DeCemBeR 2012 www.TheOncologyPharmacist.com VOl 5, NO 8

Onco360 is an oncologypharmaceutical servicescompany dedicated to ad-

vancing the continuum of pharma-ceutical cancer care for patients.To that end, the company has de-veloped specialized clinical andsupportive care oncology pharma-cy care programs and servicesthat are managed by board-certified oncology pharmacists(BCOPs) with the goal of providingquality services and improving out-comes for patients. Onco360 provides services to

more than 1800 oncologists; 43 major BlueCross/BlueShield pro-grams; commercial, Medicare, and Medicaid managed care payers;hospital systems; and the National Comprehensive Cancer Network(NCCN) Centers of Excellence through its national network of certifiedand JCAHO-accredited OncoMed pharmacies.

The Oncology Pharmacist spoke with Burt Zweigenhaft, CEO ofOnco360, about the company and the future of oncology pharmacy.

What role do you see Onco360 playing in the current healthcare environment? Burt Zweigenhaft (BZ): We don’t believe the market has fully grasped the

potential value of oncology pharmacists, outside of some of the better-knownhospitals and NCCN centers like MD Anderson or Roswell Park.What keeps us awake at night is the ASCO-projected shortage of 4000 treat-

ing oncologists, and the corresponding aging of America fueled by 10,000 newMedicare beneficiaries a day until 2020; this will create a cancer care access cri-sis. Additionally, delivering cancer care will become exponentially more com-plex as we move to personalized medicine. Thus, the greater focus on patientcare plan personalization, based on the specific tumor diagnosis using predictivesciences and targeted, evidence-based guidelines, will be the norm.

Prostate CanCer . . . . . . . . . . . . .12Proton Beam Therapy

ComPlimentary Ce

Considerations in Multiple

Myeloma—Ask the Experts:

Retreatment Settings . . . . . . . . . . . . . .18Considerations in Multiple

Myeloma—Ask the Experts:

Bone Health . . . . . . . . . . . . . . . . . . . . . . .32

neuroendoCrine tumors . . 29Advances in the Treatment of

Pancreatic Neuroendocrine Tumors

ConferenCe news: esmo . . . 40

I N S I D E

Anticoagulation prophylaxis is effective in preventing bothsymptomatic and asymptomatic

catheter-related deep vein thrombosis inambulatory cancer patients with locallyadvanced or metastatic solid tumors,French investigators reported at theEuropean Society for Medical Oncology(ESMO) 2012 Congress, held inVienna, Austria.1Among cancer patients who have

catheters in place for chemotherapy,

catheter-related deep vein thrombosiscauses morbidity and mortality. The inci-dence of symptomatic events ranges from0.3% to 28.3%, and the incidence rises to 27% to 66% when asymptomaticepisodes are included. Current guidelines from American and

European societies do not recommendprophylactic anticoagulation for canceroutpatients, but symptomatic catheter-related deep vein thrombosis is still a sub-ject of active research, and the value of

SUPPORTIVE CARE

Catheter-Related ThrombosisCan Be PreventedBy Caroline Helwick

Continued on page 8

In a phase 3 head-to-head comparisontrial, the anaplastic lymphoma ki-nase (ALK) inhibitor crizotinib

proved more effective than standardchemo therapy with pemetrexed or doce -taxel as a second-line treatment for

non–small cell lung cancer (NSCLC) pa-tients with the ALK genetic abnormality.The results of the global PROFILE

1007 trial were reported by Alice Shaw,MD, of Massachusetts General Hospitalin Boston, at the European Society for

Burt Zweigenhaft, CEO of Onco360

PROFILE

Onco360The Changing Role of Oncology Pharmacy

©2012 Green Hill Healthcare Communications, LLC

LUNG CANCER

Crizotinib Superior toChemotherapy in First Head-to-Head ComparisonPROFILE 1007 Was a Headliner at ESMO

By Audrey Andrews

Continued on page 17

CONFERENCE NEWS

Highlights From ASTROBy Alice Goodman

The 2012 American Society forRad iation Oncology (ASTRO)Annual Meeting, held in Boston,

Massachusetts, coincided with Super -storm Sandy. Despite the havocwreaked by the storm, Boston waslargely spared, although ASTRO can-

celed Monday afternoon’s PlenarySession when public transportationwas shut down. Below are some high-lights from the meeting, includingsome news stories from the PlenarySession, which was available online.

Continued on page 26

Continued on page 28

Who’s Your T.O.P. Pharmacist Nominee?

Nominate a pharmacist atwww.TheOncologyPharmacist.com/award

For more information, see page 7.

A

R

W

The median age of patients in the VISTA† trial was 71 years(range: 48-91).

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATIONVELCADE (bortezomib) is indicated for the treatment ofpatients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS▼ Peripheral neuropathy: Manage with dose modi� cation

or discontinuation. Patients with preexisting severeneuropathy should be treated with VELCADE only aftercareful risk-bene� t assessment.

▼ Hypotension: Use caution when treating patientstaking antihypertensives, with a history of syncope,or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease.

▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.

▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected.

▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement.

▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment.

▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden.

▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

▼

In treating multiple myeloma

What is the value of VELCADE® (bortezomib)?▼ Overall survival advantage▼ De� ned length of therapy▼ Medication cost

IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE:VELCADE (bortezomib) combination delivered a >13-month overall survival advantage

At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)†

At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of

50 weeks (54 planned)1

IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition

Cost for VELCADE is $1,506 per 3.5-mg vial as of July 2012

When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm.

▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVERSE REACTIONSMost commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.*Melphalan+prednisone.† VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the ef� cacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespeci� ed interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in signi� cantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

1-2 1

Cancer research is fundedby the federal governmentprimarily through the

National Cancer Institute(NCI), part of the NationalInstitutes of Health (NIH).1

More than $30 billion annu-ally is invested into med-ical research by the NIH.1

Greater than 80% of NIH’sfunding is awarded throughcompetitive grants to re-searchers at more than3000 locations in all 50states across the country.1

Between fiscal years 2010and 2012, NIH federal appropriations fluctuatedonly slightly, with a low of$30,399 million (FY 2011)and a high of $31,010 (FY 2010).1

Over half of NCI’s budget isassigned to more than 6500research grants funded atmore than 150 research fa-cilities located in 49 states.1

NCI federal appropriationsalso varied only marginallybetween fiscal years 2010and 2012, with a low of$5058 million (FY 2011) anda high of $5103 (FY 2010).1

The National CancerSociety annually spendsapproximately $5.2 billionin its fight against cancer.2

Many times, research fund-ing is appropriated to aspecific cancer that has sci-entific groundwork alreadyestablished. Therefore, thelittle known and/or less understood cancers tend to receive less funding than the more understood cancers, such as breastcancer.3

Sources 1. www.aacr.org.2. www.StatisticBrain.com.3. www.everydayhealth.com.

Billions of dollars are spent each year to fund research as scientists continue to identify the causes of cancer and to develop

strategies for prevention, detection, treatments, and cures. The following statistics allow a glimpse into the immense field of

cancer research funding.

www.TheOncologyPharmacist.com4 DECEMBER 2012 I VOL 5, NO 8

Noteworthy Numbers

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA

Brief Summary

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

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

V-12-0306 11/12

11:06 AM

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,PhD(c), MSN,APRN-BC,AOCNCleveland 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,BSOncoMed Onco360Great Neck, NY

Marlo Blazer, PharmD, BCOPJames 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

www.TheOncologyPharmacist.com DECEMBER 2012 I VOL 5, NO 8 5

PUBLISHING STAFF

Senior Vice President, Sales & MarketingPhilip Pawelko

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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, 1249 South RiverRoad, Suite 202A, Cranbury, NJ 08512. 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 DECEMBER 2012 I VOL 5, NO 8 www.TheOncologyPharmacist.com

In this month’s issue of The Oncology Pharmacist (TOP),we wrap up the year with highlights of the news from the2012 American Society for Radiation Oncology Annual

Meeting and the European Society for Medical Oncology2012 Congress. Also, we continue our coverage of the newsfrom the 2012 Annual Meeting of the American Society ofClinical Oncology. The information we present from theseprofessional meetings helps keep you up-to-date with the

latest research and may affect your daily practice as an on-cology pharmacist.Our new TOP reader poll asks, “What inspired you to

enter the oncology field?” Please go to our website, www.TheOncologyPharmacist.com, and tell us what motivated you tobecome an oncology pharmacist. We’ll publish some of yourresponses in the first issue of the new year.All of us at TOP wish you the best for 2013. l

From the Editors

Patrick Medina, PharmD, BCOPEditor-in-Chief

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

Recent FDA NewsOmacetaxine mepesuccinate Approved to Treat CmlThe US Food and Drug Administration (FDA) has ap-

proved omacetaxine mepesuccinate subcutaneous injection(Synribo, Teva Pharmaceutical Industries) for the treat-ment of adult patients with chronic myeloid leukemia(CML) with resistance and/or intolerance to 2 or more ty-rosine kinase inhibitors (TKIs). Approval for omacetaxinemepesuccinate was granted on October 26, 2012.The FDA approval was based on the combined results of

2 open-label, single-arm trials that enrolled patients withCML in chronic phase or accelerated phase. Patients in thetrials had received 2 or more prior TKIs, including imat -inib. The end points for the studies were major cytogenet-ic response for chronic-phase CML and major hematologicresponse for accelerated-phase CML. For those with chron-ic-phase CML, major cytogenetic response was achieved in18.4% of patients (median response duration of 12.5months). For patients with accelerated-phase CML, 14.3%achieved major hematologic response (median response duration of 4.7 months).Thrombocytopenia, anemia, neutropenia, diarrhea, nau-

sea, fatigue, asthenia, injection-site reaction, pyrexia, infec-tion, and lymphopenia were the most common (≥20%)grades 1 to 4 adverse drug reactions. Thrombocytopenia,anemia, neutropenia, febrile neutropenia, asthenia/fatigue,pyrexia, and diarrhea were the most common (≥5%) grades3 to 4 adverse drug reactions. Among the patients in thetrials, 10 died within 30 days of the last omacetaxine mepe-succinate dose: 4 deaths were attributed to progressive dis-ease, 4 to cerebral hemorrhage, 1 to multiorgan failure, and1 to unknown causes.Omacetaxine mepesuccinate was reviewed under the

FDA’s accelerated approval review program that providesan expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when noadequate therapy exists. In addition, the FDA designatedomacetaxine mepesuccinate as an orphan product becauseit is intended to treat a rare disease or condition. Richard Pazdur, MD, director of the Office of

Hematology and Oncology Products in the FDA’s Centerfor Drug Evaluation and Research, stated that the approvalof omacetaxine mepesuccinate “provides a new treatmentoption for patients who are resistant to or cannot tolerateother FDA-approved drugs for chronic or accelerated phas-es of CML.” He also noted that it “is the second drug ap-proved to treat CML in the past two months.”

expanded labeling for PemetrexedThe FDA expanded the labeling of pemetrexed

(Alimta, Eli Lilly and Company) to include the results ofan additional trial evaluating its safety and efficacy for theinitial treatment of patients with locally advanced ormetastatic, nonsquamous, non‒small cell lung cancer fol-lowed by pemetrexed maintenance in patients with dis-ease that has not progressed after 4 cycles of platinum andpemetrexed as first-line chemotherapy. The approval forexpanded labeling was granted on October 17, 2012.The expanded labeling describes the results of a multi-

center, randomized (2:1), double-blind, placebo-con-trolled trial that evaluated pemetrexed maintenance inpatients with stage IIIB/IV nonsquamous, non‒small celllung cancer whose initial treatment was 4 cycles of peme-trexed plus cisplatin. There were 539 patients randomizedto receive 500 mg/m2 pemetrexed intravenously on day 1of each 21-day cycle (359 patients) or matching placebo(180 patients). All patients had an ECOG performancestatus of 0 or 1 and had completed 4 cycles of pemetrexedplus cisplatin with a best response of stable disease, partialresponse, or complete response.Investigator-assessed progression-free survival (PFS)

was significantly improved in patients randomized to re-ceive pemetrexed maintenance, compared with thosewho received placebo. Median PFS was 4.1 months for pa-tients in the pemetrexed arm and 2.8 months for patientsreceiving placebo. Overall survival, a secondary endpoint, also was significantly improved for patients receiv-ing pemetrexed maintenance, with median survival timeof 13.9 months, compared with 11.0 months for patientsreceiving placebo.Neutropenia, anemia, fatigue, nausea, vomiting, stoma -

titis, and edema were the most common (>5%) adverseevents for patients in the pemetrexed arm. Anemia andneutropenia were the most common severe adverse reac-tions. Approximately 25% of patients receiving peme-trexed maintenance had treatment reduced or delayed be-cause of toxicity. l

Sourceshttp://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm325990.htmhttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm325895.htmhttp://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm324239.htm

Nominate a pharmacist at TheOncologyPharmacist.com/award

The Oncology Pharmacist is pleased to announce the 2013

T.O.P. Pharmacist Award, sponsored by Teva Oncology.

This annual award recognizes an oncology pharmacist for

outstanding contributions to oncology pharmacy practice,

research, or education in 2012.

Nominate a pharmacist before December 31, 2012.

The 6 leading nominees will be profiled online and in the

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Supportive Care

8 DECEMBER 2012 I VOL 5, NO 8 www.TheOncologyPharmacist.com

prophylaxis in this population is contro-versial, said Sandrine Lavau-Denes,MD, of the University Hospital atLimoges in France.Lavau-Denes reported the results of a

phase 3 single-center prospective, ran-domized, open-label trial, conductedover a 10-year period (1999-2010), thatcompared a prophylactic strategy to noprophylaxis over 3 months of chemo -therapy among 420 patients with ad-vanced solid tumors.“We found that prophylaxis with ei-

ther warfarin or low-molecular-weightheparin was effective in preventingthrombotic events, and there was no in-crease in bleeding with prophylaxis,” saidLavau-Denes.The study was initiated prior to the

publication of the current guidelines.The primary end point was the rate of symptomatic and asymptomaticcatheter-related deep vein thromboses ofthe ipsilateral upper limbs and cervicalveins of patients who received, versusthose who did not receive, thrombopro-phylaxis. It excluded intra luminalthrombosis.Investigators randomized 142 patients

starting a first line of treatment to low-molecular-weight heparin (at the recom-

mended dose), 138 to warfarin (1 mg/day), and 140 to a control arm.Patients were evaluated at baseline andon day 90 (sooner, in the case of symp-toms), using Doppler ultrasound of theupper limbs and cervical veins, andvenography.

effectiveness of ProphylaxisIn 407 evaluable patients, 42 catheter-related deep vein thromboses occurred(10.3%), 30 (15.1%) of which wereasymptomatic. This included 20 of 135(14.8%) patients in the control arm and22 of 272 (8.1%) patients receiving ei-ther warfarin or low-molecular-weightheparin.The effect of prophylaxis amounted

to a 45% reduction in risk that was sta-tistically significant (P = .0357).Warfarin and low-molecular-weight

heparin were equally effective, Lavau-Denes noted. Rates of symptomatic events were

6.7% in controls, versus 1.1% afterprophylaxis; asymptomatic events oc-curred in 8.1% and 7.0%, respectively.Unrelated deep vein thromboses alsowere prevented. Adverse events were not significant-

ly increased with thromboprophylaxis.Bleeding occurred in 0.7% of controls,2.2% of the low-molecular-weight hep -arin arm, and 4.5% of the warfarin arm(P = .1361). However, there was an increase in thrombopenia in patients receiving thromboprophylaxis (P <.0001), particularly with low-mo -lecular-weight heparin. However, thiswas grade 3/4 in only 12 (8.8%), 4(3.0%), and 7 (5.0%) patients, respec-tively, with no difference among thearms (P = .1039), she said. Prophylaxis was discontinued by

25% in the control arm, 27% in thewarfarin arm, and 33% in the low-mo -lecular-weight heparin arm. For 12.5%of patients in the control arm the rea-son was the occurrence of a thrombot-ic event, compared with 2.2% in thewarfarin arm and 2.2% in the low-mo -lecular-weight heparin arm.

