february 2012 vol5, no 1

©2012 Green Hill Healthcare Communications, LLC

FEBRUARY 2012 www.TheOncologyPharmacist.com VOL 5, NO 1

Gary Jean, PharmD, BCOP, and Jill Comeau, PharmD, BCOP, clinical pharmacists at LSUHealth Shreveport and the Feist-Weiller Cancer Center.

LSU Health Feist-WeillerCancer CenterEvolution of cancer treatments provides challenge

The Feist-Weiller Cancer Center, a department of Louisiana StateUniversity (LSU) Health Shreveport, provides comprehensive can-cer care in a translational research environment. It was founded in

1993 as the Center for Excellence in Cancer Treatment, Research,Education and Prevention by an act of the Louisiana Board of Regents.In 1997, it was renamed the Feist-Weiller Cancer Center in acknowl-edgment of a philanthropic gift from the Feist and Weiller families. Thisgift led to the construction of a multidisciplinary outpatient cancer cen-ter that is also home to 1 of the 6 St. Jude Children’s Research Hospital

CANCER CENTER PROFILE

Continued on page 19

ConferenCe news

Survivors With BRCA Mutations Are at Increased Risk ofContralateral Breast Cancer . . . . . 9Management of Lymphoma During Pregnancy Feasible . . . . . . 9New Look at Discontinued Drug in Older Patients With Acute Myeloid Leukemia . . . . . . . . . . . . . . 10PharmaCoeConomiCs . . . . . . 11Should Everyone Be Required to Have Health Insurance?

multiPle myeloma . . . . . . . . . 13The Health Burden of MultipleMyeloma

I N S I D E

The Oncotype DX breast cancerassay for ductal carcinoma insitu (DCIS) is a strong and sig-

nificant predictor of 10-year risk ofrecurrence in women with DCIS,according to a study presented at theCTRC-AACR San Antonio BreastCancer Symposium (SABCS) held inDecember 2011. It is the first clinicallyvalidated genomic assay to predict riskof local recurrence for women with

DCIS, and it is now available fromGenomic Health.The assay utilizes a panel of 12 genes

to predict the risk of local recurrencewith DCIS and invasive breast cancerover the next 10 years. The scorederived from the assay will be useful forguiding decision making in women withDCIS treated with local excision withor without adjuvant hormonal therapy.

CONFERENCE NEWS: SABCS AND ASH

Gene Array Test for PredictingRecurrence Risk in DCISBy Alice Goodman

Updated results of the phase 3BOLERO-2 trial demonstratedthat adding everolimus to hor-

monal therapy extends progression-freesurvival (PFS) in hormone receptor–positive (HR+) metastatic breast cancer

that progressed on hormonal therapywith anastrozole or letrozole. The posi-tive outcomes observed in this studysuggest that everolimus plus exemestanewill be a new option for postmenopausalmetastatic HR+ breast cancer.

BREAST CANCER

BOLERO-2: Practice-ChangingResults With Exemestane Plus Everolimus in AdvancedBreast CancerBy Alice Goodman


Continued on page 8


LEUKEMIAS

Bruton’s Tyrosine KinaseInhibitor: Potential Efficacy WithNo Myelosuppression in CLLBy Alice Goodman

An investigational oral agent tar-geting the B-cell receptorachieved high rates of remission

with little toxicity in patients withchronic lymphocytic leukemia (CLL)refractory to at least 2 previous treat-ments, according to results from a phase 2study presented at the 53rd Annual

Meeting of the American Society ofHematology (ASH).The agent, called PCI-32765, is a first-

in-class Bruton’s tyrosine kinase (Btk)inhibitor. Btk mediates B-cell receptorsignaling, and this protein is essential forCLL cell survival and proliferation. PCI-32765 is an irreversible inhibitor of Btk

Koeller’s CornerShooting from the Hip

So You Want to Be an Oncology

Pharmacist Specialist.

What Are Your Options?

Page 23

TOP_February 2012_v6_TOP 2/15/12 3:43 PM

Reference: 1. Data on fi le. Hospira, Inc.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P11-3464-Nov., 11

Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

For more information, contact your

Hospira representative or call 1-877-946-7747. Or visit us at products.hospira.com.

ONEFOR ALL

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we’re doing our part to improve cost savings,

optimize workfl ow and enhance patient care.

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FOR PHARMACISTS—FAMILIAR STRENGTHS AND FLEXIBLE DOSING

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FOR YOUR INSTITUTION—HIGH-QUALITY MEDICATION AT A LOWER COST

HOSPIRA ONCOLOGY PORTFOLIO

160 mg/16 mL multiple-dose vial

80 mg/8 mL multiple-dose vial

20 mg/2 mL single-dose vial

2 g/52.6 mL single-dose vial

1 g/26.3 mL single-dose vial

200 mg/5.26 mL single-dose vial

See Black Box Warning

DOCETAXEL INJECTION (10 mg/mL)

GEMCITABINE INJECTION(38 mg/mL)

1 PVC BOTTOM offers shatter resistance.

2 SHRINK-WRAPPED SLEEVE provides surface protection that acts as a barrier between any cytotoxic residue that may remain on the surface of the vial and persons handling the products.

3 GLASS CLARITY allows for easy inspection of the vial as a fi nal safety check before administration.

4 PREWASHED VIALS reduce cytotoxic residue.

UNIQUE ONCO-TAIN SAFETY FEATURES

4 mg/4 mL single-dose vial

See Black Box Warning

TOPOTECAN INJECTION (1 mg/mL)

3:20 PM


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


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 TexasMD 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 February 2012 I VOL 5, NO 1 www.TheOncologyPharmacist.com


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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 ©2012 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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6 February 2012 I VOL 5, NO 1 www.TheOncologyPharmacist.com

Welcome to the first issue of The OncologyPharmacist (TOP) for 2012. We’re looking for-ward to a new year of keeping you up-to-date

about what is happening in the field of oncology and bring-ing you information you can use in your daily practice. In this issue, we tell you some of the news coming out of

the San Antonio Breast Cancer Symposium and theAmerican Society of Hematology annual meeting—newsabout therapies and tests on the horizon, and the results of astudy that takes a new look at a discontinued drug. In addi-tion, we report on the specifics of the FDA approval of a sup-plemental new drug application that updates the label forVelcade (bortezomib). Jim Koeller tells us how he entered

the field of oncology pharmacy and discusses the variouspathways to the profession today. Gary Jean, from LSUHealth Feist-Weiller Cancer Center, this month’s featuredcancer center, is a relatively new practitioner who tells ushow he was inspired to become an oncology pharmacist.Both Jim and Gary acknowledge the importance of lovingthe job. As always, I encourage you to visit our Web site,

www.TheOncologyPharmacist.com. Please answer thismonth’s Reader Poll about the health insurance mandateissue and let us know how you feel. Be sure to tell us whattopics you want to see covered in TOP. We want to hearfrom you, and we appreciate your feedback. �

From the Editor

Vismodegib Capsule Approved for MetastaticBasal Cell CarcinomaThe FDA approved Erivedge (vismodegib; Genentech) cap-sule for the treatment of adults with metastatic basal cell car-cinoma, or with locally advanced basal cell carcinoma thathas recurred after surgery or who are not candidates for sur-gery, and who are not candidates for radiation. Basal cell car-cinoma is the most common type of skin cancer, and vis-modegib is the first drug approved by the FDA for metastaticbasal cell carcinoma.Vismodegib inhibits the hedgehog pathway, a channel

used by cells to communicate. Malfunctions in the hedgehogpathway are thought to play a role in several types of cancer,and this pathway is a focus of research. The hedgehog path-way is crucial to embryonic development.The most common adverse reactions (≥10%) for vismo -

degib were muscle spasms, alopecia, dysgeusia, weight loss,fatigue, nausea, diarrhea, decreased appetite, constipation,arthralgias, vomiting, and ageusia. Three of 10 pre-menopausal women developed amenorrhea in clinical trials.Vismodegib approval carries a black box warning for the riskof fetal death or severe birth defects.

