December 2011, Vol 4, No 8

©2011 Green Hill Healthcare Communications, LLC

DECEMBER 2011 www.TheOncologyPharmacist.com VOL 4, NO 8

One of the outpatient pharmacies at the Cleveland Clinic. The Cleveland Clinic operates 9 outpatient pharmacies in addition to the specialized inpatient pharmacies.

The Cleveland Clinic TaussigCancer InstituteFor Oncology Pharmacists, Patient Education Is Key

The Cleveland Clinic was founded in 1921 in Cleveland, Ohio, by 4physicians. At that time, it was one of only a few group practicesin the United States. This group practice model was very familiar

to 3 of the founders—George Crile Sr, Frank Bunts, William Lower—asthey served together in military hospitals near the front lines of WorldWar I. These 3 colleagues were determined to establish a not-for-profitclinic that combined the best of military and civilian medical practices.Joined by a fourth physician—John Phillips—they set about building a

CANCER CENTER PROFILE

Continued on page 18

Complimentary Ce . . . . . . . . . . . 22Metastatic Breast Cancer: Advancesin Treatment and Management

lung CanCer . . . . . . . . . . . . . . . . . . 30Positive Data Continue to Accrue forCrizotinib in ALK-Positive NSCLC

Side effeCt management . 36Management of Radiation-InducedSkin Reactions Up to IndividualPractices

pharmaCoeConomiCS . . . . . . . 37Thromboembolism AfterChemotherapy Raises HealthcareCosts About 30%

I N S I D E

Ahigher dose of radiation (74Gy) does not improve overallsurvival for non–small cell lung

cancer (NSCLC) that has spread to thelymph nodes compared with the stan-dard radiation dose (60 Gy), according to a new study presented at the 53rdAnnual Meeting of the AmericanSociety for Radiation Oncology.“Most radiation oncologists and lung

cancer specialists are surprised by thisfinding. Although the optimal radiationdose for lung cancer patients has notbeen tested in a randomized phase 3trial for over 30 years, most believedthat higher doses of radiation curedmore patients with lung cancer,” said study investigator Jeffrey Bradley,MD, radiation oncologist at the Wash -

CONFERENCE NEWS: ASTRO

Higher Radiation Doses May Not HelpLung Cancer Patients Live LongerBy John Schieszer

Many malignancies currentlyhave oral medication optionsfor cancer therapy. The use of

oral therapy can avoid complex intra-venous (IV) regimens that negativelyaffect patient quality of life.1 Accordingto the literature, cancer patients favororal medications over IV chemotherapy.2

Many of the newly approved anticanceragents are administered orally, suggestinga paradigm shift from IV administration.3While oral medications for cancer thera-py offer improved quality of life and con-venient and flexible administration forpatients, many agents have the potentialfor overlapping drug toxicities and drug-

Drug Interactions With CommonlyPrescribed Oral Chemotherapeuticand Targeted AgentsBy Shannon Hough, PharmD; Emily Mackler, PharmD, BCOPUniversity of Michigan Pharmacy Services and College of Pharmacy, Ann Arbor




BREAST CANCER

Emerging Therapies in theTreatment of Breast CancerBy Caroline Helwick

Promising data on several new breastcancer agents, including one newcytotoxic, were presented at the

American Society of Clinical OncologyBreast Cancer Symposium 2011 heldSeptember 8-10 in San Francisco,California. The addition of the novel histone

deacetylase (HDAC) inhibitor entinostatto exemestane significantly delayed recur-rences and showed a trend for a survivalbenefit in the phase 2 ENCORE 301(ENtinostat Combinations Overcoming

REsistance) study reported by DeniseYardley, MD, of Sarah Cannon ResearchInstitute and Tennessee Oncology inNashville.The regimen is based on the concept

that HDAC inhibitors can restore estro-gen receptor (ER) sensitivity in thetumor, allowing patients to respond againto an endocrine agent. “This combina-tion may allow patients to remain on hor-monal therapy longer, delaying the needfor chemotherapy,” she suggested.ENCORE 301 randomized 114 post-

Types of Amyloidosis and AvailableTreatment Options

Page 38

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TOP_December 2011_v5_TOP 12/19/11 10:41 AM Page 1

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EDITOR-IN-CHIEFPatrick Medina,PharmD, BCOPOklahoma UniversityCollege of PharmacyTulsa, OK

ASSOCIATEEDITOR-IN-CHIEFSteve Stricker,PharmD, MS,BCOPSamford UniversityMcWhorter School ofPharmacyBirmingham, AL

John F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

David Baribeault,RPh, BCOPBoston Medical CenterBoston, MA

Betty M. Chan,PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Steven L.D’Amato, RPh,BCOPMaine Center for CancerMedicineScarborough, ME

Anjana Elefante,PharmD, BSc,BSc Pharm, RPhRoswell Park CancerInstituteBuffalo, NY

Beth Faiman, RN,MSN, APRN,BC, AOCN Cleveland Clinic TaussigCancer InstituteCleveland, OH

ChristopherFausel, PharmDIndiana University Simon Cancer CenterIndianapolis, IN

Rebecca S. Finley,PharmD, MSJefferson School ofPharmacyPhiladelphia, PA

David C. Gammon, BSPhOncologyPharmacist.net Warwick, RI

Lew Iacovelli, BS,PharmD, BCOP,CPP Moses H. Cone HealthSystemGreensboro, NC

Dwight Kloth,PharmD, FCCP,BCOPFox Chase CancerCenterPhiladelphia, PA

Jim Koeller, MSUniversity of Texas atAustinSan Antonio, TX

Christopher J.Lowe, PharmDIndiana UniversityHospitalIndianapolis, IN

Emily Mackler,PharmD, BCOPUniversity of MichiganHealth System & Collegeof PharmacyAnn Arbor, MI

Laura BoehnkeMichaud, PharmD,BCOP, FASHPThe University of TexasM. D. Anderson CancerCenterHouston, TX

LeAnn BestNorris, PharmD,BCPS, BCOPSouth Carolina Collegeof PharmacyColumbia, SC

Timothy G. Tyler,PharmD, FCSHPDesert Regional MedicalCenterPalm Springs, CA

John M. Valgus,PharmD, BCOPUniversity of NorthCarolina Hospitals andClinicsChapel Hill, NC

Gary C. Yee,PharmD, FCCP,BCOPUniversity of NebraskaCollege of PharmacyOmaha, NE

Burt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Marlo Blazer, RPh, PharmDJames Cancer Hospital & Solove ResearchInstituteColumbus, OH

Heidi D. Gunderson, PharmD,BCOPMayo Clinic Cancer CenterRochester, MN

Kamakshi V. Rao, PharmD,BCOPUniversity of North Carolina Hospitals and ClinicsChapel Hill, NC

Editorial Board

4 December 2011 I VOL 4, NO 8 www.TheOncologyPharmacist.com


BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

Docetaxel Injection For intravenous infusion only. 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


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

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

INDICATIONS AND USAGEGemcitabine 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)


• Infusion time and dose frequency: Increased toxicity with infusion time >60 minutes or dosing more frequently than once weekly. (5.1)

• Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7)

• Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3)

• Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4)

• Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5)

• Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)

• Radiation toxicity. May cause severe and life-threatening toxicity. (5.8)

ADVERSE REACTIONS

The most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at [email protected], or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 07/2011


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

Topotecan Injection Must be diluted before intravenous infusionInitial U.S. Approval: 1996

WARNING: BONE MARROW SUPPRESSIONSee 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)


• 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.

Manufactured by:Hospira Australia Pty LtdMulgrave VIC 3170 Australia

Manufactured for:Hospira, Inc.Lake Forest, IL 60045 USAProduct of Australia

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

Made in India

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 USAGUJ DRUGS/G/28/1267


© 2011 Genentech USA, Inc. All rights reserved. ACS0000716800 Printed in USA.

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN1944-9593 (online) is published 8 times a year by GreenHill Healthcare Communications, LLC, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. Telephone:732.656.7935. Fax: 732.656.7938. Copyright ©2011 byGreen Hill Healthcare Communications LLC. All rightsreserved. The Oncology Pharmacist® logo is a registeredtrademark of Green Hill Healthcare Com munications,LLC. No part of this publication may be reproduced ortransmitted in any form or by any means now or hereafterknown, electronic or mechanical, including photocopy,recording, or any informational storage and retrieval sys-tem, without written permission from the Publisher.Printed in the United States of America.

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As 2011 comes to an end, I have great news for read-ers of The Oncology Pharmacist (TOP). SteveStricker, PharmD, MS, BCOP, a member of our edi-

torial board, has agreed to join me as associate editor-in-chief. Steve will bring great energy to his new role here atTOP and will help us address the issues that affect us asoncology pharmacists, including the drug shortage situa-tion and how to deal with it at the clinical level, theexpanding use of oral oncolytics, and the increasing roleof personalized medicine in oncology and the implicationsfor 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 youinformation you can use in your day-to-day pharmacy prac-tice. In this issue, Shannon Hough and Emily Mackler dis-cuss drug interactions that can occur with some commonlyprescribed oral chemotherapeutic and targeted agents. We

also report on some of the therapies on the horizon fortreating breast cancer and provide information about howyou and your colleagues can help patients manage radia-tion-induced skin reactions. Take note of the statisticspresented in Noteworthy Numbers about overall health-care literacy and its connection to a patient’s health sta-tus—a good reminder that we need to do everything wecan to make sure patients understand all of the informa-tion we give them.Please be sure to visit our Web site, www.TheOncology

Pharmacist.com. Answer this month’s reader questionabout the drug shortage issue and tell us how your patientsare reacting. Submit a question to our column, YourFAQs…Answered! Let us know what you like (or don’tlike), and tell us what issues you want to see us cover. Wewant to hear from you!All of us at TOP wish you the best in the new year. �

From the Editor

Bortezomib Median Overall Survival Update forPreviously Untreated Multiple MyelomaThe US Food and Drug Administration (FDA) has approveda supplemental new drug application for Velcade (bor tez-omib) for Injection (Millennium: The Takeda OncologyCompany) that updates the label to include additional long-term (median follow-up 60.1 months) overall survival (OS)data from the VISTA trial. The VISTA trial examined theuse of bortezomib-based therapy in patients with previouslyuntreated 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 longerOS (median OS 56.4 vs 43.1 months, P <.05) than thosetreated with melphalan and prednisone (MP) alone, a recog-nized standard of care. These results translated into a 43.9%improvement in OS when patients received the bortezomib-containing regimen. A complete data set from the trial waspresented at the December 2011 meeting of the AmericanSociety 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 advantageover MP that was not regained despite the use of subsequenttherapies 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 trialcompared VcMP to MP in patients with previously untreat-ed MM who were not eligible for stem cell transplantation.The safety profile of bortezomib in combination with MP wasconsistent with the known safety profiles of both bortezomiband MP. The prescribing information is also being updated to pro-

vide the information that the concomitant use of strongCYP3A4 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% vs55%), 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% vs17%), 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 eventsfor both combinations were rash, back pain, pneumonia,dizziness, dyspnea, headache, pain in extremity, abdominalpain, paresthesia, herpes zoster, bronchitis, hypokalemia,hypertension, upper abdominal pain, hypotension, dyspepsia,naso pharyngitis, bone pain, arthralgia, and pruritus. �

Recent FDA Approvals

Patrick Medina, PharmD, BCOPEditor-in-Chief

Steve Stricker, PharmD, MS, BCOPAssociate Editor-in-Chief

Check out our user-friendly Web site

www.TheOncologyPharmacist.comIn addition to Web-only exclusives, news coverage, and journal articles,

you’ll have the opportunity to participate in our current reader poll.


These highly and moderately emetogenic chemotherapy regimens increase the risk of CINV.Breast Cancer1,2

AC (doxorubicin + cyclophosphamide)TAC (docetaxel + doxorubicin + cyclophosphamide)TC (docetaxel + cyclophosphamide)CMF (cyclophosphamide + methotrexate + fluorouracil)TCH (docetaxel + carboplatin + trastuzumab)

Lymphoma1,5

ABVD (doxorubicin + bleomycin + vinblastine + dacarbazine) CHOP (cyclophosphamide + doxorubicin + vincristine + prednisone) ± rituximabCVP (cyclophosphamide + vincristine + prednisone)

Lung Cancer1,3

Carbo-Tax (carboplatin + paclitaxel)Cisplatin + vinorelbineCisplatin + gemcitabineCisplatin + pemetrexed

Colorectal Cancer1,6,7

FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) FOLFIRI (irinotecan + leucovorin + 5-fluorouracil)CapeOX (capecitabine + oxaliplatin)IrinotecanCisplatin-based regimens

Head and Neck Cancer1,4

Cisplatin-based regimensCarboplatin-based regimens

Ovarian Cancer1,8

Carbo-Tax (carboplatin + paclitaxel) IP cis (intraperitoneal cisplatin)Cisplatin

Help stop CINV before it starts, with a regimen including EMEND, a 5-HT3 antagonist, and a corticosteroid

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 InformationEMEND 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 couldbe 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 f icacy 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. www.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. www.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.

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EMEND from Cycle 1?

CINV=chemotherapy-induced nausea and vomiting.

Merck OncologyCopyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1012122-0000 emend.com

An antiemetic regimen including


CAPSULES

Brief Summary of the Prescribing Information for INDICATIONS AND USAGEPrevention 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 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.CONTRAINDICATIONSEMEND 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 PRECAUTIONSCYP3A4 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 REACTIONSThe 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, 3.1Digestive 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; epigas-tric discomfort: 4.0, 3.1Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8Hemic and lymphatic system: neutropenia: 3.1, 2.9Metabolism and nutrition: anorexia: 10.1, 9.5Nervous system: headache: 8.5, 8.7; insomnia: 2.9, 3.1Respiratory system: hiccups: 10.8, 5.6In 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 aprepi-tant 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, 5.6Metabolism and nutrition disorders: anorexia: 6.2, 7.2Psychiatric disorders: insomnia: 2.6, 3.7Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7Skin and subcutaneous tissue disorders: alopecia: 12.4, 11.9General disorders and general administration site conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6In 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 infectionNeoplasms benign, malignant, and unspecified (including cysts and polyps): malignant neoplasm, non–small-cell lung carcinomaBlood and lymphatic system disorders: anemia, febrile neutropenia, thrombocytopeniaMetabolism and nutrition disorders: appetite decreased, diabetes mellitus, hypokalemiaPsychiatric disorders: anxiety disorder, confusion, depressionNervous system: peripheral neuropathy, sensory neuropathy, taste disturbance, tremorEye disorders: conjunctivitisCardiac disorders: myocardial infarction, palpitations, tachycardiaVascular disorders: deep venous thrombosis, flushing, hot flush, hypertension, hypotensionRespiratory, thoracic, and mediastinal disorders: cough, dyspnea, nasal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, respiratory insufficiency, vocal disturbanceGastrointestinal disorders: abdominal pain upper, acid reflux, deglutition disorder, dry mouth, dysgeusia, dysphagia, eructation, flatulence, obstipation, salivation increasedSkin and subcutaneous tissue disorders: acne, diaphoresis, pruritus, rashMusculoskeletal and connective tissue disorders: arthralgia, back pain, muscular weakness, musculoskeletal pain, myalgiaRenal and urinary disorders: dysuria, renal insufficiencyReproductive system and breast disorders: pelvic painGeneral disorders and administrative site conditions: edema, malaise, pain, rigorsInvestigations: weight lossStevens-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, 5.3ALT increased: 6.0, 4.3Blood urea nitrogen increased: 4.7, 3.5Serum creatinine increased: 3.7, 4.3AST 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, 3.2Blood and lymphatic system disorders: anemia: 3.0, 4.3Psychiatric disorders: insomnia: 2.1, 3.3Nervous system disorders: headache: 5.0, 6.5Cardiac disorders: bradycardia: 4.4, 3.9Vascular disorders: hypotension: 5.7, 4.6; hypertension: 2.1, 3.2Gastrointestinal disorders: nausea: 8.5, 8.6; constipation: 8.5, 7.6; flatulence: 4.1, 5.8; vomiting 2.5, 3.9Skin and subcutaneous tissue disorders: pruritus: 7.6, 8.4General disorders and general administration site conditions: pyrexia: 5.9, 10.6The 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 infectionMetabolism and nutrition disorders: hypokalemia, hypovolemiaNervous system disorders: dizziness, hypoesthesia, syncopeVascular disorders: hematomaRespiratory, thoracic, and mediastinal disorders: dyspnea, hypoxia, respiratory depressionGastrointestinal disorders: abdominal pain, abdominal pain upper, dry mouth, dyspepsiaSkin and subcutaneous tissue disorders: urticariaGeneral disorders and administrative site conditions: hypothermia, painInvestigations: blood pressure decreasedInjury, poisoning, and procedural complications: operative hemorrhage, wound dehiscenceOther adverse experiences (incidence ≤0.5%) reported in patients treated with aprepitant 40 mg for postoperative nausea and vomiting included:Nervous system disorders: dysarthria, sensory disturbanceEye disorders: miosis, visual acuity reducedRespiratory, thoracic, and mediastinal disorders: wheezingGastrointestinal disorders: bowel sounds abnormal, stomach discomfortThere 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, urticariaImmune system disorders: hypersensitivity reactions including anaphylactic reactionsDRUG 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 recom-mended.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


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 Cmax by approximately 20% of both aprepitant and paroxetine.USE IN SPECIFIC POPULATIONSPregnancy: Teratogenic effects: Pregnancy Category B: Reproduction studies have been performed in rats at oral doses up to 1000 mg/kg twice daily (plasma AUC0–24hr

day (plasma AUC0–24hr

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 TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr

125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice.Aprepitant was not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test, and the mouse micronucleus test.Aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).PATIENT COUNSELING INFORMATION[See FDA-Approved Patient Labeling.] Instructions: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND and to reread it each time the prescription is renewed.Patients should be instructed to take EMEND only as prescribed. For prevention of chemotherapy-induced nausea and vomiting (CINV), patients should be advised to take their first dose (125 mg) of EMEND 1 hour prior to chemotherapy treatment. For prevention of postoperative nausea and vomiting (PONV), patients should receive their medication (40-mg capsule of EMEND) within 3 hours prior to induction of anesthesia.Allergic reactions, which may be serious, and may include hives, rash, and itching, and cause difficulty in breathing or swallowing, have been reported in general use with EMEND. Physicians should instruct their patients to stop taking EMEND and call their doctor right away if they experience an allergic reaction.EMEND may interact with some drugs including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products.Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND 125 mg/80 mg with each chemotherapy cycle, or following administration of a single 40-mg dose of EMEND for prevention of postoperative nausea and vomiting.Administration of EMEND may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with EMEND and for 1 month following the last dose of EMEND.

For detailed information, please read the Prescribing Information. Rx only

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. ONCO-1012122-0000

EMEND® (aprepitant) capsules

December 2011 I VOL 4, NO 8 9www.TheOncologyPharmacist.com

Noteworthy Numbers IN

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atients may not understand the information medical careproviders give them for a number of reasons, but signifi-cant among them is poor healthcare literacy, which is theability to understand health information and to use that

information to make good decisions about health and medicalcare. Unfortunately, about 33% of the adult population in theUnited States has limited healthcare literacy. Yet, the need forthis proficiency is greater than ever because medical care hasbecome progressively more complex. Let us take a look athealthcare literacy facts and figures:

In addition to basic literacy skills, healthcareliteracy requires under-standing of health topicsand number skills.1

Healthcare literacy is oneof the strongest predictorsof health status. In fact,studies of the issue showliteracy as a stronger pre-dictor of an individual’shealth status than income,employment status, education level, and racialor ethnic group.2

Healthcare literacy influ-ences people’s ability to:• Participate in thehealthcare system (fillout complex forms,locate providers andservices, etc)

• Communicate infor-mation, such ashealth history, withproviders

• Manage self-care andchronic disease

• Understand mathe-matical concepts (ie,probability and risk)1

The 2003 NationalAssessment of AdultLiteracy, issued by the USDepartment of Education,estimated the healthcareliteracy skills of adultsbased on the followingcategories: Below Basic,Basic, Intermediate, andProficient. The study findings include:• Proficient health literacy was presentin only 12% of adults

• Nearly 9 of 10 adultsmay lack the neces-sary skills to managetheir health and pre-vent disease

• In the US, 14% ofadults (30 millionpeople) have BelowBasic health literacy

• Adults with BelowBasic health literacywere more likely toreport their health aspoor (42%) and aremore likely to lackhealth insurance(28%) compared toadults with Proficienthealth literacy

• Lower average health-care literacy wasfound among adultsaged 65 and oldercompared to adults inyounger age groups1,3

Strategies for improvingpatient communicationand understandinginclude:• Using plain, nonmed-ical language

• Showing or drawingpictures to enhanceunderstanding

• Encouraging questions2

Sources1. US Department of Health and HumanServices. http://www.health.gov/communication/literacy/quickguide/factsliteracy.htm.2. Weiss BD. Health literacy and patientsafety: 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/HealthLiteracyFactst2009/HealthLiteracyFactst2009.pdf.