Who Should Receive Prophylaxis?Fausto Roila, MD, of Terni, Italy, whochairs ESMO’s Supportive Care Track,reiterated that routine prophylaxis forambulatory patients with solid tumorsis not recommended by any society, ex-cept when patients are considered at high risk. However, he noted,“Thrombosis is a potentially deadlycomplication, and it is not rare.” Therefore, Roila suggested that pri-

mary prophylaxis be considered underthe following circumstances: • The incidence within one’s insti-tution is 8% to 10%

• The tip of the central venouscatheter is not positioned at thejunction between the atrium andthe vena cava

• The patient has factor V Leidenmutation or a previous venousthromboembolism

• The patient has mediastinal syndrome l

Reference1. Tubiana-Mathieu N, Lavau-Denes S, Lacroix P, et al.Prophylaxis of catheter-related deep vein thrombosis incancer patients with low-dose warfarin, low molecularweight heparin, or control: a randomized, controlled,phase III study. Presented at: European Society forMedical Oncology 2012 Congress; October 1, 2012;Vienna, Austria. Abstract 1546O PR.

Catheter-Related Thrombosis Can Be Prevented Continued from cover

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On Cycle 1, Day 1, start with Triple Therapy—EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid—for first-line prevention of CINV.

Merck Oncology

Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1029338-0014 09/12emendforinjection.com

PREVENTION BEGINS WHERE TRIPLE THERAPY STARTS

For appropriate patients receiving highly emetogenic chemotherapy who are at risk of chemotherapy-induced nausea and vomiting (CINV)

EMEND for Injection, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.

Selected Important Safety InformationEMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine.Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.

Selected Important Safety Information (continued)

There have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use.Coadministration of EMEND for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle.The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection.Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. In clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%).In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

Please see the adjacent Brief Summary of the Prescribing Information.

An antiemetic regimen including

Vascular disorders: hot flush, flushing

Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation

Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, hard feces, neutropenic colitis, flatulence, stomatitis

Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion

Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness

Renal and urinary disorders: polyuria, dysuria, pollakiuria

General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance

Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, decreased weight, decreased neutrophil count

In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy.

The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1.

Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared with 1,169 patients receiving the 3-day regimen of EMEND. The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared with those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above:

General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain

Investigations: increased blood pressure

Skin and subcutaneous tissue disorders: erythema

Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis)

Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study.

Postmarketing Experience: The following adverse reactions have been identified during postapproval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug.

Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis

Immune system disorders: hypersensitivity reactions including anaphylactic reactions

DRUG INTERACTIONS

Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant.

Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9.

Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4 and does not induce CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs that are substrates for the P-glycoprotein transporter.

The following information was derived from data with oral aprepitant, 2 studies conducted with fosaprepitant and oral midazolam, and 1 study conducted with fosaprepitant and dexamethasone.

Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 Substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications].

5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron).

Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0–24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg I.V. on Day 1.

An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant.

Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant.

Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions].

Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions].

Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks posttreatment.

The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant.

Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as , decrease as , no change as ):

Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC 1.8-fold on Day 1 and AUC on Day 4

Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC 1.6-fold

Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC 2.3-fold on Day 1 and 3.3-fold on Day 5

Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day

Brief Summary of the Prescribing Information for INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin.

Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting.

Chronic continuous administration is not recommended [see Warnings and Precautions].

CONTRAINDICATIONS

Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions].

Concomitant Use With Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions].

WARNINGS AND PRECAUTIONS

CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions].

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions].

Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy.Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use.

Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions].

Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions].

Chronic Continuous Use: Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.

ADVERSE REACTIONS

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse-reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection.

The overall safety of fosaprepitant was evaluated in approximately 1,100 individuals and the overall safety of aprepitant was evaluated in approximately 6,500 individuals.

Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the multiple-cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone.

In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy.

The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence of >1% and greater than with standard therapy (n=550), respectively, are listed below:

Respiratory system: hiccups 4.6 vs 2.9

Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6

Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9

Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9

Nervous system: headache 2.2 vs 1.8

Metabolism and nutrition: anorexia 2.0 vs 0.5

A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than with standard therapy are presented in the Less Common Adverse Reactions subsection below.

In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverse-experience profile was generally similar to that seen in the other HEC studies with aprepitant.

Less Common Adverse Reactions: Adverse reactions reported in either HEC or moderately emetogenic chemotherapy (MEC) studies in patients treated with the aprepitant regimen with an incidence of <1% and greater than with standard therapy are listed below.

Infection and infestations: candidiasis, staphylococcal infection

Blood and lymphatic system disorders: anemia, febrile neutropenia

Metabolism and nutrition disorders: weight gain, polydipsia

Psychiatric disorders: disorientation, euphoria, anxiety

Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence

Eye disorders: conjunctivitis

Ear and labyrinth disorders: tinnitus

Cardiac disorders: bradycardia, cardiovascular disorder, palpitations

EMEND®

(fosaprepitant dimeglumine) for Injection

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regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC 25% on Day 4, AUC 19% on Day 8, and AUC 4% on Day 15

Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC 1.5-fold

A difference of less than 2-fold increase of midazolam AUC was not considered clinically important.

The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant.

CYP2C9 Substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle.

Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15.

Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution.

Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy.

Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously.

Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold.

Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.

Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs 15.6 [±4.1] mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood pressure (mean [SD] of 29.5 [±7.9] mmHg with fosaprepitant vs 23.8 [±4.8] mmHg without fosaprepitant), which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval beyond those changes induced by diltiazem alone.

In the same study, administration of aprepitant once daily as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone.

Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by ap-proximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine.

USE IN SPECIFIC POPULATIONS

Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant of up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcg hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcg hr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of EMEND for Injection in pediatric patients have not been established.

Geriatric Use: In 2 well-controlled CINV clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary.

Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients.

OVERDOSAGE

There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant.

In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis.

Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcg hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals

were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant.

Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test.

Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure).

PATIENT COUNSELING INFORMATION

[See FDA-Approved Patient Labeling]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed.

Patients should follow the physician’s instructions for the regimen of EMEND for Injection.

Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely.

Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation.

EMEND for Injection may interact with some drugs, including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products.

Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle.

Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant.

For detailed information, please read the Prescribing Information.

Rx only

Copyright © 2012 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.All rights reserved. ONCO-1029338-0014

EMEND®

(fosaprepitant dimeglumine) for Injection

The use of proton beam radiationtherapy (PBRT) for the treat-ment of prostate cancer is in-

creasing across the United States, butthere is no evidence from randomizedcontrolled trials to suggest that PBRT is

more effective than intensity modulatedradiation therapy (IMRT), which is thecurrent standard of care. A study pre-

sented at the 2012 American Society forRadiation Oncology Annual Meetingfound few differences in toxicity betweenthe 2 techniques, but demonstratedthat PBRT was associated with a 57%increase in median cost per patient.

Similar efficacy, Double the Cost“PBRT is an emerging treatment formen with prostate cancer, yet it ismuch more expensive than IMRT,”said James B. Yu, MD, AssistantProfessor of Therapeutic Radiology,Yale School of Medicine, New Haven,Connecticut. “We need a prospectivelarge study comparing radiation tech-niques to justify widespread use ofPBRT for prostate cancer,” he ex-plained.The population-based, retrospec-

tive, observational study was based on22,647 Medicare beneficiaries be-tween the ages of 66 and 94 years whoreceived PBRT or IMRT for prostatecancer in 2008 and 2009; 421 patients(2%) received PBRT and 27,226 pa-tients (98%) received IMRT.

The median Medicare reimburse-ment per patient is $32,428 for PBRTand $18,575 for IMRT, which repre-sents a 57% difference.PBRT was associated with a signifi-

cant reduction in urinary toxicity at 6months versus IMRT (6.1% vs 12%,respectively); however, by 1 year,there was no difference betweengroups for urinary toxicity (18.9% forPBRT vs 21.9% for IMRT). No signif-

Prostate Cancer

12 DECEMBER 2012 I VOL 5, NO 8 www.TheOncologyPharmacist.com

��� �� ��� ���Editor in ChiefSagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of Medicine

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

Topics include:• Newly Diagnosed Patients• Maintenance Settings• Transplant-Eligible and -Ineligible Patients• Retreatment Settings• Bone Health

Newsletter Series

���������������� ���������������� �� ���™

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Topics include:• Mantle Cell Lymphoma• Follicular Lymphoma

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AccreditationThese activities will be accredited for physicians, nurses, and pharmacists.

For complete accreditation information, please refer to each activity.

This activity is jointly sponsored by Medical Learning Institute, Inc.and Center of Excellence Media, LLC.

ALL NEW CONTENT FOR 2012

YOUR QUESTIONS ANSWERED

COEAsize71912AskExperts

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Spectrum Pharmaceuticals.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Celgene Corporation.

� �� �� � �� �

Proton Beam Therapy: Similar Toxicity to StandardRadiation, at much Higher CostBy Phoebe Starr

A study presented at the

2012 American Society for

Radiation Oncology

Annual Meeting found few

differences in toxicity

between the 2 techniques,

but demonstrated that

PBRT was associated with

a 57% increase in median

cost per patient.

icant differences were observed at 6months and at 1 year between the 2groups in gastrointestinal (GI) orother toxicities.“The longer-term effects, costs, and

other clinical and patient-reportedoutcomes are needed to inform theadoption of PBRT for prostate can-cer,” Yu stated.The study had several limitations,

he continued. It is a retrospectivestudy that is a claims-based analysiswith no staging information andwith no data on the extent or field ofradiation.

Potential Differences in SideeffectsA second study found minimal differ-ences between PBRT, IMRT, and theolder 3-dimensional conformal radia-tion therapy (3D-CRT).The study included 153 patients

treated with IMRT, 123 patients treat-ed with 3D-CRT, and 94 patients treat-ed with PBRT. Quality of life (QOL)was assessed by the Expanded ProstateCancer Index Composite in the IMRTcohort and by the Prostate CancerSymptom Index in the PBRT and 3D-CRT cohorts.The main difference in QOL scores

in the GI domain was found 2 to 3months posttreatment, when 3D-CRTand IMRT—but not PBRT—were as-sociated with a clinically meaningfuldecrement in QOL scores. Over 12months, the 3 cohorts had similarQOL scores for GI effects.For urinary irritation, all 3 groups

had lower QOL scores at 2 to 3 monthsof follow-up, but this was clinicallymeaningful only for IMRT. Sexual

function QOL scores were lower in all3 groups at 24 months, but this wasnot clinically meaningful (defined in

this study as scores exceeding half ofthe standard deviation of the base-line mean score).“These findings are a unique addi-

tion to existing research in the field,and suggest that PBRT may lead tofewer immediate side effects inprostate cancer patients,” notedPhillip Gray, MD, a resident atHarvard Radiation Oncology Pro -gram, Boston, Massachusetts. He sug-gested that a prospective, randomizedcontrolled trial is needed to comparethese technologies. l

DECEMBER 2012 I VOL 5, NO 8 13www.TheOncologyPharmacist.com

Prostate Cancer

In the October issue, we published an article about the results of a meta-analysis reported at ASCO 2012 that supported thenew guidelines that recommend weight-based chemotherapy dosing for obese cancer patients. We asked our online readingcommunity if they had experience with dosing for obese patients.

• 89% have dealt with weight-based dosing, with 1 reader commenting “every day” • 11% have not had experience with dosing for obese patients

Have you had experience in determining theappropriate chemotherapy dose for patients whoare obese?

Our sincere thanks to all who participated in this survey. If you want to participate in the new survey, see page 8 for details.

www.TheOncologyPharmacist.com

Reader Survey

Influencing the Patient-Impact Factor TM

REGISTER TODAY AT www.AVBCConline.org

May 2-5, 2013 Westin Diplomat • Hollywood, Florida

THIRD ANNUAL CONFERENCE

� �� �� � �� �

“PBRT is an emerging treatment for men with

prostate cancer, yet it is much more expensive than

IMRT. The longer-term effects, costs, and other

clinical and patient-reported outcomes are needed to

inform the adoption of PBRT for prostate cancer.”

—James B. Yu, MD

TREANDA® (bendamustine HCI) for Injection is his chemo. This is his therapy.

S

Single-agent TREANDA tripled median PFS*

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Effi cacy relative to fi rst-line therapies other than chlorambucil has not been established.

20100 30 4025155

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

35

TREANDA(n=153)

Chlorambucil(n=148)18 months

median PFS

45

0.10.20.30.40.5

Surv

ival

dis

tribu

tion

func

tion

0.60.70.80.91.0

Months

HR†=0.27 (95% CI‡: 0.17, 0.43) P<.0001

6 monthsmedian PFS

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6).†HR=hazard ratio.‡CI=confi dence interval.

