wort should not be used with sunitinib, and when used with other CYP3A4 inducers, dose increases of sunitinib should be considered. Phase 2 Reactions The second phase of hepatic metabolism includes glucuronidation and sulfation reactions to form inactive water-soluble metabolites for elimination. Glucuronidation occurs through UDP-glucuronosyltransferase (UGT) enzymes, and interactions are well described in vitro.27,28 The clinical implications of these interactions are currently not known. Sorafenib metabolism by UGT1A9 is inhibited by valproic acid and is competitive with other substrates such as propofol and acetaminophen.6,29 Sorafenib also inhibits UGT1A9 and UGT1A1, increasing propofol and irinotecan concentrations, respectively.6 Nilotinib and imatinib also inhibit UGT1A1 metabolism, increasing concentrations of UGT1A1 substrates such as carvedilol, levothyroxine, acetaminophen, and raloxifene.6,28,30

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Table 3 Drug Interactions With Warfarin and Commonly Used Oral Chemotherapeutic and Targeted Agents Interacting Agent Capecitabine16,33

Description of Interaction Inhibition of CYP2C9 decreases warfarin metabolism and increases INR Increased INR via multiple proposed mechanisms6,34: 1. Protein displacement 2. Minor metabolism by CYP3A4 3. Decreased intestinal absorption of vitamin K 4. Decreased intestinal colonization of vitamin K–producing bacteria

Management of Interaction Increase INR monitoring. Decrease warfarin dose by 40%. Increase INR monitoring, especially in the presence of severe diarrhea.

Imatinib6,19

Inhibition of CYP2C9 and CYP3A4, leading to decreased warfarin metabolism and increased INR

Increase INR monitoring. No empiric dose changes. Consider low-molecular-weight or standard heparin instead of warfarin.

Sorafenib6,23,24

Increased INR via multiple proposed mechanisms23,24: 1. Decreased warfarin metabolism via competitive inhibition of CYP3A4, CYP2C9 2. Increased unbound warfarin due to protein-binding displacement Additive risk of bleeding

Increase INR monitoring. Dose decreases may be necessary. Increase monitoring for bleeding.

Sunitinib6

Additive risk of bleeding

Increase monitoring for bleeding.

Erlotinib6,34

Table 4 Inducers, Inhibitors, and Substrates of P-gp and Selected CYP Enzymes Enzyme or Transporter Inducers Inhibitors

Substrates

P-glycoprotein

Carbamazepine Rifampin St. John’s wort Yohimbine

Atorvastatin Diltiazem Fluconazole Hydrocortisone Propranolol Tacrolimus Tamoxifen Verapamil

Amiodarone Cyclosporine Dexamethasone Digoxin Loperamide Ondansetron Sirolimus Tacrolimus

CYP1A2

Cigarette smoke Omeprazole Phenobarbital Rifampin

Ciprofloxacin Erythromycin Olanzapine Propranolol Ritonavir

Clozapine Melatonin Propranolol Verapamil Zolpidem

CYP2C9

Carbamazepine Ethanol Phenytoin Rifampin

Amiodarone Cimetidine Fluconazole Metronidazole Sulfamethoxazole Trimethoprim

Amitriptyline Carvedilol Mirtazapine Phenytoin Sertraline Warfarin

CYP2C19

Rifampin

Fluoxetine Ketoconazole Modafinil Omeprazole

CYP3A4

Carbamazepine Dexamethasone Phenytoin Rifampin St. John’s wort

Anastrozole Clarithromycin Diltiazem Ketoconazole Sertraline Voriconazole

Carisoprodol Citalopram Diazepam Imipramine Alprazolam Amitriptyline Cyclosporine Diltiazem Granisetron Simvastatin

Adapted from Hartshorn EA, Tatro DS. Principles of drug interactions. In: Tatro DS, ed. Drug Interaction Facts 2008: The Authority on Drug Interactions. St Louis, MO: Wolters Kluwer Health, Inc; 2008. Copyright 2008 by Lippincott Williams & Wilkins.