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www.TheOncologyPharmacist.com10 December 2011 I VOL 4, NO 8

Hematologic Malignancies

Myeloproliferative neoplasms(MPNs) are a group of closelyrelated hematologic malignan-

cies that arise from abnormal developmentand function of the body’s bone marrowcells. Primary myelofibrosis (PMF), poly-cythemia vera (PV), and essential throm-bocythemia (ET) comprise the Philadel -phia chromosome (Ph)-negative MPNs.1

Myelofibrosis (MF) can arise on itsown, which is called PMF, or it can resultfrom the progression of other MPNs, suchas postpolycythemia vera MF (PPV-MF)and postessential throm bocythemia MF(PET-MF).1

The Burden of Disease and Its ImpactMF is characterized by cytopenias,splenomegaly, poor quality of life, andshortened survival.1 Because chronicMPNs previously were not classified ashematologic malignancies, limited epi-demiologic studies are available to esti-mate the incidence of MF. Multipleregional studies suggest that an estimated6328 new cases of chronic myeloprolifera-tive disorders (CMPDs as they were previ-ously known) occurred in the US popula-tion in 2004.2 Of these patients, 45% hadPV, 24% had ET, and 10% had PMF.2

The average annual age-adjusted inci-dence in the United States between 2001and 2003 was 2.1 per 100,000 persons,

with rates ranging among states from alow of 0.8 per 100,000 persons inDelaware to as high as 4.1 per 100,000persons in Idaho.2 The incidence was sig-nificantly higher in males (2.6 per100,000) than in females (1.8 per100,000; P <.05).2 In addition, the inci-dence increased significantly with age,reaching 13.3 per 100,000 persons amongindividuals aged ≥80 years.2

Although appropriate treatment ofpatients with ET and PV is associatedwith prolonged survival, patients withsymptomatic forms of PMF have a mediansurvival of <5 years.1 The prognosis of MFis quite variable; however, those whodevelop anemia generally have a poorerprognosis. Patients with a good prognosis

can live for many years without experi-encing major symptoms, whereas thosewith a poor prognosis may have a signifi-cantly shorter survival. A small percent-age of patients with MF can transform toacute myeloid leukemia, which is oftendifficult to treat and can be fatal. Few treatment options exist for patients

with MF. Until recently, the choice oftreatment was often dictated by a patient’ssymptoms and specific circumstances.Some patients with MF may remain symp-tom-free for many years, without undergo-ing treatment; however, monitoring for anysigns or symptoms that may suggest wors-ening of the disease is required. For patientswho require symptomatic treatment,chemotherapeutic agents, immunomodu-latory drugs, and biological response modi-fiers (eg, hydroxyurea, androgen therapies,cortico steroids, thalidomide, lenalidomide,and interferon) are often used. It is important to note that these ther-

apies are not always directed to the bio-logical processes that underlie the originof disease or lead to progression of PMF.Therefore, these strategies are often pri-marily palliative in nature, and theireffect on survival is uncertain. Finally,surgery or radiation therapy may also beused in those who fail to respond to othertreatments. For many patients with MF,however, available treatments may beineffective and allogeneic stem cell trans-plantation may be the only potentialknown cure.A decisive advance in our understand-

ing of the underlying molecular mecha-nisms of MPNs has been the discovery of asomatic gain-of-function point mutation inthe Janus kinase (JAK) 2 gene, which is acommon clinical feature in patients withET, PV, and PMF.3,4 We now know thatapproximately 50% of patients with MFhave a gain-of-function mutation in theJAK2 gene.5,6 Discoveries in the molecularpathogenesis of PV, ET, and PMF enabledthe genetic classification and moleculardiagnosis of these neoplasms. The WorldHealth Organi zation diagnostic criteria,which were based largely on clinical andpathologic descriptions, were subsequentlyrevised for PV, ET, and PMF to include theincorporation of testing for JAK2 and othergenetic mutations.7

In addition to modifying the criteria fordiagnosing, monitoring, and assessingpatients with ET, PV, and PMF, the dis-covery of JAK2 involvement in patientswith MF also led to the development ofsmall-molecule inhibitors that specifically

target JAK2. Although JAK2 mutationsare responsible for the majority of dysreg-ulated signaling in Ph-negative MPNs,JAK1 and JAK2 may interact, resulting intheir transactivation.8,9

Armed with this information and agreater understanding of the cellular andmolecular events that lead to the devel-opment of PMF, the possibility of moretargeted and effective therapies for thisdisorder has become a reality. In November 2011, the US Food and

Drug Administration (FDA) granted mar-keting approval of oral Jakafi (ruxolitinib;Incyte) tablets for the treatment of patientswith intermediate- or high-risk MF, includ-ing PMF, PPV-MF, and PET-MF.10

Clinical PharmacologyMechanism of ActionRuxolitinib, a kinase inhibitor, inhibitsthe Janus-associated kinases JAK1 andJAK2, which mediate the signaling of anumber of cytokines and growth factorsthat are important for hemato poiesis andimmune function. JAK signaling involvesrecruitment of signal transducers and acti-vators of transcription (STATs) to cytokinereceptors, activation, and subsequent local-ization of STATs to the nucleus, leading tomodulation of gene expression.10

MF is known to be associated with dys-regulated JAK1 and JAK2 signaling. In amouse model of JAK2V617F-positiveMPN, oral administration of ruxolitinibprevented splenomegaly, preferentiallydecreased JAK2V617F mutated cells inthe spleen, and decreased circulatinginflammatory cytokines (eg, tumor necro-sis factor–alpha and interleukin-6).10

Pharmacodynamics. In healthy personsand in patients with MF, ruxolitinibinhibited cytokine-induced STAT3 phos-phorylation in whole blood. The maximalinhibition of STAT3 phosphorylationoccurred 2 hours after dosing, returning tonear-baseline levels by 10 hours in bothgroups of people.

Pharmacokinetics. Maximal plasmaconcentration (Cmax) of ruxolitiniboccurred 1 to 2 hours after oral adminis-tration. Pharmacokinetic studies demon-strated no evident food effect on theabsorption of ruxolitinib; when adminis-tered with a high-fat meal, the meanCmax decreased moderately (24%) andthe area under the curve remained near-ly unchanged (ie, 4% increase). In earlyclinical trials, the volume of distributionat steady state was between 53 L and 65L in patients with MF.10

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

Baseline CharacteristicStudy 1

(N = 309)Study 2

(N = 219)

Median age, yrs (range) 68 (40-91) 66 (35-85)

Patients aged >65 yrs, % 61 52

Male patients, % 54 57

Disease state

Primary myelofibrosis, % 50 53

Postpolycythemia vera myelofibrosis, % 31 31

Postessential thrombocythemia myelofibrosis, % 18 16

Hematologic value

Median hemoglobin, g/dL 10.5 10.4

Median platelet count, × 109/L 251 236

Median palpable spleen length below the costal margin, cm 16 15

Median spleen volume, cm3 (range) 2595 (478-8881) 2381 (451-7765)

Source: Reference 10.

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

In November 2011, theFDA approved Jakafi(ruxolitinib) tablets for thetreatment of patients withintermediate- or high-riskMF, including PMF, PPV-MF, and PET-MF.


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Phase 3 Clinical TrialsJakafi was approved by the FDA based onthe results of 2 randomized, phase 3 trials(Study 1 and Study 2) conducted inpatients with MF.10 These trials aredescribed in detail in the product pre-scribing information, with key data high-lighted in this article.

Trial DesignsStudy 1 was a randomized, double-blindtrial that compared ruxolitinib with place-bo in patients with MF who were refracto-ry to or were not candidates for availabletherapy. The primary end point was theproportion of patients achieving a reduc-tion in spleen volume of ≥35% from base-

line at week 24, as measured by magneticresonance imaging (MRI) or computedtomography (CT). Secondary end pointsincluded the duration of ≥35% reductionin spleen volume from baseline and theproportion of patients with a ≥50% reduc-tion in Total Symptom Score from

baseline to week 24. The latter was meas-ured using the modified MyelofibrosisSymptom Assessment Form (MFSAF)v2.0 diary.10

Study 2 was a randomized, open-labeltrial that compared ruxolitinib with thebest available therapy in patients withMF. The study investigators selected thebest available therapy on a patient-by-patient basis, with the most frequentlyused agents, including hydroxyurea (N =47%) and glucocorticoids (N = 16%).The primary end point of this trial wassimilar to that in Study 1—the proportionof patients achieving a reduction in spleenvolume of ≥35% from baseline, but atweek 48 (as measured by MRI or CT).The secondary end point of Study 2 wasthe proportion of patients achieving a≥35% reduction in spleen volume frombaseline to week 24.10

In both trials, patients were required tohave palpable splenomegaly >5 cm belowthe costal margin, as well as an MF riskcategory of intermediate-2-risk (2 prog-nostic factors) or high-risk (>3 prognosticfactors).10

Dosing in these trials was based onplatelet counts. The starting dose of ruxoli-tinib was 15 mg administered orally twicedaily in patients with baseline plateletcounts of 100 to 200 x 109/L and 20 mgadministered orally twice daily in patientswith baseline platelet counts >200 x 109/L.The doses of ruxolitinib were then adjustedduring the course of therapy based on effi-cacy and tolerability. Maximum dosesbased 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 PopulationsBaseline characteristics of patientsenrolled in Study 1 and Study 2 are shownin Table 1. The 2 patient populationswere very similar in terms of demograph-ics and the extent of disease before studytreatment.10

EfficacyThe primary end point in both phase 3 tri-als was the proportion of patients achiev-ing a reduction in spleen volume of ≥35%from baseline at week 24 in Study 1 andat week 48 in Study 2 (Table 2). A signif-icantly greater percentage of ruxolitinib-treated patients achieved this magnitudeof reduction in baseline spleen volume

compared with either placebo (41.9% vs0.7%, respectively; P <.001) or best avail-able therapy (28.5% vs 0%, re spectively;P <.001).10

In Study 1, a secondary end point wasimprovement in symptoms, as measured bythe MFSAF v2.0. This scale captures MF-related symptoms, including abdominaldiscomfort, pain under the left ribs, nightsweats, itching, bone or muscle pain, andearly satiety. A higher proportion of ruxoli-tinib-treated patients experienced a ≥50%reduction in Total Symptom Score com-pared with placebo (45.9% vs 5.3%,respectively; P <.001). The median time tosymptom response was <4 weeks.10

Safety ProfileBecause clinical trials are conductedunder widely varying conditions, rates ofadverse reactions observed in the clinicaltrials of a particular drug cannot be com-pared directly with rates observed in theclinical trials of another drug and maynot reflect the rates observed in clinicalpractice. The safety of ruxolitinib wasassessed in 617 patients in 6 clinicalstudies with a median duration of follow-up of 10.9 months, including 301patients with MF in 2 phase 3 studies. Inthese 2 studies, patients had a medianduration of exposure to ruxolitinib of 9.5months (range, 0.5-17 months), with88.7% of patients treated for >6 monthsand 24.6% treated for >12 months. Atotal of 111 patients started treatment at15 mg orally twice daily and 190 patientsstarted at 20 mg orally twice daily.10

The most often reported adverseevents were thrombocytopenia and ane-mia; the most frequent nonhematologicadverse events were bruising, dizziness,and headache.9 A total of 11.0% ofpatients receiving ruxolitinib and 10.6%of patients receiving placebo discontin-ued therapy because of adverse events.9

The rates of adverse reactions and lab-oratory abnormalities reported in Study 1are summarized in Table 3. The mediantime to onset of grade 2 or higher anemiawas approximately 6 weeks. Meandecreases in hemoglobin of 1.5 to 2 g/dLbelow baseline after 8 to 12 weeks oftherapy were reported in ruxolitinib-treated patients, recovering gradually toreach a new steady state of approximate-ly 1.0 g/dL below baseline.10 The mediantime to onset of grade 3 or 4 thrombocy-topenia was approximately 8 weeks.Patients with baseline platelet counts of100 to 200 x 109/L experienced a higherincidence of grade 3 or 4 thrombocy-topenia than did those with baselineplatelet counts >200 x 109/L.10

DosingRuxolitinib is dosed orally and can beadministered with or without food. If adose is missed, the patient should nottake an additional dose, but should takethe next usual prescribed dose. Whendiscontinuing ruxolitinib therapy for rea-



Table 2 Percentage of Patients With ≥35% Reduction in Baseline Spleen Volume

Study 1 (24 wks) Study 2 (48 wks)

Ruxolitinib(N = 155)

Placebo(N = 154) P Value

Ruxolitinib (N = 146)

Best available Treatment (N = 73) P Value

41.9% 0.7% <.001 28.5% 0% <.001


Table 3 Adverse Reactions and Laboratory Abnormalities Reported in Study 1: Ruxolitinib Versus Placebo

Reported Outcomes

Ruxolitinib (N = 155) Placebo (N = 151)

All grades,%

Grade 3,%

Grade 4,%

All grades,%

Grade 3,%

Grade 4, %

Adverse reaction

Bruisinga 23.2 0.6 0 14.6 0 0

Dizzinessb 18.1 0.6 0 7.3 0 0

Headache 14.8 0 0 5.3 0 0

Urinary tract infectionc 9.0 0 0 5.3 0.7 0.7

Weight gaind 7.1 0.6 0 1.3 0.7 0

Flatulence 5.2 0 0 0.7 0 0

Herpes zostere 1.9 0 0 0.7 0 0

Laboratory abnormalityf

Thrombo -cytopenia 69.7 9.0 3.9 30.5 1.3 0

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 0 7.3 0 0

Elevated AST 17.4 0 0 6.0 0 0

aIncludes contusion, ecchymosis, hematoma, injection-site hematoma, periorbital hematoma,vessel puncture-site hematoma, increased tendency to bruise, petechiae, and purpura.bIncludes dizziness, postural dizziness, vertigo, balance disorder, Ménière disease, andlabyrinthitis.cIncludes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidneyinfection, pyuria, bacteria urine, bacteria urine identified, and nitrite urine present.dIncludes weight increased and abnormal weight gain.eIncludes herpes zoster and postherpetic neuralgia.fWorst grade values are presented, regardless of baseline.

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase.


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


sons other than thrombocytopenia, grad-ual tapering of the dose may be consid-ered—for example, by 5 mg twice dailyeach week.10

In patients who are unable to ingesttablets, ruxolitinib can be administeredthrough a nasogastric tube (8 French orgreater) by suspending 1 tablet inapproximately 40 mL of water and stir-ring for approximately 10 minutes.Within 6 hours after the tablet has dis-persed, the suspension can be adminis-tered via a nasogastric tube using anappropriate syringe. After use, the tubeshould be rinsed with approximately 75mL of water. The effect of tube-feedingpreparations on ruxolitinib exposure dur-ing administration through a nasogastrictube has not been evaluated.10

The recommended starting dose of rux-olitinib is based on platelet count (Table4). A complete blood count (CBC) andplatelet count must be performed prior toinitiating therapy, every 2 to 4 weeks untildoses are stabilized, and then as clinicallyindicated. Doses may be titrated based onsafety and efficacy.10

Treatment with ruxolitinib should beinterrupted in patients with plateletcounts <50 x 109/L. Once the plateletcount recovers to >50 x 109/L, dosingmay be restarted or increased followingrecovery of platelet counts to acceptablelevels. Table 5 shows the maximumallowable dose that may be used whenrestarting ruxolitinib therapy following aprevious interruption.10

Patients who develop anemia mayrequire blood transfusions. Dose modifi-cations of ruxolitinib in patients whodevelop anemia may also be consid-ered.10 Neutropenia (absolute neutrophilcount [ANC] <0.5 x 109/L) was general-ly reversible and was managed by tem-porarily withholding ruxolitinib. CBCsshould be monitored as clinically indi-cated, with dosing ad justed as required.10

Dose Modification Based on ResponseIf efficacy is considered insufficient andplatelet and neutrophil counts are ade-quate, doses may be increased in 5-mgtwice-daily increments to a maximum of25 mg twice daily. Doses should not beincreased during the first 4 weeks of ther-apy and not more often than every 2weeks. Discontinue treatment after 6months if no reduction in spleen size orsymptom improvement is observed sinceinitiation of ruxolitinib therapy.10

Based on limited clinical data, long-term maintenance with a 5-mg twice-daily dose has not demonstrated respons-es, and continued use of this dose shouldbe limited to patients in whom the ben-efits outweigh the potential risks.10

Dose increases may be considered inpatients who meet all of the followingcriteria10:• Failure to achieve a reduction from pre-treatment baseline in either palpable

spleen length of 50% or a 35% reduc-tion in spleen volume, as measured byCT or MRI

• Platelet count >125 x 109/L at 4 weeksand platelet count never <100 x 109/L

• ANC >0.75 x 109/L.

Dose Adjustment, ConcomitantStrong CYP3A4 InhibitorsOn the basis of pharmacokinetic studies inhealthy volunteers, when administeringruxolitinib along with strong cytochrome(CY)P3A4 inhib itors (eg, boceprevir, clar-ithromycin, conivaptan, grapefruit juice,indinavir, itraconazole, ketoconazole,lopinavir/ritonavir, mibefradil, nefa-zodone, nelfinavir, posaconazole, riton-avir, sa quinavir, telaprevir, telithromycin,voriconazole), the recommended startingdose is 10 mg twice daily for patients withplatelet counts ≥100 x 109/L. Additionaldose modifications should be made withcareful monitoring of safety and efficacy.Concurrent administration of ruxolitinibwith strong CYP3A4 inhibitors should beavoided in patients with platelet counts<100 x 109/L.10

Contraindications, GeneralWarnings, and PrecautionsThere are no black box warnings or con-traindications associated with the use ofruxolitinib. Warnings and precautionsassociated with use of the agent includesuch hematologic ad verse reactions asthrombocytopenia, anemia, and neu-tropenia. As indicated earlier, a CBC andplatelet count must be performed prior toinitiating therapy with ruxolitinib.In clinical trials, patients with platelet

counts <200 x 109/L at the start of therapywere more likely to develop thrombocy-topenia during treatment. Thrombocyto -penia was generally reversible, however,and was usually managed by modifying orinterrupting the dose of ruxolitinib in clin-ical trials. Patients may also require aplatelet transfusion, if clinically indicated.Dose reductions should be considered ifplatelet counts decrease, with the goalbeing to avoid dose interruptions forthrombocytopenia (Table 6).10

Patients should be assessed for the riskof developing serious bacterial, mycobac-terial, fungal, and viral infections. Active

serious infections should have resolvedprior to initiating ruxolitinib therapy.Physicians should carefully observepatients receiving ruxo litinib for signsand symptoms of infection, and shouldinitiate appropriate treatment promptly.Physicians should inform patients aboutearly signs and symptoms of herpeszoster, and should advise patients to seektreatment as early as possible. �

References1. Verstovsek S, Kantarjian H, Mesa R, et al. Safety andefficacy of INCB018424, a JAK1 and JAK2 inhibitor, inmyelofibrosis. N Engl J Med. 2010;363:1117-1127. 2. Rollison DE, Howlader N, Smith MT, et al.Epidemiology of myelodysplastic syndromes and chronicmyeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs.Blood. 2008;112:45-52.3. Levine RL, Wadleigh M, Cools J, et al. Activatingmutation in the tyrosine kinase JAK2 in polycythemiavera, essential thrombocythemia, and myeloid metaplasiawith myelofibrosis. Cancer Cell. 2005;7:387-397.4. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function 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 studyof CEP-701, an orally available JAK2 inhibitor, in patientswith primary or post-polycythemia vera/essential thrombo-cythemia myelofibrosis. Blood. 2010;115:1131-1136.