2

≥≥

Important Safety Information

≥ ≥

LEARN MORE AT WWW.TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2510a August 2012

Discover the elements of ef� cacy and safety

1-2 9 11:57 AM

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions]WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

Number (%) of patientsTREANDA Chlorambucil(N=153) (N=143)

System organ classPreferred term All Grades Grade 3/4 All Grades Grade 3/4Total number of patients with atleast 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17)Gastrointestinal disordersNausea 31 (20) 1 (<1) 21 (15) 1 (<1)Vomiting 24 (16) 1 (<1) 9 (6) 0Diarrhea 14 (9) 2 (1) 5 (3)General disorders and administration site conditionsPyrexia 36 (24) 6 (4) 8 (6) 2 (1)Fatigue 14 (9) 2 (1) 8 (6) 0Asthenia 13 (8) 0 6 (4) 0Chills 9 (6) 0 1 (<1) 0Immune system disordersHypersensitivity 7 (5) 2 (1) 3 (2) 0Infections and infestationsNasopharyngitis 10 (7) 0 12 (8) 0Infection 9 (6) 3 (2) 1 (<1) 1 (<1)Herpes simplex 5 (3) 0 7 (5) 0InvestigationsWeight decreased 11 (7) 0 5 (3) 0Metabolism and nutrition disordersHyperuricemia 11 (7) 3 (2) 2 (1) 0Respiratory, thoracic and mediastinal disordersCough 6 (4) 1 (<1) 7 (5) 1 (<1)Skin and subcutaneous tissue disordersRash 12 (8) 4 (3) 7 (5) 3 (2)Pruritus 8 (5) 0 2 (1) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

TREANDA Chlorambucil(N=150) (N=141)

Laboratory AbnormalityAll Grades Grade 3/4 All Grades Grade 3/4

n (%) n (%) n (%) n (%)Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9)Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10)Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3)Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4)Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions]OVERDOSAGE: The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. Aseptically

Sterile Water for Injection, USP Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be

immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The

reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride

drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Distributed by:Cephalon, Inc.Frazer, PA 19355TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved.©2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 April 2012(Label Code: 00016287.06) This brief summary is based on TRE-006 TREANDA full Prescribing Information.

TRE-2511a August 2012

This brief summary is based on TRE-2527 TREANDA full Prescribing Information.

DECEMBER 2012 I VOL 5, NO 8 17www.TheOncologyPharmacist.com

Lung Cancer

Medical Oncology (ESMO) 2012 Con gress, held in Vienna, Austria.1Rearrangements of the ALK gene are

found in about 5% of all NSCLC. In pre-vious studies, crizotinib was shown to in-duce significant clinical responses in pa-tients with advanced ALK-positiveNSCLC, but this is the first phase 3 studyto directly compare the novel agent withstandard chemotherapy. The study com-pared crizotinib with pemetrexed ordoce taxel (by physician choice) in 347patients with ALK-positive, stageIIIB/IV NSCLC who had already beentreated with chemotherapy. Crizotinib was superior to standard

single-agent chemotherapy in terms ofresponse, progression-free survival(PFS), and quality of life in ALK-posi-tive patients who progressed after first-line, platinum-based chemotherapy,Shaw reported.“These results establish crizotinib as

the standard of care for patients withadvanced, previously treated, ALK-pos-itive NSCLC,” she maintained.

Doubling in PFSAt 12 months’ median follow-up,crizotinib prolonged median PFS to 7.7months, compared with 3.0 monthswith chemotherapy, a highly signifi-cant 51% reduction in the risk of pro-gression (P <.0001). By type ofchemotherapy, median PFS was 4.2months with pemetrexed (P = .0004)and 2.6 months with docetaxel (P <.0001).The overall response rate was also

significantly higher with crizotinib(65% vs 20%; P <.0001).

All subgroups experienced a PFSbenefit with crizotinib, with the great-est advantages seen in patients withnonadenoma histology (hazard ratio[HR], 0.12).

Survival, TolerabilityAt this point, overall survival (OS) dif-ferences have not been observed, but thesurvival analysis is immature, with only40% of events occurring. Also, 87% ofchemotherapy-treated patients havecrossed over to receive crizotinib uponprogression, and this would dilute anyOS differences, Shaw said.Median OS at this point is approxi-

mately 22 months in each arm. Whenadjusted for confounding by cross -overs, there was still a 17% reducedrisk of dying from the disease for pa-tients who received ALK inhibitor,she pointed out.Side effects were more frequent with

crizotinib, but Shaw pointed out thatcrizotinib-treated patients received anaverage of 11 cycles, compared with 4with pemetrexed or docetaxel, whichpartly explains these differences.Toxicities with crizotinib are, however,

distinct from those observed withchemotherapy, but are “generally toler-able and manageable,” she noted.The most common treatment-related

adverse events with crizotinib were diar-rhea (60%), vision disturbance (60%),nausea (55%), and vomiting (47%), butfew grade 3 or 4 toxicities were reported,except for elevated transaminases, whichoccurred in 16% of this arm. Patients re-ceiving chemotherapy had more fatigue,alopecia, dyspnea, and rash. Six percent of crizotinib patients,

compared with 10% of pemetrexed/doce taxel patients, discontinued the trialdue to treatment-related adverse events.

Better Quality of life With CrizotinibPatients on crizotinib also reported im-proved quality of life, compared withchemotherapy. “They reported greater improvement

from baseline in cough, dyspnea, fatigue,alopecia, insomnia, and pain with crizo-tinib,” Shaw said, “and all of these werestatistically significant (P <.0001).”They also showed greater improve-

ment from baseline in global quality of

life (P <.0001). Furthermore, “time todeterioration in lung cancer symptoms”was significantly extended with crizo-tinib treatment, to 5.6 months, com-pared with 1.4 months with chemother-apy (HR, 0.54; P <.0001).

Crizotinib “Changes the NaturalHistory” of lung CancerDiscussing the paper at the meeting,Jean-Charles Soria, MD, of the InstitutGustave Roussy in Villejuif, France,noted that 2 months’ extended survivalin advanced NSCLC is essentially “un-heard of ” in the general population ofNSCLC patients.“Comparison with historical data sug-

gests that crizotinib has changed the nat-ural history of the disease, with a medianOS now of 22 months, versus 9 monthsin the past,” he said, “and this is accom-plished with very mild toxicity.”Even patients in the trial who initially

received chemotherapy had a medianOS of nearly 23 months “because theyreceived crizotinib,” he added. Soria suggested that clinicians become

familiar with the toxicity profile, whichis quite distinct from chemotherapy, butis generally manageable with the excep-tion of “some rare side effects you need tobe aware of,” he told attendees. l

Reference1. Shaw AT, Kim DW, Nakagawa K, et al. Phase III studyof crizotinib versus pemetrexed or docetaxel chemother-apy in patients with advanced ALK-positive non-smallcell lung cancer (NSCLC) (PROFILE 1007). Presentedat: European Society for Medical Oncology 2012Congress; September 30, 2012; Vienna, Austria.Abstract LBA1 PR.

“These results establish crizotinib

as the standard of care for patients

with advanced, previously treated,

ALK-positive NSCLC.”

—Alice Shaw, MD Pho

to ©

ESMO 201

2.

Crizotinib Superior to Chemotherapy... Continued from cover

Crizotinib Is Just the Beginning By Audrey Andrews

If the abstracts presented at ESMO were any indication,the US Food and Drug Administration approval of crizotinibonly opened the door to a virtual roomful of next-generationALK inhibitors. While crizotinib targets only the 5% of non– small cell lung cancer (NSCLC) patients with the ALKgenetic translocation, it makes a huge impact on this subset,doubling the time that patients with advanced disease spendin remission.“Crizotinib is the poster child for precision medicine,” ac-

cording to Mace Rosenberg, MD, Senior Vice President ofClinical Development and Medical Affairs at PfizerOncology. At a press briefing, he noted that the robust re-sponses observed in phase 1 trials of ALK-positive patientsled to a “rapid reduction of our clinical development program.” At ESMO, data from phase 1 and 2 trials suggest that the

following next-generation ALK inhibitors may follow in thefootsteps of crizotinib:• AP26113 is an oral agent that also targets mutations inthe epidermal growth factor receptor (EGFR). A study

of 29 patients with NSCLC showed activity in both thefirst-line and resistant cohorts.

• LDK378, a potent oral small molecule ALK inhibitor,showed a high level of activity in patients who pro-gressed after crizotinib.

• CH5424802, an oral agent, produced 3 complete re-sponses and 36 partial responses among 46 NSCLC pa-tients with no prior ALK therapy; 40 patients remain ontreatment.

• AUY922, a heat shock protein 90 inhibitor that is de-livered by weekly infusion, was highly active in 121 pa-tients with previously treated NSCLC who had ALK orEGFR mutations. Responses were observed in 32% of ALK-positive patients and 20% of EGFR-mutated patients.

NSCLC investigators at the meeting emphasized that newALK inhibitors will be needed for treating patients, who in-evitably become resistant to crizotinib, in spite of its initialefficacy. They also said that next-generation ALK inhibitorsappear to be even better tolerated than crizotinib.

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CONTINUING EDUCATION

CONSIDERATIONS inMultiple Myeloma™5th Annual

ASK THE EXPERTS: Retreatment Settings

Jeffrey Wolf, MDClinical ProfessorDepartment of Medicine, UCSFDirector, Myeloma Program UCSF Helen DillerFamily Comprehensive Cancer CenterSan Francisco, CA

Jennifer Knoche, RN, BSNLead Practice NurseUCSF Hematology/BMT AmbulatoryCare CenterSan Francisco, CA

Helen T. Wu, PharmD, BCOPClinical PharmacistAdult Hematology/Oncology and Health SciencesAssociate Clinical Professor School of Pharmacy, UCSFSan Francisco, CA

Supported by educational grants from Celgene Corporation andMillennium: The Takeda Oncology Company.

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LETTER FROM THE EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). Thisis due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinicalinvestigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria fordiagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management ofcomorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regardingthe application and interpretation of recent clinical advances.

In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently askedquestions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questionsare answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowl-edge, and professional experience regarding evidence-based care. In this fourth issue, experts from the University ofCalifornia, San Francisco answer questions pertaining to the management of patients in the retreatment setting.

Sincerely,

Sagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

FACULTY

NOVEMBER 2012 • VOLUME 5 • NUMBER 4

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www.TheOncologyPharmacist.com18 DECEMBER 2012 I VOL 5, NO 8

CONSIDERATIONS IN MULTIPLE MYELOMA

IntroductionNovel agents and regimens have greatly improved the manage-

ment of multiple myeloma (MM). However, the retreatment setting

remains complex, since many patients have already received nu -

merous therapies at the time of disease progression. The result can

be resistance to specific agents and/or cumulative toxicities, which

may influence the choice of therapy. In this article, Jeffrey Wolf, MD,

discusses therapeutic decision-making in relapsed and refractory MM

and the latest evidence on investigational drugs that may expand

treatment options for the disease.

When a patient experiences a first relapse, what factors do youconsider in choosing retreatment with previously used therapyversus treatment with different agents?

Because first-line therapy for MM often involves several different combi-nations,1 choosing second-line therapy can be a challenge. In the setting ofinitial treatment, we are using doublet and triplet combinations that mayinclude bortezomib, lenalidomide, cyclophosphamide, or dexamethasone.

Eligible patients advance to autologous stem cell transplantation (ASCT)following this therapy. More and more patients receive maintenance thera-py, either with lenalidomide or bortez omib. Therefore, when patients re -lapse, they have already re ceived quite a bit of therapy. The choice of treat-ment for relapsed MM must take into account the resultant toxicities andefficacy of prior drugs.

For example, if a patient has progressed on lenalidomide maintenance, wewould not choose lenalidomide as part of second-line therapy. However, ifthat same patient achieved a very good partial response (VGPR) or a com-plete response during induction with a bortezomib-based regimen, we mightutilize bortezomib at relapse, provided that the patient did not have signifi-cant peripheral neuropathy (PN) or other adverse events (AEs) associatedwith treatment. Bortezomib-related AEs might suggest the use of an alkylatoralone at the time of relapse in such a patient. Another example is a patient who relapses after initial therapy with a com-

bination of lenalidomide, bortezomib, and dexamethasone (RVD)2 but whohas not undergone transplant or maintenance therapy. We could go back toRVD, which has been shown to be effective (Figure),3 or we may switch thepatient to a regimen of cyclophosphamide, bortezomib, and dexametha-

Making Treatment Decisions in Relapsed andRefractory Multiple Myeloma

Jeffrey Wolf, MDClinical Professor, Department of Medicine, UCSFDirector, Myeloma ProgramUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, CA

SponsorsThis activity is jointly sponsored by Medical Learning Institute Inc andCenter of Excellence Media, LLC.

Commercial Support AcknowledgmentThis activity is supported by educational grants from Celgene Corporationand Millennium: The Takeda Oncology Company.

Target AudienceThe activity was developed for physicians, nurses, and pharmacists in -volved in the treatment of patients with multiple myeloma (MM).

Purpose StatementThe purpose of this activity is to enhance competence of physicians, nurs-es, and pharmacists concerning the treatment of MM.

Physician Credit DesignationThe Medical Learning Institute Inc designates this enduring material for a max-imum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim onlythe credit commensurate with the extent of their participation in the activity.This activity has been planned and implemented in accordance with theEssential Areas and policies of the Accreditation Council for ContinuingMedical Education through the joint sponsorship of the Medical LearningInstitute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for ContinuingMedical Education to provide continuing medical education for physicians.

Registered Nurse DesignationMedical Learning Institute IncProvider approved by the California Board of Registered Nursing, Pro viderNumber 15106, for 1.25 contact hours.

Registered Pharmacy DesignationThe Medical Learning Institute Inc is accredited by the Accredi -tation Council for Pharmacy Education as a provider of continu-

ing pharmacy education. Completion of this knowledge-based activityprovides for 1.25 contact hours (0.125 CEUs) of continuing pharmacyeducation credit. The Universal Activity Number for this activity is0468-9999-12-030-H01-P.

Learning ObjectivesUpon completion of this activity, the participant will be able to:• Review data from recent clinical trials evaluating novel agents for MM

in the relapsed/refractory setting • Apply evidence-based retreatment strategies for MM, taking into con-

sideration patient- and disease-related factors • Describe appropriate prophylactic measures for managing adverse

events to optimize treatment efficacy

DisclosuresBefore the activity, all faculty and anyone who is in a position to have con-trol over the content of this activity and their spouse/life partner will dis-close the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses,grants, consulting roles, speakers’ bureau membership, stock ownership, orother special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vettedby Medical Learning Institute Inc for fair balance, scientific objectivity ofstudies mentioned in the materials or used as the basis for content, andappropriateness of patient care recommendations.

Planners’ and Managers’ DisclosuresDana Delibovi,Medical Writer, has nothing to disclose.William J. Wong, MD, MLI Reviewer, has nothing to disclose.Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosedthat her spouse is investigator on a study for Agenix, ImClone, and Lilly;on the data monitoring committee for Infinity; on the Advisory Com -mittee for Boehringer Ingelheim; and on the data monitoring committeeand principal investigator on a study for Pfizer.

Faculty Disclosures*Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, CelgeneCorporation, Merck, Millennium: The Takeda Oncology Company,Novartis, and Onyx.*Jeffrey Wolf, MD, is on the speakers’ bureau for Celgene Corporation,Millennium: The Takeda Oncology Company, and OnyxPharmaceuticals, Inc.Helen T. Wu, PharmD, BCOP, has nothing to disclose.Jennifer Knoche, RN, BSN, is on the speakers’ bureau for CelgeneCorporation.