Pharmacodynamic Interactions

Prolongation of QTc Interval A number of medications are known to prolong the QTc interval, including some of the TKIs. Prolongation of the QTc interval can place patients at risk

for arrhythmias, including torsades de pointes and sudden cardiac death. Utilization of multiple medications with the propensity to cause QTc prolongation can increase the risk for these cardiac complications. Dasatinib, nilotinib,

lapatinib, and sunitinib all prolong the QTc interval.6 Other commonly used medications that prolong the QTc interval include digoxin, quinolone antibiotics, methadone, and antipsychotics. Use of these agents with the aforemen-

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Drug Interactions tioned TKIs should be done with additional EKG monitoring.

therapy and other medications or additive side effects with other agents. â&#x2014;?

Conclusion Oral chemotherapy agents offer the convenience of dosing from home and can improve patient quality of life. It is important to consider the potential for DDIs for patients who receive these medications to avoid increased toxicity from TKI

References

1. Oâ&#x20AC;&#x2122;Neill VJ, Twelves CJ. Oral cancer treatment: developments in chemotherapy and beyond. Br J Cancer. 2002;87:933-937. 2. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol. 1997;15:110-115. 3. Aisner J. Overview of the changing paradigm in cancer treatment: oral chemotherapy. Am J Health Syst Pharm. 2007;64(suppl 5):S4-S7.

4. Riechelmann RP, Saad ED. A systematic review on drug interactions in oncology. Cancer Invest. 2006; 24:704-712. 5. Haouala A, Widmer N, Duchosal MA, et al. Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib. Blood. 2011;117:e75-e87. 6. US National Library of Medicine. DailyMed. http://dailymed.nlm.nih.gov. Accessed October 13, 2011. 7. Hartshorn EA, Tatro DS. Principles of drug interactions. In: Tatro DS, ed. Drug Interaction Facts 2008: The Authority on Drug Interactions. St Louis, MO: Wolters Kluwer Health, Inc; 2008. 8. Duong S, Leung M. Should the concomitant use of erlotinib and acid-reducing agents be avoided? The drug

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IN SUPPORTIVE CARE NEUTROPENIA

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TARGET AUDIENCE The educational series is intended for nurses, pharmacists, and others with clinical, research, and management interests of neutropenia management

EDUCATIONAL OBJECTIVES On completion of this activity, participants should be able to: â&#x20AC;˘ Outline the risk factors for neutropenia in patients with cancer undergoing chemotherapy â&#x20AC;˘ Review advances in the prevention and management of neutropenia, including updated evidence-based guidelines â&#x20AC;˘ Examine approaches for improving patient outcomes by identifying patients at risk and preventing or reducing the incidence of neutropenia

ACCREDITATION STATEMENTS Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. This knowledge-based activity has been assigned ACPE # 02450000-11-017-H01-P and will award 1.0 contact hour (0.10 CEUs) of continuing pharmacy education credit. CEC complies with the Criteria for Quality for continuing education programming. NURSING Creative Educational Concepts, Inc. (CEC) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Centerâ&#x20AC;&#x2122;s Commission on Accreditation.

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Kathleen Colson, RN, BSN, BS Clinical Research Nurse Multiple Myeloma Dana Farber Cancer Institute Boston, MA