6. Baxter EJ, Scott LM, Campbell PJ, et al. Acquiredmutation of the tyrosine kinase JAK2 in human myelopro-liferative disorders. Lancet. 2005;365:1054-1061.7. Cervantes F, Dupriez B, Pereira A, et al. New prognos-tic scoring system for primary myelofibrosis based on astudy of the International Working Group forMyelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.8. Mertens C, Darnell JE Jr. SnapShot: JAK-STAT signal-ing. Cell. 2007;131:612.e1.9. Jatiani SS, Baker SJ, Silverman LR, Reddy EP.JAK/STAT pathways in cytokine signaling and myelopro-liferative disorders: approaches for targeted therapies.Genes Cancer. 2010;1:979-993.10. Jakafi [prescribing information]. Wilmington, DE:Incyte Corporation; 2011.



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


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 <10010 mg twice daily for at least 2 wks; if patient is sta-ble, may increase to 15 mg twice daily

50 to <755 mg twice daily for at least 2 wks; if patient is stable,may increase to 10 mg twice daily

<50 Continue holdaWhen restarting therapy, begin with a dose at least 5 mg twice daily below the dose atinterruption.


Table 6 Dosing Recommendations for Thrombocytopenia

PlateletCount, × 109/L

Dose at Time of Platelet Decline

25 mg twicedaily

20 mg twicedaily

15 mg twicedaily

10 mg twicedaily

5 mg twicedaily

New Dose

100 to <125 20 mg twicedaily

15 mg twicedaily

No change No change No change


10 mg twicedaily

10 mg twicedaily

No change No change


5 mg twicedaily

5 mg twicedaily

5 mg twicedaily

No change

<50 Hold Hold Hold Hold Hold


The most often reportedadverse events werethrombocytopenia andanemia; the mostfrequent non hematologicadverse events werebruising, dizziness, andheadache.

Janet Woodcock, director of the FDA’sCenter for Drug Evaluation and Re search,expressed cautious hope for the future ofpersonalized drug therapy, acknowledgingthat “we’re now out of the generalskepticism phase [and] into the long slogphase.” Woodcock spoke at a conferencehosted by the FDA and the Drug Infor -mation Association in October.

—American Society of

Health-System Pharmacists

Did You Know?


New Data: 5-Year Median Follow-up

I

W

P

H

P

N

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.

M

New Data: 5-Year Median Follow-up

il f i dd


Patie

nts

Surv

ivin

g (%

)

Months

604836 7224120

VELCADE+MP (n=344)

MP (n=338)

100

90

80

70

60

50

40

30

20

10

0

IMPORTANT SAFETY INFORMATIONVELCADE Warnings and Precautions ▼ 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

Adverse Reactions 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.

Median overall survival:

56.4 vs 43.1 months HR=0.695 (95% CI, 0.57-0.85); P<0.05

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

Kaplan-Meier estimate.

1 AM 9:26 AM


The following articles are based on presentations at the 53rd Annual Meeting of the AmericanSociety 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 Medicinein St. Louis.

The goals of the current phase 3 trialwere to find out if high doses of radia-tion improved survival and also if the

chemotherapy drug cetuximab in -creased survival among patients withstage III NSCLC. Investigators random-ized 423 patients to different doses ofradiation therapy and concurrent

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

with or without cetuximab.Two types of external beam radia-

tion therapy were used during the trial:three-dimensional conformal radiationtherapy (3D-CRT), and intensity-modulated radiation therapy (IMRT),a newer, specialized form of 3D-CRTthat further limits the radiation dose tothe healthy tissues.

The researchers found that thepatients who received the higher doseof radiation (74 Gy) did not have bettersurvival rates than those receiving thestandard dose (60 Gy). Subsequently,the 2 arms of the trial that used high-dose radiation therapy were closed topatient accrual.

Bradley said the trial provides pivotalevidence that the standard dose of radi-ation therapy for stage III lung cancershould remain at 60 Gy, as doses as highas 74 Gy do not achieve better outcomesin stage III lung cancer. He said it isuncertain why this is the case. The dataare still being carefully reviewed.

Bradley noted that these findings areimportant because this is an area thathad not been carefully studied in morethan 20 years. He noted that it hasbeen 30 years since the radiation doseof 60 Gy was established. However, thetechniques of radiation therapy haveimproved a great deal. “This is thelargest study to look at this question,and it is a definitive study for stage IIIlung cancer,” said Bradley. �

The National Cancer Institute currentlydesignates 66 research institutions asCancer Centers. These centers are en -gaged in transdisciplinary research toreduce cancer incidence, morbidity,and mortality.

—National Cancer Institute Office of

Cancer Centers

Did You Know?


Conference News

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc.Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139Copyright © 2011, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA

Brief Summary

INDICATIONS:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphomawho have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastictherapy. 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 treatmentwith 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 2neuropathy 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 aredehydrated. 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 treatment-emergent 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% and4%, 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 previouslyexperiencing 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 andelectrolyte 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 recoveringprior 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 approximately40% 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 onboth the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to eachdose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and scheduleof VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the:complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant :medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

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 becomingpregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesisat a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeksfollowed 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 ofVELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (includingfatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheralneuropathy 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 combinationwith melphalan/prednisone is consistent with the known safety profiles of both VELCADE andmelphalan/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, hadno effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4inducer, 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 greaterthan 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and mshould 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 exposureof 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 renalinsufficiency. 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.

V-11-0264 12/11

Bradley noted that thesefindings are importantbecause this is an areathat had not beencarefully studied inmore than 20 years.


Patients with rectal cancer whoreceive a combination of chemo -therapy (capecitabine) and 5

weeks of radiation (50 Gy) prior to sur-gery may have an 88% chance of surviv-ing the cancer 3 years after treatment.“The results of the trial allow us to

recommend a new preoperative treat-ment, the Cap50 regimen, in locallyadvanced rectal cancer. It’s safe andreduces the risk of the cancer comingback to less than 5%,” said study inves-tigator Jean-Pierre Gérard, MD, radia-tion oncologist at Centre Antoine-Lacassagne in Nice, France.Currently, the primary treatment for

cancer of the rectum (the lower 15 cm ofthe bowel) is surgery. However, there is a risk of cancer recurrence within thebowel and the surrounding tissue. In themajority of cases, this recurrence is incur-able. Depending on the location andstage of the cancer, physicians usuallyrecommend radiation therapy andchemotherapy before surgery. However,the optimal regimen is still unknown.This current study involved 598

patients with locally advanced rectalcancer who were diagnosed and treatedin 50 hospitals in France between 2005and 2008. Researchers wanted to findthe most effective and safe preoperativetreatment for rectal cancer by comparinga combination of 2 different chemother-apies and 2 different radiation doses.Patients were randomized to receiveeither Cap45 (capecitabine and radia-tion treatment to 45 Gy) or Capox50(capecitabine plus oxaliplatin and radia-tion to 50 Gy).At 3 years after treatment, the

researchers found that the Capox50regimen did not have a significantlylower rate of local recurrence com-pared with the Cap45 treatment.Oxaliplatin, given as part of theCapox50 treatment, was shown toimmediately increase side effects,including severe diarrhea, and was noteffective in increasing the chance oflocal tumor sterilization. However, theincrease of the radiation dose from 45to 50 Gy over 5 weeks was effective,well tolerated, and did not extend theduration of treatment.Gérard said the Cap50 regimen should

be the standard treatment for locallyadvanced rectal cancer. He noted thatusing capecitabine avoids the intra-venous injection of fluorouracil, while aradiation dose to 50 Gy in 25 fractionsover 5 weeks increases the chance oftumor sterilization and limits the riskof local recurrence to 5% or less. “Weknow now that if we add chemothera-

py before surgery, you can improve sur-vival,” said Gérard.He and his colleagues are now devis-

ing new guidelines for the manage-ment of rectal cancer patients. Gérardsaid that currently there is a wide vari-

ety in practice patterns in the treatmentof these patients.“Many patients are getting neoadju-

vant therapy in the United States, but itis not considered the standard care of yet.This study may change that,” said TimWilliams, MD, medical director of radia-tion oncology at Boca Raton RegionalHospital in Florida. �

Chemo Plus Radiation Prior to Surgery MayIncrease Tumor Response for Rectal CancerBy John Schieszer


Conference News

TARGET AUDIENCEThis activity was developed for physicians, nurses, pharmacists, and managed care professionals who areinvolved in the care of patients with cancer.

CONFERENCE GOALThe 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 ofvarious points of view regarding cost, quality, and access in cancer care.

EDUCATIONAL OBJECTIVES• Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care

delivery• Define the barriers associated with cost, quality, and access as it relates to healthcare reform and

what solutions are currently being considered• Compare and contrast the different approaches/tools that providers and payers are utilizing to

manage and deliver care collaboratively• Examine the current trends in personalized care and companion diagnostics• Analyze the patient issues around cost, quality, and access to care

DESIGNATION OF CREDIT STATEMENTSPhysician Accreditation – Joint SponsorThe Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 AMAPRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent oftheir participation in the activity. This activity has been planned and implemented in accordance withthe 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 Associationfor Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCMEto provide continuing medical education for physicians.

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

Registered Pharmacy DesignationMedical 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.

The One Conference You Can’t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care ConferenceStrategies for Optimizing Value in Cancer Care Delivery

REGISTER TODAY

SAVE $100

March 29-31, 2012 • JW Marriott • Houston, Texas

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

REGISTER TODAY at www.regonline.com/avbcc2012

��

Gary Owens, MDPresident Gary Owens Associates

Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for Clinical InvestigationsRobert H. Lurie ComprehensiveCancer Center Northwestern University

Burt Zweigenhaft, BSPresident, CEO OncoMed

CONFERENCE CO-CHAIRS

CONFERENCE REGISTRATION

SAVE $100 off full Conference Tuition

REGISTER TODAY FOR ONLY $275at www.regonline.com/avbcc2012

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Cancer Center Profile

practice where medical specialists workedtogether to achieve the best outcomes inpatient care while furthering the goalsof research and education.

From the very beginning, the missionof the Cleveland Clinic has been to pro-vide “better care of the sick, investiga-tion into their problems, and furthereducation of those who serve.” To helpensure the success of their mission, thefounders decided to commit 25% of theirnet income to an endowment that sup-ported medical research, education, andcare of the indigent. Today, theCleveland Clinic has facilities through-out Ohio, as well as in Florida, Nevada,Canada, and Abu Dhabi.

In the field of oncology,the Cleveland Clinic has adistinguished history. GeorgeCrile Jr, MD, the son of oneof the founders, was a pioneerin establishing alternatives toradical mastectomy to treatbreast cancer. His book,Cancer and Common Sense,was written for the publicand endorsed conservativetreatment for cancer whilerailing against what Dr Crilecalled “the unnecessarilymutilating results of the sur-gery being done at some of the so-called cancer centers.” These were con-troversial ideas in 1955, and Lifemagazine published excerpts from hisbook. Today, the Cleveland ClinicTaussig Cancer Institute is internation-ally recognized for its clinical, transla-tional, and basic cancer research and isa National Cancer Institute–designatedcancer center, as part of the CaseComp rehensive Cancer Center.

The Cleveland Clinic’s Department ofPharmacy is at the forefront of usingtechnology and automation to let phar-macists focus on patient care and physi-cian support—ensuring that all membersof the oncology team are able to offerhigh-level care to their patients. MarcEarl, PharmD, BCOP, a hematology/oncology clinical specialist, answered ourquestions about the Cleveland Clinicand how oncology pharmacists are work-ing with patients to educate and counselthem about their medication therapy.

What is your hospital doing that isdifferent from other cancer centers?

Marc Earl (ME): We are using technol-ogy to increase the amount of time phar-macists spend with patients. We haverecently instituted physician order entryfor chemotherapy as well as robotic tech-nology for chemotherapy compounding.Over time, these things will allow ourpharmacists to interact with more of ouroncology patients.

How does that translate to better outcomes for your patients?

ME: It helps us meet our goal in thatevery cancer patient at the ClevelandClinic has his or her own pharmacist.This technology will be safer and moreefficient, allowing our pharmacists tointeract with patients in a one-on-onemanner. We will be able to work throughissues in supportive care and medicationdischarge counseling that will translateto improved care for our patients.

The Cleveland Clinic believes ineducating the patient and his/herfamily about cancer as a means ofincreasing the chance for a betteroutcome of therapy. Can you share apatient success story illustrating thisbelief?

ME: My biggest impact has been withadult patients who have recently beendiagnosed with acute myeloid leukemia.It is an overwhelming time for theentire family. I am able towork with these patients andtheir families on a daily basisto answer any medication-related questions while theyare in the hospital. I alsolook for a variety of medica-tion-related problems duringtheir 4- to 6-week stay in thehospital. I meet with thembefore they are discharged togo through any new medica-tions. Many of these patientsare not on any medications when diag-nosed but must go home on 5 to 10 newmedications. This is overwhelming forthe patient and his/her family and pro-vides an opportunity to answer questionsand improve patient safety.

How has the oncology pharmacist’srole changed in the past 5 years?

ME: The majority of the changes havebeen related to patient safety. We areactively involved in developing preprint-ed and electronic chemotherapy orders,which help decrease errors. It helps stan-dardize the treatment approach for manymalignancies. This ensures that everycancer patient receives a similar treat-ment with the exact same supportivecare management.

What is in the future for theCleveland Clinic?ME: I am excited about the future ofpharmacy at the Cleveland Clinic. We

have grown significantly inthe past few years, and thiswill allow us to become moreinvolved with our patients.We are also going to be incor-porating more pharmacy stu-dents and residents into theseprograms so that we can reachmore patients. I think thereare opportunities in supportivecare and discharge educationour pharmacists can assistwith. Our goal is that one day

every patient will personally interactwith a pharmacist on each visit to theCleveland Clinic. �

The Cleveland Clinic Taussig Cancer Institute Continued from cover

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

Marc Earl, PharmD, BCOP

The founders decided tocommit 25% of their netincome to an endowmentthat supported medicalresearch, education, andcare of the indigent.

For fiscal year 2010, the National CancerInstitute had $5.098 billion in availablefunds, representing a 2.6% increase overfiscal year 2009. Of the total fiscal year2010 budget, 43% of the funds wereallocated for research project grants. A totalof 5079 of these grants were awarded.

—National Cancer Institute Office of

Budget and Finance

Did You Know?


Jaka� is a trademark of Incyte Corporation.© 2011, Incyte Corporation. All rights reserved. RUX-1004C 11/11

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jaka� 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 Jaka� . 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 Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions.

Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jaka� for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly

• A dose modi� cation is recommended when administering Jaka� 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 ef� cacy

• There are no adequate and well-controlled studies of Jaka� in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jaka� 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.

NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK

MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION


An investigational alpha-phar-maceutical not only preventedskeletal-related events (SREs)

in patients with prostate cancer withbone 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

bone metastases in prostate cancer toimprove survival,” said lead investiga-tor Chris Parker, MD, Royal MarsdenHospital, London. “There are otherbone drugs used in prostate cancer, butthey help to minimize symptoms; theydon’t improve survival. In my opinion,radium-223 is likely to become a newstandard of treatment for advancedprostate cancer,” Dr Parker told jour-nalists at a press briefing.Jean-Charles Soria, MD, Institut

Gustave Roussy, Villejuif, France, whocochaired the meeting’s scientific pro-gram, agreed. “This is really practicechanging, and after regulatory approval, Ithink this is going to be a major player inadvanced prostate cancer.”A US coinvestigator of the trial,

Oliver Sartor, MD, Tulane University,New Orleans, Louisiana, said the radio-pharmaceutical is far superior to priorcompounds of the sort, and the studyresults were highly impressive.Radium-223 chloride (Alpharadin;

Algeta/Bayer) was recently granted afast-track designation by the US Foodand Drug Administration. The companyplans to file a New Drug Application inmid-2012.The Alpharadin in Symptomatic

Prostate Cancer (ALSYMPCA) trialwas a phase 3, randomized, double-blind, placebo-controlled, internation-al study that compared radium-223chloride plus current standard of carewith placebo plus current standard ofcare in 922 men with symptomatic cas-tration-resistant prostate cancer thathad spread to the bone. Patients hadmultiple skeletal metastases on bonescan and were taking regular analgesicsfor bone pain.At a planned interim analysis,

patients who received radium-223 hadthe following positive outcomes:• Median overall survival: 14

months compared with 11.2months for the placebo group, a30% reduction in mortality (P = .00185)

• Time to first SREs: 13.6 monthsversus 8.4 months, a 64%improvement (P = .00046)

• Total alkaline phosphatase (bonemarker) normalization: 33% ver-sus 1% (P <.001)

• Time to prostate-specific antigenprogression: 49% improvement (P = .00015).

Nonhematologic adverse eventswere not significantly worse with radi-um-223 versus placebo; the most com-mon grade 3/4 adverse events werebone pain (18% vs 23%, respective-ly). Other serious toxicities wereuncommon.Based on the interim analysis, the

data monitoring committee recom-mended the study be stopped andpatients in the placebo arm be offeredradium-223. �

New Bone-Targeting Compound ImprovesSurvival in Metastatic Prostate CancerBy Caroline Helwick


Prostate Cancer

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-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 treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith 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 andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011 Incyte Corporation. All rights reserved.Issued: November 2011 RUX-1040


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Oncology providers face a multitude of disruptive changes...

REACT TO CHANGESEEK PROVEN SOLUTIONS

What to do?

Pharmacy / 877.662.6633 Fax / 877.662.6355 Website / OncoMed.net


Although an estimated 207,090cases of breast cancer will bediagnosed in the United States

in 2010,1 mortality rates from the dis-ease have been on the decline since1990, especially in women younger than50 years of age.2 This decrease is likelyattributable to early detection throughscreening, increased general awareness,and improved therapies.2 Nevertheless,breast cancer remains the second lead-ing cause of cancer-related death inwomen, and is responsible for morethan 40,000 deaths a year in theUnited States alone.1,2 The majority ofbreast cancer–related deaths are aresult of complications from recurrentor metastatic disease.Metastatic breast cancer (MBC) is

uncommon at initial presentation,occurring in only about 6% of newlydiagnosed cases.2,3 However, approxi-mately 30% of women initially diag-nosed with earlier stages of breast can-cer eventually develop recurrentadvanced or metastatic disease.3,4 The5-year relative survival rate for patientswith MBC is only 23%.1 Given thispoor prognosis, researchers continue tofocus their efforts on the developmentof more effective and tolerable treat-ments that may provide prolonged sur-vival and improved quality of life.Investigators are also striving to moreclearly identify biomarkers in breastcancer that can be used to assess prog-nosis and guide the selection of thera-pies, in the hopes of offering more indi-

vidualized treatment. As integral mem-bers of the oncology team, it is essentialthat nurses and pharmacists are aware ofthe latest advances in the treatment andmanagement of MBC, including safetyand efficacy data from clinical trialsevaluating novel biologic and cytotoxicagents, as well as administration guide-lines and side-effect managementstrategies pertaining to these therapies.

Breast Cancer DiseaseStratification: Predictive andPrognostic MarkersAdvances have recently been made inthe area of molecular profiling, whichmay help clinicians more accuratelyclassify subtypes of breast cancer, as wellas predict risk of recurrence andresponse to therapy.5 A number of geneshave been identified as important pre-dictive markers of chemotherapeuticand targeted therapy efficacy, and maybe used to guide more pa tient-specifictreatment. The technology of DNAmicroarray gene expression profiling hasled to a system of classifying breast can-cer into the following major subtypes:estrogen receptor (ER)-positive/humanepidermal growth factor receptor 2(HER2)-negative (lu minal A and Bsubtypes); ER-negative/HER2-negative(basal subtype); HER2-positive; andtumors that are similar to normal breasttissue (normal breast-like).6 Retro -spective analyses have shown that char-acteristic relapse-free survival and over-all survival (OS) are associated with

these gene expression subtypes.6 Keytumor markers and their role in themanagement of breast cancer are shownin Table 1.7Additional gene-based approaches

have been developed for prognostic andpredictive purposes. OncotypeDX is a21-gene assay used to estimate the riskof recurrence in patients with early-stage, ER-positive, node-negative breastcancer, and to identify patients whomay be successfully treated with tamox-ifen alone (without chemotherapy).6,7This test uses reverse transcription poly-merase chain reaction on RNA isolatedfrom paraffin-embedded breast cancertissue. MammaPrint is an assay that usesmicroarray technology to analyze a 70-gene expression profile from frozenbreast tumor tissue of patients withearly-stage, node-negative disease todetermine their risk of developing dis-tant metastases.6,8 Both of these multi-gene expression tests are commerciallyavailable and have been incorporatedinto several diagnostic protocols. It isimportant to note, however, that resultsfrom prospective trials evaluating theclinical value of these assays have yet tobe reported, al though 2 such trials(TAILORx and MINDACT) are cur-rently under way.