*Content will include non–FDA-approved uses.The associates of Medical Learning Institute Inc, the accredited providerfor this activity, and Center of Excellence Media, LLC, do not have any

financial relationships or relationships to products or devices with anycommercial interest related to the content of this CME/CPE/CE activityfor any amount during the past 12 months.

Disclaimer The information provided in this CME/CPE/CE activity is for continuingeducation purposes only and is not meant to substitute for the indepen -dent medical judgment of a healthcare provider relative to diagnostic andtreatment options of a specific patient’s medical condition. Recommenda -tions for the use of particular therapeutic agents are based on the best availablescientific evidence and current clinical guidelines. No bias towards or promotionfor any agent discussed in this program should be inferred.

Instructions for Credit

There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest,posttest, and evaluation. The pretest, posttest, and evaluation can be com-pleted online at www.mlicme.org/P12028.html. Upon completion of theevaluation and scoring 70% or better on the posttest, you will immediatelyreceive your certificate online. If you do not achieve a score of 70% or bet-ter on the posttest, you will be asked to take it again. Please retain a copyof the Certificate for your records.

For questions regarding the accreditation of this activity, please contactMedical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

Estimated time to complete activity: 1.25 hoursDate of initial release: November 13, 2012Valid for CME/CPE/CE credit through: November 13, 2013

SCAN HERE to Download the PDF or Apply for Credit.

To use 2D barcodes, download the ScanLife app:• Text “scan” to 43588• Go to www.getscanlife.com on your smartphone’s

Web browser, and select “Download”• Visit the app store for your smartphone

The choice of treatment for relapsed MM must take into account the resultant toxicities and efficacy of prior drugs.

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DECEMBER 2012 I VOL 5, NO 8 19www.TheOncologyPharmacist.com

CONTINUING EDUCATION

sone.4,5 Both of these regimens yield a response rate of about 75% in therelapsed setting.3-5 We could consider ASCT as part of second-line therapy,usually with some initial therapy to get better control pretransplant. If themyeloma is particularly aggressive at relapse, we may use a combination suchas bortezomib and dexamethasone with cisplatin, doxorubicin, cyclophos-phamide, and etoposide (VD-PACE) and then go to transplant.6 If thepatient has renal insufficiency, we will use modified HyperCVAD(cyclophosphamide, bortezomib, doxorubicin, and dexamethasone; withbortezomib in place of vincristine) instead of VD-PACE.7

How would you choose therapy for a patient who is resistant toinitial treatment?

Drug resistance is a topic of ongoing investigation, and therapeutic choicesin this setting require careful consideration. Recently, we had a patient whowas treated with a 2-drug regimen of bortezomib and dexamethasone andattained only a partial response. We added lenalidomide, and his responseimproved to a VGPR. At the time of relapse, we might be disinclined to usebortezomib for such a patient, because of the modest initial response. Thereis a caveat here, however. Evidence suggests that, if you wait long enough,you can often go back to a drug such as bortezomib despite initial resistance(Table 1).8,9 We now believe that myeloma is made up of various clones withmultiple sensitivity and resistance patterns to different drugs. Sometimes, if apatient has not received a drug for a period of time, the clone that may berelapsing most recently may be one that is sensitive to bortezomib. Therefore,it may be worth retrying this agent. Often we do see a response in patients

who exhibited resistance earlier in the clinical course of the disease. In otherwords, “once resistant, always resistant” may not be true.Of course, one could argue that the best option for a patient resistant to

bortezomib would be treatment with carfilzomib. That is an argument thatwill play out now that both agents are available. My point is that going backto a proteasome inhibitor makes sense, even if a patient had only a modestprior response to bortezomib.

Has the approval of carfilzomib impacted treatment approachesin the retreatment setting?

The next-generation proteasome inhibitor carfilzomib is now availablefor use in the relapsed/refractory setting for MM, but it is approved by theUS Food and Drug Administration only for patients who have re ceived atleast 2 prior therapies including bortezomib and an immuno modulatoryagent.10 Clinical trials have shown the efficacy of carfilzomib in this set-ting and have also indicated that carfilzomib is less likely than bortezomibto cause PN.11,12

Because we see many patients who have run through all of the other treat-ment options and have progressed on bortezomib-based therapies, our teamhas used carfilzomib frequently since its approval. However, in patients whoreceived bortezomib with good response a long time ago, or in patients whoprogressed on bortezomib 2 to 5 years ago, retreatment with bortezomib couldbe considered at relapse. In such cases, the decision of which drug to use maybe influenced by possible prior toxicities.

For instance, in a patient who still has PN that developed during priortreatment with bortezomib, I would probably lean toward using carfilzomib.Even though you can give bortezomib subcutaneously (SC) and possiblyavoid making neuropathy worse,13 it may not be worth taking that chance. Incontrast, if there is no neuropathy and the patient did not progress on bor -tezomib initially, I would lean toward bortezomib retreatment. Convenienceis a consideration here. At the present time, carfilzomib is cumbersome toadminister. It is given intravenously over 2 to 10 minutes 2 days in a row,weekly for 3 weeks followed by a 12-day rest period.10 Bortezomib, which cannow be given SC twice a week,13 is more convenient.

For the patient with relapsed or refractory MM, what investigationaltherapies show the most promise?

The immunomodulator pomalidomide is the first agent that comes tomind, as it may be approved in the next 6 months. Clinical data support theefficacy of this agent when combined with weekly dexamethasone in therelapsed/refractory setting for MM, and it is fairly well tolerated. In 2 phase 2trials of pomalidomide plus dexamethasone in patients refractory to bortez -omib and lenalidomide, overall response rates were 43% to 49%.14 In an ear-lier report, this combination showed a 63% response rate in patients receiv-ing 1 to 3 prior therapies; however, the incidence of grade �2 toxicities washigh, including neutropenia, fatigue, leukopenia, and anemia (Table 2).15

Elotuzumab is an antibody that does not have a lot of activity on its own,but looks good when combined with lenalidomide and dexamethasone.16

Figure. Response rates with RVD in a phase 2 trial ofrelapsed/refractory MM (N=64).3

Pati

ents

(%

)

100

90

80

70

60

50

40

30

20

10

0

CR indicates complete response; MR, minimal response; NR, no response; ORR, overall responserate; PR, partial response; RVD, lenalidomide, bortezomib, and dexamethasone.

CR/near CR PR NR ORR (��MR)

25%

64%

22%

78%

Table 1. Response to Bortezomib-Based Retreatment FollowingResponse to Initial Bortezomib-Based Therapy (N=22)8

Response to Initial Therapy, n (%) Response to Retreatment, n (%)

Complete orpartial response

No response

15 (68%)

7 (32%)

Complete or partial response

No response

Complete or partial response

No response

9 (60%)

6 (40%)

2 (29%)

5 (71%)

Drug resistance is a topic of ongoing investigation,and therapeutic choices in this setting require careful consideration.

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www.TheOncologyPharmacist.com20 DECEMBER 2012 I VOL 5, NO 8

CONSIDERATIONS IN MULTIPLE MYELOMA

There are also CD38 antibodies—daratumumab and SAR650984—inphase 1/2 trials that look promising.17,18

Additional drugs that are progressing through clinical trials include theBruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765)19 and the mam-malian target of rapamycin inhibitor MLN0128.20 The histone deacetylaseinhibitor vorinostat and the pan-deacetylase inhibitor panobinostat do notseem to have very good antimyeloma activity on their own. Vorinostat hasprovided a slight advantage in combination with bortezomib, but it appearsto add quite a bit of toxicity.21 Panobinostat is in trials in combination witha proteasome inhibitor,22-24 but it is not yet clear if this drug will perform bet-ter than vorinostat.

ConclusionOver the past decade, we have witnessed spectacular progress in the area

of treating myeloma. Today, a majority of patients are alive and doing wellat 5 years following initial treatment. It is becoming apparent that manypatients can hope for very extended survival because of novel drugs and ourability to treat relapsed and refractory disease. �

References1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in

Oncology™: Multiple Myeloma.Version 1.2013. http://www.nccn.org. Accessed October 12, 2012.2. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone com-

bination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686.3. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib,

and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma(MM): updated efficacy and safety data after >2 years of follow-up. Blood (ASH Annual MeetingAbstracts). 2010;116:Abstract 3049.

4. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophos-phamide, Velcade and dexamethasone (CVD) induces high response rates with comparabletoxicity to Velcade alone (V) and Velcade plus dexamethasone (VD). Haematologica. 2007;92:1149-1150.

5. Fu W, Delasalle K, Wang J, et al. Bortezomib-cyclophosphamide-dexamethasone for relapsingmultiple myeloma [published online ahead of print June 18, 2011]. Am J Clin Oncol.doi:10.1097/COC.0b013e31822043f6.

6. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment formultiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176-185.

7. Pegylated liposomal doxorubicin hydrochloride, bortezomib, cyclophosphamide, and dexa -methasone in treating patients with multiple myeloma (NCT00849251). http://www.clinicaltrials.gov. Accessed October 22, 2012.

8. Wolf J, Richardson PG, Schuster M, LeBlanc A, Walters IB, Battleman DS. Utility of bor -tezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter caseseries. Clin Adv Hematol Oncol. 2008;6:755-760.

9. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination forpatients with multiple myeloma following an initial response to bortezomib. Am J Hematol.2009;84:657-660.

10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.11. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-

A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.12. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent

carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previ-ously treated with bortezomib. Br J Haematol. 2012;158:739-748.

13. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

14. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myelomarefractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118:2970-2975.

15. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexametha-sone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008-5014.

16. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide andlow-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30:1953-1959.

17. Gimsing P, Plesner T, Nahi H, et al. A phase I/II, dose-escalation study of daratumumab, aCD38 Mab in patients with multiple myeloma—preliminary safety data. Blood (ASH AnnualMeeting Abstracts). 2011;118:Abstract 1873.

18. Dose escalation study of anti-CD38 monoclonal antibody in patients with selected CD38+hematological malignancies (NCT01084252). http://www.clinicaltrials.gov. Accessed October22, 2012.

19. Study of the Bruton’s tyrosine kinase inhibitor in subjects with relapsed or relapsed and refractorymultiple myeloma (NCT01478581). http://www.clinicaltrials.gov. Accessed October 22, 2012.

20. Dose escalation study of MLN0128 in relapsed or refractory multiple myeloma or Waldenstrommacroglobulinemia (NCT01118689). http://www.clinicaltrials.gov. Accessed October 28, 2012.

21. Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage 088: vorinostat in combination withbortezomib in patients with relapsed/refractory multiple myeloma: results of a global, random-ized phase 3 trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 811.

22. San Miguel JF, Hungria VTM, Yoon S-S, et al. Update on a phase III study of panobinostatwith bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORA-MA 1. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3976.

23. Richardson PG, Alsina M, Weber DM, et al. Phase II study if the pan-deacetylase inhibitorpanobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (PANORAMA 2). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 814.

24. Carfilzomib plus panobinostat in relapsed/refractory multiple myeloma (MM) (NCT01301807).http://www.clinicaltrials.gov. Accessed October 22, 2012.

Table 2. Toxicities Grade ��2 with Pomalidomide PlusDexamethasonea in a Phase 2 Trial (N=60)15

Toxicity Patients, n (%)

Anemia 20 (33%)

Lymphopenia 4 (7%)

Neutropenia 30 (50%)

Thrombocytopenia 6 (10%)

Leukopenia 24 (40%)

Fatigue 27 (45%)

Nausea 1 (2%)

Diarrhea 5 (8%)

Constipation 11 (18%)

Pneumonia 6 (10%)

Hyperglycemia 10 (17%)

Confusion 5 (8%)

Insomnia 7 (12%)

Agitation 7 (12%)

Peripheral neuropathy 6 (10%)

Thrombosis 1 (2%)

aPatients also received aspirin 325 mg once daily for thromboprophylaxis. Patients wereallowed to substitute full-dose anticoagulation with either low-molecular-weight heparinor warfarin at physician discretion.

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DECEMBER 2012 I VOL 5, NO 8 21www.TheOncologyPharmacist.com

CONTINUING EDUCATION

Nursing Interventions in the Relapsed andRefractory Settings for Myeloma

IntroductionFor patients with multiple myeloma (MM), prompt and effective

nursing interventions can make a significant difference in care—from

minimizing adverse events (AEs) to protecting bone health and alle-

viating pain. In this article, Jennifer Knoche, RN, BSN, examines key

strategies for improving outcomes in the relapsed/refractory setting

for myeloma, and discusses best practices for whole-patient care.

When patients are retreated with agents such as bortezomib orthalidomide, what strategies are effective for minimizing the risk ofperipheral neuropathy (PN)?

The main strategy for minimizing this risk remains dose adjustment ortreatment interruption. With thalidomide, which is administered orally, PNcan be an especially challenging toxicity to manage. We often use thalido-mide at a low dose in the relapsed/refractory setting; therefore, to reduce theamount even further may require patients to cut their pills in half or taketheir medication every other day—neither of which are ideal options. Withintravenous (IV) bortezomib, reducing or holding the dose is easier. Rec -ommended dose reductions for thalidomide- and bortezomib-based PN areshown in Tables 1 and 2.1,2

Of course, we cannot make an informed decision regarding dose adjust-ment without an accurate assessment of a patient’s condition. In therelapsed/refractory setting, we must look at current symptoms as well as treat-ment history. What drugs have been administered previously? Did thepatient experience neuropathy with prior treatment, and if so, did dosereduction or discontinuation provide relief? Did supportive therapies help toreduce symptoms? Are there comorbid conditions associated with the exist-ing PN? Is the patient taking any medications for comorbidities that maycontribute to neuropathy? Answers to these questions help us to plan theschedule and dose of agents at the time of relapse.Complementary therapies, such as alpha lipoic acid, L-carnitine, and vita-

min B6 may be helpful.3 At our institution, we begin patients on these ther-apies prior to antimyeloma treatment to prevent or minimize PN. In thosewho already exhibit symptoms, we may add these therapies as supplements,to keep neuropathy from progressing. Some patients need a more robust med-ical intervention, in which case we may prescribe gabapentin, pregabalin, tri-cyclic antidepressants, or even nonopioid analgesics.3 Our goal is to do what-ever works to manage pain, tingling, burning, and functional impairment tokeep the patient on therapy.PN may cause the nerves that control intestinal muscle contractions to

malfunction, leading to gastrointestinal problems, including constipation.4 Ifthis occurs, a good bowel regimen, proper diet, hydration, and exercise, and

laxation become important components of therapy, in addition to dosereduction. Fortunately, we now have the option of administering bortezomibsubcutaneously (SC), which has been shown to help reduce the incidenceand severity of PN.5

How has the recent approval of carfilzomib affected yourapproach to treating relapsed and/or refractory disease?