Ingenol Mebutate Gel Approved for ActinicKeratosisPicato (ingenol mebutate; LEO Pharma) gel was approved inJanuary by the FDA for the topical treatment of actinic ker-atosis (AK) on the face, scalp, trunk, and extremities. AK isa precancerous condition caused by cumulative sun exposurethat has the potential to progress to squamous cell carcino-ma, which is the second most common type of skin cancer.AK is a dry, scaly, rough-textured patch or lesion that formson the outermost layer of the skin after cumulative exposure

to ultraviolet light, including sunlight. Ingenol mebutate0.015% gel is used once daily on the face and scalp for 3 con-secutive days, and ingenol mebutate 0.05% gel is used oncedaily on the trunk and extremities for 2 consecutive days.In four phase 3 clinical studies of more than 1000

patients with AK, a higher proportion of those treatedwith ingenol mebutate gel (n=503) saw complete clear-ance of AKs in the field of treatment compared withplacebo (n=502). The most common adverse events werelocal skin reactions, including erythema, flaking/scaling,crusting, and swelling. Pain, pruritus, and infection at theapplication site, as well as periorbital edema andheadache, were other adverse events that occurred in ≥2%of individuals treated with ingenol mebutate gel.

Bevacizumab Approval for Breast CancerRevokedThe FDA revoked approval of the breast cancer indica-tion for Avastin (bevacizumab; Genentech), ruling thatthe drug has not been proved to be safe and effective forthat use. Bevacizumab remains on the market as approvedfor use for certain types of other cancers, including colon,kidney, lung, and brain (glioblastoma multiforme) cancer.Bevacizumab had received accelerated approval for thebreast cancer indication in 2008; however, the FDA’sOncologic Drugs Advisory Committee later recommend-ed this approval be withdrawn. Bevacizumab’s manufac-turer filed an appeal, and the FDA held a 2-day publichearing on the issue in June 2011. The FDA issued thedecision to revoke the breast cancer indication for beva-cizumab on November 18, 2011.

The Oncology Nurse-APN/PA will address the implicationsof the FDA’s decision in an upcoming issue. �

Recent FDA Approvals

Patrick Medina, PharmD, BCOPEditor-in-Chief

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

TOP_February 2012_FINAL_TOP 2/16/12 9:56 AM

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


www.TheOncologyPharmacist.com8 February 2012 I VOL 5, NO 1

Conference News: SABCS and ASH

The following articles are based on presentations at the CTRC-AACR SABCS held December 6-10, 2011, in SanAntonio, Texas, and the 53rd Annual ASH Meeting held December 10-13, 2011, in San Diego, California.

Gene Array Test for Predicting... Continued from cover

The score can identify low-riskpatients who can forgo further treat-ment, as well as high-risk patients whorequire more aggressive therapy; it can

also identify intermediate-risk pa -tients, who comprise a small but chal-lenging group for treatment decisions.Some insurance plans cover the DCIS

assay, and Genomic Health has anassistance program to help patientsgain reimbursement from plans that maynot cover the test.

“The DCIS score [derived from themultigene RT-PCR assay] can be used toquantify an individual patient’s 10-yearrisk of developing a recurrence. Thescore provides independent informationon recurrence risk beyond clinical andpathological variables. We are not justreinventing the wheel here,” said leadauthor Lawrence J. Solin, MD, chair ofradiation oncology at Einstein MedicalCenter in Phila delphia, Pennsylvania.The increased incidence of DCIS is

attributed to increased use of screeningmammography finding cancers at veryearly stages. The majority of patientsdiagnosed with DCIS will not have arecurrence. However, until now therehas been no validated method to pre-dict recurrence, so all patients withDCIS typically receive radiation and/orhormonal therapy if they are estrogenreceptor positive.

The validation study presented atSABCS was based on paraffin-embed-ded tumor samples from 327 patientsenrolled in ECOG 5194, a multi-insti-tutional study of patients with low-,intermediate-, or high-grade DCIS whounderwent breast conservation surgerywith wide negative margins but did notreceive radiation; treatment withtamoxifen was optional. The Oncotype DX DCIS multigene

assay was used to classify patients as low,intermediate, or high risk according toprespecified characteristics. Solin notedthat about 75% were low risk.The DCIS score was a significant

and strong predictor of local recurrence(P = .02) and invasive local recurrence(P = .01) over a 10-year period. The cost of the DCIS test will be sim-

ilar to that of the Oncotype DX 21-geneassay. Solin said the cost should be off-set by the ability to avoid radiation andfurther treatment in low-risk DCIS.“Treatment selection is not clear for

intermediate-risk patients, but thistest allows us to provide informationon their individual risk level. Thenumbers of patients in the intermedi-ate-risk group are actually very small.Most patients with DCIS are lowrisk,” Solin said. �

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

The majority of patientsdiagnosed with DCIS will not experience arecurrence.


February 2012 I VOL 5, NO 1 9www.TheOncologyPharmacist.com


BRCA mutation carriers whohave had breast cancer are atincreased risk of developing con-

tralateral breast cancer, according to astudy presented at the 2011 CTRC-AACR San Antonio Breast CancerSymposium. In fact, women with aBRCA1 or BRCA2 mutation had agreater than 10% risk of developing con-tralateral breast cancer, and the risk wasstrongly associated with younger age atdiagnosis and a diagnosis of triple-nega-tive (estrogen receptor–negative, proges-terone receptor–negative, and HER2-negative) breast cancer.“As far as we know, this is the first

study to show that subgroups of BRCA1or BRCA2 carriers have an increased ordecreased risk of contralateral breast can-cer,” said Alexandra J. van den Broek,MSc, a doctoral candidate at theNetherlands Cancer Institute inAmsterdam.

The study included 5061 women whowere diagnosed with unilateral, invasivebreast cancer at 10 different institutionsin the Netherlands. Of these, 211 (4.2%)were carriers of the BRCA1 or BRCA2mutation. At a median follow-up of 8.4years, 8.6% of the women developedcontralateral breast cancer.The overall 10-year risk for develop-

ing contralateral breast cancer was 6%

in noncarriers versus 17.9% in carriers.Among carriers who were diagnosedwith their first breast cancer before age40, the 10-year risk of developing con-tralateral breast cancer rose to 26%;carriers between the ages of 40 and 50years at first diagnosis had a 10-yearrisk of 11.6%. Mutation carriers diag-nosed at first with triple-negativebreast cancer had a 10-year risk of

developing contralateral breast cancerthat reached 18.9%, compared with11.2% among carriers whose first can-cer was not triple-negative.When asked whether knowing their

risk of developing contralateral breastcancer might be overwhelming to car-riers, who are already anxious overtheir mutational status, van den Broeksaid it is crucial to know who is at riskand by how much. In her view, thesefindings point to the importance ofrevisiting current guidelines for muta-tion carriers and incorporating risk fac-tors such as younger age at first diagno-sis of breast cancer and a diagnosis oftriple-negative breast cancer whenconsidering prophylactic measures andscreening.“If these findings are confirmed, it

will be possible to personalize theguidelines for these specific subgroups,”she stated. �

Survivors With BRCA Mutations Are at Increased Risk ofContralateral Breast CancerBy Alice Goodman

Women with a BRCA1 or BRCA2 mutation had agreater than 10% risk of developing contralateralbreast cancer, and the risk was strongly associatedwith younger age at diagnosis and a diagnosis oftriple-negative breast cancer.

Although management of lym-phoma during pregnancy is notwell studied, a retrospective

review at 10 academic centers in theUnited States suggests that in selectedcases, lymphoma can be treated withminimal maternal and fetal complica-tions, and that treatment can bedeferred until after giving birth inpatients with low-risk lymphomas. Thestudy was presented at the 53rdAnnual Meeting of the AmericanSociety of Hematology held December2011 in San Diego, California.“To our knowledge, this represents one

of the largest experiences reported oflymphoma during pregnancy. There isnot much published data in the literatureto guide us. Therefore, 10 different cen-ters came together to collect our experi-ences for guidance for not only ourselves,but treating oncologists across theworld,” said lead author of this study,Andrew M. Evens, DO, MSc, Universityof Massachusetts Medical School,Worcester, Massachusetts. “The mainpoint of our study is that the outcomeswe found were consistent with non–pregnancy-associated lymphoma out-comes.”In the United States, approximately

3500 new cases of cancer are diagnosedeach year in pregnant women. Breastcancer is the most common type, andhematologic malignancies (about 20% ofall cases) are the second most common.