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December 2011 I VOL 4, NO 8

interaction between erlotinib and acid-reducing agents. J Oncol Pharm Pract. Published online August 17, 2010. doi:10.1177/1078155210381794. 9. Eechoute K, Sparreboom A, Burger H, et al. Drug transporters and imatinib treatment: implications for clinical practice. Clin Cancer Res. 2011;17:406-415. 10. de Vries NA, Buckle T, Zhao J, et al. Restricted brain penetration of tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Invest New Drugs. Published online October 21, 2010. doi:10.1007/s10637010-9569-1. 11. Tang SC, Lagas JC, Lankheet NA, et al. Brain accumulation of sunitinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by oral elacridar and sunitinab coadministration. Int J Cancer. 2012;130:223-233. 12. Engler JR, Frede A, Saunders VA, et al. Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity. Leukemia. 2010;24:765-770. 13. Minematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. Mol Cancer Ther. 2011;10:531-539. 14. Grenader T, Gipps M, Shavit L, et al. Significant drug interaction: phenytoin toxicity due to erlotinib. Lung Cancer. 2007;57:404-406. 15. Brickell K, Porter D, Thompson P. Phenytoin toxicity due to fluoropyrimidines (5FU/capecitabine): three case reports. Br J Cancer. 2003;89:615-616. 16. Janney LM, Waterbury NV. Capecitabine-warfarin interaction. Ann Pharmacother. 2005;39:1546-1551. 17. Hughes AN, Oâ&#x20AC;&#x2122;Brien ME, Petty WJ, et al. Overcoming CYP1A1/1A2 mediated induction of metabolism by escalating erlotinib dose in current smokers. J Clin Oncol. 2009;27:1220-1226. 18. Veeraputhiran M, Sundermeyer M. Rhabdomyolysis resulting from pharmacologic interaction between erlotinib and simvastatin. Clin Lung Cancer. 2008; 9:232-234. 19. Breccia M, Santopietro M, Loglisci G, et al. Concomitant use of imatinib and warfarin in chronic phase chronic myeloid leukemia does not interfere with drug efficacy [letter]. Leuk Res. 2010;34:e224-e225. 20. Smith DA, Koch KM, Arya N. Effects of ketoconazole and carbamazepine on lapatinib pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2009;67:421-426. 21. Flaherty KT, Lathia C, Frye RF, et al. Interaction of sorafenib and cytochrome P450 isoenzymes in advanced melanoma: a phase I/II pharmacokinetic interaction study. Cancer Chemother Pharmacol. Published online February 25, 2011. doi:10.1007/s00280-011-1585-0. 22. Gomo C, Coriat R, Faivre L, et al. Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma. Invest New Drugs. 2011;29:1511-1514. 23. Moretti LV, Montalvo RO. Elevated International Normalized Ratio associated with concurrent use of sorafenib and warfarin. Am J Health Syst Pharm. 2009;66:2123-2125. 24. Laber DA, Mushtaq M. Compassionate use of sorafenib in patients with advanced renal cell cancer. Clin Genitour Cancer. 2009;7:34-38. 25. Hamberg P, Steeghs N, Loos WJ. Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies. Br J Cancer. 2010;102:1699-1706. 26. van Erp NP, Baker SD, Zandvliet AS, et al. Marginal increase of sunitinib exposure by grapefruit juice. Cancer Chemother Pharmacol. 2011;67:695-703. 27. Liu Y, RamĂrez J, House L, et al. Comparison of the drug-drug interactions potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. Drug Metab Dispos. 2010;38:32-39. 28. Williams JA, Hyland R, Jones BC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004;32:1201-1208. 29. Ethell BT, Anderson GD, Burchell B. The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases. Biochem Pharmacol. 2003;65:1441-1449. 30. Liu Y, RamĂrez J, Ratain MJ. Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. Br J Clin Pharmacol. 2011;71:917-920. 31. Morgan RG. Leucovorin enhancement of the effects of the fluoropyrimidines on thymidylate synthase. Cancer. 1989;63(6 suppl):1008-1012. 32. Di Gennaro E, Piro G, Chianese MI, et al. Vorinostat synergises with capecitabine through upregulation of thymidine phosphorylase. Br J Cancer. 2010;103:1680-1691. 33. Shah SR, Martin R, Dowell JE, et al. Comparison of the 5-fluorouracil-warfarin and capecitabine-warfarin drug interactions. Pharmacotherapy. 2010;30:1259-1265. 34. Thomas KS, Billingsley A, Amarshi N, et al. Elevated international normalized ratio associated with concomitant warfarin and erlotinib. Am J Health Syst Pharm. 2010;67:1426-1429.