With the approval of carfilzomib, we now have another treatment optionat our disposal, which is extremely important. Given the challenges pa -tients face in the relapsed/refractory setting, including the fact that theyhave already been treated with so many therapies, it matters greatly to haveone more way to attack the disease. In addition to demonstrating good effi-cacy, carfilzomib has been associated with low rates of PN (Figure).6

Anecdotally, we are not seeing this toxicity among patients receiving carfil-zomib. How ever, since these individuals are on so many drugs, sequencedover time, it can be hard to determine whether AEs are related to past orcurrent regimens. For instance, an agent may cause some degree of neu-

Jennifer Knoche, RN, BSNLead Practice NurseUCSF Hematology/BMT Ambulatory Care CenterSan Francisco, CA

Table 1. Thalidomide Dose Modifications Based on Severity ofPeripheral Neuropathy1

Severity of Peripheral Neuropathy Modification of Dose and Regimen

Grade 1 (mild)

Grade 1 with pain or grade 2

Grade 3

Grade 4 (permanent sensory loss that interferes with function)

No action

Intermittent symptoms:Continue therapy

Continuous symptoms:Withhold thalidomide until toxicity resolves, then reduce dose

Withhold thalidomide until toxicity resolves, then restart at reduced dose

Discontinue thalidomide

Table 2. Bortezomib Dose Modifications Based on Severity ofPeripheral Neuropathy2

Severity of Peripheral Neuropathy Modification of Dose and Regimen

Grade 1 (paresthesia or loss of reflex) without pain or loss of function

Grade 1 with pain or grade 2 (interferes with function but not with activities of daily living)

Grade 2 with pain or grade 3 (interferes with activities of daily living)

Grade 4 (permanent sensory loss that interferes with function)

No action

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

Withhold bortezomib until toxicity resolves, then reinitiate at a dose of 0.7 mg/m2 once weekly

Discontinue bortezomib

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www.TheOncologyPharmacist.com22 DECEMBER 2012 I VOL 5, NO 8

CONSIDERATIONS IN MULTIPLE MYELOMA

ropathy, but symptoms do not appear until later, after another therapy isgiven.Administration of carfilzomib—2 days in a row intravenously, weekly for 3

weeks7—is not as simple as administration of bortezomib, especially borte-zomib SC. Some patients, depending on how far they live from the cancercenter, may have to spend the night once a week to receive carfilzomib. Theinfusion time for this drug is longer than it is for IV bortezomib. Additionally,if you compare IV carfilzomib administration to the use of bortezomib SC,

there is a big difference in convenience favoring bortezomib. Dose adjustment schedules for carfilzomib-related PN are available, along

with those for hematologic, cardiac, pulmonary, and hepatic toxicities. Insome patients, we have noticed a decline in red blood cells with carfilzomibuse, typically during the first cycle. As with any agent, careful monitoring ofblood counts and vital organ functions are an essential part of nursing care.

How do you support bone health and manage skeletal-relatedevents over the course of care in the relapsed/refractory setting?

Supporting bone health in this setting is essential but can be complex.Many myeloma patients are older, with comorbidities such as osteoarthritis

and osteoporosis. When treating a patient for osteoporosis, we need to assesshis or her current bisphosphonate regimen and see how it dovetails with theneed for myeloma bone support.In a patient who has experienced a long clinical course and relapsed, prior

bisphosphonate treatment is a given. Currently, the American Society of Clin -ical Oncology recommends 2 years of bisphosphonate therapy for myeloma-related bone disease. After that, treatment is at the discretion of the physician.8

Unfortunately, there is no road map to guide us in restarting or continuing bis-phosphonates in a relapsed or refractory patient who has already had 2 years oftherapy. Our biggest concern is the risk for osteonecrosis of the jaw, whichincreases with prolonged time on bisphosphonate therapy.9

As the myeloma disease process continues, and as patients age, they mayneed supportive devices, surgical care, and pain management strategies.Functional limitations and pain can be improved with antimyeloma thera-py and bisphosphonates, but for some individuals, canes, walkers, wheel-chairs, or braces may be necessary. We may also refer patients with spineinvolvement for vertebroplasty or kyphoplasty, which can be very effec-tive.10 Local irradiation is occasionally used for supportive care, especiallyif there is a plastocytoma. Bone pain often requires opioid analgesics, andwe encourage our patients to accept such medications when necessary.11

Pain can delay healing and diminish quality of life and must therefore beminimized whenever possible.

ConclusionNurses need to carefully monitor relapsed and refractory MM patients, and

be ready to intervene to ensure the continuation of treatment and the abilityto perform activities of daily living. The detection and effective managementof AEs, skeletal-related complications, and pain are essential components ofevidence-based care, which will lead to better clinical outcomes. �

References1. Thalomid [package insert]. Summit, NJ: Celgene Corporation; 2012.2. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; June 2012.3. Tariman JD, Love G, McCullagh E, et al. Peripheral neuropathy associated with novel therapies

in patients with multiple myeloma: Consensus statement of the IMF Nurse Leadership Board.Clin J Oncol Nurs. 2008;12:29-36.

4. National Institute of Neurological Disorders and Stroke. Peripheral neuropathy fact sheet.http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm.Accessed October 27, 2012.

5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

6. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

7. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals Inc.; July 2012.8. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical

practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

9. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients:clinical features and risk factors. J Clin Oncol. 2006;24:945-952.

10. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture man-agement for treatment of painful vertebral body compression fractures in patients with cancer:a multicentre, randomised controlled trial. Lancet Oncol. 2011;13:225-235.

11. Definitions related to the use of opioids for the treatment of pain: Consensus statement of theAmerican Academy of Pain Medicine, the American Pain Society, and the American Society ofAddiction Medicine. www.asam.org. Accessed October 30, 2012.

Figure. Carfilzomib-related, nonhematologic adverse eventswith an incidence ��5% in a single-agent study ofrelapsed/refractory MM patients (N=266).6

Patients (%)

40

35

30

25

20

15

10

5

0Fat

igue

Nausea

Diarrh

ea

Dyspne

a

Headac

he

Increa

sed serum

creatin

ine Vomitin

gPyr

exia

Periph

eral ne

uropat

hy

Hypoph

osphat

emia

Unfortunately, there is no road map to guide us in restarting or continuing bisphosphonates in a relapsed or refractory patient who has already had 2 years of therapy.

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DECEMBER 2012 I VOL 5, NO 8 23www.TheOncologyPharmacist.com

CONTINUING EDUCATION

Pharmacologic Considerations in theRetreatment Setting for Multiple Myeloma

IntroductionIn patients with relapsed/refractory multiple myeloma (MM), re -

treatment can contribute to longer survival and better quality of life,

but can also pose a number of clinical challenges. When choosing

therapies for this indication, it is necessary to consider numerous fac-

tors, including preexisting toxicities, patient preferences and perfor -

mance status, and agents used during initial therapy. In this article,

Helen T. Wu, PharmD, BCOP, shares her perspective on these issues in

both the transplant and nontransplant settings and discusses recent

advances that may promote better patient outcomes.

How do comorbidities and other patient factors affect selectionand administration of therapy in the retreatment setting?

An important issue to consider is how well a patient has tolerated a specif-ic agent or regimen in the frontline setting, as this may affect administrationand dosing at the time of retreatment. For example, if a patient did not expe-rience serious adverse events (AEs) with frontline therapy, we can typicallystart retreatment at the standard, recommended dose of the same agent.Conversely, if a patient did suffer significant toxicities, we may choose toretreat with an agent from a different class. However, studies have shown atherapeutic benefit when patients are retreated with agents they have re -ceived previously.1-5 Therefore, if a patient has achieved a good response to aspecific agent as induction, we may try using dose modifications to reduce theincidence of AEs.For example, we can consider a patient with preexisting peripheral neu-

ropathy (PN) who relapses after being treated with lenalidomide, bortez -omib, and dexamethasone (RVD) and autologous stem cell transplantation(ASCT). According to the most recent National Comprehensive CancerNetwork (NCCN) guidelines for the treatment of MM, RVD is a recom-mended primary therapy (category 2A) for transplant candidates.6 If relapseoccurs at >6 months, the same primary regimen may be repeated. However,in a patient who has residual PN, clinicians may consider avoiding bortez -omib and instead select a regimen that has less potential for neurotoxicity. Inaddition, because of previous ASCT and lenalidomide treatment, a regimenthat has the least hematologic toxicity would be preferred. It would be nec-essary to look at which agents are available for salvage therapy, based onthese factors.In a different type of scenario, you may be treating a relapsing patient who

is not eligible for transplant and who has renal impairment. Such a patientmay have been treated initially with bortezomib, melphalan, and prednisoneor lenalidomide plus low-dose dexamethasone—regimens that are recom-

mended in the NCCN guidelines for this indication.6 In the salvage setting,choosing therapies that are least likely to be toxic to the kidneys is a must. Itis also important to remember that myeloma patients with renal dysfunctionoften have other comorbidities and poor performance status.7 Therefore,therapeutic benefit must be balanced with drug-related toxicities.Although lenalidomide can be effective in the retreatment setting, this

agent needs to be dose-adjusted for patients with varying degrees of renal dys-function.8 Bortezomib and carfilzomib, which have also demonstrated effi -cacy as second-line therapies, do not require dosing adjustments in renallyimpaired patients.9,10

How has the approval of subcutaneous (SC) bortezomib impactedyour approach to retreatment?

In January 2012, the US Food and Drug Administration (FDA) approvedSC administration of bortezomib for the treatment of MM. This mode ofdelivery has several advantages, as shown in a recent multicenter trial byMoreau and colleagues.11 These investigators compared the efficacy and safe-ty of SC versus intravenous (IV) bortezomib in patients with relapsed MMwho had received �3 previous lines of therapy. The end point was to shownoninferiority of SC versus IV bortezomib in terms of overall response rate(ORR) following 4 treatment cycles. After these cycles, ORR was 42% inboth groups, showing noninferiority (P=.002). After a median follow-up of11.8 months in the SC group and 12.0 months in the IV group, there wereno significant between-group differences in time to progression and 1-yearoverall survival. PN of any grade was significantly reduced with SC versus IVbortezomib (Figure). Grade 3 or higher AEs were reported in 57% of patientsin the SC group versus 70% in the IV group; the most common were throm-bocytopenia (13% vs 19%), neutropenia (18% vs 18%), and anemia (12%vs 8%), respectively.11

It is important for pharmacists to be aware of how to prepare SC bortez -omib for administration. The concentration for IV infusion of bortezomib is1 mg/mL, which is significantly different from the concentration for SCinjection, which is 2.5 mg/mL.9 Pharmacists should be cautious when recon-stituting this medication and calculating the volume to be administered.However, the amount of work involved in preparing bortezomib for SC ver-sus IV administration is really no different, and SC bortezomib appears to bea much-preferred route of administration for several reasons. For nurses, itsimplifies care, since there is no need to obtain IV access, and the potentialrisks and complications of inserting IV lines are eliminated. In addition, itreduces chair time, allowing for a much quicker turnaround time forappointments. For patients, it is easier and generally less stressful to receivean SC injection compared with IV administration. Since there is no need

Helen T. Wu, PharmD, BCOPClinical PharmacistAdult Hematology/Oncology and Health SciencesAssociate Clinical Professor, School of Pharmacy, UCSFSan Francisco, CA

if a patient has achieved a good response to a specific agent as induction, we may try using dosemodifications to reduce the incidence of AEs.

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www.TheOncologyPharmacist.com24 DECEMBER 2012 I VOL 5, NO 8

CONSIDERATIONS IN MULTIPLE MYELOMA

to insert an IV line, wait time is much shorter, which can potentially im -prove quality of life.

How is the recently approved agent carfilzomib being used at yourcenter in the retreatment setting?

On July 20, 2012, the FDA approved carfilzomib, a next-generation pro-teasome inhibitor, for the treatment of patients with MM who havereceived at least 2 prior therapies, including bortezomib and an immuno -modulatory agent, and who have demonstrated disease progression on orwithin 60 days of therapy completion. Many patients who have re -lapsed/refractory MM are being treated with carfilzomib at our institution,given its proven efficacy and good safety profile. In a phase 2 study conduct-ed by Siegel and colleagues, patients received single-agent IV carfilzomib forrelapsed/refractory MM; all of these individuals were heavily pretreated.12

Of the evaluable patients in this study, 95% were refractory to their lasttherapy, and 80% were refractory to both bortezomib and lenalidomide. Thetreatment regimen was designed as IV carfilzomib 20 mg/m2 (cycle 1) fol-lowed by 27 mg/m2 (cycle �2), on days 1, 2, 8, 9, 15, and 16 of each 28-daycycle. The ORR was 23.7%, median duration of response was 7.8 months,and median overall survival was 15.6 months. Reported AEs included

fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%).The rate of treatment-related PN was 12.4%.Our institution was one of the participating centers for clinical trials of

carfilzomib prior to its FDA approval. Now, we are able to offer this agentto patients off study, and we make sure to follow the recommended dosing,reconstitution, and administration guidelines to ensure maximum benefitand safety. Although we rarely use carfilzomib in the inpatient setting, wedo utilize it in patients who come in for emergent plasmapheresis after fail-ing transplant, administering concomitant IV hydration to prevent tumorlysis syndrome. I think this agent is becoming an important retreatmentoption in MM.

ConclusionAlthough MM remains an incurable disease, retreatment with novel

agents is leading to higher response rates, prolonged survival, and better qual-ity of life. An important goal in this setting is the prevention and manage-ment of AEs, which allows the cancer care team to maximize dose intensityand provide continuation of therapy. This requires careful consideration ofcomorbidities and other patient factors, as well as a thorough understandingof the doses, schedules, and modes of administration recommended for avail-able agents. �

References1. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for

patients with multiple myeloma following an initial response to bortezomib. Am J Hematol.2009;84:657-660.

2. Berenson JR, Jagannath S, Barlogie B, et al. Safety of prolonged therapy with bortezomib inrelapsed or refractory multiple myeloma. Cancer. 2005;104:2141-2148.

3. Hrusovsky I, Emmerich B, von Rohr A, et al. Bortezomib retreatment in relapsed multiple myelo-ma—results from a retrospective multicentre survey in Germany and Switzerland. Oncology.2010;79:247-254.

4. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial oflenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J ClinOncol. 2009;27:5713-5719.

5. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory drugs(IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma.Blood. 2011;118:1763-1765.

6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines inOncology™: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed October 24, 2012.

7. Glade J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma presenting featuresand predictors of outcome in a series of 94 patients from a single institution. Arch Intern Med.1998;158:1889-1893.