Prior to this study, knowledge about lym-phoma during pregnancy came primarilyfrom case reports, Evens explained.The retrospective review included

82 evaluable cases of lymphoma inpregnant women over a 13-year period.Treatment of selected cases of localizeddisease during the second and thirdtrimester was associated with minimalmaternal and fetal risk of complica-tions. The data suggest that treatmentfor lymphoma can be safely deferreduntil after giving birth in patients withlow-risk lymphomas, such as indolentnon-Hodgkin lymphoma (NHL),and/or diagnosis late in gestation.Evens said that this approach canachieve survival similar to that of non-pregnant patients with lymphoma.

Almost all of the cases of lymphomaduring pregnancy were comanagedwith high-risk maternal fetal medicine,with the goal of carrying the fetus toterm (beyond 36 weeks’ gestation). Inthe 82 evaluable patients, median agewas 31 years, about 38% were nulli-parous, and lymphoma was diagnosedat a median of 24 weeks’ gestation(range, 5-40): 15% during the firsttrimester, 46% during the secondtrimester, 35% during the thirdtrimester, and 4% was preexisting.Of the 82 evaluable cases, 43 were

NHL and 39 were Hodgkin lymphoma(HL). Median weight gain was 3.1%,which is considered low. Since lym-phoma is associated with weight loss,this low weight gain makes sense,Evens noted. Almost two-thirds (63%)of NHL patients had advanced-stagedisease (most of them diffuse large B-cell lymphoma), and 46% of thosewith HL were in advanced stage; 25%of HL patients had stage IIB.Six patients (4 NHL, 2 HL) termi-

nated pregnancy to initiate chemo -therapy (5 in the first trimester and 1 inthe early second trimester). Chemo -therapy was based mainly on cyclo phos-phamide, doxorubicin, vincristine, andprednisone (CHOP) or rituximab plusCHOP (R-CHOP) for NHL and dox-orubicin, bleomycin, vinblastine, anddacarbazine for HL patients. Therapywas deferred in 34% of patients (n=28).

Seventy-two percent of patients hada vaginal delivery. Among 48 patientswho received chemotherapy duringpregnancy, full-term gestation occurredin 73% (85% delivered at 35 weeks’gestation or longer). Among 28patients who deferred chemotherapy,delivery was at a median of 38 weeks,and 86% of pregnancies were carried tofull term. Most common preterm complica-

tions were induction of labor (45%),pre-eclampsia (8%), spontaneous rup-ture of membranes (5%), and diabetesmellitus (4%). No difference in eventswas observed between patients treatedduring pregnancy and those whodeferred treatment. One stillbirthoccurred in an NHL patient treatedwith 1 cycle of R-CHOP.Fetal outcomes were evaluable in 76

live births. No difference was seen inmedian birth weight between infantsof chemotherapy-treated patients andthose who deferred therapy. Only 1fetal malformation was found: micro-cephaly in an NHL patient treatedwith 4 cycles of CHOP.For all patients, 3-year progression-free

survival (PFS) and overall survival (OS)were 79% and 89%, respectively: for B-cell NHL, 73% and 82%; for T-cellNHL, 50% and 90%; and for HL, 90%and 95%, respectively. Among the 6patients who terminated pregnancy, 3-year PFS and OS were 100%. � —AG

Management of Lymphoma During Pregnancy Feasible

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Administering gemtuzumabozogamicin (GO) on a newschedule achieved impressive

progression-free survival (PFS) and over-all survival (OS) compared with stan-dard chemotherapy in older patients

with acute myeloid leukemia (AML)with favorable cytogenetics, according toa phase 3 study presented at the PlenarySession of the 53rd Annual Meeting ofthe American Society of Hematology(ASH). GO was taken off the market in

2010 due to toxicity concerns and is nolonger available in the US.“Research has demonstrated that

GO has very potent anti-cancer prop-erties, and with this study, we haveidentified a dosing regimen that gives

patients the therapeutic benefit of thedrug without some of the toxicitiesreported at higher doses,” stated leadauthor Sylvie Castaigne, MD, profes-sor, department of hematology atHôpital de Versailles, Versailles,France. “The standard of care has beendaunorubicin plus cytarabine for manyyears. There hasn’t been a new thera-peutic option for several decades, andwith this research we are encouragedthat GO may be able to improve over-all outcomes for these AML patientswith limited alternatives.”GO is an anti-CD33 antibody con-

jugated with a toxin; the antibodybinds to the surface of CD33-positiveleukemia cells and releases the toxin(ie, calicheamicin) into the leukemiacells. The antibody is specifically tar-geted to the leukemia cells and theo-retically spares toxicity to other cellsthat do not express CD33.The phase 3, prospective, open-

label, randomized trial enrolled newlydiagnosed de novo AML patients aged50 to 70 years. The new 3,3,3 regimen(ie, 3 mg/m2 GO IV on days 1, 4, 7) wasdesigned to give lower but repeated dosesthat might enhance the efficacy of GOand minimize hepatic and hematologictoxicities reported earlier with this anti-body. Patients (N = 280) were random-ized to arm A (standard daunorubicinplus cytarabine) or arm B (the samechemotherapy plus the GO 3,3,3 regi-men). Those who achieved remission on2 cycles of treatment were further ran-domized to 2 courses of consolidationtherapy with the same treatments.The experimental arm extended

event-free survival (EFS) by just under 8 months. At 2 years, median EFS was11.9 months with standard therapy ver-sus 19.6 months with the addition ofGO, a result that was highly significant(P = .0018). The addition of GO alsoextended OS: median OS was 19.2 months with standard chemothera-py versus 34 months with chemotherapyplus GO (P = .046).Improvement in EFS and OS was

observed in patients with favorable cyto-genetics, but not in those with unfavor-able cytogenetics, Castaigne emphasized.Fatal events occurred in 6.7% in thestandard therapy arm versus 8.7% in GOarm. Adverse events of note in the GOarm included prolonged grade 3 throm-bocytopenia in 19 patients and sinu-soidal obstructive syndrome in 3 patients(2 fatal). No differences were observedbetween the treatment arms in the rateof severe sepsis or intensive care admis-sion during therapy.This study, and 2 other positive stud-

ies of GO reported at ASH will put pres-sure on Pfizer to reconsider applying forapproval for GO. A Pfizer spokespersonsaid that the company plans to reviewresults of the positive studies presentedat ASH. � —AG

New Look at Discontinued Drug in OlderPatients With Acute Myeloid Leukemia

“Managing patients with myeloma means staying current.”

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Multiple Myeloma

In 2011, the American CancerSociety projected there would be20,520 cases of newly diagnosed mul-

tiple myeloma (MM) and 10,610 deathsfrom the disease that year.1 MM is anincurable hematologic cancer marked bygreat heterogeneity in terms of its biolo-gy and clinical course. Morbidity and sur-vival rates vary widely, even in the age ofnovel, molecularly based targeted thera-pies. Many factors account for the differ-ences in prognoses among patients withMM, including genomic aberrations inthe plasma cells of the myeloma neo-plasm. Survival outcomes range from <1year in patients with aggressive disease to>10 years in those with indolent disease.2

A variety of patient-, disease-, andtherapy-related characteristics have beenidentified to predict the disease courseand outcome among patients with MM.Evaluation of prognostic factors and riskstratification is important to defineappropriate treatment strategies, com-pare therapeutic outcomes, and predictsurvival among patients.2

The Approach to Therapy inMultiple Myeloma Use of the proteasome inhibitor bortez -omib (Velcade), the im mu no modulato-ry agents lenalidomide (Revlimid) andthalidomide (Thalomid), and bisphos-phonates such as zoledronic acid(Zometa) and pamidronate (Aredia) hasrevolutionized the management ofpatients with MM. These therapies,however, are all associated with poten-tially serious side effects, which can neg-atively affect a patient’s quality of life.

The majority of preferred regimensfor initial therapy are 3-drug combina-tions, although some 2-drug combina-tions are also recommended in the cur-rent guidelines from the NationalComprehensive Cancer Network, be -cause these multidrug regimens areassociated with the best response rates.3

New Treatment Option The proteasome is an enzyme complexthat exists in all cells and plays animportant role in degrading proteinsthat control the cell cycle and cellularprocesses. By blocking the proteasome,bortezomib disrupts biologic pathwaysrelated to the growth and survival ofcancer cells.4

Bortezomib was approved by the FDAin 2003 for IV injection for the treat-ment of patients with MM who had

received at least 2 previous therapiesand had demonstrated disease progres-sion on their last therapy.4

In 2008, the FDA approved anexpanded indication for bortezomib forthe first-line treatment of patients withpreviously untreated MM. The approvalwas based on data from the VISTA trial,which compared the addition of bortez -omib to melphalan plus prednisone(MP) versus MP without bortezomib (ie,control group) in 682 patients withnewly diagnosed MM. At a median fol-low-up of 16.3 months, the addition ofbortezomib to the MP regimen resultedin significantly improved outcomes,including improved response rates,increased time to disease progression,overall survival (OS), and progression-free survival.5 The trial was stopped earlyand patients in the control group werepermitted to cross over to the bortez -omib regimen.