Current Management Strategies forPatients With MBCAlthough survival rates for MBC haveimproved over the past 20 years, the pri-mary goal of treatment is still palliation.

The decision-making pro cess regardingthe choice of agents and the sequencingand duration of therapy for metastaticdisease is complex, and requires consid-eration of numerous key factors, includ-ing the pathology, histology, and clini-cal characteristics of the tumor(s),axillary node status, hormone receptor(HR) and HER2 status, and patient-related factors (eg, age, menopausal status, and comorbid conditions).6

HR-Positive MBCThe goals of systemic therapy for recur-rent or metastatic disease are prolongingsurvival and improving quality of life.Therefore, treatments with minimaltoxicity are usually preferred and ofteninclude endocrine therapies (as opposedto cytotoxic therapies). Pa tients withHR-positive MBC (ie, those withtumors that are ER- and/or pro gesteronereceptor [PR]-positive) may benefitfrom initial endocrine therapy. Recentdata support treatment with a selectivearomatase inhibitor (AI) for post-menopausal women with previousantiestrogen therapy who are within 1year of antiestrogen exposure.6 For post-menopausal women who are anti estro-gen naïve or more than 1 year from pre-vious treatment with an antiestrogen,tamoxifen or an AI is an appropriatetherapeutic option.6 In this setting, AIshave shown a modestly superior out-come compared with tamoxifen.6Sequential treatment with endocrine

therapy may be beneficial at the time of

Metastatic Breast Cancer: Advances in Treatment andManagement

EXPIRATION DATE: FEBRUARY 4, 2012 • ESTIMATED TIME TO COMPLETE: 1.0 HOUR

COMPLETE THE POSTTEST AT WWW.THEONCOLOGYPHARMACIST.COM

TARGET AUDIENCE

This activity was developed for oncology nursesand pharmacists who wish to enhance their com-petence concerning the treatment of patients withmetastatic breast cancer.

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After completing this activity, the reader should beable to:• Discuss the impact of metastatic breast cancerand key parameters for disease stratification

• Describe the role of prognostic/genetic markersand tumor histology in classifying breast cancersubtypes and predicting treatment response

• Review advances in the treatment of metastaticbreast cancer, in cluding the role of endocrinetherapy, chemotherapy, targeted therapy, andbisphosphonates, with emphasis on targetedtherapies

• Examine effective patient-tailored treatmentapproaches, based on recent data and clinicalpractice guidelines

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Peer reviewers—Jayshree Shah, RN, APN-C, MSN,BSN, BS, is on the speakers’ bureau for Bristol-Myers Squibb, Celgene, Merck, and Novartis, andis on the advisory board for Bristol-Myers Squibband Novartis. Nancy Nesser, JD, PharmD, hasnothing to disclose.

• Joanna Schwartz, PharmD, BCOP, has nothingto disclose.

• Georgia Litsas, MSN, ANP-BC, AOCNP, is on thespeakers’ bureau for Genentech, Novartis, andPfizer.

The associates of Medical Learning Institute, Inc.,the accredited provider for this activity, andCenter of Excellence Media, LLC, do not have anyfinancial relationships or relationships to prod-ucts or devices with any commercial interestrelated to the content of this CE activity for anyamount during the past 12 months.

DISCLAImER

The information provided in this CE activity is forcontinuing education purposes only and is notmeant to substitute for the independent medicaljudgment of a healthcare provider relative todiagnostic and treatment options of a specificpatient’s medical condition. Trade names usedin this article are for the learner’s referenceonly. No promotion of or bias toward any prod-uct should be inferred.

COmmERCIAL SUPPORT

ACkNOwLEDGmENT

This activity is supported by an educational grantfrom Eisai, Inc.

CONTINUING EDUCATION



disease progression.6 Subsequent en -docrine therapy may include non-steroidal AIs (anastrozole or letrozole); asteroidal AI (exemestane); fulvestrant;tamoxifen or toremifene; meg estrolacetate; fluoxymesterone; or ethinylestradiol.6 For women with HR-positivemetastatic disease who have been previ-ously treated with an AI or antiestrogen,fulvestrant is an option that appears to bewell tolerated as a monthly injection,with an efficacy profile similar to anastro-zole and a longer duration of response.6

ER-Negative MBCBoth the American Society of Clini calOncology (ASCO) and the Nation alCom prehensive Cancer Network(NCCN) guidelines indicate an ab senceof benefit with endocrine therapy inwomen with ER-negative, invasivebreast cancer, based on large, random-ized, clinical trials.6,9 Chemo ther apy hasbeen shown to be more effective in thetreatment of patients with this type ofbreast cancer (compared with adjuvantendocrine therapy),6,10 with a dose-dense regimen of doxorubicin, cyclo -phosphamide, and paclitaxel showingthe greatest benefit in terms of reducingthe risk for recurrence and death.11

HER2-Positive MBCHER2 protein overexpression oc curs in 20% to 25% of breast tumors, oftenleading to aggressive disease and pooroutcomes.12 Consequently, successfultargeting of HER2-positive tumors is animportant therapeutic goal. Patientswith this type of MBC may benefit fromtreatment with trastuzumab as mono -therapy or in combination with selectchemotherapy agents; or with a combi-nation of capecitabine plus lapatinib forpatients who are refractory to treatmentwith an anthracycline, a taxane, andtrastuzumab. The preferred first-lineagents for treating HER2-positive dis-ease are listed in Table 2.6Trastuzumab, a recombinant human

anti-HER2 monoclonal antibody, spe -cifically targets signaling mechanisms ofHER2, which inhibits the growth oftumor cells that overexpress the re cep-tor. The addition of trastuzumab toanthracycline or taxane chemotherapyin patients with HER2-positive breastcancer has been shown to significantlyimprove time to progression, rate ofobjective response, and median sur-vival.13 Trastuzumab combined withother chemotherapeutic agents is also aviable option, and a number of combi-nations are available.6 Clinical trialsevaluating trastuzumab combined withother targeted agents, including per-tuzumab and lapatinib, are currentlyunder way.12Cardiac toxicity is a concern with

tras tuzumab treatment, particularlywhen this agent is combined with ananthracycline.6,14 According to NCCN

guidelines, trastuzumab should not beadministered concurrently with ananthracycline because of the risk of car-diac toxicity, except as part of theneoadjuvant regimen of trastuzumabplus paclitaxel followed by cyclophos-phamide/epiru bicin/fluorouracil.6 Closemonitoring of cardiac function isadvised for patients receiving trastu zu - mab therapy.6 Less serious side effectsassociated with this agent include nausea,vomiting, hot flashes, and joint pain.14,15

Resistance to trastuzumab often de -velops over time.16 One strategy forovercoming this resistance involvesswitching patients to lapatinib, a dualtyrosine kinase inhibitor that blocksHER2 signaling through an alternativemechanism.16 Lapatinib was approvedby the US Food and Drug Adminis -tration (FDA) in 2007 for use in combi-nation with capecitabine for the treat-ment of patients with advanced ormetastatic disease whose tumors over-express HER2 and who have receivedprior therapy, including an anthracy-cline, a taxane, and trastuzumab.17,18 In February 2010, lapatinib receivedapproval for an expanded indication incombination with letrozole for the treat-ment of postmenopausal women withHR-positive/HER2-positive MBC forwhom hormonal therapy is indicat-

ed.17,18 The approved labeling includes acaution stating that hepatotoxicity is apotentially serious adverse effect associ-ated with lapatinib.18

HR-Negative MBC and HR-Positive,Endocrine-Refractory MBCCytotoxic chemotherapy is recommend-ed for patients with HR-negative MBCas well as HR-positive disease refractoryto endocrine treatment. The NCCNguidelines recommend first-line single-agent chemotherapy until progression ofdisease.6 However, the adverse eventsassociated with this therapy may neces-sitate dose reductions or treatment ces-sation.6 Preferred single-agent and com-bination chemo therapy regimens forHR-negative and HR-positive, en -docrine-refractory breast cancer, as out-lined in these guidelines, are shown inTable 3.6

Recent Advances in the Treatmentof MBCTreatment options for patients withMBC continue to expand as investiga-tors learn more about the biology of thedisease and the process of metastasis.Recent advances in treatment in cludethe development of novel targetedagents, new formulations of existingdrugs, and more effective combinationregimens.

Microtubule-Targeting AgentsEribulin MesylateEribulin mesylate, a nontaxane micro- tubulin, was highlighted as a “notableadvance” in the treatment of breast cancer in ASCO’s annual report titledClinical Cancer Advances 2010.19 Re -presenting a new class of agents, eribulinis an analog of a chemical derived froma marine sponge. This drug wasapproved by the FDA in November2010 for the treatment of patients withMBC who previously received at least 2

chemotherapy regimens. This decisionwas based on preliminary results of thepivotal phase 3 EMBRACE trial (N =762), in which a significant improve-ment in OS (median of 2.47 months)was seen with eribulin compared withtreatment of physi cian’s choice (TPC).20Results from an updated analysis of thistrial, presented at the 2010 San AntonioBreast Cancer Symposium, were consis-tent with these earlier findings, with amedian OS of 13.2 months for eribulinversus 10.5 months for TPC.21 The mostrecently updated NCCN practice guide-lines list eribulin as a preferred singleagent for recurrent or metastatic disease.6The most common adverse events

(incidence ≥25%) associated with thisagent include neutropenia, asthenia/fatigue, anemia, peripheral neuropathy,nausea, and constipation.22

IxabepiloneIxabepilone, a semisynthetic analog ofepothilone B, received FDA ap proval in2007 as both a single agent and in com-bination with capecitabine for the treat-ment of locally advanced and metastaticdisease.6 Phase 2 clinical trials evaluat-ing ixabepilone mono therapy in thefirst-line setting have reported signifi-cant activity in patients who havereceived prior therapy with anthracy-clines and taxanes.23In a pivotal phase 3 trial comparing

ixabepilone plus capecitabine versus

decembeR 2011 I vol 4, No 8 23www.Theoncologypharmacist.com

To Receive cRediT, compleTe The posTTesT aTTheOncologyPharmacist.com

Table 1 Key Tumor Markers in Breast Cancer7

Tumor Marker Role

Estrogen receptor (ER)

Progesterone receptor (PR)

Determine whether the cancer is likelyto be successfully treated with hormonetherapy, such as tamoxifen.

Human epidermal growth factorreceptor 2 (HER2)

Determines whether the cancer can be treated with an anti-HER2 treatment,such as trastuzumab; in some cases, mayindicate whether additional treatmentwith chemotherapy may be beneficial.

Cancer antigen 15-3 (CA 15-3)

Cancer antigen 27.29 (CA 27.29)

Carcinoembryonic antigen (CEA)

Found in 50% to 90% of patients withmetastatic disease, these tumor markersmay point to early recurrence or indicatewhether the cancer is responding totreatment.

Urokinase plasminogen activator(uPA)

Plasminogen activator inhibitor (PAI-1)

High levels of these markers may indicate that the cancer is aggressive;these markers may guide the use ofchemotherapy after surgery for patientswith node-negative disease.

Table 2 NCCN Guidelines: PreferredFirst-Line Therapies for HER2-Positive Breast Cancer6

Preferred First-Line Agents

Trastuzumab with:• Paclitaxel + carboplatin• Docetaxel• Vinorelbine• Capecitabine

Preferred Chemotherapy Agents for Trastuzumab-Exposed HER2-Positive Breast Cancer

Lapatinib plus capecitabine• Trastuzumab plus other first-lineagents• Trastuzumab plus capecitabine• Trastuzumab plus lapatinib (without cytotoxic therapy)

HER2 indicates human epidermal growth factor receptor2; NCCN, National Comprehensive Cancer Network.

The goals of systemic therapy for recurrent ormetastatic disease are prolonging survival andimproving quality of life.


capecitabine alone in patients withresistance to previous anthracycline andtaxane therapy, a significant im prove-ment in progression-free survival (PFS)was seen with the combination regimen(6.2 months vs 4.4 months, respective-ly; P = .0005).24

The most common adverse events(≥20% incidence) associated withixabepilone include peripheral neu-ropathy, fatigue/asthenia, myalgia/arthralgia, alopecia, nausea, vomiting,stomatitis/mucositis, diarrhea, andmusculoskeletal pain.24

Nab-paclitaxelNanoparticle albumin-bound (nab)-paclitaxel is a solvent-free, albumin-bound 130-nm particle form of paclitax-el that was developed to avoid toxicitiesassociated with the cremo phor vehicleused in solvent-based paclitaxel. Thisagent was approved by the FDA inJanuary 2005 for the treatment of breastcancer after failure of combination ther-apy for metastatic disease or relapsewithin 6 months of adjuvant chemo -therapy.25 A phase 3 trial (N = 454)compared nab-paclitaxel with a conven-tional formulation of the drug in MBC,showing a higher target-lesion responseand objective response rates with nab-paclitaxel.25 In a separate phase 2 trial(N = 302) in previously un treatedMBC, nab-paclitaxel demonstrated sig-nificantly longer PFS than docetaxel byboth independent radiologist assess-ment (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 HER2-Positive MBCIn a recent phase 3 trial, dual HER2-targeted therapy with lapatinib andtrastuzumab showed an increase in PFScompared with lapatinib alone (12weeks vs 8.1 weeks; P = .008) in

patients with heavily pretreated MBCand disease progression on trastuzumabtherapy.27 In addition, according torecent data, the combination of lapa-tinib, trastuzumab, and paclitaxel wasassociated with a significant improve-

ment in tumor response rate comparedwith individual agents in patients withHER2-positive disease.28

According to preliminary findingsfrom a phase 1b/2 trial, trastuzumab-DM1 (T-DM1) plus pertuzumab dem -onstrated encouraging safety and effica-cy in women with HER2-positive,locally advanced or metastatic diseasewho were previously treated with tras -tuzumab.29 T-DM1, an HER2-targetedantibody-drug conjugate, is composedof the cytotoxic agent DM1, an anti -microtubule agent, conjugated to themonoclonal antibody trastuzumab.29,30Pertuzumab, a humanized monoclonalantibody, is the first HER2-directeddimerization inhibitor for the treatmentof HER2-positive breast cancer. T-DM1and pertuzumab bind to different HER2receptors; combining these agents hasshown synergistic antitumor activity inHER2-positive xeno graft models.29,30

Emerging Therapies for Triple-Negative DiseaseTriple-negative breast cancer (TNBC)is a term used to describe tumors thatlack expression of ER, PR, and HER2.This type of breast cancer is associatedwith rapid disease progression and poorprognosis. Therefore, advances in treat-ment for this subtype of disease are par-ticularly noteworthy. A recent studyfound that TNBC patients withBRCA1/BRCA2 mutations appear tohave better survival than patients with-out these mutations.31

PARP InhibitorsPoly(adenosine diphosphate–ribose)polymerase (PARP) inhibitors appear tohave clinical activity in BRCA1-/BRCA2-associated cancer. Results froma phase 2 study (N = 123) showed thatthe PARP inhibitor, iniparib, pluschemotherapy was associated with sig-nificantly prolonged OS in TNBC,compared with chemotherapy alone

(12.3 months vs 7.7 months, respective-ly; hazard ratio for death, 0.57; P = .01).32In addition, another PARP inhibitor,olaparib, is being investigated for itspotential activity when combined withpaclitaxel.33 In a small study (N = 10), 4patients achieved a partial response withthis combination; however, acceptabledose intensity was delayed or notachieved because neutropenia wasreported in a number of patients.34 Inanother small study (N = 24), noresponses were observed in patientswith TNBC treated with olaparib pluspaclitaxel.33

CetuximabCetuximab, an antibody that targetsepithelial growth factor receptor, isbeing studied for its potential role intreating TNBC. Based on results of arecent phase 2 trial (N = 173), addingcetuximab to cisplatin chemotherapyin heavily pretreated patients withTNBC resulted in twice the responserate and twice the time to progressioncompared with patients who receivedcisplatin alone.35

Bone Disease in Patients With MBCBone metastasis, which occurs in approx-imately 70% of patients with advancedbreast cancer,36 can lead to significantskeletal morbidity, including bone pain,pathologic fracture, hypercalcemia ofmalignancy, and spi nal cord compres-sion.36 Patients with breast cancer whoare treated with AIs (eg, anastrozole,letrozole, exemestane) are at increasedrisk for bone loss and fractures.37

Bisphospho nates have dem onstrated effi-cacy in delaying the onset and reducingthe incidence of skeletal-related events(SREs) associated with bone metasta-sis.38 The recently approved agent, deno-sumab, has also been shown to be effec-tive in preventing these events inpatients with bone metastases from solidtumors.39



In February 2008, the FDA granted acceleratedapproval of bevacizumab in combination withpaclitaxel for the first-line treatment of HER2-

negative MBC. This approval was based on re sults ofE2100, a phase 3 trial in which initial treatment withthis combination almost doubled PFS compared withpaclitaxel alone in women with recurrent or metasta-tic disease (11.8 months vs 5.9 months, respectively;P <.001).1 Subsequent phase 3 trials also demonstrat-ed longer PFS when bevacizumab was added to vari-ous first-line che motherapeutic regimens for MBC,but these gains were not as clinically significant asthose seen in the E2100 trial.2,3 A recent meta-analy-sis of these trials failed to show an improvement inOS with the addition of bevacizumab.4

Given the fact that bevacizumab use has beenassociated with serious ad verse events, including

hypertension, bleed ing, and febrile neutropenia,2,3,5the FDA is now questioning whether the benefits ofthis drug outweigh the risks for women with MBC.6After consideration of the data, the agency’s reviewpanel announced that it was revoking this indica-tion.6 The manufacturer of bevacizumab has re quest-ed a hearing to maintain their drug as a treatmentoption for HER2-negative MBC.7 It should be noted,however, that the European Medicines Agency andthe National Comprehensive Cancer Net work haveboth indicated that bevacizumab plus paclitaxelshould remain a therapeutic option for women withthis type of breast cancer.8

References1. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versuspaclitaxel 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 plusdocetaxel compared with placebo plus docetaxel for the first-line treat-ment of human epidermal growth factor receptor 2-negative metastaticbreast cancer. J Clin Oncol. 2010;28:3239-3247.3. Robert NH, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or withoutbevacizumab (B) for first-line treatment of HER2-negative locally recur-rent 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 sur-vival data from three randomized trials of bevacizumab (BV) and first-linechemotherapy 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 removebreast 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 in dication. http://ascopost.com/articles/january-15-2011/fda-recommends-removal-of-bevacizumab’s-breast-cancer-indication. Accessed January 13, 2011.

Update on Bevacizumab Use in Breast Cancer

Table 3 NCCN Guidelines: PreferredFirst-Line Chemotherapies

for Patients With HR-Negative or HR-Positive, Endocrine-Refractory BreastCancer6

Single Agents

Anthracyclines• Doxorubicin• Epirubicin• Pegylated liposomal doxorubicin

Taxanes• Paclitaxel• Docetaxel• Albumin-bound paclitaxel

Antimetabolites• Capecitabine• Gemcitabine

Nontaxane Microtubule Inhibitors• Eribulin• Vinorelbine

Combination Regimens

Cyclophosphamide, doxorubicin, and fluorouracil (FAC/CAF)

Fluorouracil, epirubicin, cyclophosphamide (FEC)

Doxorubicin, cyclophosphamide(AC)

Epirubicin, cyclophosphamide (EC)

Doxorubicin in combination witheither docetaxel or paclitaxel (AT)

Cyclophosphamide, methotrexate, fluorouracil (CMF)

Docetaxel, capecitabine

Gemcitabine, paclitaxel

HR indicates hormone receptor; NCCN, NationalComprehensive Cancer Network.