8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2012.9. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; June 2012.10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.11. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of

bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

Figure. Incidence of peripheral neuropathy in a phase 3 trialcomparing SC versus IV bortezomib dosing in relapsedmyeloma (N=222).11

Patients (%)

60

50

40

30

20

10

0

IV indicates intravenous; SC, subcutaneous.

Any grade �Grade 2 �Grade 3

SC bortezomib

IV bortezomib

38%

53%

24%

41%

6%

16%

P=.044

P=.012

P=.026

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DECEMBER 2012 I VOL 5, NO 8 25www.TheOncologyPharmacist.com

www.TheOncologyPharmacist.com26 DECEMBER 2012 I VOL 5, NO 8

Conference News: ASTRO

Sildenafil is often used by men treatedwith radiation or radical prostatectomyfor prostate cancer to achieve an erec-tion sufficient for sexual intercourse,and it is effective to varying degreeswhen used on an as-needed basis. Arandomized controlled trial has foundthat prophylactic daily use of sildenafilimproved overall sexual function, aswell as domains of sexual function, inprostate cancer patients undergoing ra-diation therapy.1 This is the first time aphase 3 study has demonstrated the ef-fectiveness of prophylactic sildenafil inthe setting of radiation.“Prostate cancer patients treated

with sildenafil and adjuvant radiationtreatment had improved overall erec-tile function and overall satisfaction oftheir sexual activity and function. The

most significant improvements wereseen at 6 and 12 months after treat-ment, with a slight dip at the 24-monthmark, suggesting that future trials needto be conducted to demonstrate iflonger treatment duration can furtherimprove outcomes,” said lead authorMichael Zelefsky, MD, of MemorialSloan-Kettering Cancer Center in NewYork City. No benefit for sildenafil wasseen among a small group of 31 patientswho were also treated with androgendeprivation therapy.The prospective, randomized, dou-

ble-blind, placebo-controlled trial in-cluded 295 patients with clinically lo-calized prostate cancer who weretreated with external beam radiationtherapy and/or brachytherapy (perma-nent interstitial implantation of radio -

active “seeds”). Patients were random-ized in a 1:1 ratio to receive either dailysildenafil 50 mg or placebo. Treatmentwas initiated 3 days before radiationtreatment and was continued daily for6 months, when the drug was stopped.After that, sildenafil could be used asneeded. Sexual function was assessed at3-month intervals for the first year andthereafter at 18 and 24 months withthe international index of erectilefunction (IIEF) and the internationalprostate symptom score (IPSS) ques-tionnaires. At baseline, all patients hadexcellent erectile function, as assessedby IIEF.Among 144 patients treated with radi-

ation only who completed IIEF and IPSSquestionnaires, overall sexual functionwas improved with daily sildenafil versus

placebo at all time points. IIEF scoreswere 58.6 for sildenafil versus 49.4 forplacebo at 6 months (P = .006); 56.3versus 48.2, respectively, at 12 months(P = .02); and 54.9 versus 47.6, respec-tively, at 24 months (P = .04). Sig -nificant im provement in overall func-tion, orgasmic function, sexual desire,intercourse satisfaction, and overall sat-isfaction were reported with sildenafilversus placebo. Overall IPSS was alsosignificantly improved with sildenafilversus placebo (P <.001).

Reference1. Zelefsky MJ, Shasha D, Kollmeier M, et al. Results of aprospective randomized double-blind placebo-controlledtrial evaluating the use of prophylactic sildenafil citrateduring radiation therapy in the treatment of prostate can-cer. Presented at: American Society for RadiationOncology 54th Annual Meeting; October 29, 2012;Boston, MA. Abstract 3.

Memantine delayed cognitive decline inpatients treated with whole-brain radia-tion therapy (WBRT) for brain metas-tases, according to results of a randomizedphase 3 trial.1Cognitive decline is common with

WBRT, occurring in about 50% to 60%of patients by 4 months after radiation.Because the mechanism of radiation-induced cognitive decline appears to besimilar to that of vascular or Alzheimer’sdementia, the researchers postulated thatmemantine, a drug used to treatAlzheimer’s disease, would be of benefitin patients treated with WBRT. “We are excited to see that adding me-

mantine to the treatment plan for braintumor patients helps preserve their cogni-tive function after whole-brain radiother-apy even 6 months after treatment. Ourfindings suggest that memantine mayprevent the changes that occur in thebrain following radiation therapy, im-pacting future treatment practices forthese patients, and suggest a role for fur-ther study in patients receiving radiationto the brain,” said presenter Nadia N.Laack, MD, radiation oncologist at theMayo Clinic in Rochester, Minnesota.

Formal discussant of this trial, VinaiGondi, MD, associate director of theCentral Dupage Hospital’s Proton Centerin Warrenville, Illinois, called this study“a good first step” in understanding thecognitive changes resulting from brain ra-diation and the role of memantine in pre-venting or delaying them. He said that

the effect of memantine was modest inthis trial and that other strategies to im-prove cognitive effects of radiation arebeing pursued by researchers. The study included 508 patients with

brain metastases who received WBRTbetween March 2008 and June 2010.WBRT was delivered as 37.5 Gy in 15daily fractions. Patients were randomizedto memantine 20 mg/day or placebowithin 3 days of the start of radiationtherapy. Six domains of cognitive func-

tion (memory, processing speed, execu-tive function, global function, self-report-ed cognitive function, and quality of life)were assessed by different instruments atbaseline and weeks 8, 16, 24, and 52. Theprimary end point was memory as as-sessed by the Hopkins Verbal LearningTest-Revised (HVLT-R).

Compliance with the cognitive testingprotocol was suboptimal, with 32% of thepatients completing drug therapy andcognitive assessments. The reasons fornoncompliance appeared to be death,disease progression, and difficulty in get-ting patients to stay longer during a clin-ic visit or in physicians scheduling theextra 20 minutes to 1 hour required forcognitive testing. Of the 508 patientsrandomized to the 2 arms, only 149 pa-tients were analyzable at 24 weeks.

For the primary end point of memorydecline as assessed by the HVLT-R, me-mantine reduced the decline in HVLT-Rdelayed recall, with a median decline of 0versus –2 for placebo at 24 weeks, with astatistical significance of P = .059. Thisresult was “teetering on the edge of sig-nificance,” according to Laack, due to thesmall numbers of patients. At 24 weeks, memantine reduced

the relative risk of cognitive decline by17% versus placebo (P = .01), and it re-duced the rate of decline in cognitive,executive, and global function as wellas processing speed (P <.01). Patientsin both groups experienced similarrates of grade 3 and 4 toxicities, includ-ing alopecia, fatigue, headache, andnausea.The investigators plan to evaluate

the effect of memantine on overall sur-vival and progression-free survival inthese patients. Also, tissue specimenswill be studied to identify biomarkers ofcognitive decline as well as of responseto memantine.

Reference1. Brown PD, Shook S, Laack N, et al. Memantine for theprevention of cognitive dysfunction in patients receivingwhole-brain radiation therapy (WBRT): first report ofRTOG 0614, a placebo-controlled, double-blind, ran-domized trial. Presented at: American Society forRadiation Oncology 54th Annual Meeting; October 29,2012; Boston, MA. Abstract 1.

Continued from cover

memantine Delays Cognitive Decline in Patients With Brainmetastases Treated With Whole-Brain Radiation

Influencing the Patient-Impact Factor TM

REGISTER TODAY AT www.AVBCConline.org

May 2-5, 2013 Westin Diplomat

Hollywood, Florida

THIRD ANNUAL CONFERENCE

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Prophylactic Sildenafil Improves Sexual Function in Prostate Cancer PatientsUndergoing Radiation

“Our findings suggest that memantine may prevent

the changes that occur in the brain following

radiation therapy.”

—Nadia N. Laack, MD

DECEMBER 2012 I VOL 5, NO 8 27www.TheOncologyPharmacist.com

Conference News: ASTRO

Doxepin, a tricyclic antidepres-sant approved for the treatmentof depression and anxiety, as

well as moderate pruritus, significantlyimproved oral mucositis pain in patientstreated with radiation therapy for headand neck cancer in a phase 3 trial.1 Inthe study, doxepin was combined withwater and used as an oral rinse. Oral mucositis pain is a significant

problem in patients with head and neckcancer treated with radiation, and treat-ments such as narcotics and mouth rinsesare not particularly effective in alleviat-ing this pain. Smaller studies have sug-gested that doxepin is safe and effectivein reducing oral mucositis pain, and thepresent study establishes its effectivenessin a randomized controlled trial. “Our study validates doxepin rinse as

an effective way to alleviate oral painand sets a new standard of care,” said thelead author of the study, Robert C.Miller, MD, of the Mayo Clinic inRochester, Minnesota.

For the N09C6 study, pain was as-sessed on a visual analog scale andscored from 0 to 10, with a score of 10signifying severe pain. N09C6 was adouble-blind, randomized, placebo-con-trolled trial of 140 patients with headand neck cancer who had an oral mu-cositis pain score above 4 on the visualanalog scale. Patients were enrolled be-tween December 2010 and May 2012and were treated with radiation at dosesabove 50 Gy involving more than one-third of the oral cavity for head andneck cancer. The dosage of the oral dox-epin rinse was 25 mg dissolved in 5 mLof water and used for 1 minute. Patientswere treated on day 1 with either thedoxepin rinse or placebo; on day 2, pa-tients crossed over to the other treat-ment arm. Patients could elect to con-tinue treatment with the doxepin rinseon an as-needed basis.On day 1, doxepin-treated patients

reported area under the curve (AUC)pain score reduction to –9.1 versus –4.7for placebo patients (P = .0003).Crossover data from day 2 showed simi-lar findings, with an AUC pain score of

–7.9 in the doxepin group versus –5.6 inthe placebo group (P = .009).Doxepin was well tolerated, but it was

associated with more stinging and burn-ing (mean pain score of 3.7 for doxepinvs 1.1 for placebo) as well as an unpleas-ant taste (mean unpleasant taste at 5

minutes 2.9 for doxepin vs 1.6 forplacebo), and it caused greater drowsi-ness (mean drowsiness score of 3.9 fordoxepin vs 2.8 for placebo). During theoptional continuation phase, the ma-jority (64%) of patients elected to con-tinue doxepin. l

Reference1. Miller RC, Leenstra J, Qun R, et al. N09C6(Alliance) - a phase III, randomized double-blindstudy of doxepin rinse versus placebo in the treatmentof acute oral mucositis pain in patients receiving headand neck radiotherapy with or without chemotherapy.Presented at: American Society for RadiationOncology 54th Annual Meeting; October 29, 2012;Boston, MA. Abstract LBA1.

Doxepin Rinse Improves Oral mucositis in Patients Treated With Radiation for Headand Neck Cancer

TARGET AUDIENCEThis initiative will target medical oncologists, hematologists, breast surgeons, radiationoncologists, oncology nurses, advanced practice nurses, nurse practitioners, physicianassistants, oncology pharmacists, managed care professionals, and others with clinicalresearch and management interest in treatment of ductal carcinoma in situ (DCIS) andearly-stage breast cancer.

STATEMENT OF NEEDAbility to detect DCIS has dramatically improved in recent decades, and the current inci-dence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increaseduse of mammography screening.1,2 However, attempts to identify subsets of DCIS womenwho may be spared radiotherapy and perhaps treated with surgery alone have heretoforebeen unsuccessful. This inability to predict which patients will develop recurrent DCIS orinvasive disease has complicated DCIS management. Many clinicians and other health-care professionals dealing with patients diagnosed with DCIS are unaware or incomplete-ly knowledgeable about the most recent results from a clinical trial examining the abilityof the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, andthe implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141.2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence,treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVESAfter completion of this activity, participants will be better able to:

• Identify approaches currently available or in development to predict recurrence riskin DCIS patients

• Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer

• Describe the design and findings of the ECOG 5194 validation study• Apply the 12-gene assay for DCIS into clinical decision-making• Explain relevant information about the 12-gene DCIS assay and DCIS score topatients

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches

www.coexm.com/ace09LOG ON TODAY TO PARTICIPATE

Release Date: May 8, 2012Expiration Date: May 7, 2013

FACULTYChair:Lawrence J. Solin, MD, FACR,FASTROChairman Department of Radiation OncologyAlbert Einstein Medical CenterPhiladelphia, PA

E. Shelley Hwang, MD, MPHProfessor and Chief, Breast SurgeryDuke University Medical CenterDurham, NC

Kathy D. Miller, MDAssociate Professor Department of MedicineIU School of MedicineIndianapolis, IN

ACCREDITATIONPhysicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing MedicalEducation (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activityfor a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of theirparticipation in the activity.Nurses:CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC)Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status doesnot imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity.Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case ManagerCertification. Case Managers number 790005057.

This activity is supported by an educational grant from Genomic Health, Inc.

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“Our study validates

doxepin rinse as an

effective way to alleviate

oral pain and sets a new

standard of care.”

—Robert C. Miller, MD

www.TheOncologyPharmacist.com28 DECEMBER 2012 I VOL 5, NO 8

Profile

So, a stagnant supply of 12,000 on-cologists will have twice as many can-cer patients to manage, and, given thescience, twice the evidence work com-ponents to review to develop the bestplan of care. Thus, the opportunity forthe oncology pharmacist; preferably,the BCOP. We predict that the only viable solu-

tion to the projected patient cancercare access crisis will be oncology phar-macists functioning as physician ex-tenders and working in concert withtreating oncologists or hematologists.This will allow experts in oncologydrug care to support physicians in for-mulating the best treatment care plan-ning, and, just as importantly, the on-going management of patients tominimize side effects and adverseevents to drive a desired outcome forthe patients.We researched the cancer care phar-

macy marketplace and thought to our-selves, why can’t the great multidisci-plinary approach in an NCCN cancercenter be deployed outside the 4 wallsof the hospital? We decided we couldprovide community and smaller re-gional hospital systems with the sameintensive oncology pharmacist clinicalsupport and patient care infrastructureoutside those 4 walls. We also recognized that the

Onco360 service model was differentthan the traditional specialty generalistpharmacies that typically manage single,high-cost, self-injectable, and biologicalpharmaceuticals for patients on a pre-dictable 30-, 60-, or 90-day therapyschedule. To create our service model weheld extensive one-on-one meetingswith key opinion leaders in pharmacy,pharma, and treating physicians to engi-neer a solution that addressed the gaps incare and service.

How do your services translate tobetter outcomes for patients withcancer?BZ: Our BCOPs are well trained andexperienced. Their expertise helps can-cer patients through the challenges ofundergoing treatment.

OncoMTM, our Medication TherapyManagement program, is built aroundthe customized care and attention thateach patient needs in order to stay com-pliant with his or her regimen, minimizeadverse events, and improve outcomes.By marrying our just-in-time dose

dispensing with our clinical expertise,we seek to minimize drug waste tomanage a very dynamic disease andtreatment regimen by focusing onquality measures.