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Side Effect Management

Management of Radiation-Induced Skin Reactions Up to Individual Practices By Alice Goodman

lthough cancer patients who undergo radiation therapy frequently have acute and chronic skin reactions, there are no hard and fast guidelines on management of radiationinduced skin reactions or the best products to use. Each center or practice should develop its own clinical guide about how patients should manage skin reactions and which products are recommended for patient use, said Maureen McQuestion, RN, Princess Margaret Hospital, Toronto, Ontario, Canada. She spoke at a symposium called “New Perspectives in Oncology Practice” held in conjunction with The Chemotherapy Foundation Symposium. “Your practice should be consistent regarding recommendations for products, so that the oncologist, nurses, and nurse practitioner are all telling patients the same thing,” she said. Pharmacists should also be included in the discussion about product recommendations. Radiation techniques have evolved over the past few decades, and now most patients receive targeted therapy with conformal radiation delivered to the

The goal of management of radiation-induced skin reaction is healing, and the principles are similar to general ones for wound healing.

tumor cells, sparing more healthy tissue than in the past. Nevertheless, skin reactions do occur, and some are quite severe and painful. “Acute reactions are worse at the end of radiation, but they will improve 2 to 3 weeks later,” said McQuestion. Acute reactions can include mild erythema, dry desquamation, moist desquamation, alopecia, pruritus, altered pigmentation, and fibrosis. She said that reactions can be mixed, with both wet and moist desquamation in the radiated area. Patient factors that affect skin reaction include older age, nutritional status, comorbidities, hygiene, and chronic sun exposure. Treatment-related factors

include the area radiated and the total dose and fraction size. Hyperfractionated treatment twice a day increases the chances of more severe skin reactions. Patients can experience pain, difficulty ambulating and sitting, discomfort wearing clothes, impaired body image, increased urination and bowel movements, loss of independence with decreased ability for self-care, and they have to bear the cost of the products to treat the skin reactions. “Dressings and creams are typically not covered by drug plans,” Ms McQuestion told the audience. The goal of management of radiationinduced skin reaction is healing, and the

principles are similar to general ones for wound healing. Promoting moisture is important, “but some patients think they should dry the affected area,” she noted. Patients should be instructed to gently wash the affected area with a mild soap such as Dove and not to rub or abrade the skin. They should not use cornstarch or talc, but they can use deodorants that do not contain aluminum. Although a multitude of creams and lotions can be purchased over the counter, McQuestion said that at her center they have found that hyaluronic acid cream and calendula cream can be helpful. Cavilon No Sting Barrier Film prevents moisture loss. Antimicrobials are not needed if the patient is practicing good hygiene. “Corticosteroids are not recommended unless the patient has pruritus or documented folliculitis,” she stated. Other recommendations for patients include avoiding swimming in chlorinated water or hot tubs and keeping the skin area well moisturized, especially if the patient has moist desquamation. ●

Breast Cancer

CLEOPATRA Affirms Principle of Dual HER2 Blockade in HER2-Positive Metastatic Breast Cancer By Alice Goodman

ual HER2 blockade with trastuzumab plus pertuzumab combined with docetaxel chemotherapy significantly extended progression-free survival (PFS) by about 6 months compared to trastuzumab plus docetaxel plus placebo in patients with metastatic HER2-positive breast cancer, according to results from the CLEOPATRA trial presented at the CTRCAACR San Antonio Breast Cancer Symposium. “These findings represent a significant advance in the treatment of advanced breast cancer. The results may be practice changing,” said senior author Jose Baselga, MD, PhD, Professor at Harvard Medical School and Associate Director of Massachusetts General Hospital in Boston. These results affirm the concept of dual HER2 blockade in HER2-positive

December 2011 I VOL 4, NO 8

metastatic breast cancer. Pertuzumab and trastuzumab have distinct mechanisms of action and bind at different sites. “The 2 antibodies are extremely complementary and synergistic in preliminary studies,” he said.

These results affirm the concept of dual HER2 blockade in HER2positive metastatic breast cancer.