In December 2011, results of 5-yearmedian follow-up of the VISTA trialconfirmed a >13-month OS advantageof the bortezomib plus MP regimen forpatients with previously untreated MM.Bortezomib is also indicated for thetreatment of patients with mantle celllymphoma who have received at least 1previous therapy.5

In January 2012, the FDA approved anew route of administration for bor - tezomib. The new subcutaneous (SC)form of bortezomib for injection offerspatients an easier mode of administra-tion, with a safety profile comparable tothe IV form but with significantlyreduced peripheral neuropathy (6% vs16%, respectively),5 providing patientswith MM a new option for route ofadministration.

Clinical Pharmacology ofBortezomibMechanism of ActionBortezomib is a reversible inhibitor of

the chymotrypsin-like activity of the26S proteasome in mammalian cells; the26S proteasome degrades ubiquitinatedproteins. The ubiquitin-proteasomepathway plays an essential role in regu-lating the intracellular concentration ofspecific proteins, thereby maintaininghomeostasis within cells. Inhibition ofthis pathway can therefore affect multi-ple signaling cascades within the celland can lead to cell death.5

PharmacodynamicsAfter twice-weekly administration ofbortezomib 1 mg/m2 and 1.3 mg/m2, themaximum inhibition of 20S proteasomeactivity, relative to baseline, occurred 5 minutes after drug administration.5

PharmacokineticsAfter IV administration of bortezomib 1 mg/m2 and 1.3 mg/m2 in 24 patientswith MM, the maximum plasma con-centrations (Cmax) of bortezomib were57 ng/mL and 112 ng/mL, respectively.The mean elimination half-life ofbortezomib with multiple dosingranged from 40 to 193 hours afteradministration of the 1 mg/m2 dose and76 to 108 hours after administration ofthe 1.3 mg/m2 dose.

After an IV or a bolus SC injection ofa 1.3 mg/m2 dose in patients with MM,the total systemic exposure with a repeatdose administration was equivalent forthe SC and the IV routes of administra-tion. The Cmax after SC administration(20.4 ng/mL) was lower than that afterIV administration (223 ng/mL).5

In vitro studies suggest that bortez -omib is primarily oxidatively metabo-lized via the cytochrome P450 enzymes3A4, 2C19, and 1A2.5

Phase 3 Clinical Trials: SC Versus IV BortezomibThe FDA approval of SC bortezomibwas based on a randomized, open-label,phase 3, noninferiority trial that com-pared the efficacy and safety of SC ver-

The Health Burden of Multiple Myeloma: Subcutaneous Bortezomib a New, Convenient Route of Administration Option By Rhonda Williams

SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IVadministration at the same dose and schedule, withno deleterious effect on efficacy.

Table 1 Summary of Efficacy Analyses in the Relapsed MM Study of BortezomibSC Versus IV5

Intent-to-Treat PopulationBortezomib SC

(n = 148)Bortezomib IV

(n = 74)

Primary end pointResponse rate at 4 cyclesORR (CR + PR), n (%) 63 (43) 31 (42)

Ratio of response rates (95% CI) 1.01 (0.73, 1.40)

CR, n (%) 11 (7) 6 (8)PR, n (%) 52 (35) 25 (34)nCR, n (%) 9 (6) 4 (5)

Secondary end points Response rate at 8 cyclesORR (CR + PR), n (%) 78 (53) 38 (51)CR, n (%) 17 (11) 9 (12)PR, n (%) 61 (41) 29 (39)nCR, n (%) 14 (9) 7 (9)

Median time to progression, months 10.4 9.4

Median progression-free survival, months 10.2 8.0

1-year overall survival, %* 72.6 76.7*Median duration of follow-up is 11.8 months.CI, confidence interval; CR, complete response; MM, multiple myeloma; nCR, near-complete response; ORR, overallresponse rate; PR, partial response; SC, subcutaneous.

TOP_February 2012_v6_TOP 2/15/12 3:44 PM Page 13


Multiple Myeloma

sus IV administration of bortezomib inpatients with relapsed MM.

A total of 222 bortezomib-naivepatients were randomly assigned, in a2:1 ratio, to receive bortezomib 1.3mg/m2 by either SC injection (n = 148)or IV infusion (n = 74) for 8 cycles.Patients were stratified according to thenumber of lines of previous therapy theyhad received (1 previous line vs >1 pre-vious line of therapy) and stage of dis-ease, using International StagingSystem (ISS) stage I, II, or III.5

The primary study end point was todemonstrate noninferiority of single-agent SC bortezomib with respect tooverall response rate (ORR)—completeresponse (CR) plus partial response(PR). In this study, noninferiority wasdefined as retaining at least 60% of theORR relative to single-agent IV bor -tezomib after 4 cycles of therapy.5

Patients who did not obtain an opti-mal response (less than CR) to treat-ment with bortezomib alone after 4cycles were allowed to receive oral dex-

amethasone 20 mg daily on the day ofand day after bortezomib administration (n = 82 in the SC treatment group; n = 39 in the IV treatment group).Patients with baseline grade ≥2 peripher-al neuropathy or neuropathic pain, orplatelet counts <50,000/μL, were exclud-ed from trial participation. A total of 218patients were evaluable for response.5

The baseline demographic and othercharacteristics of the 2 treatmentgroups were similar. The medianpatient age was approximately 64 years

(range, 38-88 years), and the majorityof patients were male (SC, 50%; IV,64%). The primary type of myelomawas immunoglobulin G. ISS stageI/II/III was 27%, 41%, and 32%,respectively, with both SC and IVroutes of administration.

The Karnofsky performance statusscore was ≤70 in 22% of SC-treatedpatients and 16% of IV-treated patients.Creatinine clearance was 67.5 mL/minin the SC group and 73 mL/min in theIV group. The median years from diag-nosis were 2.68 years and 2.93 years inthe SC and IV groups, respectively. Theproportion of patients with >1 prior lineof therapy was 38% with SC treatmentversus 35% with IV treatment.5

This study met its primary objective(noninferiority) that treatment withsingle-agent SC bortezomib retains atleast 60% of the ORR after 4 cycles ver-sus IV bortezomib (Table 1).5

Safety Profile: Reduced PeripheralNeuropathy With SC AdministrationThe safety data reported herein arefrom the randomized, open-label studythat compared the SC administrationof bortezomib with IV administrationof bortezomib at the recommendeddose of 1.3 mg/m2 in 222 patients withrelapsed MM.

Overall, the safety data were similarbetween the SC and IV treatmentgroups (Table 2), but with significantdifferences in some adverse events(AEs) favoring the SC form of bor tez -omib. Differences of ≥5% between the2 groups favoring the SC administra-tion were reported for neuralgia (3%SC vs 9% IV), peripheral neuropathygrade ≥3 (6% SC vs 16% IV) and allgrades (38% vs 53%), and thrombocy-topenia (13% SC vs 19% IV).5

In the SC treatment group, localreactions, primarily redness, werereported in 6% of patients; 2 patients(1%) experienced local reactions thatwere considered severe (1 case of pruri-tus and 1 case of redness). These reac-tions resolved in a median of 6 days.Local reaction led to study discontinu-ation in 1 patient and reduction indose concentration in 1 patient.5

Dose reductions associated withdrug-related AEs were reported in 31%of patients in the SC group comparedwith 43% of patients in the IV group.The most common AEs leading to dosereduction included sensory peripheralneuropathy (17% SC vs 31% IV) andneuralgia (11% SC vs 19% IV).5

Warnings and PrecautionsAssociated With BortezomibPeripheral NeuropathyPeripheral neuropathy has long beenrecognized as a problem, because it isfrequently associated with both MMand its treatment. The peripheral neu-ropathy associated with bor tezomib use

Table 2 Most Common Adverse Events (≥10%) in the Relapsed MM Study of Bortezomib SC Versus IV5

MedDRA System OrganClassMedDRA preferred term

Totaln (%)