Bisphosphonate TherapyThe use of bisphosphonates is consid-ered a palliative care measure in patientswith MBC; these agents may also play arole in preventing skeletal complica-tions associated with bone loss.6 The 2 intravenous (IV) bisphosphonatesapproved by the FDA for the treatmentof bone metastases are zoledronic acidand pamidronate. Both of these agentshave been studied in numerous clinicaltrials, and zoledronic acid appears to besuperior to pami dronate in patients withlytic breast metastasis.6 Recent data alsosuggest that zoledronic acid may haveantitumor properties.40 Zoledronic acidand pamidronate may help to decreasethe pain related to bone metastasis,thereby reducing the need for supple-mental analgesics in some patients.41Generally, IV bisphosphonates are

well tolerated. However, osteonecrosisof the jaw (ONJ), a rare but serious com-plication, may occur.6 Most reportedcases of ONJ during bisphosphonatetherapy have been associated with den-tal procedures such as tooth extractions.A dental examination is recommendedprior to treatment, and invasive proce-dures during therapy should be avoidedwhenever possible.6In addition, serum creatinine should

be monitored prior to each dose of zole-dronic acid or pamidronate. Accordingto recent data, short-term use (≤12months) of these agents is associatedwith a low risk of renal dysfunction.41However, the effects of extended thera-py have not been studied extensively.41

Denosumab Denosumab, a fully human monoclonalantibody, was approved by the FDA inNovember 2010 for the prevention ofSREs in patients with bone metastasesfrom solid tumors.39 This novel agentinhibits bone resorption by specificallytargeting the receptor activator ofnuclear-factor kappa beta ligand(RANKL) and its receptor, RANK, keymediators of osteoclast formation andfunction.42 Phase 3 data presented at the 2010

San Antonio Breast Cancer Sympo -sium showed that denosumab was supe-rior to zoledronic acid in delaying thetime to first on-study SREs by 18%, anddenosumab delayed the time to first-and-subsequent on-study event by22%.43 Moreover, in patients withadvanced breast cancer and bonemetastases who were at risk, the medi-an time to first on-study SRE was 5months longer in the denosumab groupcompared with the zoledronic acidgroup. Denosumab was also associatedwith less pain, less interference withdaily functioning, and improvedhealth-related quality of life, based onother data presented at this meeting.43In general, the rate of adverse events

associated with denosumab was similarto the rate observed with zoledronicacid; cases of ONJ were rare, andhypocalcemia was more frequent in thedenosumab arm.39 Calcium levels mustbe monitored in patients receivingdenosumab, and administration of calci-um, magnesium, and vitamin D may berequired.39 The most common ad verseevents associated with denosu mab werefatigue/asthenia, hypo phos phatemia,and nausea; dyspnea was the most com-mon serious adverse event.39

ConclusionExtended survival and improved qualityof life are of paramount importance inpatients with MBC. Advances in sys-temic, hormonal, and targeted therapiesare yielding novel ap proaches and pro-tocols that hold promise for improvingclinical outcomes. Addressing pain andother disease-related comorbidities andpreventing SREs are also key aspects ofmanaging patients with MBC. Theapproach to treatment continues alongthe path of personalized care plans thatare based on tumor/disease profile,patient-specific factors, and patient andphysician preferences. Increasing atten-tion is being directed toward the use ofgenetic markers and other tools thathelp clinicians stratify patients who willreceive maximal benefit from a specifictherapy while sparing those patientswho may not benefit from such regi-mens. Research continues to focus onthe development of novel therapies thatincrease response and survival time forpatients with MBC, while minimizingtoxicity and other adverse events. �

References1. 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 thekey statistics about breast cancer? Reviewed September17, 2010. http://www.cancer.org/cancer/breastcancer/detailedguide/breast-cancer-key-statistics. AccessedDecember 28, 2010.3. O’Shaughnessy J. Extending survival with chemother-apy in metastatic breast cancer. Oncologist. 2005;10(suppl 3):20-29.4. MBC Advocacy Working Group. Metastatic breastcancer patients: addressing their unmet needs-SpecialReport. Commun Oncol. 2008;5:645-647.5. Moulder S, Hortobagyi GN. Advances in thetreatment of breast cancer. Clin Pharmacol Ther.2008;83:26-36.6. National Comprehensive Cancer Network. NCCN

Clinical Practice Guidelines in On cology™. BreastCancer, V.2.2011. December 16, 2010. http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf. AccessedDecem ber 29, 2010. 7. American Society of Clinical Oncology. What toknow: ASCO’s guideline on tumor markers for breastcancer. Updated October 6, 2010. http://www.cancer.net/patient/Publications+and+Resources/What+to+Know%3A+ASCO%27s+Guidelines/What+to+Know%3A+ASCO%27s+Guideline+on+Tumor+Markers+for+Breast+Cancer?sectionTitle=Introduction&sectionId=102827&vgnextrefresh=1. Accessed December 29, 2010.8. Knauer M, Rutgers EJ, Mook S, et al. Evalu ation ofthe 70-gene prognosis MammaPrint signature for theprediction of prognosis of breast cancer independentlyfrom 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 ofAmerican Pathologists guideline recommendations forimmunohistochemical testing of estrogen and proges-terone receptors in breast cancer. J Clin Oncol.2010;28:2784-2795.10. Early Breast Cancer Trialists’ Collaborative Group(EBCTCG). Effects of chemotherapy and hormonaltherapy for early breast cancer on recurrence and 15-yearsurvival: an over view of the randomised trials. Lancet.2005;365:1687-1717.11. Berry DA, Cirrincione C, Henderson IC, et al.Estrogen-receptor status and outcomes of modernchemotherapy for patients with node-positive breastcancer. JAMA. 2006;295:1658-1667.12. Brufsky A. Trastuzumab-based therapy for patientswith HER2-positive breast cancer: from early scientificdevelopment to foundation of care [abstract]. Am J ClinOncol. Epub August 11, 2009 [ahead of print].13. Cobleigh MA, Vogel CL, Tripathy D, et al.Multinational study of the efficacy and safety of human-ized anti-HER2 monoclonal antibody in women whohave HER2-overexpressing metastatic breast cancer thathas progressed after chemotherapy for metastatic disease.J Clin Oncol. 1999;17:2639-2648.14. Herceptin (trastuzumab) [package insert]. SanFrancisco, CA: Genentech, Inc; 2010.15. National Cancer Institute. US National In stitutes ofHealth. Adjuvant and neoadjuvant therapy for breastcancer. Rev June 16, 2009. http://www.cancer.gov/cancertopics/fact sheet/Therapy/adjuvant-breast.Accessed De cember 29, 2010.16. Geyer CE, Forster J, Lindquist D, et al. Lapa tinibplus capecitabine for HER2-positive advanced breastcancer. 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]. ResearchTriangle Park, NC: GlaxoSmithKline; 2010.19. Clinical cancer advances 2010—ASCO’s annualreport on progress against cancer. J Clin Oncol. Epubahead of print. November 8, 2010. http://www.cancer.net/patient/Publications%20and%20Resources/Clinical%20Cancer%20Advances/CCA_2010.pdf.Accessed Decem ber 10, 2010.20. Twelves C, Loesch D, Blum JL, et al. A phase III study(EMBRACE) of eribulin mesylate versus treatment ofphysician’s choice in pa tients with locally recurrent ormetastatic breast cancer previously treated with ananthracycline and a taxane. Presented at the 2010 annualmeeting 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 survivalanalysis of a phase III study (EMBRACE) of eribulinmesylate versus treatment of physician’s choice in sub-jects with locally recurrent or metastatic breast cancerpreviously treated with an anthracycline and a taxane.Presented at the 33rd annual San Antonio BreastCancer Symposium. December 8-12, 2010. SanAntonio, 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 agentwith low susceptibility to multiple tumor resistancemechanisms. Oncologist. 2008;13:214-221.24. Sparano JA, Vrdolja E, Rixe O, et al. Ran domizedphase III trial of ixabepilone plus capecitabine versuscapecitabine in patients with metastatic breast cancerpreviously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28:3256-3263.25. Robinson DM, Keating GM. Albumin-bound pacli-taxel: in metastatic breast cancer. Drugs. 2006;66:941-948. 26. Gradishar WJ, Krasnojon D, Cheporov S, et al.Significantly longer progression-free survival withnab-paclitaxel compared with docetaxel as first-line

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 combinationwith trastuzumab in women with ErbB2-positive,trastuzumab-refractory meta static breast cancer. J ClinOncol. 2010;28:1124-1130.28. Combination therapy reduced HER2-positive breastcancers. 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 trialof trastuzumab-DM1 (T-DM1) with pertuzumab (P) forwomen with HER2-positive, locally advanced ormetastatic breast cancer (BC) who were previously treat-ed with trastuzumab (T). J Clin Oncol. 2010;28(suppl).Abstract 1012.30. Susman E. ASCO: new agents show promise inHER2-positive breast cancer [press release]. MedpageToday. Released June 8, 2010. http://www.medpagetoday.com/tbprint.cfm?tbid+20550. Article 20550. 31. University of Florida—Shands Cancer Center.BRCA1/2 mutations linked with better outcome intriple-negative breast cancer. Breast cancer news.http://cancer.ufl.edu/2010/10/13/brca12-mutations-linked-with-better-outcome-in-triple-negative-breast-cancer/. Accessed De cember 30, 2010.32. O’Shaughnessy J, Osborne C, Pippen JE, et al.Iniparib plus chemotherapy in metastatic triple-negativebreast cancer. N Engl J Med. Epub ahead of print. January5, 2011.33. Susman E. Olaparib may have promise in breast can-cer. Medpage Today. June 8, 2010. http://www.medpagetoday.com/MeetingCoverage/ASCO/ 20546. AccessedDecember 30, 2010.34. Dent RA, Lindeman GJ, Clemons M, et al. Safetyand efficacy of the oral PARP inhibitor olaparib(AZD2281) in combination with paclitaxel for the first-or second-line treatment of patients with metastatictriple-negative breast cancer: results from the safetycohort of a phase I/II multicenter trial. J Clin Oncol.2010;28:15s(suppl). Abstract 1018.35. Triple-negative breast cancer responds well to cetux-imab addition to chemotherapy [press release]. MedicalNews Today. October 12, 2010. http://www.medicalnewstoday.com/articles/204334.php. Accessed December 30,2010. 36. Roodman GD. Mechanisms of bone metastasis. NEngl J Med. 2004;350:1655-1664. 37. Cancer treatment may result in bone loss [pressrelease]. Medical News Today. November 16, 2008.http://www.medicalnewstoday.com/articles/129429.php.Accessed Decem ber 8, 2010.38. Coleman R. On the horizon: can bisphos phonatesprevent bone metastases? Breast. 2007;(3)Suppl;S21-7.Epub November 7, 2007. Review.39. FDA approves Amgen’s Xgeva (denosumab) for theprevention of skeletal-related events in patients withbone 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 pre-menopausal breast cancer. N Engl J Med. 2009;360:679-691. 41. Hillner BE, Ingle JN, Chlebowski RT, et al. AmericanSociety of Clinical Oncology 2003. Update on the role ofbisphosphonates and bone health issues in women withbreast cancer. J Clin Oncol. 2003;21:4042-4057.42. Lipton A, Jun S. RANKL inhibition in the treat-ment of bone metastases. Curr Opin Support Palliat Care.2008;2:197-203.43. Amgen presents new XGEVA (denosumab) breastcancer skeletal-related event prevention data atSABCS. December 11, 2010. Medical News Today.http://www.medicalnewstoday.com/articles/211175.php.Accessed December 14, 2010.


HER2 protein over-expression occurs in20% to 25% of breasttumors, often leading toaggressive disease andpoor outcomes.


Breast cancer is the most commonfemale malignancy worldwide,with an annual global incidence

of over 1 million and a resulting450,000 deaths.1 Although the diagno-sis of localized breast cancer is morecommon since the advent of screeningmammogram guidelines, the number ofwomen diagnosed with metastatic dis-ease is still significant.2 The prognosisfor advanced metastatic breast cancer(MBC) is very poor, with only 1 in 5women surviving for 5 years.2Anthracyclines and taxanes are

among the most active drugs used totreat breast cancer; however, a signifi-cant number of patients become resis - tant to these therapies over time, result-ing in low response rates.3,4 In somecases, resistance is due to the ex pressionof multidrug-resistant (MDR) proteinproducts of the MDR gene, such as P-glycoprotein. This results in the produc-tion of drug efflux pumps, which active-ly transport many chemo therapy agents,such as taxanes, out of cancer cells.5Drug resistance is especially problem-

atic for patients with triple-negativebreast cancer (TNBC) and/or breastcancer with the BRCA mutation (defi-ciency), as these types of malignanciesare inherently resistant to most cytotox-ic therapies.6 In the case of TNBC,patients who develop resis tance are leftwith very limited treatment options, asthey are not candidates for hormonal ortargeted agents, due to a lack of tumorreceptors. Fur thermore, TNBC is themost aggressive type of breast cancer andis associated with the poorest prognosis.7There is an important need for novel

agents to address these challenges inthe treatment of breast cancer. Twonew cytotoxic drug classes, epothilonesand halichondrins, and 1 new targeteddrug class, poly(adenosine diphos-phate–ribose) polymerase (PARP) in -hibitors, have been developed to meetthis need.

Novel Microtubule-TargetingAgents IxabepiloneIxabepilone was the first agent from theepothilone class to be approved by theUS Food and Drug Administration(FDA) for the treatment of metastaticor locally advanced breast cancer.Epothilones are naturally occurringmacrolide antibiotics, produced by themyxobacterium Sorangium cellulosum,and are nontaxane microtubule inhib -itors. The taxanes exert their cytotoxic

effect by binding tubulin, and stabiliz-ing the microtubule and inhibiting itsdisassembly, ultimately leading to celldeath by apoptosis. Although epo -thilones have a similar mechanism ofaction, these novel agents bind to tu -bulin at a different site. Importantly,epothilones appear to retain activity incell lines expressing the P-glycoproteinpump, which, as mentioned earlier, is aknown cause of resistance to agentssuch as taxanes.8

The combination of ixabepilone pluscapecitabine was evaluated in a phase 3randomized double-blind clinical trialof patients with MBC resistant to treat-ment with anthracyclines and taxanes.As shown in the Table, this combina-tion was associated with significantlylonger median progression-free survival(PFS) than capecitabine alone (6.2 vs4.2 months; P = .0005), as well as ahigher response rate (43% vs 29%; P <.0001).9 Ixabepilone monotherapyhas also demonstrated clinical activityin patients with MBC after failure ofcapecitabine in several phase 2 trials,with objective response rates rangingfrom 12% to 18%.10-12The main toxicities observed in clin-

ical trials of ixabepilone have includedperipheral neuropathy, fatigue, myal-gia/arthralgia, diarrhea, neutropenia,and less commonly, hypersensitivityinfusion reactions. Ixabepilone is re con-stituted with a supplied diluent contain-ing polyethoxylated castor oil, which isa known cause of reactions with otheragents, such as paclitaxel.13 Based on data from the above-men-

tioned trials, ixabepilone was ap provedby the FDA in 2007 for the followingindications: (1) in combination withcapecitabine for treatment of pa tientswith metastatic or locally ad vancedbreast cancer resistant to treatmentwith an anthracycline and a taxane orwhose cancer is taxane resis tant and forwhom further anthracycline therapy iscontraindicated, and (2) as single-agenttherapy for the treatment of metastaticor locally advanced breast cancer inpatients whose tumors are resistant orrefractory to anthracyclines, taxanes,and capecitabine.14 According to the approved package

labeling, ixabepilone should be admin-istered intravenously (IV) over 3 hoursat a dose of 40 mg/m2 (to a maximum of88 mg for patients with a body surfacearea >2.2 m2) every 3 weeks. Patientsshould be premedicated with a hista-mine-1 antagonist such as diphenhy-dramine and a histamine-2 antagonistsuch as ranitidine 1 hour before ixabepi-lone and should be closely monitoredfor hypersensitivity reactions prior tothe first 2 infusions. Ixabepilone isextensively metabolized by the liver,and the package labeling contains spe-cific dosing recommendations forpatients with hepatic impairment.14 Infact, the combination of ixabepiloneand capecitabine is contraindicated

when the total bilirubin rises over theupper limit of normal. This prescribinginformation should be consulted forspecific dose adjustments for patientswith elevated liver function tests or sig-nificant toxicities, such as neutropeniaor neuropathy. Com plete blood counts,examination for neurologic symptoms,and liver function tests should be per-formed prior to every dose, and the useof strong cytochrome P-450 3A4inhibitors (including grapefruit juice)should be avoided.14

Eribulin MesylateEribulin mesylate is a novel microtubuleinhibitor with a distinct mechanism ofaction. Other microtubule inhibitors,such as taxanes, vinca alkaloids, andepothilones, inhibit both growth andshortening of microtu bules. In contrast,eribulin suppresses microtubule growthwith no effect on microtubule shorten-ing, and also sequesters tubulin intononfunctional aggregates. It is a syn-thetic analog of the marine naturalmacrolide halichondrin B, which wasfirst isolated from the Japanese spongeHalichondria okadai, and is the first inclass of the halichondrins.15Eribulin was FDA approved in

November 2010 for the treatment ofpatients with MBC who have previous-ly received anthracyclines and taxanes,based on the results of the pivotal phase3 EMBRACE trial. This study wasdesigned to represent common practicesituations in that the 762 enrolledpatients with metastatic or locallyrecurrent breast cancer had been heavi-ly pretreated with 2 to 5 previouschemotherapy regimens that includedan anthracycline and a taxane.16Furthermore, patients were randomizedto eribulin or a treatment of physician’schoice (TPC), which could be anymonotherapy (cytotoxic, hormonal,biologic) or supportive care only. Thischoice was considered representative ofactual practice scenarios, since there isno current standard of care for breastcancer patients after failure of anthracy-clines and taxanes. The primary endpoint of this trial was overall survival(OS); secondary end points were objec-tive response rate, PFS, and duration ofresponse. Median OS was significantlyprolonged with eribulin compared withTPC (13.12 vs 10.65 months, a differ-ence of 2.47 months; P = .041). The 1-year survival was 53.9% with eribulinand 43.7% with TPC (Figure 1).16Although the trial did not show a statis-



Novel Targeted Agents for the Treatment of Metastatic Breast CancerBy Joanna Schwartz, PharmD, BCOP

Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Colchester, VT

Table Phase 3 Trial of Ixabepilone Plus Capecitabine Versus Capecitabine Alone inMBC Resistant to Anthracyclines and Taxanes9

Ixabepilone + Capecitabine Capecitabine P Value

Median PFS,months

6.2 4.2 .0005

ORR, % 43 29 .0001Best response, N (%)

CRPRSDPD

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.