CLEOPATRA was a randomized registration phase 3 study for pertuzumab. The study randomized 808 patients in a 1:1 ratio to trastuzumab/docetaxel

chemotherapy with pertuzumab or placebo. Docetaxel was given every 3 weeks for 6 cycles in both arms, and investigators could decide whether to continue it on an individual basis. Both monoclonal antibodies were given every 3 weeks until evidence of disease progression. Patients had no prior therapy for metastatic disease, except 1 line of prior hormone therapy was allowed. Prior chemotherapy was allowed if 1 year had passed. More than three-quarters of patients had visceral metastases; the remainder had metastases confined to the bone. By independent review, median PFS was 12.4 months in the control arm versus 18.5 months in the experimental arm, which was highly statistically significant (P <.0001). All prespecified subgroups benefitted from dual HER2 blockade, with the

exception of patients with nonvisceral metastasis. A strong trend toward improved overall survival was observed for the experimental arm, but this was an interim analysis, and the data need to be more mature for meaningful survival results, Baselga said. Treatment was safe and tolerable, with no cardiac toxicity observed. Only minimal side effects were seen with the addition of pertuzumab, including grades 1 and 2 diarrhea and neutropenia. “This represents an advance in treatment of HER2-positive breast cancer,” said Lisa Carey, MD, University of North Carolina at Chapel Hill, North Carolina, who moderated the press conference where CLEOPATRA was discussed. “The challenge now is to find biomarkers to identify which patients will derive benefit from dual HER2 blockade,” she said. ●

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Pharmacoeconomics

Thromboembolism After Chemotherapy Raises Healthcare Costs About 30% By Caroline Helwick

he development of venous thromboembolism (VTE) in patients with cancer has a significant impact in terms of morbidity and mortality and healthcare costs, according to a “real-world analysis” reported at the 2011 European Multidisciplinary Cancer Congress. Gary H. Lyman, MD, MPH, an oncologist at Duke University School of Medicine, Durham, North Carolina, was principal investigator. Dr Lyman is a frequent contributor in the area of health economics and comparative effectiveness research. “VTE development was associated with a significant economic burden in terms of healthcare expenditure,” he noted. Dr Lyman and colleagues assessed the economic impact of VTE occurrence using the US-based InVision Data Mart Multiplan/Integrated Health Care Information Solutions database. They retrospectively identified 30,552 patients with cancer who initiated chemotherapy in the 4-year period ending in 2008. Healthcare costs such as inpatient, pharmacy, emergency department, and outpatient expenses were assessed 1 year preindex and postindex treatment (first day of chemotherapy after cancer diagnosis). The incidence of VTE 3.5 months after the initiation of chemotherapy ranged from 4.8% to 11.9%, depending on tumor site. The highest risk was observed in patients with pancreatic, stomach, and lung cancers. The incidence continued to increase over time postindex treatment, peaking at 9.9% to 21.5% at 12 months, Dr Lyman reported.

High Healthcare Costs Patients who developed VTE within 3.5 months postindex treatment had healthcare costs at baseline that were comparable with persons not developing VTE. During the first year postindex, costs in patients with VTE were significantly higher than in those without VTE, primarily driven by higher inpatient and outpatient costs. The overall healthcare costs 1 year before receiving chemotherapy were $37,542 for patients developing VTE and $35,342 for those without VTE. By 1 year postindex treatment, costs had risen to $110,362 and $77,984, respectively, Dr Lyman reported. Costs were higher for patients with VTE in each category of expenditure: inpatient, outpatient, emergency department, and pharmacy. “Similar results were seen for pa -

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tients who developed VTE within 12 months postindex,” he said. “The decision for the use of thromboprophylaxis in cancer patients

undergoing chemotherapy should be based on the balance between the potential benefits and harms, including any bleeding risk associated with a

therapy,” Dr Lyman pointed out. There is a need to assess cost-effectiveness of prevention in this setting, he added. ●

April 20-22, 2012 • Le Westin Montreal Montreal, QC, Canada CO-CHAIRS

PROGRAM OVERVIEW The goals of this interactive, CME/CE-certified meeting are to update participants on advances in the field of cutaneous malignancies, including biology, pathology, staging, personalized therapy, novel agents, and ongoing research. In addition to didactic lectures, this program will also include debates and discussions of controversial topics, extensive panel discussions with case scenarios, multidisciplinary tumor boards, question-and-answer sessions, poster sessions, as well as workshops focusing on future strategies for the treatment of cutaneous T-cell lymphoma (CTCL), basal cell carcinoma (BCC), and melanoma. This is the inaugural meeting of what is envisioned as an annual global forum to facilitate integration of contemporary and evolving standards of care for the optimal management of patients with cutaneous malignancies into clinical practice for oncologists and dermatologists.