Bortezomib SC(n = 147)* toxicity

Totaln (%)

Bortezomib IV(n = 74)* toxicity

grade 3 grade ≥4 grade 3 grade ≥4

n (%) n (%) n (%) n (%)

Blood and lymphatic system disorders

Anemia 53 (36) 14 (10) 4 (3) 26 (35) 6 (8) 0

Leukopenia 29 (20) 9 (6) 0 16 (22) 4 (5) 1 (1)

Neutropenia 42 (29) 22 (15) 4 (3) 20 (27) 10 (14) 3 (4)

Thrombocytopenia 52 (35) 12 (8) 7 (5) 27 (36) 8 (11) 6 (8)Gastrointestinal disorders

Abdominal pain 5 (3) 1 (1) 0 8 (11) 0 0

Abdominal pain upper 3 (2) 0 0 8 (11) 0 0

Constipation 21 (14) 1 (1) 0 11 (15) 1 (1) 0

Diarrhea 35 (24) 2 (1) 1 (1) 27 (36) 3 (4) 1 (1)

Nausea 27 (18) 0 0 14 (19) 0 0

Vomiting 17 (12) 3 (2) 0 12 (16) 0 1 (1)

General disorders and administration site conditions

Asthenia 23 (16) 3 (2) 0 14 (19) 4 (5) 0Fatigue 17 (12) 3 (2) 0 15 (20) 3 (4) 0Pyrexia 28 (19) 0 0 12 (16) 0 0Infections and infestations

Herpes zoster 16 (11) 2 (1) 0 7 (9) 1 (1) 0Investigations

Weight decreased 22 (15) 0 0 2 (3) 1 (1) 0

Metabolism and nutrition disorders

Decreased appetite 14 (10) 0 0 7 (9) 0 0

Musculoskeletal and connective tissue disorders

Back pain 21 (14) 1 (1) 0 8 (11) 1 (1) 1 (1)Pain in extremity 8 (5) 1 (1) 0 8 (11) 2 (3) 0

Nervous system disordersHeadache 5 (3) 0 0 8 (11) 0 0Neuralgia 35 (24) 5 (3) 0 17 (23) 7 (9) 0Peripheral neuropathiesNEC†

56 (38) 8 (5) 1 (1) 39 (53) 11 (15) 1 (1)

Psychiatric disordersInsomnia 18 (12) 0 0 8 (11) 0 0Respiratory, thoracic, and mediastinal disorders

Dyspnea 11 (7) 2 (1) 0 9 (12) 2 (3) 0

Vascular disorders

Hypertension 14 (10) 3 (2) 0 3 (4) 0 0*Safety population: 147 patients in the SC treatment and 74 patients in the IV treatment who received at least 1 dose of study medication.†Represents MedDRA high-level term.MedDRA, Medical Dictionary for Regulatory Affairs; NEC, not elsewhere classified; SC, subcutaneous.



Multiple Myeloma

is primarily sensory; however, cases ofsevere sensory and motor peripheralneuropathy have been reported withuse of the agent. Patients with preex-isting symptoms such as numbness,pain, or a burning sensation in thefeet or hands, and/or signs of periph-eral neuropathy, may experienceworsening of peripheral neuropathy,including grade ≥3, during treatmentwith bortezomib.5A paradigm shift regarding bor tez omib

use currently exists, with recent datasuggesting that changing the mode ofadministration or dosing schedule cansubstantially impact the incidence ofneuropathy. The results of a phase 3study by Moreau and colleagues thatincluded patients with relapsed MMwho had received 1 to 3 previous lines oftherapy showed that SC administrationof bortezomib 1.3 mg/m2 twice weeklysignificantly reduced the incidence ofperipheral neuropathy compared withIV administration at the same dose andschedule, with no deleterious effect onefficacy.6The protocol of this study provided

for a robust comparison of the 2 routesof administration, since it specified 4cycles of single-agent bortezomib withthe addition of oral dexamethasone 20 mg to enhance response at the endof cycle 4 in patients who achieved asuboptimal response.6 In this trial, theincidence of grade ≥2 peripheral neu-ropathy was 24% in patients whoreceived SC bortezomib and 41% inthose who received IV bortezomib.5,6Also in this trial, grade ≥3 peripheralneuropathy occurred in 6% of patientsin the SC treatment group and 16% ofthose in the IV treatment group.5,6When initiating bortezomib therapy,

SC administration may be consideredfor patients with preexisting peripheralneuropathy or those who are at highrisk for developing peripheral neuropa-thy. In patients with preexisting, severeperipheral neuropathy, the risk-benefitshould be carefully assessed prior tobeginning bortezomib therapy.5Pre vention rather than treatment is

the best approach to use when address-ing bortezomib-related neuropathy.One advantage of bortezomib is thatmost episodes of grade 3/4 neuropathycan be prevented by closely adheringto the algorithm for dose modificationand interruption provided in the pre-scribing information (Table 3). By fol-lowing these recommendations, theseverity of peripheral neuropathy canusually be decreased to grade 1 or 2,and in many cases, patients mayresume bortezomib therapy.5

HypotensionThe incidence of hypotension, whichincluded postural hypotension, ortho-static hypotension, and hypotension nototherwise specified, reported with the use

of bortezomib was 13%. These eventsoccurred throughout treatment. Cautionshould be used when administeringbortezomib to patients with a history ofsyncope, those receiving medicationsknown to be associated with hypoten-sion (eg, antihypertensive agents), andpersons who are dehydrated.5

Cardiac DisordersExacerbation or acute development ofcongestive heart failure and new onsetof decreased left ventricular ejectionfraction (LVEF) have been reported inpatients receiving treatment withbortezomib, including those with noknown risk factors for decreased LVEF.Thus, patients at risk for the develop-ment of heart disease or those with ahistory of existing heart diseaseshould be monitored closely.5

Pulmonary DisordersReports of acute diffuse infiltrativepulmonary disease of unknown etiolo-gy, such as pneumonitis, interstitialpneumonia, acute respiratory distresssyndrome, and lung infiltration, havebeen noted among patients receivingtreatment with bortezomib.5

Reversible PosteriorLeukoencephalopathy SyndromeReversible posterior leukoencepha -

lopathy syndrome (RPLS), a rare,reversible neurologic disorder that canpresent with seizure, hypertension,lethargy, head ache, blindness, confu-sion, and other visual and neurologicdisturbances, has been reported inpatients receiving bortezomib therapy.Bortezomib should be discontinued inpatients who develop RPLS that hasbeen confirmed by brain imaging,preferably MRI.5

Gastrointestinal EventsNausea, diarrhea, constipation, andvomiting, at times requiring the use ofantiemetic therapy and antidiarrhealagents, have been reported in patientsreceiving bortezomib. In order to pre-vent dehydration, fluid and electrolytereplacement should be administered tothese patients.5

Thrombocytopenia andNeutropeniaBortezomib is associated with thedevelopment of thrombocytopenia andneutropenia that follows a cyclical pat-tern, with nadirs that generally occurfollowing the last dose of each cycleand typically recover prior to initiationof the next cycle of therapy. This cycli-cal pattern remained consistent over 8cycles of twice-weekly therapy, with noevidence of cumulative thrombocy-

topenia or neutropenia observed. Inpatients experiencing thrombocytope-nia, platelet counts should be moni-tored prior to the administration ofeach dose; an adjustment in doseand/or schedule may be required.There have been reports of gastroin-testinal and intracerebral he morrhageassociated with the use of bortezomib.5

Tumor Lysis SyndromeTumor lysis syndrome may occur withthe use of bortezomib because theagent is cytotoxic and can rapidly killmalignant cells. Patients with a hightumor burden prior to therapy may beat a higher risk for the development oftumor lysis syndrome.5

Hepatic EventsAcute liver failure has occurred inbortezomib-treated patients receivingmultiple concomitant medications andin those with serious underlying med-ical conditions. Other hepatic eventsreported with the use of bortezomibinclude elevations in liver enzymes,hyperbilirubinemia, and hepatitis.5

Hepatic ImpairmentBecause bortezomib is metabolized bythe liver, exposure is increased inpatients with moderate or severe hepaticimpairment. Therefore, such patientsshould be started on reduced doses ofbortezomib and closely monitored for thedevelopment of toxicities.5

Use in PregnancyWomen of childbearing potentialshould avoid becoming pregnant whilebeing treated with bortezomib.5

DosingBortezomib is for IV or SC administra-tion only and should not be adminis-tered by any other route. The recom-mended starting dose of bortezomib is1.3 mg/m2 for both SC and IV forms ofadministration. Because each route ofadministration has a different reconsti-tuted concentration, caution should beused when calculating the volume ofdrug to be administered. With IVadministration, the recommended con-centration of bortezomib is 1 mg/mL;with SC administration, the recom-mended concentration of bortez omib is2.5 mg/mL.5

Dosage in Patients With PreviouslyUntreated MMIn patients with previously untreatedMM, bortezomib is administered incombination with oral melphalan andoral prednisone for a total of nine 6-week treatment cycles. In cycles 1through 4, bortezomib is administeredtwice weekly (on days 1, 4, 8, 11, 22,25, 29, and 32). In cycles 5 through 9,bortezomib is administered once week-ly (on days 1, 8, 22, and 29). At least

The primary study end point was to demonstratenoninferiority of single-agent SC bortezomibwith respect to overall response rate.