How is the relationship between on-cology pharmacists and patientschanging? BZ: The major change will be that anoncology pharmacist will be muchmore directly involved in patient care.This reflects how the multidisciplinaryteams operate at Cancer Care Centers. The American Cancer Society esti-

mates there will be 1.7 million newcancer cases in the United States in

2013. This fact, coupled with the pre-dicted shortage of oncologists, presentsan opportunity for oncology pharma-cists to be more involved with inter-ventions and patient management. We believe that BCOPs will be well

equipped to fill that clinical gap, toprovide the personal attention andcare that every patient not only needs,but also deserves. So clearly, the depthand level of interaction between pa-tients and oncology pharmacists willundoubtedly continue to increase overthe coming years. This multidiscipli-nary partnership will be a part of everyaccountable care organization or on-cology medical home model thatemerges.

How will this changing relationshipaffect the training needed for oncol-ogy pharmacists?BZ: We are working with severalschools of pharmacy, including theUniversity of Buffalo, to develop 1-year and 2-year oncology pharmacytracks that include hands-on residencyand other programs. We expect pro-grams like this will foster a learning en-vironment where oncology pharma-cists can be trained and integrated intothe cancer care community to addressthe shortage of oncologists. Clearly, a higher level of education,

training, and experience will be neces-sary to prepare pharmacists for an ex-panded role within the continuum ofcare. We feel this need will be bestserved by BCOPs, which is why we

support our pharmacists in their pur-suit of such rigorous certification, as itwill ultimately best serve our patientsand physician partners.

What are the biggest challenges facing the field of oncology pharmacy?Are compounding issues and safetypart of these challenges?BZ: In addition to the challenges al-ready noted, the unknown effect ofhealthcare reform and the new worldof accountable care will require oncol-ogy pharmacy to move beyond dispens-ing of medications. It’s no secret thatcancer costs are out of control, andmore and more focus will come frommanaged care and the government interms of pharmacy partners that canhelp control those costs without com-promising care. Expect comparative ef-fectiveness and value-based contract-ing to become common.The heightened concern over com-

pounding and pharmacy safety broughton by the unfortunate meningitistragedy will certainly add to thosechallenges. We see stepped-up stateand federal regulation around cancerpharmacy standards in terms of storage,dispensing, and waste. Oncology phar-macy must be prepared to not onlymeet but also exceed the minimum re-quirements for safely compoundingand dispensing cancer drugs.

What are you excited about right nowin the field of oncology pharmacy?BZ: I am most excited about the shifttoward accountable care and, as a nat-ural extension, the increased need formeaningful cost containment. As thehead of an organization, I am workingwith my team to build our oncologymedical home model. We’ve built our company by creating a

model that fits the disease of cancer andaddresses the needs of oncologists byleveraging the partnership opportunitiesBCOPs can bring to improve quality andoutcomes for patients. In doing so, wehave a unique ability to define the valueoncology pharmacy can contribute tothe cancer care solution. l

Onco360... Continued from cover

“The depth and level of

interaction between patients

and oncology pharmacists

will undoubtedly continue

to increase over the

coming years.”

—Burt Zweigenhaft

Take action: get YOUR cancer center profiled!

We are looking to interview oncology pharmacists from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for more information.

The American CancerSociety estimates therewill be 1.7 million newcancer cases in theUnited States in 2013.

DECEMBER 2012 I VOL 5, NO 8 29www.TheOncologyPharmacist.com

Neuroendocrine Tumors

Interest in pancreatic neuroen-docrine tumors (pNETs) has grownsince the recent approval of targeted

agents for advanced disease, as was evi-dent by the attendance at several ses-sions during the European Society forMedical Oncology (ESMO) 2012Congress in Vienna, Austria.1Kjell Öberg, MD, of Uppsala

University in Sweden, noted, “These tu-mors are steadily increasing, comparedwith other malignant neoplasms. It’s nota rare disease any longer, and we don’tknow why. Partly, it’s better awarenessamong physicians. This room at ESMOis filled. And also, better diagnosticmethods and treatment opportunities.” “Still, there is usually a delay of 4 to 5

years from first symptom to diagnosis,and 50% of patients present withmetastatic disease. They have an indo-lent course, but median overall survival[OS] is only 33 months, and that is notvery impressive,” he said. The good news, added Tim Meyer,

MD, of University College London inthe United Kingdom, “is that withpNETs we are now in the luxurious po-sition of having lots of treatments. Thequestion now is, which is best?”

Treatment Options Prior to May 2011, options were limit-ed. For patients with hormonal symp-toms, octreotide LAR could be benefi-cial, and for oncologic controlstreptozocin-based chemotherapy wasindicated. Upon disease progression, pa-tients went on to investigational agentsor regional therapy; no approved thera-pies were available.

But identification of somatic muta-tions in the mTOR pathway in pNETformed the scientific rationale for test-ing mTOR inhibitors in this disease.The 410-patient RADIANT-3 trialdemonstrated that everolimus could ef-fectively prolong remission, from a me-dian progression-free survival (PFS) of4.6 months with best supportive care

alone to 11.0 months with everolimus,representing a 65% reduction in risk (P <.0001).An understanding of the role of the

angiogenesis pathway in pNETs also ledto the development of sunitinib for thismalignancy. The phase 3 trial showedmedian PFS increased from 5.5 monthswith placebo to 11.4 months with suni-tinib, which was a 58% reduction in

risk; this did not reach statistical signifi-cance due to early termination of thestudy and truncated enrollment.“We have clear and convincing evi-

dence that everolimus and sunitinib areeffective in improving PFS,” Meyer toldattendees.James C. Yao, MD, of the University

of Texas MD Anderson Cancer Center,

Houston, added, “Both everolimus andsunitinib result in about 6 months of PFSbenefit, but neither study was designed toevaluate overall survival.” He explainedthat because these tumors are rare, andpatients live for years, clinical trials withan OS end point are not feasible, and anOS might not be formally demonstrated.“Nonetheless, we actually do have

improved survival,” he suggested.“When we only had streptozocin, medi-an OS was 16 to 24 months. With thenewer drugs, we are pushing OS to 3years and beyond.”He added that while the drugs have

almost equivalent PFS benefit, ever -olimus has activity in controlling hor-monal output from pNETs. “It is themost active agent I have seen for con-trolling hypoglycemia in patients withinsulinoma,” he noted, “and it may re-duce gastrin and glucagon as well.”

Algorithm for managing Patients Yao said he approaches the initial man-agement of pNETs by considering thedisease burden (ie, the percentage ofliver involvement), the aggressiveness ofthe tumor (ie, Ki67 levels, tumor grade),and the primary site of the tumor.“If I have a patient with low-volume,

very low-grade disease, I think that sur-veillance or a somatostatin analogue isreasonable. For the opposite, a patientwith 50% liver involvement and a highKi67, chemotherapy may be the beststarting point. For the intermediate pa-tient, targeted therapy is a good choice,”he maintained.To decide whether to treat with

everolimus or sunitinib, Yao said,“There has been no head-to-head com-parison. Practically speaking, mostpNET patients will receive both agentsat some time, but there are some factorsto help you decide.”He believes that everolimus is the

preferred choice for the patient with afunctional tumor or a high risk of bleed-ing, such as patients with a primarytumor at the tail of the pancreas andthose with gastric varices. Everolimusalso is preferred for patients with coro-nary artery disease, congestive heartfailure, or uncontrolled hypertension.Sunitinib would be favored for patientswith severe lung disease and uncon-trolled diabetes, he said. l

Reference1. Öberg K, Meyer T. NETs and endocrine tumors.Presented at: European Society for Medical Oncology2012 Congress; September 29, 2012; Vienna, Austria.Proffered paper session.

Advances in the Treatment of PancreaticNeuroendocrine TumorsBy Caroline Helwick

New Data Presented at eSmO Neuroendocrine tumors are highly vascular, expressing

vascular endothelial growth factor (VEGF) and demon-strating angiogenesis. Since the mTOR inhibitoreverolimus has antiangiogenic activity, RADIANT-3 in-vestigators evaluated several VEGF pathway tumor mark-ers for their prognostic and predictive potential. The re-sults were presented by James C. Yao, MD, in an abstractpresentation at ESMO.1Yao and colleagues evaluated pretreatment plasma samples

for levels of the angiogenic cytokines VEGF-A, solubleVEGF receptors (sVEGFR1 and sVEGFR2), and placentalgrowth factor (PlGF). The multivariate analysis showed thatsVEGFR1 and PlGF were significant prognostic markers,with lower baseline levels associated with longer progression-free survival (PFS). This means that patients with highsVEGFR1 and high PlGF are likely to have a worse progno-sis. None of the markers, however, proved predictive of abenefit with everolimus, he reported.“PFS was significantly improved to a similar extent in pa-

tients receiving everolimus, compared with patients who re-ceived placebo, regardless of baseline levels of these mark-ers,” he said, “suggesting that none of these markers areassociated with the efficacy of everolimus in patients withpNET. The markers are prognostic but not predictive.”An updated overall survival (OS) analysis of the phase 3

sunitinib trial was also reported at ESMO by SandrineFaivre, MD, of Clichy, France.2“At trial closure, there was an advantage for sunitinib

over placebo in OS, a secondary end point. At that time69% of patients on placebo crossed over to sunitinib upondisease progression or trial closure, potentially confound-ing the OS analysis. We now present OS data 2 years afterstudy closure and after adjusting for crossover,” she said.The intent-to-treat analysis without adjustment for

crossover showed OS to be 33 months with sunitinib and26.7 months with placebo (hazard ratio [HR], 0.71). The in-vestigators then adjusted for crossover using 4 different sta-tistical methods, which showed median OS with sunitinibto range from 16.4 months (HR, 0.43) to 26.7 months (HR,0.49), depending on the model employed. This yielded anOS benefit that ranges from 6.3 to 16.7 months.“Four methods of adjusting for crossover suggested that

the effect of sunitinib on OS may have been more pro-nounced had no crossover occurred,” she said. “Theseanalyses demonstrate a survival advantage and further sup-port the clinical benefit of sunitinib for patients with ad-vanced, progressive pNET.”

References1. Yao JC, Shah M, Panneerselvam A, et al. The VEGF pathway in patients withpancreatic neuroendocrine tumors: efficacy of everolimus by baseline marker level,and prognostic and predictive effect analyses from RADIANT-3. Presented at:European Society for Medical Oncology 2012 Congress; September 29, 2012;Vienna, Austria. Abstract 11540.2. Niccoli P, Faivre S, Raoul J, et al. Updated overall survival (OS) analysis froma phase III study of sunitinib vs. placebo in patients (Pts) with advanced, unre-sectable pancreatic neuroendocrine tumor (NET). Presented at: European Societyfor Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria.Abstract 11550.

“These tumors are steadily increasing, compared

with other malignant neoplasms. It’s not a rare

disease any longer, and we don’t know why.”

—Kjell Öberg, MD

www.TheOncologyPharmacist.com30 DECEMBER 2012 I VOL 5, NO 8

Leukemia

The management of relapsed/re-fractory acute lymphoblasticleukemia (ALL) is a vexing prob-

lem and requires extensive, aggressive

supportive care throughout the course oftherapy, explained Joseph C. Alvarnas,MD, City of Hope Comp rehensiveCancer Center, Duarte, Cali fornia, in a

presentation at the National Com -prehensive Cancer Network (NCCN)7th Annual Congress on HematologicMalignancies.1

The NCCN guidelines for ALL reveala dichotomy between Philadelphia-posi-tive (PH+) and Philadelphia-negative(PH-) relapsed/refractory ALL. In PH+ ALL, gene mutation testing is

important. Patients with PH+ diseasewho relapse following cessation of tyro-sine kinase inhibitors (TKIs) can restartTKI-based therapy. For those who are re-fractory or relapse on TKI-based therapy,perform mutational analysis. If the T315Imutation is present, consider hematopoi-etic cell transplant (HCT) or clinicaltrial; for V299L, T315A, F317L/V/CI/C,consider nilotinib rather than dasatinib.For Y253H, E255K/V, or F359 V/C/I,consider dasatinib rather than nilotinib.For any other mutation, consider high-dose imatinib, dasatinib, or nilotinib. PH- ALL is far more difficult to

treat. Most regimens are front-loadedwith the best therapeutic agents, leav-ing few options for second-line treat-ment at relapse. Patients with PH-ALL should be considered for clinicaltrial or allogeneic hematopoietic stemcell transplant if in remission or onchemotherapy.

Several challenges exist for salvagetherapy for adults with relapsed/refrac-tory ALL, Alvarnas continued. It maybe difficult to identify a non‒cross-resis-tant regimen for reinduction. L-asparag-inase –containing regimens may be diffi-cult to administer to older patients.Even very intensive regimens mayachieve response rates <30%.Comorbidities may limit therapeuticchoices. Allogeneic HCT representsthe only potentially curative option foradolescents/young adults (AYAs) andadults with ALL. Patients with signifi-cant residual disease are not candidatesfor allogeneic HCT. “The lessons from our experience

with relapsed/refractory ALL are

MAY

2-5

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Influencing the Patient-Impact Factor !

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Relapsed/Refractory All Vexing ProblemBy Alice Goodman

The NCCN guidelines for acute lymphoblasticleukemia (ALL) reveal a dichotomy between

Philadelphia-positive andPhiladelphia-negative

relapsed/refractory ALL.

twofold. First, we would like to avoid re-lapse, and we recommend strong riskstratification at the time of diagnosis.Second, move to transplant after firstcomplete response is achieved,” he stat-ed. Five-year overall survival was 62% atCity of Hope when adults with ALLwere transplanted in first remission. “Unrelated donor transplant pro-

duces similar outcomes as relateddonor transplant. Don’t let the lack ofsibling donor keep you from moving onto transplant,” he told listeners.Alvarnas commented that trans-

plant outcomes have not improved ap-preciably over the past 3 decades. “Wehave a long way to go,” he said. “At thesame time, intensification of the trans-plant regimen is not feasible.”Experience with transplant raises

the importance of timely transplanta-tion and the need for better drugs thatmight improve outcomes, he said. Alvarnas discussed several new

agents that may be useful in re-lapsed/refractory ALL. Two agentsthat have shown promising results in

small phase 2 trials are nelarabine, aprodrug of ara-G, and clofarabine, asecond-generation purine nucleosideanalog. Both drugs have distinct side-effect profiles, with different toxici-ties. Neurologic toxicity is the keydose-limiting toxicity with nelara-

bine. Other significant toxicities in-clude cytopenia, gastrointestinal ef-fects, and pyrexia. Toxicities ofclofarabine include elevations of liverenzymes, febrile neutropenia, skin rash,

and cytomegalovirus reactivation.“The use of novel therapeutics in re-

lapsed/refractory ALL is exciting tome. We would like to identify a paral-lel drug to rituximab in lymphoma. Weare still early on in this process. Twodrugs might be interesting in this re-

gard [blinatumomab and inotuzumabozogamicin]. These antibodies are im-pressively tolerable in heavily pretreat-ed patients, compared with chemo -therapy,” Alvarnas said. l

Reference1. Alvarnas JC. New approaches to the management ofrelapsed/refractory acute lymphoblastic leukemia.Presented at: National Comprehensive CancerNetwork (NCCN) 7th Annual Congress onHematologic Malignancies; September 14, 2012; NewYork, NY.