In the case of TNBC,patients who develop resistance are left withvery limited treatmentoptions.


tically significant improvement in PFS(albeit a strong trend in favor of eribu-lin), the results are still significant inthat eribulin is the first agent to demon-strate an OS advantage for MBC sincedocetaxel was approved more than 10years ago. The main toxicities observed in the

eribulin arm of the trial were neutro -penia, anemia, peripheral neuropathy,alopecia, nausea (mostly mild), myal-gia/arthralgia, fatigue, constipation, andQT prolongation (rare).16 Ac cording tothe package labeling, eribulin should beavoided in those with congenital longQT syndrome, and electrolytes shouldbe corrected prior to initiating therapy,and monitored periodically duringtreatment.17Eribulin should be administered IV

over 2 to 5 minutes at a dose of 1.4mg/m2 on days 1 and 8 of a 21-day cycle.Because eribulin is extensively hepati-cally cleared with some metabolitesbeing renally cleared, the package label-ing should be consulted for suggesteddosing modifications for mild-to- moderate hepatic impairment and/or acreatinine clearance <50 mL/min.There is no safety data or dosing recom-mendations for those with a creatinineclearance <30 mL/min. Patients shouldbe assessed for peripheral neuropathyand with complete blood counts prior to each dose, and therapy should bedelayed for significant neuropathy or anabsolute neutrophil count <1000/mm3

and/or platelets <75,000/mm3. Thepackage labeling should also be consult-ed for suggested dosage reductions inthe event of very low blood counts,febrile neutropenia, or toxicities that donot resolve within 7 days.17

PARP Inhibitors for MBCPARP inhibitors appear to be amongthe most promising agents being studiedfor the treatment of BRCA-mutatedbreast cancer and TNBC. Both BRCA1and BRCA2 are involved in the repairof DNA damage (in particular, double-strand DNA breaks), which arises fromexposure to chemotherapy. This pro cessis known as homologous recombina-tion. DNA damage is essential in thetreatment of cancer, as it triggers cellcycle arrest and cell death.18 In womenwith BRCA-mutated breast cancer, thetumor loses the wild-type allele ofBRCA1 or 2 and is left with a nonfunc-tioning BRCA1 or 2 protein.19-21 Whenthis occurs, another pathway of DNArepair, known as base excision repair,allows the cancer cell to recover fromDNA damage. This pathway is de pend-ent on the function of enzymes calledPARPs, which repair single-strandDNA breaks. Investigators havehypothesized that PARP inhibition, inconjunction with the loss of DNArepair via BRCA-dependent mecha-

nisms, may result in synergistic tumorcell death (Figure 2).22 Triple-negativetumors, while not all stemming fromBRCA mutation, share characteristicswith BRCA1-associated breast tumorsand may harbor other genetic lesionsthat impair double-strand repair.21 Currently, there are 8 PARP inhib -

itors in clinical trial developmentworldwide, but only 3 agents are beingevaluated in late-stage clinical trials:olaparib, veliparib, and iniparib. Todate, the largest and most promising tri-als of PARP inhibitors in breast cancerinclude a phase 2 multicenter, single-arm trial of olaparib in patients withrefractory, advanced BRCA-mu tatedbreast cancer,23 and a randomized, phase

2 trial investigating iniparib in combi-nation with gemcitabine and carbo-platin in patients with TNBC.24Additionally, re sults of a small phase 2trial of veliparib in combination withtemozolomide in patients with ad -vanced refractory breast cancer (notrestricted to BRCA or triple-negativestatus) were recently presented at the2010 American Society of ClinicalOncology annual meeting. Althoughthese were only preliminary findings,several excellent clinical responses werereported, including 1 complete re sponseand 2 partial responses in 24 evaluablepatients.25 In the phase 2 single-agent study,23 54

women with recurrent MBC and con-

firmed BRCA mutations were ad minis-tered olaparib 100 or 400 mg orallytwice daily. The overall response ratewas 22% in the 100-mg group and 41%in the 400-mg group. In the phase 2combination study,24 123 women withmetastatic TNBC were randomized toeither gemcitabine and carboplatinalone, or the same agents in combina-tion with IV iniparib on days 1, 4, 8, and11 of a 21-day cycle. Updated re sults ofthis trial showed that the combinationwith iniparib extended OS by approxi-mately 4 months compared with gemcitabine/carboplatin alone (12.3 vs 7.7months, P = .01).Results of these studies indicate the

potential of PARP inhibition as atumor-specific target in specific patientpopulations, considering most of theparticipants had been refractory to sev-eral prior therapies. As a class, thePARP inhibitors are well tolerated,and the most common toxicities seenin clinical trials have included low-grade fatigue and nausea.23-25 BeforePARP inhibitors can be considered forpossible wider use outside of clinicaltrials, it will be necessary to identifythe best candidates for this therapy andto determine which agents will be mosteffective when used in combination withspecific PARP inhibitors. In addition,the clinical activity of these agents needsto be assessed in ongoing randomized,comparative, phase 3 trials.

ConclusionsLimited options make the successfultreatment of MBC difficult. Currenttreatment options include anthracy-clines, taxanes, and capecitabine. Re -sistance to these classes of drugs is oftenacquired, thus highlighting the need fornewer agents capable of managing treat-ment-resistant disease. Two new agents,ixabepilone and eribulin, are novelmicrotubule agents that have been FDAapproved and provide op tions forpatients who are resistant or intolerantto other therapies. The addition ofthese therapies into the breast cancerarmamentarium has expanded treat-ment options for patients with MBC.Several PARP inhibitors are in late-phase development and in the futuremay provide promising treatmentoptions to specific patients, especiallywomen with BRCA mutations orTNBC. Continued research into theseagents will be necessary to further


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

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

Reprinted with permission from Iglehart JD, Silver DP: Synthetic lethality―a new direction in cancer-drug development. N Engl J Med. 2009;361:189-191. Copyright © 2009 Massachusetts MedicalSociety.

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


Two new agents, ixabepilone and eribulin, are novelmicrotubule agents that have been FDA approvedand provide options for patients who are resistant orintolerant to other therapies.


define their place in therapy. Furtherresults of ongoing studies with all ofthese agents are keenly awaited. �

References1. 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 glob-al health concern. Cancer Epidemiol. 2009;33:315-318. 3. Hortobagyi GN. Treatment of breast cancer. N Engl JMed. 1998;339:974-984. 4.O’Shaughnessy J, Twelves C, Aapro M. Treat ment foranthracycline-pretreated metastatic breast cancer.Oncologist. 2002;7(suppl 6):4-12.5. Kruh GD. Introduction to resistance to anticanceragents. Oncogene. 2003;22:7262-7264. 6. Greenberg S, Rugo HS. Challenging clinical scenar-ios: treatment of patients with triple-negative or basal-like metastatic breast cancer. Clin Breast Cancer.2010;10(suppl 2):S20-S29.7. Foulkes WD, Smith IE, Jorge RS. Triple negativebreast 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. Randomizedphase III trial of ixabepilone plus capecitabine versuscapecitabine in patients with metastatic breast cancerpreviously 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 safe-ty of ixabepilone (BMS-247550) in a phase II study ofpatients with advanced breast cancer resistant to ananthracycline, a taxane, and capecitabine. J Clin Oncol.2007;25:3407-3414.11. Thomas E, Tabernero J, Fornier M, et al. Phase IIclinical trial of ixabepilone (BMS-247550), anepothilone B analog, in patients with taxane-resistantmetastatic breast cancer. J Clin Oncol. 2007;25:3399-3406. 12. Low JA, Wedam SB, Lee JJ, et al. Phase II clinicaltrial of ixabepilone (BMS-247550), an epothilone Banalog, in metastatic and locally advanced breast can-cer. J Clin Oncol. 2005;23:2726-2734. 13.Taxol [package insert]. Princeton, NJ: Bristol-MyersSquibb 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 primaryantimitotic mechanism of action of the synthetic hali-chondrin 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 ofphysician’s choice in patients with locally recurrent ormetastatic breast cancer previously treated with ananthracycline and a taxane. Presented at the 2010 annu-al meeting of the American Society of Clinical Oncology.June 4-8, 2010. Chicago, IL. Abstract CRA 1004.17. Halaven [package insert]. Woodcliff Lake, NJ: EisaiInc; November 2010.18. Fong PC, Boss DS, Yap TA, et al. Inhibition ofpoly(ADP-ribose) polymerase in tumors from BRCAmutation carriers. N Engl J Med. 2009;361:123-134.19. Chen S, Parmigiani G. Meta-analysis of BRCA1and BRCA2 penetrance. J Clin Oncol. 2007;25:1329-1333.20. Sorlie T, Perou CM, Tibshirani R, et al. Geneexpression patterns of breast carcinomas distinguishtumor subclasses with clinical implications. Proc NatlAcad Sci U S A. 2001;98:10869-10874.

21. Tommiska J, Bartkova J, Heinonen M, et al. TheDNA damage signaling kinase ATM is aberrantlyreduced or lost in BRCA1/BRCA2-deficient andER/PR/ERBB2-triple-negative breast cancer. Oncogene.2008;27:2501-2506.22. Iglehart JD, Silver DP. Synthetic lethality—a newdirection 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 patientswith BRCA1 or BRCA2 mutations and advanced breastcancer: 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 demon-strating efficacy and safety of BSI-201, a PARP-inhibitor, in combination with gemcitabine/carboplatinin metastatic triple negative breast cancer (abstract3122). Presented at the 2009 San Antonio BreastCancer Symposium, December 9-12, 2009, SanAntonio, TX.25. Isakof SJ, Overmoyer B, Tung NM, et al. A phase IItrial of the PARP inhibitor veliparib (ABT888) andtemozolomide for metastatic breast cancer. J Clin Oncol.2010;28:15s(suppl; abstract 1019).



menopausal patients with ER-positiveadvanced breast cancer progressing on anonsteroidal aromatase inhibitor toexemestane alone or exemestane plusweekly entinostat. Median progression-free survival (PFS) was 4.28 monthswith entinostat/exemestane versus 2.27months with exemestane alone, a 27%statistically significant reduction in risk.

Median overall survival (OS) was 26.9months and 20.3 months, respectively, a54% reduction in risk that trendedtoward significance.HDAC inhibitors induce hyperacety-

lation of lysines on histones and a num-ber of other proteins. In a biomarkeranalysis of 49 patients, protein lysineacetylation measured in blood samples

found that subjects who hyperacetylat-ed experienced a 77% reduction in riskwith the combination; median PFSwas 8.54 months on the combinationversus 1.92 months with exemestanealone. The finding suggests that hyper-acetylation “may be a potential markerof benefit,” Yardley said. Symposium session moderator Joyce

O’Shaughnessy, MD, of Baylor SammonsCancer Center in Dallas, called the useof entinostat in advanced ER-positivebreast cancer “very, very promising,”and added, “It’s time for a phase 3 trialof this agent.”

Topoisomerase Inhibitor ShowsSignificant ActivityNKTR-102, an intravenous topoiso-merase-1 inhibitor-polymer conjugate,showed significant antitumor activityin metastatic breast cancer, includingpoor-prognosis patients with triple-negative disease having received prioranthracycline/taxane therapy. Thephase 2 study evaluated the drug in 70patients, most with visceral metastases.The response rate was 29%, and theclinical benefit rate (response + stabledisease) was 46%, including 2 com-plete and 4 near-complete re sponses.Fully 39% of the triple-negative subsetresponded, reported Agustin Garcia,MD, of the Uni versity of SouthernCalifornia Norris ComprehensiveCancer Center, Los Angeles.Median PFS was 4.6 months, and

median OS was 10.3 months. Themost common grade 3/4 side effect wasdiarrhea (20%-23%), typically occur-ring after 3 months of treatment.NKTR-102, given every 21 days, is

being evaluated in multiple cancerindications, and phase 3 planning isunder way in advanced breast cancerand platinum-resistant ovarian cancer.William Gradishar, MD, director of

the Maggie Daley Center for Women’s

Cancer Care at Northwestern Uni -versity, Chicago, said the key questionsare how NKTR-102 will compare withother salvage cytotoxics (eribulin,ixabepilone) and whether there is anoptimal sequence into which to incor-porate the new cytotoxic.

Insulin Growth Factor InhibitorIntriguingThe list of agents targeting the insulingrowth factor (IGF) is steadily grow-ing, with almost 20 tyrosine kinase in -hibitors and monoclonal antibodies inpreclinical and clinical trials. Joiningthis list is a neutralizing antibody,MEDI-573. The drug neutralizes IGF-Iand IGF-II ligands and inhibits IGFreceptor signaling pathways. The first-in-human safety and phar-

macokinetic profiles were described atthe symposium by Paul Haluska, MD,of the Mayo Clinic, Rochester. In aphase 1 study in 37 patients whoreceived various doses and schedules ofthe intravenous agent, IGF-I and IGF-II levels were fully suppressed, and noclinically significant changes in glu-cose, insulin, or somatotropin levelswere observed. A phase 2 study ofMEDI-573 plus an aromatase inhibitoris ongoing.

Everolimus Shows Promise inTriple-Negative Breast CancerClinical benefit was observed in 8 of 12evaluable patients (56%) in a phase 2study of 14 heavily pretreated meta -static patients receiving everolimusplus carboplatin. The average respon-der has been stable for 22 weeks, andresponse approaches 1 year in severalpatients. Dose-limiting thrombocy-topenia was an unexpected side effectthat required protocol amendment, butthe results are impressive, according toJ. C. Singh, MD, and colleagues at NewYork University School of Medicine. �

Emerging Therapies in the Treatment of Breast Cancer Continued from cover

Have patients asked youabout the situation withbevacizumab and the FDA?

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

www.TheOncologyPharmacist.com

Readers Survey

©iS

tockphoto

.com

/Yin

Yang

In the October issue, we pub-lished an article about theFDA review of bevacizumab

for use in metastatic breast can-cer. We asked our online read-ing community if this is some-thing they have discussed withpatients.

• 31% indicated patients haveasked them about the situa-tion

• 65% said patients have notasked about it

• 4% only discuss it if the pa -tient brings it up


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In patients with advanced non–smallcell lung cancer with ALK generearrangements, treatment with crizo-

tinib provided clinically meaningful anti-tumor activity, producing responses in51% of patients, in a multicenter phase 2study reported at the 2011 European

Multidisciplinary Cancer Congress.Rearrangements in ALK are seen in up

to 5% of patients, and crizotinib—a first-in-class, oral, potent, and selective smallmolecular—competitively inhibits ALK.The report was based on data from

the first 133 evaluable patients who

received crizotinib 250 mg twice dailyon a continuous basis until progressionin an ongoing open-label phase 2 study.Objective responses were observed in50.4% of patients, one being a com-plete response. Stable disease wasobserved in another 33.8%, reported

Dong-Wan Kim, MD, Clinical Re -searcher at Seoul National UniversityHospital in South Korea.Among the responders, 79.4% de -

monstrated a response within the first 8weeks of treatment and maintained theresponse for an average of 42 weeks.Although 32% of patients discontinuedthe study, only 4.4% did so as a result ofadverse events. Treatment-related grade3/4 adverse events, mainly elevated liverenzymes and neutropenia, were reportedin 26% of patients.About half the patients completed

patient-reported outcomes for keysymptoms and global quality of life.Clinically meaningful improvements(≥10-point change) were reported forpain, dyspnea, and cough from as earlyas cycle 2, and for fatigue, cycle 5;these positive changes were main-tained through subsequent cycles.Global quality of life was also main-tained over treatment, with clinicallymeaningful improvement seen by cycle7, Dr Kim reported.One of the most commonly reported

side effects of treatment with crizotinibis visual events. These are described asimage carryover, flashing/trailing lightsand floaters, and/or blurry vision, oftenoccurring during light adaptation. Apatient-reported questionnaire (VisualSymptom Assessment Questionnaire[VSAQ]) was developed to furthercharacterize these symptoms and theireffect on activities of daily living.At the meeting, Ben Solomon, MD,

of Peter MacCallum Cancer Centre inMelbourne, Australia, reported a pre-liminary analysis of VSAQ findings in57 patients, showing that the visualeffects associated with crizotinib hadno or only minimal impact on patients’activities of daily living in the ongoingPROFILE 1005 study of the drug.“The majority of patients reported

that each visual effects event was tran-sient, lasting either 30 seconds or lessor between 30 and 60 seconds,” DrSolomon noted.Approximately 56% of patients at

cycle 2 and 50% at cycle 3 and cycle 4reported visual effects, but these didnot require dose alterations, he said.The frequency of visual effects variedduring cycles 2 to 4. In cycle 2, mostpatients reported visual effects on mul-tiple days per week, whereas duringcycles 3 and 4 most patients reportedvisual effects no more than once aweek. Most patients experienced theseevents in the morning or evening,rather than midday.Most patients said they were not both-

ered by the visual effects events or foundthem “only a little bothersome,” DrSolomon said. Patients did not have reg-ular difficulty seeing at night or adaptingto changes in lighting. No clinicallymeaningful changes were noted on oph-thalmic examinations. �

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


Lung Cancer

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

EDUCATIONAL OBJECTIVESAfter completing this activity, the participants should be better able to:• Assess emerging data and recent advances in the discovery of tumor biomarkers, their impact on thetreatment of patients with solid tumors and hematologic malignancies, and how to integrate key findings into clinical practice.

• Discuss the role of tumor biomarkers in designing personalized therapy for patients with cancer, including management of treatment-related adverse events.

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

ACCREDITATION INFORMATIONSPONSORSThis activity has been planned and implemented in accordance with the Essential Areas and policies ofthe Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorshipof the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, andCore Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to providecontinuing medical education for physicians.

PHYSICIAN CREDIT DESIGNATIONThe University of Cincinnati designates this live activity for a maximum of 12 AMA PRA Category 1Credits™. Physicians should only claim the credit commensurate with the extent of their participationin the activity.

REGISTERED NURSE DESIGNATIONMedical Learning Institute, Inc. (MLI)Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to12.0 contact hours.

REGISTERED PHARMACY DESIGNATIONMedical 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.

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

CO-CHAIRS

Hope S. Rugo, MD Professor of Medicine

Director, Breast Oncology and Clinical Trials EducationUCSF Helen Diller Family

Comprehensive Cancer CenterSan Francisco, California

Rüdiger Hehlmann, MD Chief and Professor of Medicine

University of HeidelbergMannheim, Germany

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Drug Interactions

drug interactions (DDIs). In addition,oncology patients may be at anincreased risk for DDIs due to malab-sorption, malnutrition, and other dis-ease states, as well as complex medica-tion regimens.4Many of the more commonly used

oral cancer therapy agents include thenewer tyrosine kinase inhibitors (TKIs),including but not limited to dasatinib,erlotinib, imatinib, lapatinib, nilotinib,sorafenib, and sunitinib. Capecitabine isalso a commonly used oral chemothera-py agent and is included in this review.Each of these agents exhibits clinicallysignificant DDIs as reported in the liter-ature. The interactions of imatinib, nilo-tinib, and dasatinib were recently re -viewed and published in a number ofcomprehensive tables.5 It is important toconsider the pharmacokinetic and phar-macodynamic properties of the chemo -therapeutic or targeted agent and anyconcomitant medications to explore thepotential for DDIs not yet reported inthe literature, as many of these medica-tions have been available for only ashort time.

MethodsA systematic search of MEDLINE wasperformed using the following MeSHterms: drug interactions, cytochromep450, P-glycoprotein, ABCB1, organiccation transporter 1, protein binding,glucuronidation, UGT, and warfarin,along with the aforementioned drugnames. The official drug monographswere also used.6This review is organized by character-

izing drug interactions as either pharma cokinetic or pharmacodynamic.7Phar m a cokinetic interactions includechanges in the absorption, distribution,or metabolism of a drug due to anotherdrug. Pharmacodynamic changes includechanges to the patient’s re sponse to adrug, without pharmacokinetic changes.

Pharmacokinetic InteractionsAbsorptionA number of mechanisms are involvedin the absorption of drugs, including dis-ruption of gastrointestinal (GI) micro -flora required for absorption, changes inthe gut pH, and interactions mediatedby drug transporters. Sorafenib absorp-tion is dependent on GI microflora. Oralneomycin has been implicated in alter-ations of the GI microflora, leading todecreased sorafenib absorption.6 Oralantimicrobials expected to alter the GImicroflora should therefore be used withcaution. Dasatinib,6 erlotinib,6,8 andnilotinib6 display pH-dependent solubil-ity, and an increase in stomach pH byacid-lowering medications decreasestheir absorption. For example, protonpump in hibitors have been shown to

decrease absorption more than hista-mine receptor antagonists. Antacidsmay be used, but their dosing should beseparated from administration of theaforementioned TKIs by several hours.In these cases, the indication for acid-lowering medications should bethoughtfully considered.Drug transporters such as ATP-bind-

ing cassette proteins (ABCB1) or P-gly-coprotein (P-gp) and organic cationtransporters (OCT1) also play a role indrug interactions with oral chemothera-peutic and targeted agents. As an effluxtransporter on endothelial cells of thebrain capillaries, P-gp can modulatedrug concentrations within the brain; asa transporter on hepatocytes, and onepithelial cells in the small intestine, P-gp can also modulate systemic andintracellular drug concentrations.9Dasatinib,5 erlotinib,10 imatinib,5 lapa-tinib,6 nilotinib,6 and sunitinib11 are sub-strates of P-gp. Brain and intracellularconcentrations of these agents can beincreased with P-gp inhibitors such asatorvastatin, diltiazem, fluconazole,hydrocortisone, propranolol, tacrolimus,tamoxifen, and verapamil.6,7 Inducers ofP-gp (rifampin, St. John’s wort) may

decrease concentrations of these agentsby increasing efflux.6,7 Lapatinib andnilotinib also inhibit P-gp, increasingdrug concentrations of other P-gp sub-strates. This interaction should be mon-itored carefully in patients also receivingagents with a narrow therapeutic win-dow, such as digoxin, cyclosporine, andtacrolimus. For example, digoxin andlapatinib coadministration has beenreported to increase digoxin levels by2.8-fold, suggesting the need for closemonitoring.6OCT1 is another drug transporter

that has been shown to modulate druginteractions among TKIs in vitro. Thisinflux transporter is predominantlylocated on the membrane between theportal vein and hepatocytes,9 wheredrugs are metabolized and enter systemiccirculation. Imatinib is a substrate forOCT1, and intracellular concentrationscan be decreased by inhibitors such asprazosin.12 Imatinib and erlotinib havealso been shown to be inhibitors ofOCT1. Metformin influx into hepato-cytes, a major site of action, has beenshown to be OCT1 dependent, andinhibition of OCT1 by imatinib anderlotinib may decrease efficacy of met-

formin, although in vivo data are notavailable.13

DistributionAll of the TKIs included in this reviewhave reported protein binding greaterthan 90%, mainly to albumin.6 Whiledisplacement DDIs with other agentshave not been reported, TKIs are poten-tially implicated in DDIs with otheragents with high protein binding, suchas phenytoin and warfarin. In a casereport of phenytoin toxicity, the pro-tein-binding interaction betweenphenytoin and erlotinib was reasonablypostulated as a potential contributor ofthe toxicity.14

MetabolismPhase 1 ReactionsPhase 1 hepatic metabolism reactionsinclude oxidation, demethylation, andhydrolysis of drugs by hepatic micro- somal enzymes, which include thecytochrome (CYP) P450 isoenzymes.7The CYP isoenzymes are often implicat-ed in DDIs, and oral chemotherapeuticand targeted agents are no exception.Many of these drug interactions requiredosage adjustments, and all warrantincreased monitoring for adverse effects.Capecitabine is a prodrug, activated

and metabolized by tissue enzymes.However, capecitabine is an inhibitor ofCYP2C9 and therefore potentiallyincreases concentrations of CYP2C9substrates. Case reports of phenytointoxicity with capecitabine use havebeen published.15 A case report of war-farin and capecitabine coadministrationresulting in a supratherapeutic interna-tional normalized ratio (INR) has alsobeen published.16 Therefore, patientsreceiving phenytoin and warfarin withcapecitabine should be closely moni-tored for potential toxicity.Dasatinib is metabolized by CYP3A4.