Table 3 Recommended Dose Modification for Bortezomib-Related NeuropathicPain and/or Peripheral Sensory or Motor Neuropathy5

Severity of Peripheral Neuropathy Signs and Symptoms* Modification of Dose and Regimen

Grade 1 (asymptomatic; loss of deeptendon reflexes or paresthesia) withoutpain or loss of function

No action

Grade 1 with pain or grade 2 (moderatesymptoms; limiting instrumental activities of daily living [ADL])†

Reduce bortezomib to 1 mg/m2

Grade 2 with pain or grade 3 (severesymptoms; limiting self-care ADL)‡

Withhold bortezomib therapy untiltoxicity resolves; when toxicityresolves reinitiate with a reduced doseof bortezomib at 0.7 mg/m2 onceweekly

Grade 4 (life-threatening consequences; urgent intervention indicated)

Discontinue bortezomib

*Grading is based on NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0.†Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using telephone, managing money.‡Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and notbedridden.


72 hours should elapse between consec-utive doses of bortezomib.5

Dosage in Patients With RelapsedMM or Mantle Cell LymphomaIn patients with relapsed MM or man-tle cell lymphoma, bortezomib 1.3mg/m2 per dose is administered twiceweekly for 2 weeks (on days 1, 4, 8, and11), followed by a 10-day rest period(days 12 through 21). For extended ther-

apy of more than 8 cycles, bortezomibmay be administered according to thestandard schedule or on a mainte-nance, once-weekly schedule for 4weeks (days 1, 8, 15, and 22), followedby a 13-day rest period.5

Dose ModificationsA patient’s platelet count should be≥70 ¥ 109/L and his or her absoluteneutrophil count should be ≥1.0 ¥

109/L before receiving any cycle oftherapy with bortezomib in combina-tion with melphalan and prednisone.All nonhematologic toxicities shouldhave resolved to grade 1 or to baselinelevel.5 Dose modification guidelines forpatients with relapsed MM or mantlecell lymphoma state that bortezomibtherapy should be withheld at theonset of any grade 3 nonhematologicor grade 4 hematologic toxicities

excluding neuropathy, which is dis-cussed separately. Once the symptomsof the toxicity have resolved, bortez -omib therapy may be reinitiated at a25% reduced dose.5

Administration PrecautionsWhen the SC route of administrationis used, the site for each injection(thigh or abdomen) should be rotated.New injections should be given atleast 1 inch from an old site and neverinto areas where the site is tender,bruised, erythematous, or indurated.5If local injection site reactions

occur after SC bortezomib administra-tion, a less concentrated bortezomibsolution (1 mg/mL instead of 2.5 mg/mL)may be used for SC administration.Alternatively, the IV route of admin-istration may be considered.5

ConclusionMM is an incurable hematologic cancerwith great clinical burden. The use ofbortezomib, and lenalidomide andthalidomide, as well as zoledronic acidand pamidronate, has revolutionizedthe management of patients with MM.These therapies, however, are all associ-ated with potentially serious side effects.A 3-drug combination therapy is thepreferred approach to treatment, butsome 2-drug combinations are also rec-ommended in current guidelines. Peripheral neuropathy has long been

recognized as a problem, because it isfrequently associated with both MMand its treatment. A paradigm shiftregarding bortezomib use has emerged,with recent data suggesting that chang-ing the mode of administration or dos-ing schedule can substantially impactthe incidence of neuropathy. �

References1. American Cancer Society. Cancer Facts & Figures2011. Atlanta, GA: American Cancer Society; 2011.2. Munshi NC, Anderson AC, Bergsagel PL, et al; forthe International Myeloma Workshop Consensus Panel2. Consensus recommendations for risk stratification inmultiple myeloma: report of the International MyelomaWorkshop Consensus Panel 2. Blood. 2011;117:4696-4700.3. National Comprehensive Cancer Network (NCCN).NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines™). Multiple Myeloma, Version 1. 2012.www.nccn.org. Accessed February 5, 2012.4. CenterWatch. Drug information. Velcade (bor -tezomib). www.centerwatch.com/druginformation/fda-approvals/drug-details.aspx?DrugID=830. AccessedFebruary 5, 2012.5. Velcade prescribing information. Cambridge, MA:Millennium Pharmaceuticals, Inc; 2012. 6. Moreau P, Pylypenko H, Grosicki S, et al.Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myeloma:a randomised, phase 3, non-inferiority study. LancetOncol. 2011;12:431-440.


Multiple Myeloma

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

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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

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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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Prevention rather thantreatment is the bestapproach to use whenaddressing bortezomib-related neuropathy.

TOP_February 2012_FINAL_TOP 2/16/12 9:44 AM Page 16

BOLERO-2: Practice-Changing Results With Exemestane... Continued from cover

First results of this study, calledBOLERO-2, were presented inSeptember 2011 at ECCO/ESMO/ESTRO. Updated results with addi-tional follow-up, presented at the2011 CTRC-AACR San AntonioBreast Cancer Symposium, confirmthe PFS benefit of adding everolimusto exemestane in this group of women.Overall survival (OS) data are not yetmature.“We believe these results underline

that everolimus is the first agent to sig-nificantly enhance the efficacy of hor-monal therapy in patients with HR+breast cancer. The addition ofeverolimus in advanced breast cancercould represent a paradigm shift in themanagement of this patient popula-tion,” stated Gabriel N. Hortobagyi,MD, professor of medicine and directorof the Multidisciplinary Breast CancerResearch Program at the University ofTexas MD Anderson Cancer Center inHouston, Texas“Endocrine therapy is the treatment

of choice for the majority of breast can-cers that express the estrogen receptor,which represents about 75% ofpatients over age 50. The standard is touse multiple endocrine regimens insequence to get multiple mileage. Butthe sad truth is that after a few monthsof suppression of tumor cells on oneagent, tumor cells become smarter andresistant and we need to changeagents,” Hortobagyi explained.Everolimus is an mTOR inhibitor.

This pathway is activated in hormone-resistant advanced breast cancer. Phase2 clinical trials of everolimusmonotherapy and in combination withendocrine therapy were encouraging inadvanced HR+ breast cancer,Hortobagyi explained. Positive resultsof phase 2 trials with everolimus addedto hormonal therapy led to the strategytested in BOLERO-2, he said.BOLERO-2 was a prospective, dou-

ble-blind, placebo-controlled, phase 3trial. The study population included724 postmenopausal women with HR+metastatic breast cancer with diseaseprogression on previous hormonaltherapy (ie, resistance). Patients wererandomized 2:1 to exemestane pluseverolimus (n=485) versus exemestaneplus placebo (n=279).Baseline demographics and disease

characteristics were similar betweenthe arms. At baseline, median age was62 years, 56% had visceral metastases,and 84% had documented benefit fromprevious endocrine therapy with letro-zole or anastrozole (100%), tamoxifen(48%), fulvestrant (16%), andchemotherapy for advanced disease(25%). Sixty percent had excellentperformance status. The study popula-

tion reflects a variety of ethnic groups,he said.At a median follow-up of 12.5

months, median PFS was 7.4 monthsfor the combination versus 3.2 monthsfor exemestane plus placebo. The per-centage of patients who experiencedclinical benefit (complete response,partial response, stable disease, amount

of pain, and overall benefit of the drug)was almost double in the combinationarm: 50.5% for the combination versus25.5% for exemestane plus placebo.The combination of exemestane

plus everolimus was well tolerated,Hortobagyi told listeners. The mostcommon grade 3 or higher adverseevents for the combination versus

exemestane plus placebo, respectively,were stomatitis (8% vs 1%), anemia(7% vs 1%), hyperglycemia (5% vs<1%), dyspnea (4% vs 1%), andfatigue (4% vs 1%). Adverse eventswere manageable with dose delays ordose reductions. Quality of life was almost identical

in both arms of the study. �


Breast Cancer

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

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In a randomized phase 2 study ofmetastatic breast cancer patients,peripheral neuropathy (PN) was

less likely to occur in patients receiv-

ing eribulin mesylate than withixabepilone.“Peripheral neuropathy is a big prob-

lem in the treatment of breast cancer.