Kim A. Margolin, MD

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatment of CTCL, BCC, or malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

Professor, Department of Medical Oncology University of Washington School of Medicine Seattle Cancer Care Alliance Seattle, Washington

TARGET AUDIENCE This global educational program is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to attend.

Teresa Petrella, BSc, MD, MSc, FRCPC Medical Oncologist Chair, National Cancer Institute of Canada Melanoma Group Chair, Melanoma Site Group Odette Cancer Centre Assistant Professor, University of Toronto Toronto, Ontario, Canada

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12.5 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity. REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.5 contact hours.

Early registration of $425 ends January 13, 2012!

REGISTERED PHARMACY DESIGNATION Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.5 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-089-L01-P.

December 2011 I VOL 4, NO 8

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Answered!

Your FAQs... Q:

What are the different types of amyloidosis and what treatment options are available?

out multiple myeloma.1 Congo red staining performed on the biopsy will be The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progrespositive for amyloid in <60% of patients.1 Congo red staining of tissue from an 1 involved organ or surrogate site (fat pad, gingiva, or rectum) may also lead to sive organ damage. The incidence of immunoglobulin light chain (AL) amyloidosis (also referred to as primary amyloidosis) diagnosis.3 Deciphering the type of amyloidosis is essential in establishing the 1 appropriate intervention and treatment.3 is approximately one-tenth that of multiple myeloma, a more common cancer of the bone marrow plasma Treatment cells. In approximately 10% of patients, both AL amyloidosis Treatment for AL amyloidosis is highly individualized and is and multiple myeloma are present at the time of diagnosis.2 The process of amyloid formation results in cellular based on age, organ dysfunction, and regimen toxicities.1 The prognosis for The goals of therapy are prompt elimination of the misfoldinjury, tissue damage, and organ dysfunction through patients with ed amyloidogenic light chains, minimization of treatment mechanisms that are not completely understood.1 Patients with amyloidosis usually present with a small plasma cell toxicity, and support of the function of target organs.1 For amyloidosis many years, melphalan plus prednisone was considered the clone with evidence of dysfunction in 1 or more involved varies standard therapy for patients with AL amyloidosis who are organs.1 Most commonly, this includes renal involvement in approximately 70% of amyloidosis patients, with not candidates for autologous stem cell transplantation.2 considerably More recently, dexamethasone has been substituted for nephrotic range proteinuria or renal failure; cardiomyopadepending on the prednisone in association with melphalan, resulting in thy in approximately 60%; and peripheral neuropathy in nature, number, much higher hematologic responses.1 A reduction in proapproximately 20%.1 Among newly diagnosed patients, 3 30% have 3 or more major organ systems involved. teinuria has been noted in up to 50% of patients treated and extent of The prognosis for patients with amyloidosis varies conwith these regimens, though they are not without risk.2 organ involvement. Melphalan-induced cytogenetic abnormalities can lead to siderably depending on the nature, number, and extent of pancytopenia and/or secondary myelodysplastic syndromes, organ involvement.2 Median survival may be as short as 4 Median survival to 6 months, with cardiac failure, hepatic failure, and/or with an incidence of these complications of up to 6.5%.2 may be as short as 2 However, the actual risk may exceed 20% in those who infection being the major causes of death. However, those 4 to 6 months. patients with limited organ involvement can expect a appear to have a good amyloid response and survive for median survival in excess of 5 years.2 more than 3.5 years.2 Thalidomide as a single agent has limited efficacy and is Types of Amyloid Diseases poorly tolerated, with fatigue and sedation being the major To date, at least 28 different proteins have been identified as causative agents dose-limiting toxicities, followed by fluid retention, constipation, orthostasis, of amyloid diseases.4 AL amyloidosis is the most common form of amyloid peripheral neuropathy, and worsening renal function.1 Somewhat better results disease and is due to deposition of protein derived from immunoglobulin have been obtained when thalidomide was combined with dexamethasone.2 4 Thalidomide/dexamethasone can be considered an option alone or in combilight chain fragments. It is considered a plasma cell dyscrasia in which a monoclonal protein is detectable in the serum or urine in approximately 80% nation with cyclophosphamide for the treatment of patients who relapse after of cases.4 AA (or secondary) amyloidosis is characterized by extracellular tismelphalan/dexamethasone or stem cell transplantation.2 Lenalidomide in combination with dexamethasone may also be reasonable sue deposition of fibrils composed of fragments of serum amyloid A (SAA) for patients who relapse after melphalan/dexamethasone or stem cell transprotein, an acute-phase reactant. AA amyloidosis is related to a chronic disease in which there is ongoing or recurring inflammation, such as rheumatoid arthritis or inflammatory bowel disease.4 Dialysis-related amyloidosis is due to deposition of fibrils derived from beta-2 microglobulin, which accumulates in patients with end-stage renal disease on long-term dialysis therapy.4 Amyloid deposition may also be isolated to a single organ, such as the skin, eye, heart, etc, and has been shown to be biochemically identical to systemic forms of amyloid.4