Inducers of CYP3A4 should be avoided

Drug Interactions With Commonly... Continued from cover

Table 1 Drug Interactions With Capecitabine

Interacting Agent Description of Interaction Management of Interaction

Leucovorin31 Enhanced 5-fluorouracil toxicity viaintracellular mechanisms

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

Phenytoin15 Inhibition of CYP2C9 metabolism of phenytoin bycapecitabine, leading to increased phenytoin levels

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

Vorinostat32 Increased antitumor effects ofcapecitabine by downregulation ofthymidine synthase and upregulation ofthymidine phosphorylase

Monitor efficacy of therapy and toxicity.

Warfarin16 Inhibition of CYP2C9 metabolism ofwarfarin by capecitabine, leading toincreased effects of anticoagulation

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

Other CYP2C9 substrates:See Table 4

Potential for inhibition of metabolism,increased drug effects

Frequent monitoring for adverse effects,increased drug effect.

Shannon Hough, PharmD Emily Mackler, PharmD, BCOP



Drug Interactions

due to decreased concentrations of dasa-tinib. When coadministered, rifampindecreased both Cmax and AUC of dasa-tinib by approximately 80%.6 Inhibitorsof CYP3A4 should also be avoided dueto increased concentrations of dasa-tinib.6 Dasatinib also inhibits the metab-olism of CYP3A4 and should be usedcautiously with other CYP3A4 sub-strates. Patients should be monitoredclosely for adverse effects of these agents.Erlotinib is metabolized by CYP1A2

and CYP3A4. Erlotinib concentrationscan be decreased by inducers of CYP1A2or CYP3A4. Decreased erlotinib con-centrations have been reported in cur-rent cigarette smokers, suggesting higherdoses may be required for these patients.A phase 1 study determined that a high-er dose of erlotinib (300 mg daily) can betolerated in smokers for 14 days.17Erlotinib concentrations can be in -creased by inhibitors of CYP1A2 and

CYP3A4, such as ciprofloxacin, whichmay increase erlotinib concentrationsmore than other agents.6 Interactionswith erlotinib are also possible withother CYP3A4 substrates, as both agentscan compete for sites on the enzyme formetabolism. For example, simvastatinand phenytoin have been implicated ininteractions through this mechanism.14A case report of rhabdomyolysis withthe use of erlotinib and simvastatin waspublished, implicating the decreasedclearance of simvastatin due to competi-tion for metabolism by CYP3A4 as theprecipitating factor.18Imatinib is metabolized by CYP3A4,

CYP1A2 (minor), CYP2C9 (minor),and CYP2C19 (minor). Imatinib con-centrations can be decreased by inducersof CYP3A4.6 Inhibitors of CYP3A4should also be used with caution due toincreased concentrations of imatinib.6As previously discussed, imatinib is also

a P-gp substrate. Agents that are dualinhibitors of P-gp and CYP3A4 (vera-pamil, clarithromycin, erythromycin,cyclosporine, ketoconazole, and flucona-zole) may increase both systemic andintracellular concentrations of imatinib.Imatinib also inhibits CYP2C9, andCYP3A4 should be used with cautionwith other CYP3A4 or CYP2C9 sub-strates. Patients receiving concomitantwarfarin therapy should also be moni-tored closely for increases in INR, as themetabolic pathway for warfarin includesboth CYP2C9 and CYP3A4. Although areport of 8 patients receiving concomi-tant warfarin and imatinib included noINR deviations or bleeding events,patients should still be monitored closelyfor the effects of this interaction.19Lapatinib is metabolized by CYP3A4.

Studies in healthy subjects indicate thatconcentrations of lapatinib are in -creased 2-fold by the CYP3A4 inhibitor

ketoconazole and decreased more than50% by the CYP3A4 inducer carba-mazepine.20 Lapatinib doses may need tobe adjusted for other CYP3A4 inhibitorsand inducers. Lapatinib also inhibitsCYP3A4 and should be used cautiouslywith other CYP3A4 substrates.6Nilotinib is another agent metabo-

lized by CYP3A4. Inhibitors of CYP3A4may increase nilotinib concentrations,while inducers of CYP3A4 may decreasenilotinib concentrations. Nilotinibinhibits the metabolism of CYP3A4 andCYP2C9. The CYP3A4 inhibition isevidenced by increased midazolam con-centrations in the presence of nilotinib.Substrates of CYP2C9 can also beincreased due to concomitant nilotinibadministration.6 The potential interac-tion between nilotinib and warfarinshould be monitored closely in patientsreceiving both agents.Much of the data regarding the

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 GImicroflora

Carefully consider use of broad-spectrumantibiotics.

Dasatinib6Erlotinib6,8Nilotinib6

Acid-lowering medications: proton pumpinhibitors, histamine receptor antagonists,antacids

↓ TKI absorption due to pH-dependent solubility

Consider indication for acid-lowering, avoidif possible. Use antacids, separated by severalhours if possible.

Dasatinib5Erlotinib10Imatinib5Lapatinib6Nilotinib6Sunitinib11

P-glycoprotein inhibitors

P-glycoprotein inducers

↑ TKIs due to inhibition of efflux pump

↓ TKIs due to inhibition of efflux pump

Monitor for excess toxicity of TKI agents.

Avoid inducer use, which can compromiseefficacy of TKI.

Nilotinib6Lapatinib6

P-glycoprotein substrates ↑ P-gp substrates due to inhibition ofefflux pump

Monitor for excess toxicity of substrates.Utilize therapeutic drug levels for monitoringwhen able.

Imatinib12 OCT1 inhibitor: prazosin ↓ Intracellular imatinib Avoid inhibitor, which can compromise efficacy.Erlotinib13Imatinib13

OCT1 substrate: metformin ↓ Effects of metformin due to ↓ hepatocellular concentrations

Monitor blood glucose for efficacy. Considerincreased metformin dose or alternative agents.

Dasatinib6Lapatinib6Nilotinib6Sunitinib6,11

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

Additive QTc prolongation Increase EKG monitoring.

Dasatinib6Lapatinib6Sunitinib6

CYP3A4 inducers

CYP3A4 inhibitors

CYP3A4 substrates

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

Consider dose increase.

Consider dose decrease.

Monitor for excess toxicity of substrates. Utilizetherapeutic drug levels for monitoring when able.

Erlotinib6 CYP1A2/3A4 inducersCYP1A2/3A4 inhibitors

↓ Erlotinib concentrations↑ Erlotinib concentrations

Consider dose increase.Consider dose decrease.

Imatinib6Nilotinib6

CYP3A4 inducersCYP3A4 inhibitorsCYP3A4/2C9 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 monitoringwhen able.

Sorafenib6Sunitinib6

CYP3A4 inducers ↓ Sorafenib/sunitinib concentrations Consider dose increase.

Sunitinib6 CYP3A4 inhibitors ↑ Sunitinib concentrations Consider dose decreases. Increase monitoring.



Drug Interactions

metabolism of sorafenib is in vitro data.In vitro, sorafenib is metabolized byCYP3A4 and inhibits CYP2C9,CYP2C19, CYP3A4, and CYP2D6.6However, in vivo, sorafenib concentra-tions were unchanged in the presence ofketoconazole, a CYP3A4 inhibitor.6Similar studies found no differences inthe concentrations of midazolam, aCYP3A4 substrate; omeprazole, aCYP2C19 substrate; or dextromethor-phan, a CYP2D6 substrate.21 A singlereport implicates the calcium channelblocker felodipine (a CYP3A4 sub-strate) as the precipitating agent in apatient with sorafenib levels increased3-fold, suggesting competition for theCYP3A4 enzyme.22 Reports indicatingincreased effects of warfarin, most likelymediated by CYP2C9 inhibition bysorafenib, have also been published.23,24While inhibition of CYP2C19,CYP3A4, and CYP2D6 has been report-ed in vitro, it may not be seen clinically.However, concomitant CYP3A4inhibitors/inducers and substrates ofCYP2C19, CYP3A4, and CYP2D6 witha narrow therapeutic window should beused with caution with sorafenib, asindividual variability may play a role.Finally, sunitinib and an active

metabolite SU12662 are also metabo-lized by CYP3A4, but these agents donot induce or inhibit the metabolism ofany other CYP enzymes. In the presenceof the CYP3A4 inhibitor ketoconazole,sunitinib AUC was increased by 50%.6SU12662 concentrations were alsoincreased in the presence of ifosfamide,another CYP3A4 inhibitor.25 Whenusing sunitinib with other CYP3A4inhibitors, including grapefruit juice,26dose reductions should be considered. Inthe presence of rifampin, sunitinib con-centrations were decreased.6 St. John’swort should not be used with sunitinib,and when used with other CYP3A4inducers, dose increases of sunitinibshould be considered.

Phase 2 ReactionsThe second phase of hepatic metabolismincludes glucuronidation and sulfationreactions to form inactive water-solublemetabolites for elimination. Glucuro -nida tion occurs through UDP-glu-curonosyltransferase (UGT) enzymes,and interactions are well described invitro.27,28 The clinical implications ofthese interactions are currently notknown. Sorafenib metabolism byUGT1A9 is inhibited by valproic acidand is competitive with other substratessuch as propofol and acetaminophen.6,29Sorafenib also inhibits UGT1A9 andUGT1A1, increasing propofol andirinotecan concentrations, respectively.6Nilotinib and imatinib also inhibitUGT1A1 metabolism, increasing con-centrations of UGT1A1 substrates suchas carvedilol, levothyroxine, acetamino-phen, and raloxifene.6,28,30

Pharmacodynamic InteractionsProlongation of QTc IntervalA number of medications are known toprolong the QTc interval, includingsome of the TKIs. Prolongation of theQTc interval can place patients at risk

for arrhythmias, including torsades depointes and sudden cardiac death.Utilization of multiple medications withthe propensity to cause QTc prolonga-tion can increase the risk for these car-diac complications. Dasatinib, nilotinib,

lapatinib, and sunitinib all prolong theQTc interval.6 Other commonly usedmedications that prolong the QTc inter-val include digoxin, quinolone antibi-otics, methadone, and antipsychotics.Use of these agents with the aforemen-

Table 3 Drug Interactions With Warfarin and Commonly Used Oral Chemotherapeutic and Targeted Agents

Interacting Agent Description of Interaction Management of Interaction

Capecitabine16,33 Inhibition of CYP2C9 decreases warfarinmetabolism and increases INR

Increase INR monitoring. Decrease warfarindose by 40%.

Erlotinib6,34 Increased INR via multiple proposed mechanisms6,34:

1. Protein displacement2. Minor metabolism by CYP3A43. Decreased intestinal absorption ofvitamin K

4. Decreased intestinal colonization ofvitamin K–producing bacteria

Increase INR monitoring, especially in thepresence of severe diarrhea.

Imatinib6,19 Inhibition of CYP2C9 and CYP3A4, leadingto decreased warfarin metabolism andincreased INR

Increase INR monitoring. No empiric dosechanges. Consider low-molecular-weight orstandard heparin instead of warfarin.

Sorafenib6,23,24 Increased INR via multiple proposed mechanisms23,24:

1. Decreased warfarin metabolism viacompetitive inhibition of CYP3A4,CYP2C9

2. Increased unbound warfarin due toprotein-binding displacement

Additive risk of bleeding

Increase INR monitoring. Dose decreasesmay be necessary.Increase monitoring for bleeding.

Sunitinib6 Additive risk of bleeding Increase monitoring for bleeding.

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

P-glycoprotein Carbamazepine Rifampin St. John’s wortYohimbine

Atorvastatin DiltiazemFluconazoleHydrocortisonePropranololTacrolimusTamoxifenVerapamil

AmiodaroneCyclosporineDexamethasoneDigoxinLoperamide OndansetronSirolimusTacrolimus

CYP1A2 Cigarette smokeOmeprazolePhenobarbital Rifampin

CiprofloxacinErythromycinOlanzapinePropranololRitonavir

ClozapineMelatoninPropranololVerapamilZolpidem

CYP2C9 CarbamazepineEthanolPhenytoinRifampin

AmiodaroneCimetidineFluconazoleMetronidazoleSulfamethoxazoleTrimethoprim

Amitriptyline CarvedilolMirtazapinePhenytoinSertralineWarfarin

CYP2C19 Rifampin FluoxetineKetoconazoleModafinilOmeprazole

CarisoprodolCitalopramDiazepamImipramine

CYP3A4 CarbamazepineDexamethasonePhenytoinRifampinSt. John’s wort

AnastrozoleClarithromycin DiltiazemKetoconazoleSertralineVoriconazole

AlprazolamAmitriptylineCyclosporineDiltiazemGranisetronSimvastatin

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 KluwerHealth, Inc; 2008. Copyright 2008 by Lippincott Williams & Wilkins.



Drug Interactions

tioned TKIs should be done with addi-tional EKG monitoring.

ConclusionOral chemotherapy agents offer the con-venience of dosing from home and canimprove patient quality of life. It is impor-tant to consider the potential for DDIs forpatients who receive these medicationsto avoid increased toxicity from TKI

therapy and other medications or addi-tive side effects with other agents. �

References1.O’Neill VJ, Twelves CJ. Oral cancer treatment: devel-opments in chemotherapy and beyond. Br J Cancer.2002;87:933-937.2. Liu G, Franssen E, Fitch MI, Warner E. Patient pref-erences for oral versus intravenous palliative chemother-apy. J Clin Oncol. 1997;15:110-115.3. Aisner J. Overview of the changing paradigm in can-cer treatment: oral chemotherapy. Am J Health SystPharm. 2007;64(suppl 5):S4-S7.

4. Riechelmann RP, Saad ED. A systematic review ondrug interactions in oncology. Cancer Invest. 2006;24:704-712.5. Haouala A, Widmer N, Duchosal MA, et al. Druginteractions 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 interac-tions. In: Tatro DS, ed. Drug Interaction Facts 2008: TheAuthority on Drug Interactions. St Louis, MO: WoltersKluwer Health, Inc; 2008.8. Duong S, Leung M. Should the concomitant use oferlotinib and acid-reducing agents be avoided? The drug

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. Drugtransporters and imatinib treatment: implications forclinical practice. Clin Cancer Res. 2011;17:406-415.10. de Vries NA, Buckle T, Zhao J, et al. Restricted brainpenetration of tyrosine kinase inhibitor erlotinib due tothe drug transporters P-gp and BCRP. Invest New Drugs.Published online October 21, 2010. doi:10.1007/s10637-010-9569-1.11. Tang SC, Lagas JC, Lankheet NA, et al. Brain accu-mulation of sunitinib is restricted by P-glycoprotein(ABCB1) and breast cancer resistance protein (ABCG2)and can be enhanced by oral elacridar and sunitinab coad-ministration. Int J Cancer. 2012;130:223-233.12. Engler JR, Frede A, Saunders VA, et al. Chronicmyeloid leukemia CD34+ cells have reduced uptake ofimatinib due to low OCT-1 activity. Leukemia.2010;24:765-770.13. Minematsu T, Giacomini KM. Interactions of tyro-sine kinase inhibitors with organic cation transportersand multidrug and toxic compound extrusion proteins.Mol Cancer Ther. 2011;10:531-539.14. Grenader T, Gipps M, Shavit L, et al. Significantdrug interaction: phenytoin toxicity due to erlotinib.Lung Cancer. 2007;57:404-406.15. Brickell K, Porter D, Thompson P. Phenytoin toxic-ity due to fluoropyrimidines (5FU/capecitabine): threecase reports. Br J Cancer. 2003;89:615-616.16. Janney LM, Waterbury NV. Capecitabine-warfarininteraction. Ann Pharmacother. 2005;39:1546-1551.17. Hughes AN, O’Brien ME, Petty WJ, et al.Overcoming CYP1A1/1A2 mediated induction ofmetabolism by escalating erlotinib dose in current smok-ers. J Clin Oncol. 2009;27:1220-1226.18. Veeraputhiran M, Sundermeyer M. Rhabdomyolysisresulting from pharmacologic interaction betweenerlotinib 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 chronicphase chronic myeloid leukemia does not interfere withdrug efficacy [letter]. Leuk Res. 2010;34:e224-e225.20. Smith DA, Koch KM, Arya N. Effects of ketoconazoleand carbamazepine on lapatinib pharmacokinetics inhealthy subjects. Br J Clin Pharmacol. 2009;67:421-426.21. Flaherty KT, Lathia C, Frye RF, et al. Interaction ofsorafenib and cytochrome P450 isoenzymes in advancedmelanoma: a phase I/II pharmacokinetic interactionstudy. Cancer Chemother Pharmacol. Published onlineFebruary 25, 2011. doi:10.1007/s00280-011-1585-0.22. Gomo C, Coriat R, Faivre L, et al. Pharmacokineticinteraction involving sorafenib and the calcium-channelblocker felodipine in a patient with hepatocellular carci-noma. Invest New Drugs. 2011;29:1511-1514.23. Moretti LV, Montalvo RO. Elevated InternationalNormalized Ratio associated with concurrent use ofsorafenib and warfarin. Am J Health Syst Pharm.2009;66:2123-2125.24. Laber DA, Mushtaq M. Compassionate use ofsorafenib in patients with advanced renal cell cancer.Clin Genitour Cancer. 2009;7:34-38.25. Hamberg P, Steeghs N, Loos WJ. Decreased expo-sure to sunitinib due to concomitant administration ofifosfamide: results of a phase I and pharmacokineticstudy on the combination of sunitinib and ifosfamide inpatients with advanced solid malignancies. Br J Cancer.2010;102:1699-1706.26. van Erp NP, Baker SD, Zandvliet AS, et al. Marginalincrease of sunitinib exposure by grapefruit juice. CancerChemother Pharmacol. 2011;67:695-703.27. Liu Y, Ramírez J, House L, et al. Comparison of thedrug-drug interactions potential of erlotinib and gefi-tinib via inhibition of UDP-glucuronosyltransferases.Drug Metab Dispos. 2010;38:32-39.28. Williams JA, Hyland R, Jones BC, et al. Drug-druginteractions for UDP-glucuronosyltransferase substrates:a pharmacokinetic explanation for typically observedlow exposure (AUCi/AUC) ratios. Drug Metab Dispos.2004;32:1201-1208.29. Ethell BT, Anderson GD, Burchell B. The effect ofvalproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases.Biochem Pharmacol. 2003;65:1441-1449.30. Liu Y, Ramírez J, Ratain MJ. Inhibition of paraceta-mol glucuronidation by tyrosine kinase inhibitors. Br JClin Pharmacol. 2011;71:917-920.31.Morgan RG. Leucovorin enhancement of the effectsof 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 upregu-lation of thymidine phosphorylase. Br J Cancer.2010;103:1680-1691.33. Shah SR, Martin R, Dowell JE, et al. Comparison ofthe 5-fluorouracil-warfarin and capecitabine-warfarindrug interactions. Pharmacotherapy. 2010;30:1259-1265.34. Thomas KS, Billingsley A, Amarshi N, et al.Elevated international normalized ratio associated withconcomitant warfarin and erlotinib. Am J Health SystPharm. 2010;67:1426-1429.