Across the spectrum, patients have it,and we don’t know how to treat it,”said Linda T. Vahdat, MD, of WeillCornell Medical College in New York,

who presented the study at the 2011CTRC-AACR San Antonio BreastCancer Symposium (Poster P5-19-02).“If we want to be able to identify

patients at risk for peripheral neuropa-thy and develop strategies to manage itwe need to characterize it better. Thistrial was conceived and started afterthe close of the EMBRACE trial. Itgave us the opportunity to get a betterhandle on how eribulin performedfrom the perspective of side effects.The endpoint was the incidence ofneuropathy.”EMBRACE demonstrated that

eribulin treatment significantly im -proved median overall survival by 2.5months compared with standardtreatments in heavily pretreatedmetastatic breast cancer patients.The overall incidence of PN in eribu-lin-treated patients was 35% and wasmostly mild; grade 3 was seen in 8%and grade 4 in <1%.

The current study prospectivelyevaluated PN in 101 heavily pretreatedmetastatic breast cancer patients whowere randomized to eribulin orixabepilone as single agents on anevery-3-week schedule; the meannumber of treatment cycles was 6.2 inthe eribulin group and 4.8 in theixabepilone group. Almost one-third ofpatients in each arm had received atleast 6 prior agents.“We found the incidence of neu-

ropathy was about 13% lower witheribulin,” Vahdat reported. PN of anygrade occurred in 31% of the eribulingroup and 44% of the ixabepilonegroup. Grade 3/4 PN occurred in 10%versus 20%, respectively. The differ-ence numerically favored eribulin,though it was not statistically signifi-cant, she added. “Most importantly,” she said, “the

median time to the onset of treat-ment-emergent neuropathy was


Breast Cancer

�� 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.

� ��

Eribulin Associated With Less Neuropathy ThanIxabepilone in a Prospective, Randomized StudyBy Caroline Helwick

PN was less likely tooccur in patientsreceiving eribulinmesylate than withixabepilone.



Breast Cancer

Affiliate Programs located outside ofMemphis, Tennessee.As an academic institute, there are

more than 50 faculty members at workwithin the 3 divisions of the Feist-Weiller Cancer Center. Each division—the Division of Clinical CancerResearch, the Division of Basic andTranslational Cancer Research, and theDivision of Cancer Prevention andControl—encourages strong collabora-tion among researchers and clinicians toincrease the understanding of the mech-anisms regulating cancer formation andprogression, and to developing noveltechniques to detect and treat cancer, allwith the goal of providing better care forpatients.Gary Jean, PharmD, BCOP, answered

our questions about the Feist-WeillerCancer Center and the role of oncologypharmacists in patient care andresearch.

What approach does your institu-tion take to treating people withcancer?Gary Jean (GJ): LSU Health and Feist-Weiller Cancer Center engage in evi-dence-based medicine and multidiscipli-nary, translational cancer research;provide patients cutting-edge treatmentwith access to national cancer clinicaltrials; and educate both physicians andthe community about the prevention,treatment, and the science of cancer.

How does that translate to betteroutcomes for your patients?GJ: The Feist-Weiller Cancer Centerteam is committed to bringing lifesavingdiscoveries about cancer to all of

Louisiana and beyond. Collaborationbetween cancer researchers and treatingphysicians fosters a more comprehensiveunderstanding of cancer. Feist-WeillerCancer Center faculty:• Conduct laboratory and clinicalresearch to discover better methodsof preventing and treating cancer

• Provide adult and pediatric patientswith state-of-the-art cancer care,regardless of their ability to pay

• Educate and train hematology/oncology fellows, community physi-cians, and local residents about themost modern cancer treatments soall patients will receive the bestpossible cancer care

• Supply Louisiana communities withcancer screenings and educationmaterials for prevention throughPartners in Wellness, a unique com-munity cancer screening program

What are you excited about rightnow in the field of oncology?GJ: As a clinician, I am excited aboutthe constantly changing aspect in thefield of oncology. The evolution of can-cer treatment provides a challengingand rewarding career in patient care. Itis knowing that there is always going tobe something new that keeps me enthu-siastic about my work.

How has the role of the oncologypharmacist changed over the past 5 years?GJ: As a relatively new practitioner, Ihave seen a change away from a dispens-ing model to one oriented more towarddirect patient care. With so many newdrugs and changes in the standard of

care, pharmacists have to stay current toadequately take care of patients.Whether it’s verifying chemotherapyorders in clinic or making rounds on amedical oncology or bone marrow trans-plant service, every aspect of the patienthas to be evaluated to ensure that patientcare and safety come first.

What inspired you to become anoncology pharmacist?GJ: I was first exposed to oncology inmy second year of pharmacy school dur-ing a pharmacotherapy lecture. It wasthen that I became intrigued about thelevel of complexity involved inleukemia, specifically, and I quicklycame to understand, in all malignancies.The complex nature of the different dis-ease states and constantly changing treat-ment regimens drew me even closer. Bythe time I had my first “oncology” rota-tion in my third year of pharmacy school,I was hooked. Through the mentorship ofmy future program director, Sachin Shah,PharmD, BCOP, I took as many oncolo-

gy-related rotations as I could and studiedthe field at every opportunity. As myexperience grew, getting to know thepeople behind the diseases increased mylove for the field. While the success ratefor a potential cure isn’t as high as we allhope for, being able to provide care forour patients in such a difficult time intheir lives is a privilege.

Any advice for pharmacists justentering the field?GJ: There are a couple of things that Ihave noticed in my short tenure as anoncology pharmacist. Oncology is a fieldthat you either love or hate. Regardlessof the reason, if you choose the field ofoncology, choose it for the right reason.In my opinion, being an oncology phar-macist requires a high level of commit-ment and caring for this population,because a simple mistake with thesedrugs could be catastrophic. The secondpiece of advice would be to neverassume. We are human and are in noway perfect. If something doesn’t lookright, a simple phone call can solve a lotof problems ahead of time.

What are some areas of focus atyour institution?GJ: Our population has continued togrow, even in the short time that I havebeen here. We are constantly engaged inphysician-based and drug company–sponsored research. We are activelyengaged in community outreach withcancer screening and prevention initia-tives. In addition, we are activelyinvolved in integrative medicine, whichhas taken patient care from being dis-ease focused to being patient focused. �

LSU Health Feist-Weiller Cancer Center Continued from cover

Hong Nguyen, RPh, and PennyCrevoiserat, RPh, oncology pharma-cists at Feist-Weiller Cancer Center.

Figure. Waterfall graphs of percent change in summed longest diameter of target lesions from baseline to nadir inpatients receiving a) eribulin or b) ixabepilone according to RECIST (ITT population)

Figure courtesy of Prash Krishna, MBBS, MRCS.