This Monthâ&#x20AC;&#x2122;s FAQ

Answered by:

Carli Greenfield, ACNP

Diagnosis Early diagnosis is the key to effective therapy, allowing reversal of the organ damage and better tolerability of adverse effects of therapy.1 Approximately 40% of patients have light chainâ&#x20AC;&#x201C;only disease, and therefore diagnosis is often missed if only serum protein electrophoresis is performed.1 However, the combination of serum and urine immunofixation electrophoresis with serum free light chain assay approaches 100% sensitivity for diagnosis.1 If a serum monoclonal protein is present, a bone marrow biopsy should be performed to rule

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Answered!

Your FAQs... plantation.2 The most common adverse effects of this combination are cytopenia, fatigue, and rash.1 Hematologic responses have ranged from 41% to 47%.1 In addition, bortezomib has significant activity in AL amyloidosis, with the most common nonhematologic toxicities including peripheral sensory neuropathy with or without neuropathic pain, exacerbation of orthostatic hypotension, peripheral edema, and constipation or diarrhea.2 A phase 3 study comparing bortezomib/melphalan/dexa methasone with melphalan/dexamethasone is currently in progress.2

The Amyloidosis Clinical Trials Network should also be explored for those patients considering clinical trial participation, as novel agents and regimens are showing great promise in the treatment of amyloidosis.

A significant advance in myeloma chemotherapy has been the addition of stem cell transplantation, and this approach has since been adapted for patients with AL amyloidosis.1 The fragility of the amyloidosis patient population was soon evident, however, when some transplant centers reported treatment-related mortality exceeding 40% or more in those with cardiac involvement.1 In an attempt to reduce treatment-related toxicity, attenuated melphalan dosing has been used in high-risk and older patients, resulting in reduced toxicity but generally lower response rates.1 Both cardiac and renal transplantation have been successfully carried out in AL amyloidosis patients with associated organ involvement.1 The Amyloidosis Clinical Trials Network should also be explored for those patients considering clinical trial participation, as novel agents and regimens are showing great promise in the treatment of amyloidosis. â&#x2014;?

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References 1. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2011;29:1924-1933. 2. Rajkumar SV. Prognosis and treatment of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases. UpToDate

19.2. http://www.uptodate.com/contents/prognosis-andtreatment-of-immunoglobulin-light-chain-al-amyloido sis-and-light-and-heavy-chain-deposition-diseases. Updated June 3, 2011. Accessed November 7, 2011. 3. Comenzo RL. How I treat amyloidosis. Blood. 2009;114:3147-3157.

4. Gorevic PD. An overview of amyloidosis. UpToDate 19.2. http://www.uptodate.com/contents/ an-overview-ofamyloidosis?source=search_result &search=An+overview+of+amyloidosis.&selectedTitl e=1~150. Updated November 2, 2010. Accessed November 7, 2011.

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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

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