BUILDINGpillars of knowledgeIN SUPPORTIVE CARE

LOG ON TODAY TO PARTICIPATE

TARGET AUDIENCEThe educational series is intended for nurses, pharmacists, and otherswith clinical, research, and management interests of neutropeniamanagement

EDUCATIONAL OBJECTIVESOn completion of this activity, participants should be able to:• Outline the risk factors for neutropenia in patients with cancer undergoing chemotherapy

• Review advances in the prevention and management of neutropenia, including updated evidence-based guidelines

• Examine approaches for improving patient outcomes by iden tifying patients at risk and preventing or reducing the incidence of neutropenia

ACCREDITATION STATEMENTSCreative Educational Concepts, Inc. (CEC) is accreditedby the Accreditation Council for Pharmacy Education asa provider of continuing pharmacy education.

This knowledge-based activity has been assigned ACPE # 0245-0000-11-017-H01-P and will award 1.0 contact hour (0.10 CEUs)of continuing pharmacy education credit. CEC complies with theCriteria for Quality for continuing education programming.

NURSINGCreative Educational Concepts, Inc. (CEC) is accredited as a provider of continuing nursing education by the American NursesCredentialing Center’s Commission on Accreditation.

CEC provides this activity for 1.0 contact hour.

Learners are advised that accredited status does not imply endorse-ment by the provider or ANCC of any commercial products displayed in conjunction with an activity.

Your statement of credit will be issued immediately upon successful completion of the posttest and evaluation form.

For further information and to participate, please go to:www.coexm.com/ace06

This activity is supported by an educational grant from Amgen Inc.

www.coexm.com/ace06Release Date: August 8, 2011 Expiration Date: August 7, 2012

NEUTROPENIA

FACULTYLeAnne Kennedy, PharmD, BCOPPharmacy Clinical CoordinatorHematology and OncologyWake Forest Baptist HealthWinston-Salem, NC

Kathleen Colson, RN, BSN, BSClinical Research Nurse Multiple Myeloma Dana Farber Cancer InstituteBoston, MA

Regina Cunningham, PhD, RN, AOCNSenior Director, Oncology The Tisch Cancer InstituteMount Sinai Medical CenterNew York, NY

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Side Effect Management

Although cancer patients whoundergo radiation therapy fre-quently have acute and chronic

skin reactions, there are no hard and fastguidelines on management of radiation-induced skin reactions or the best prod-ucts to use. Each center or practiceshould develop its own clinical guideabout how patients should manage skinreactions and which products are recom-mended for patient use, said MaureenMcQuestion, RN, Princess MargaretHospital, Toronto, Ontario, Canada.She spoke at a symposium called “NewPerspectives in Oncology Practice” heldin conjunction with The ChemotherapyFoundation Symposium.“Your practice should be consistent

regarding recommendations for prod-ucts, so that the oncologist, nurses, andnurse practitioner are all telling patientsthe same thing,” she said. Pharmacistsshould also be included in the discussionabout product recommendations.Radiation techniques have evolved

over the past few decades, and now mostpatients receive targeted therapy withconformal radiation delivered to the

tumor cells, sparing more healthy tissuethan in the past. Nevertheless, skinreactions do occur, and some are quitesevere and painful.“Acute reactions are worse at the end

of radiation, but they will improve 2 to 3weeks later,” said McQuestion.Acute reactions can include mild

erythema, dry desquamation, moistdesquamation, alopecia, pruritus,altered pigmentation, and fibrosis. Shesaid that reactions can be mixed, withboth wet and moist desquamation inthe radiated area. Patient factors that affect skin reac-

tion include older age, nutritional stat -us, comorbidities, hygiene, and chronicsun exposure. Treatment-related factors

include the area radiated and the totaldose and fraction size. Hyper -fractionated treatment twice a dayincreases the chances of more severeskin reactions. Patients can experience pain, difficul-

ty ambulating and sitting, discomfortwearing clothes, impaired body image,increased urination and bowel move-ments, loss of independence withdecreased ability for self-care, and theyhave to bear the cost of the products totreat the skin reactions. “Dressings and creams are typically

not covered by drug plans,” MsMcQuestion told the audience. The goal of management of radiation-

induced skin reaction is healing, and the

principles are similar to general ones forwound healing. Promoting moisture isimportant, “but some patients thinkthey should dry the affected area,” shenoted.Patients should be instructed to gent -

ly wash the affected area with a mildsoap such as Dove and not to rub orabrade the skin. They should not usecornstarch or talc, but they can usedeodorants that do not contain alu-minum. Although a multitude of creamsand lotions can be purchased over thecounter, McQuestion said that at hercenter they have found that hyaluronicacid cream and calendula cream can behelpful. Cavilon No Sting Barrier Filmprevents moisture loss. Antimicrobialsare not needed if the patient is practic-ing good hygiene.“Corticosteroids are not recommend-

ed unless the patient has pruritus or doc-umented folliculitis,” she stated.Other recommendations for patients

include avoiding swimming in chlori-nated water or hot tubs and keeping theskin area well moisturized, especially ifthe patient has moist desquamation. �

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

The goal of management of radiation-inducedskin reaction is healing, and the principlesare similar to general ones for wound healing.

Dual HER2 blockade withtrastuzumab plus pertuzumabcombined with docetaxel chemo -

therapy significantly extended progres-sion-free survival (PFS) by about 6months compared to trastuzumab plusdocetaxel plus placebo in patients withmetastatic HER2-positive breast cancer,according to results from the CLEOPA-TRA trial presented at the CTRC-AACR San Antonio Breast CancerSymposium.“These findings represent a significant

advance in the treatment of advancedbreast cancer. The results may be prac-tice changing,” said senior author JoseBaselga, MD, PhD, Professor at HarvardMedical School and Associate Directorof Massachusetts General Hospital inBoston.These results affirm the concept of

dual HER2 blockade in HER2-positive

metastatic breast cancer. Pertuzumaband trastuzumab have distinct mecha-nisms of action and bind at differentsites. “The 2 antibodies are extremelycomplementary and synergistic in pre-liminary studies,” he said.

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

chemotherapy with pertuzumab orplacebo. Docetaxel was given every 3weeks for 6 cycles in both arms, andinvestigators could decide whether tocontinue it on an individual basis. Bothmonoclonal antibodies were given every3 weeks until evidence of disease pro-gression. Patients had no prior therapyfor metastatic disease, except 1 line ofprior hormone therapy was allowed.Prior chemotherapy was allowed if 1year had passed. More than three-quar-ters of patients had visceral metastases;the remainder had metastases confinedto the bone.By independent review, median PFS

was 12.4 months in the control arm ver-sus 18.5 months in the experimentalarm, which was highly statistically sig-nificant (P <.0001).All prespecified subgroups benefitted

from dual HER2 blockade, with the

exception of patients with nonvisceralmetastasis. A strong trend towardimproved overall survival was observedfor the experimental arm, but this wasan interim analysis, and the data need tobe more mature for meaningful survivalresults, Baselga said. Treatment was safe and tolerable,

with no cardiac toxicity observed. Onlyminimal side effects were seen with theaddition of pertuzumab, including grades1 and 2 diarrhea and neutropenia.“This represents an advance in treat-

ment of HER2-positive breast cancer,”said Lisa Carey, MD, University ofNorth Carolina at Chapel Hill, NorthCarolina, who moderated the press con-ference where CLEOPATRA was dis-cussed. “The challenge now is to findbiomarkers to identify which patientswill derive benefit from dual HER2blockade,” she said. �

CLEOPATRA Affirms Principle of Dual HER2Blockade in HER2-Positive Metastatic Breast CancerBy Alice Goodman

These results affirm theconcept of dual HER2blockade in HER2-positive metastatic breastcancer.

Breast Cancer


The de velopment of venousthromboembolism (VTE) inpatients with cancer has a sig-

nificant impact in terms of morbidityand mortality and healthcare costs,according to a “real-world analysis”reported at the 2011 EuropeanMultidisciplinary Cancer Congress.Gary H. Lyman, MD, MPH, an

oncologist at Duke University Schoolof Medicine, Durham, NorthCarolina, was principal investigator.Dr Lyman is a frequent contributor inthe area of health economics and com-parative effectiveness research. “VTEdevelopment was associated with a sig-nificant economic burden in terms ofhealthcare expenditure,” he noted.Dr Lyman and colleagues assessed

the economic impact of VTE occur-rence using the US-based InVisionData Mart Multiplan/Integrated HealthCare Information Solutions database.They retrospectively identified 30,552patients with cancer who initiatedchemotherapy in the 4-year period end-ing in 2008. Healthcare costs such as inpatient, pharmacy, emergencydepart ment, and outpatient expenseswere assessed 1 year preindex andpostindex treatment (first day ofchemotherapy after cancer diagnosis).The incidence of VTE 3.5 months

after the initiation of chemotherapyranged from 4.8% to 11.9%, depend-ing on tumor site. The highest riskwas observed in patients with pancre-atic, stomach, and lung cancers. Theincidence continued to increase overtime postindex treatment, peaking at9.9% to 21.5% at 12 months, DrLyman reported.

High Healthcare CostsPatients who developed VTE within3.5 months postindex treatment hadhealthcare costs at baseline that werecomparable with persons not develop-ing VTE. During the first year postin-dex, costs in patients with VTE weresignificantly higher than in those with-out VTE, primarily driven by higherinpatient and outpatient costs.The overall healthcare costs 1 year

before receiving chemotherapy were$37,542 for patients developing VTEand $35,342 for those without VTE.By 1 year postindex treatment, costshad 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, emergencydepartment, and pharmacy. “Similar results were seen for pa -

tients who developed VTE within12 months postindex,” he said.“The decision for the use of throm-

boprophylaxis in cancer pa tients

undergoing chemotherapy should bebased on the balance between thepotential benefits and harms, includingany bleeding risk associated with a

therapy,” Dr Lyman pointed out.There is a need to assess cost-effec-

tiveness of prevention in this setting,he added. �

Thromboembolism After Chemotherapy RaisesHealthcare Costs About 30%By Caroline Helwick


Pharmacoeconomics

PROGRAM OVERVIEWThe goals of this interactive, CME/CE-certified meeting are to update participants on advances in the fieldof cutaneous malignancies, including biology, pathology, staging, personalized therapy, novel agents, andongoing research. In addition to didactic lectures, this program will also include debates and discussionsof 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 thetreatment of cutaneous T-cell lymphoma (CTCL), basal cell carcinoma (BCC), and melanoma. This isthe 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 cutaneousmalignancies into clinical practice for oncologists and dermatologists.

EDUCATIONAL OBJECTIVESAfter completing this activity, the participants should be better able to:• Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatmentof CTCL, BCC, or malignant melanoma

• Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment basedon patient and tumor characteristics

• Summarize a personalized treatment strategy that incorporates current standards of care and emergingtreatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCEThis global educational program is directed toward medical and surgical oncologists, dermatologists, andradiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nursepractitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionalsinterested in the treatment of cutaneous malignancies are also invited to attend.

ACCREDITATION INFORMATIONSPONSORSThis activity has been planned and implemented in accordance with the Essential Areas and policies ofthe Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorshipof the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, andCore Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to providecontinuing medical education for physicians.

PHYSICIAN CREDIT DESIGNATIONThe University of Cincinnati designates this live activity for a maximum of 12.5 AMA PRA Category 1Credits™. Physicians should only claim the credit commensurate with the extent of their participationin the activity.

REGISTERED NURSE DESIGNATIONMedical Learning Institute, Inc. (MLI)Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to12.5 contact hours.

REGISTERED PHARMACY DESIGNATIONMedical 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.

CO-CHAIRS

Kim A. Margolin, MD Professor, Department of Medical Oncology

University of Washington School of Medicine

Seattle Cancer Care AllianceSeattle, Washington

Teresa Petrella, BSc, MD, MSc, FRCPCMedical Oncologist

Chair, National Cancer Institute ofCanada Melanoma Group

Chair, Melanoma Site Group Odette Cancer Centre

Assistant Professor, University of TorontoToronto, Ontario, Canada

CORE PRINCIPLE SOLUTIONS, LLC

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Early registration of $425 ends January 13, 2012!

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REGISTER TODAY & SAVE $100

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

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The systemic amyloidoses are a group of complex diseases causedby tissue deposition of misfolded proteins that results in progres-sive organ damage.1 The incidence of immunoglobulin lightchain (AL) amyloidosis (also referred to as primary amyloidosis)is approximately one-tenth that of multiple myeloma,1 a morecommon cancer of the bone marrow plasma

cells. In approximately 10% of patients, both AL amyloidosisand multiple myeloma are present at the time of diagnosis.2The process of amyloid formation results in cellular

injury, tissue damage, and organ dysfunction throughmechanisms that are not completely understood.1 Patientswith amyloidosis usually present with a small plasma cellclone with evidence of dysfunction in 1 or more involvedorgans.1 Most commonly, this includes renal involvementin approximately 70% of amyloidosis patients, withnephrotic range proteinuria or renal failure; cardiomyopa-thy in approximately 60%; and peripheral neuropathy inapproximately 20%.1 Among newly diagnosed patients,30% have 3 or more major organ systems involved.3The prognosis for patients with amyloidosis varies con-

siderably depending on the nature, number, and extent oforgan involvement.2 Median survival may be as short as 4to 6 months, with cardiac failure, hepatic failure, and/orinfection being the major causes of death.2 However, thosepatients with limited organ involvement can expect amedian survival in excess of 5 years.2

Types of Amyloid DiseasesTo date, at least 28 different proteins have been identified as causative agentsof amyloid diseases.4 AL amyloidosis is the most common form of amyloiddisease and is due to deposition of protein derived from immunoglobulinlight chain fragments.4 It is considered a plasma cell dyscrasia in which amonoclonal protein is detectable in the serum or urine in approximately 80%of cases.4 AA (or secondary) amyloidosis is characterized by extracellular tis-sue deposition of fibrils composed of fragments of serum amyloid A (SAA)protein, an acute-phase reactant. AA amyloidosis is related to a chronic dis-ease in which there is ongoing or recurring inflammation, such as rheumatoidarthritis or inflammatory bowel disease.4 Dialysis-related amyloidosis is dueto deposition of fibrils derived from beta-2 microglobulin, which accumulatesin patients with end-stage renal disease on long-term dialysis therapy.4Amyloid 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 systemicforms of amyloid.4

DiagnosisEarly diagnosis is the key to effective therapy, allowing reversal of the organdamage and better tolerability of adverse effects of therapy.1 Approximately40% of patients have light chain–only disease, and therefore diagnosis is oftenmissed if only serum protein electrophoresis is performed.1 However, the com-bination of serum and urine immunofixation electrophoresis with serum freelight chain assay approaches 100% sensitivity for diagnosis.1 If a serum monoclonal protein is present, a bone marrow biopsy should be performed to rule

out multiple myeloma.1 Congo red staining performed on the biopsy will bepositive for amyloid in <60% of patients.1 Congo red staining of tissue from aninvolved organ or surrogate site (fat pad, gingiva, or rectum) may also lead todiagnosis.3 Deciphering the type of amyloidosis is essential in establishing theappropriate intervention and treatment.3

TreatmentTreatment for AL amyloidosis is highly individualized and isbased on age, organ dysfunction, and regimen toxicities.1The goals of therapy are prompt elimination of the misfold-ed amyloidogenic light chains, minimization of treatmenttoxicity, and support of the function of target organs.1 Formany years, melphalan plus prednisone was considered thestandard therapy for patients with AL amyloidosis who arenot candidates for autologous stem cell transplantation.2More recently, dexamethasone has been substituted forprednisone in association with melphalan, resulting inmuch higher hematologic responses.1 A reduction in pro-teinuria has been noted in up to 50% of patients treatedwith these regimens, though they are not without risk.2Melphalan-induced cytogenetic abnormalities can lead topancytopenia and/or secondary myelodysplastic syndromes,with an incidence of these complications of up to 6.5%.2However, the actual risk may exceed 20% in those whoappear to have a good amyloid response and survive formore than 3.5 years.2 Thalidomide as a single agent has limited efficacy and is

poorly tolerated, with fatigue and sedation being the majordose-limiting toxicities, followed by fluid retention, constipation, orthostasis,peripheral neuropathy, and worsening renal function.1 Somewhat better resultshave been obtained when thalidomide was combined with dexamethasone.2Thalidomide/dexamethasone can be considered an option alone or in combi-nation with cyclophosphamide for the treatment of patients who relapse aftermelphalan/dexamethasone or stem cell transplantation.2Lenalidomide in combination with dexamethasone may also be reasonable

for patients who relapse after melphalan/dexamethasone or stem cell trans-

Your FAQs...

Q:

This Month’s FAQ Answered by:

Carli Greenfield, ACNPOhio State University Medical CenterColumbus, Ohio

Do you have a question you’d like

answered?

E-mail us at [email protected]

Answered!What are the different types of amyloidosis and what treatmentoptions are available?

A:The prognosis for

patients withamyloidosis

variesconsiderably

depending on thenature, number,and extent of

organ involvement.Median survival

may be as short as4 to 6 months.



plantation.2 The most commonadverse effects of this combinationare cytopenia, fatigue, and rash.1Hematologic responses have rangedfrom 41% to 47%.1 In addition, bor -tezomib has significant activity in ALamyloidosis, with the most commonnonhematologic toxicities includingperipheral sensory neuropathy with orwithout neuropathic pain, exacer-bation of orthostatic hypotension,peripheral edema, and constipationor diarrhea.2 A phase 3 study com-paring bortezomib/melphalan/dexa -methasone with melphalan/dexa -methasone is currently in progress.2

A significant advance in myelomachemotherapy has been the additionof stem cell transplantation, and thisapproach has since been adapted forpatients with AL amyloidosis.1 Thefragility of the amyloidosis patientpopulation was soon evident, however, when some transplant centersreported treatment-related mortalityexceeding 40% or more in those withcardiac involvement.1 In an attemptto reduce treatment-related toxicity,attenuated melphalan dosing hasbeen used in high-risk and olderpatients, resulting in reduced toxicitybut generally lower response rates.1Both cardiac and renal transplanta-tion have been successfully carriedout in AL amyloidosis patients withassociated organ involvement.1 TheAmyloidosis Clinical Trials Networkshould also be explored for thosepatients considering clinical trial par-ticipation, as novel agents and regi-mens are showing great promise inthe treatment of amyloidosis. �

References1. Merlini G, Seldin DC, Gertz MA. Amyloidosis:pathogenesis and new therapeutic options. J ClinOncol. 2011;29:1924-1933.2. Rajkumar SV. Prognosis and treatment ofimmunoglobulin light chain (AL) amyloidosis andlight and heavy chain deposition diseases. UpToDate

19.2. http://www.uptodate.com/contents/prognosis-and-treatment-of-immunoglobulin-light-chain-al-amyloidosis-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.&selectedTitle=1~150. Updated November 2, 2010. AccessedNovember 7, 2011.

Your FAQs...

�� Editor in ChiefSagar Lonial, MDAssociate Professor of Hematology and Oncology Emory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Section of HematologyRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Therapy• Transplant-Eligible Patients• Retreatment• Transplant-Ineligible Patients• Cytogenetics• Side-Effect Management• Bone Health

Newsletter Series

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Topics include:• Hodgkin Lymphoma• Follicular Lymphoma• Mantle Cell Lymphoma• Waldenstrom’s Macroglobulinemia• Diffuse Large B-Cell Lymphoma• T-Cell Lymphoma

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Target AudienceThese activities were developed for physicians, nurses, and pharmacists.

AccreditationThis activity has been approved for 1.0 AMA PRA Category 1 Credit™ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided.For complete learning objectives and accreditation information, please refer to each activity.

This activity is jointly sponsored by Global EducationGroup and Medical Learning Institute, Inc.

Coordination for this activity provided by Center of Excellence Media, LLC.

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YOUR QUESTIONS ANSWERED

COEAsize40611MM

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or [email protected].

This activity is supported by educational grant from Cephalon Oncology,Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

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The AmyloidosisClinical TrialsNetwork shouldalso be exploredfor those patients

consideringclinical trialparticipation,as novel agentsand regimens

are showing greatpromise in thetreatment ofamyloidosis.

Answered!



Documents

December 2011, Vol 4, No 8