Cancer Center Profile

longer in the eribulin group: 36 weeksversus only about 12 weeks withixabepilone. By cycle 4, only 24% ofpatients receiving eribulin had devel-oped neuropathy, compared to 44%receiving ixabepilone.”In addition, safety end points, includ-

ing objective response rate and progres-sion-free survival, based on ResponseEvaluation Criteria in Solid Tumors,showed greater reduction in the longestdiameter of target lesions (ie, reducingtumor size) with eribulin (~80%) com-pared with ixabepilone (~70%) frombaseline to nadir, as well as faster rateof change with eribulin, as shown inthe Figure.Vahdat acknowledged that if ixabepi-

lone were given weekly, as it often is, theincidence of PN would be lower. Thestudy followed the FDA-approved dos-ing schedule. �


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

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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



Leukemias

Bruton’s Tyrosine Kinase Inhibitor... Continued from cover

that induces apoptosis and inhibitscellular migration and adhesion inmalignant B cells.“It is very exciting to have agents

that are this effective and are notmyelosuppressive. The efficacy of thisagent increases over time, there is arelative lack of toxicity, and there is a

lack of myelosuppression. Theseagents should really change the para-digm for the treatment of CLL,” stat-ed lead author Susan O’Brien, MD, ofThe University of Texas MDAnderson Cancer Center, Houston.An earlier analysis of the phase

1b/2 study showed that PCI-32765

was highly active and tolerable inpatients with CLL. The data O’Brienpresented at ASH were based onlonger-term follow-up of a multicen-ter phase 1b/2 trial. The studyenrolled 61 CLL patients aged 65 orolder with previously untreated orrelapsed/refractory CLL after at least

2 prior therapies. Patients receivedoral PCI-32765 daily in 28-day cyclesuntil disease progression. Seventy-two percent of patients had at least 1poor-risk molecular feature: del(17p)31%, del(11q) 33%, or IgVH unmu-tated 57%.The study evaluated 2 doses of the

Btk inhibitor: 420 mg and 840 mg daily.The analysis presented at ASH includ-ed patients with relapsed/refractory dis-ease, but not those who were previous-ly untreated. Median follow-up for the420 mg cohort was 10.2 months and 6.5months for the 840 mg cohort.

For the 420 mg cohort, objectiveresponse rates (ORRs) improved from48% at 6 months of follow-up to 70%at 10 months; in the 840 mg cohort,ORR was 44% at a median follow-upof 6.5 months. The Btk inhibitorseems to be effective in shrinkingCLL in the lymph node compart-ment. At the time of the ASH meet-ing, nodal partial response wasobserved in 35% of patients (>50%reduction in aggregate lymph nodesize), with residual lymphocytosis.ORR appears to be independent ofmolecular risk features, O’Brien com-mented.The novel agent was well tolerated.

Two patients discontinued treatmentdue to adverse events; 6 patientsrequired dose reductions. Grade 1/2diarrhea, fatigue, nausea, and ecchy-mosis were the most frequentlyreported side effects. Ten percent ofserious adverse events were attributedto PCI-32765, as were 21% of grade≥3 adverse events. “Myelosuppressionhas not been a problem with thisagent,” O’Brien said.At the time of the ASH meeting,

82% of patients remained on treat-ment with PCI-32765. Only 8%(5/61) progressed; 6-month progres-sion-free survival was 92% in the 420mg cohort and 90% in the 840 mgcohort.Pharmacyclics, the company devel-

oping the novel Btk inhibitor, is plan-ning phase 3 trials of PCI-32765. �

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

9:27 AM

“The efficacy of this agentincreases over time, thereis a relative lack of toxicity,and there is a lack ofmyelosuppression.”

—Susan O’Brien, MD



Iwill say right up front that I am all infavor of specialty pharmacy trainingand the subsequent board certifica-

tion. The real questions are: how muchtraining is enough? how much is toomuch? and what options are available?I’ve been in the oncology business forover 30 years now and began whenthere was no real specialty training tospeak of. In fact, my introduction intothe specialty just happened; it wasn’tplanned at all. I wanted to stay inMadison, Wisconsin, when I finishedmy hospital pharmacy residency, but Iwas actually more interested in emer-gency care. I happened to come acrossan announcement that the oncologydepartment was looking for a coordina-tor to handle their new NationalCancer Institute (NCI) contract, so ona fluke I went in and talked with thephysician who was the principal investi-gator. We got along, and I was hired tomanage the University of WisconsinComprehensive Cancer Center’s phase1 NCI contract, working directly withthe principal investigator. I had workedas a pharmacist on the oncology unit ofthe university hospital but had no addi-tional formal oncology training. Therest, as they say, is history. The bottomline is that I learned on the job. I wasallowed to do what I was able to do anddemonstrate that I was competent. So, Ibasically did everything. I saw all thephase 1 patients, helped the fellows doworkups, wrote all the orders for thepatients, followed the patients, had myown clinic, started most of the IVs, keptall the experimental drugs, mixed andadministered all the drugs, did all thepharmacokinetic blood drawing, samplehandling, etc, and kept all the recordsfor the program. I managed between 70and 100 patients each year for 2 to 3active phase 1 trials. I also went to the

phase 1 meeting at the NCI and wasexpected to present our data.As I see it, specialty recognition is a

2-step process: one is training, and theother board certification. I know every-one is aware of the medical model withgeneral medical/surgical training fol-lowed by specialty training and boardcertification. This is the model thatpharmacy, for good or for bad, adoptedyears ago. First, the American Society ofHealth-System Pharmacists createdaccredited specialty residencies. Thefirst accredited oncology specialty resi-dency was in 1984. Once training wasstandardized to some degree throughspecialty residency training, it becameeasier to establish a scope of practice foroncology pharmacists. Once a scope ofpractice could be established, certifica-tion could be sought. So as far as oncol-ogy pharmacy goes, we have bothaccredited training and board certifica-tion available.

So, let’s add up the years. The aver-age PharmD program in the US is now6 years. Many students (like those at theUniversity of Texas) have completedmore than the 2-year pre-pharmacy pro-gram as our degree is now designed. Alarge percentage of our students already

have an undergraduate degree uponentering pharmacy. If the average phar-macy student has already put inbetween 6 and 8 years of college beforecompleting both a PGY-1 and then anoncology specialty PGY-2 year, the totaltime of training can easily reach 10years. Also, many students, some ofwhom are married and have children,have completed up to 8+ years of phar-macy training and need to “get out” ofschool, take a break, and earn somemoney. Note that the $40,000 to$60,000 generally earned during the res-idency process may not be adequate formany of these students. This leads tothe question, is 8 to 10+ years of train-ing to become an oncology pharmacistspecialist reasonable? Apparently manywould say yes, because this is the processand timeline today. As I tell the stu-dents I interact with, you do graduatework and residency training (or anytype of extra training) so that you canhopefully have a better chance of land-ing that job that you will love getting upfor every morning. Those with themost credentials will generally havethe better chance and more optionsavailable for getting a job they love.This brings up the issue of money. As Ialso tell the students with whom Iinteract, all the extra training you domay not mean you will make a lot ofextra money in terms of salary, buthopefully it will mean that you will behappy at work every day. I can say after30+ years of doing this, loving what youdo every day easily trumps the money.However, if you just cannot go

straight through the 10+ years foryour specialty training (includingpharmacy school), is getting out andgetting your oncology experiencewhile you work as a pharmacist OK?My answer to this is yes!

Can someone learn oncology on thejob? Absolutely! It just may not be themost efficient or ideal way of doing it.Trying to find a “clinical” position in ahospital or clinic may be difficult with-out residency training, but probablynot impossible. Back in the day whenthere was no formal specialty trainingprocess, learning on the job was muchmore common. If you were a pharma-cist who worked in oncology, sooner orlater you were viewed as the oncologypharmacist (by default). Things havecome a long way since then, and find-ing that perfect position where you canlearn on the job is probably less com-mon today. Many people hiring todaywant to bring in someone who can dothe job right off the bat.Another issue with all the training

required for specialization is that manyyoung people may not know what area ofspecialization they want to settle into atthe time of their graduation or even res-idency training. Many of these do PGY-1general training, and some even do PGY-2 specialty training in pharmacotherapy,yet they may not know exactly what theywant to do for a living. From my years oftraining here in San Antonio, I can giveyou numerous examples of residents whocompleted their pharmacotherapy spe-cialty residency training but are now“oncology pharmacists” in a variety ofpositions across the country. I havealways called these my “recent converts”(those who swore they didn’t like oncol-ogy and did pharmacotherapy instead,only to “see the light” shortly after thatand then “convert” to oncology). Evenmore recently, one of our master’s/phar-macotherapy residents is now an oncolo-gy specialist and lecturer at a college ofpharmacy.Is all the training—either going

straight through or learning on the job—worth it to be an oncology pharmacist? Ithas been for me, but I cannot answer foryou. You will have to decide.... �

Would you like straight-shooter Jim Koeller to respond to a particular topic? E-mail your ideas to [email protected].

So You Want to Be anOncology Pharmacist Specialist.What Are Your Options?

Shooting from the Hip

Koeller’s Corner

Everyone is aware of themedical model with gener-al medical/surgical trainingfollowed by specialty train-ing and board certification.This is the model thatpharmacy, for good or forbad, adopted years ago.


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february 2012 vol5, no 1

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