Supportive Care for All Patients being treated for ALL re-quire aggressive coordinated sup-portive care throughout the entirecourse of therapy. Alvarnas highlighted several sup-

portive care needs:• Preemptive management oftumor lysis syndrome

• Disseminated intravascular co- agulation and L-asparaginasecoagulopathies

• Management of therapy-relat-ed cytopenia

• Management of febrile neu-tropenia/opportunistic infection

• Antiemetic therapy

DECEMBER 2012 I VOL 5, NO 8 31www.TheOncologyPharmacist.com

Leukemia

“Unrelated donor transplant produces similaroutcomes as related donor transplant. Don’t let the lack of sibling donor keep you from moving

on to transplant.”

—Joseph C. Alvarnas, MD

Joseph C. Alvarnas, MD, discussednew drugs that might improve out-comes for relapsed/refractory acute

lymphoblastic leukemia (ALL) at theNational Comprehensive CancerNetwork 7th Annual Congress onHematologic Malignancies.1 Alvarnas isdirector of medical quality and clinicalassociate professor at City of HopeComprehensive Cancer Center inDuarte, California.Two new investigational drugs in re-

lapsed ALL are nelarabine and clofara-bine. Nelarabine, a prodrug of 9-beta-D-ara-G, is active in the management ofrelapsed/refractory ALL and is non–crossresistant with most other ALL drugs.Phase 2 trials included 39 pediatric pa-tients and 28 adults with relapsed/refrac-tory ALL.2 In pediatric patients, com-plete response (CR) rate was 5 of 39, and9 of 39 patients achieved CR or CR withincomplete marrow recovery. In adults, 5of 28 achieved CR, and 6 of 28 achievedCR or CR with incomplete marrow re-covery.Nelarabine has a distinct toxicity pro-

file. Neurotoxicity is the key dose-limit-ing toxicity. In phase 1 and 2 trials, 64%of patients experienced headache andseizures, and 1 case of fatal status epilep-ticus was reported. Additional significanttoxicities included cytopenia, gastroin-testinal disorders, and pyrexia. Clofarabine, a second-generation

purine nucleoside analog, is active inboth relapsed/refractory ALL and acute

myeloid leukemia (AML). The drugcan be used as monotherapy or as partof a preparative regimen for transplantin combination with additionalchemo therapeutic agents, such asetoposide, cytarabine, and cyclophos-phamide. It is more active in B-cell dis-ease than T-cell disease. “These combination regimens [with

clofarabine] are not for the faint of heart.Patients can develop mucositis and cy-topenia. Be prepared for a sick patientwho requires inpatient hospitalization,”Alvarnas told listeners.

In a single-agent trial of 61 pediatricpatients with ALL who had failed 2 ormore previous regimens, response ratewas 20% (7 CR and 5 CR with incom-plete marrow recovery).3 “The small per-centage of response is impressive in thisdisease,” he said.In a trial of children with refractory

AML or ALL treated with the combina-

tion of clofarabine, etoposide, and cy-tarabine, 19 of 24 ALL patients achievedCR or CR with incomplete recovery ofbone marrow; 1 of 16 AML patientsachieved CR or CR with incomplete re-covery of bone marrow; 13 of 17 re-sponders subsequently underwent allo-geneic hematopoietic cell transplant;and 24-month overall survival was 25%.3Toxicities associated with clofarabine

include elevations of liver enzymes,febrile neutropenia, infections (cy-tomegalovirus [CMV] reactivations),and skin rash.Alvarnas noted that the rate of

CMV reactivation is not high, “but itis real, and patients can develop viscer-al disease.” Investigators would like to discover a

drug for ALL that is parallel to rituximabin lymphoma, but they are still early inthis pursuit. “Two drugs might be interesting in this

regard,” he said.Blinatumomab (AMG 103) brings the

T-cell in opposition to the tumor cell andallows destruction of the tumor cell. In aphase 2 trial of 36 patients with re-lapsed/refractory ALL, 26 of 36 achievedCR or CR with incomplete bone marrowrecovery, and median survival was 9months (range, 8.2-15.8 months).4Reversible central nervous system eventswere reported in 6 patients. Inotuzumab ozogamicin was the sec-

ond drug he discussed. This is an anti-CD22 antibody conjugated with

calicheamicin that induces double-stranded DNA breaks. In a phase 2trial of 40 patients with relapsed/refrac-tory ALL who received a median of 2courses of therapy, CR was 56%; 70%of responders were alive at 6 monthsfollowing therapy; and 12 patientswent on to allogeneic stem cell trans-plant.5 Adverse events included grade3 or 4 fever in 9 patients and grade 3hypotension in 1 patient. “I am excited about the use of novel

agents in relapsed/refractory ALL. Theseantibodies are impressively tolerable inheavily pretreated patients, comparedwith chemotherapy,” he stated. l

References1. Alvarnas JC. New approaches to the management ofrelapsed/refractory acute lymphoblastic leukemia.Presented at: National Comprehensive Cancer Network7th Annual Congress on Hematologic Malignancies;September 14, 2012; New York, NY.2. Cohen MH, Johnson JR, Justice R, et al. FDA drug ap-proval summary: nelarabine (Arranon) for the treatmentof T-cell lymphoblastic leukemia/lymphoma. Oncologist.2008;13(6):709-714.3. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study ofclofarabine in pediatric patients with refractory or re-lapsed acute lymphoblastic leukemia. J Clin Oncol.2006;24(12):1917-1923.4. Topp M, Goekbuget N, Zugmaier G, et al. Effect ofanti-CD19 BiTE blinatumomab on complete remissionrate and overall survival in adult patients withrelapsed/refractory B-precursor ALL. Presented at: 2012American Society of Clinical Oncology AnnualMeeting; June 2012; Chicago, IL. Abstract 6500.5. Byrd JC, Furman RR, Coutre SE, et al. The Bruton’styrosine kinase (BTK) inhibitor PCI-32765 (P) in treat-ment-naive (TN) chronic lymphocytic leukemia (CLL)patients (pts): Interim results of a phase Ib/II study.Presented at: 2012 American Society of ClinicalOncology Annual Meeting; June 2012; Chicago, IL.Abstract 6507.

On the Horizon for Relapsed/Refractory AllBy Alice Goodman

“I am excited about the

use of novel agents in

relapsed/refractory ALL.”

—Joseph C. Alvarnas, MD

CONTINUING EDUCATION

CONSIDERATIONS in

Multiple Myeloma™

5th Annual

ASK THE EXPERTS: Bone Health

G. David Roodman, MD, PhDDirector of Hematology/OncologyDepartment of MedicineIndiana UniversityIndianapolis, IN

Raj Duggal, PharmD, BCOPOncology Clinical PharmacistIU Simon Cancer CenterIndianapolis, IN

Lori Case, RN, BSN, OCNNurse CoordinatorIU Simon Cancer CenterIndianapolis, IN

Supported by educational grants from Celgene Corporation andMillennium: The Takeda Oncology Company.

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LETTER FROM THE EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). Thisis due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinicalinvestigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria fordiagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management ofcomorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regardingthe application and interpretation of recent clinical advances.In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently asked

questions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questionsare answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowl-edge, and professional experience regarding evidence-based care. In this fifth issue, experts from Indiana University,Indianapolis, answer questions pertaining to the management of patients with myeloma-related bone disease.

Sincerely,

Sagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

FACULTY

DECEMBER 2012 • VOLUME 5 • NUMBER 5

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CONSIDERATIONS IN MULTIPLE MYELOMA

IntroductionAt the time of diagnosis, two-thirds of patients with multiple mye -

loma (MM) experience bone pain and are very likely to sustain

pathologic fractures. Therefore, an important goal of therapy when

treating the disease is the prevention of fractures and other skele-

tal-related events (SREs). In this article, G. David Roodman, MD,

PhD, discusses recent advances in the management of myeloma-

related bone disease, and novel agents that are being investigated

for their potential to improve patient outcomes.

How should bisphosphonates be used to improve outcomes inpatients with myeloma-related bone disease?

Guidelines from the American Society of Clinical Oncology1 and theEuropean Myeloma Network2 recommend bisphosphonate therapy for MMpatients with either radiographic evidence of lytic bone lesions or severeosteopenia attributable to their disease. New evidence is beginning toemerge, however, to suggest that earlier use of bisphosphonates may be war-ranted. For example, in the Medical Research Council’s Myeloma IX trial,3,4

Morgan and colleagues showed that even patients who did not present with

an SRE at the time of enrollment still obtained clinical benefit from bisphos -phonate therapy. In this trial, a 5.5-month overall survival advantage wasreported among patients who received the intravenous (IV) bisphosphonatezoledronic acid compared with those who received the oral bisphosphonateclodronic acid.3 A subsequent analysis, however, revealed that only patientswith evidence of bone disease achieved the survival benefit.5 Therefore, thesurvival advantage with bisphosphonate use among MM patients who havenot exhibited lytic lesions or osteopenia at diagnosis remains unclear.

D’Arena and colleagues evaluated patients with smoldering myelomawho received IV pamidronate (60-90 mg once a month for 1 year).6 At thetime of progression to symptomatic MM, SREs were reported in 72.7% ofpatients who were observed versus 39.2% of patients treated withpamidronate (P=.009). These results also suggest that bisphosphonates canbe beneficial early in the course of myeloma. However, we cannot be 100%certain that the patients without documented bone disease really did nothave bone disease. In the Myeloma IX trial, the investigators utilized skele-tal survey rather than the more sensitive magnetic resonance imaging(MRI) to detect myeloma-related bone disease, because that was the modal-ity available at the time.3 We now use MRI in clinical practice to obtain a

Advances in the Treatment of Myeloma-Related Bone Disease

G. David Roodman, MD, PhDDirector of Hematology/Oncology, Department of MedicineIndiana University, Indianapolis, IN

SponsorsThis activity is jointly sponsored by Medical Learning Institute Inc andCenter of Excellence Media, LLC.

Commercial Support AcknowledgmentThis activity is supported by educational grants from Celgene Corporationand Millennium: The Takeda Oncology Company.

Target AudienceThe activity was developed for physicians, nurses, and pharmacists in -volved in the treatment of patients with multiple myeloma (MM).

Purpose StatementThe purpose of this activity is to enhance competence of physicians, nurs-es, and pharmacists concerning the treatment of MM.

Physician Credit DesignationThe Medical Learning Institute Inc designates this enduring material for a max-imum of 1.0AMA PRA Category 1 Credits™. Physicians should claim only thecredit commensurate with the extent of their participation in the activity. Thisactivity has been planned and implemented in accordance with the EssentialAreas and policies of the Accreditation Council for Continuing MedicalEducation through the joint sponsorship of the Medical Learning Institute Incand the Center of Excellence Media, LLC. The Medical Learning Institute Incis accredited by the Accreditation Council for Continuing Medical Educationto provide continuing medical education for physicians.

Registered Nurse DesignationMedical Learning Institute IncProvider approved by the California Board of Registered Nursing, Pro viderNumber 15106, for 1.0 contact hour.

Registered Pharmacy DesignationThe Medical Learning Institute Inc is accredited by the AccreditationCouncil for Pharmacy Education as a provider of continuing pharma-

cy education. Completion of this knowledge-based activity provides for 1.0contact hour (0.1 CEU) of continuing pharmacy education credit. TheUniversal Activity Number for this activity is 0468-9999-12-033-H01-P.

Learning ObjectivesUpon completion of this activity, the participant will be able to:• Describe the impact and consequences of bone destruction in patientswith multiple myeloma (MM)

• Summarize recent evidence-based guidelines for the management ofmyeloma-related bone disease

• Review safety and efficacy data on current and investigational therapiesfor preventing bone loss and skeletal-related events in patients with MM

DisclosuresBefore the activity, all faculty and anyone who is in a position to have con-trol over the content of this activity and their spouse/life partner will dis-close the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses,grants, consulting roles, speakers’ bureau membership, stock ownership, orother special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vettedby Medical Learning Institute Inc for fair balance, scientific objectivity ofstudies mentioned in the materials or used as the basis for content, andappropriateness of patient care recommendations.

The associates of Medical Learning Institute Inc, the accredited providerfor this activity, and Center of Excellence Media, LLC, do not have anyfinancial relationships or relationships to products or devices with anycommercial interest related to the content of this CME/CPE/CE activityfor any amount during the past 12 months.

Planners’ and Managers’ DisclosuresDana Delibovi,Medical Writer, has nothing to disclose.She does intend to discuss either non–FDA-approved or investigationaluse for the following products/devices: pomalidomide and carfilzomib.William J. Wong, MD, MLI Reviewer, has nothing to disclose.Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosedthat her spouse is investigator on a study for Agenix, ImClone, and Lilly;on the Data Monitoring Committee for Infinity and Pfizer; on theAdvisory Committee for Boehringer Ingelheim; and principal investigoron a study for Pfizer and Sinta.

Faculty DisclosuresSagar Lonial, MD, is a consultant to Bristol-Myers Squibb, CelgeneCorporation, Merck, Millennium: The Takeda Oncology Company,Novartis, and Onyx. He does intend to discuss either non–FDA-approvedor investigational use for the following products/devices: carfilzomib,pomalidomide, MLN9708, vorinostat, panobinostat, and elotuzumab. G. David Roodman, MD, PhD, is a consultant to Amgen Inc and

Celgene Corporation. He does not intend to discuss any non–FDA-approved or investigational uses of any products or devices.Raj Duggal, PharmD, BCOP, has nothing to disclose. He does not intendto discuss any non–FDA-approved or investigational uses of any productsor devices.Lori Case, RN, BSN, OCN, has nothing to disclose. She does not intendto discuss any non–FDA-approved or investigational uses of any productsor devices.

Disclaimer The information provided in this CME/CPE/CE activity is for continuingeducation purposes only and is not meant to substitute for the indepen -dent medical judgment of a healthcare provider relative to diagnostic andtreatment options of a specific patient’s medical condition. Recommenda -tions for the use of particular therapeutic agents are based on the best availablescientific evidence and current clinical guidelines. No bias towards or promotionfor any agent discussed in this program should be inferred.

Instructions for Credit

There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest,posttest, and evaluation. The pretest, posttest, and evaluation can be com-pleted online at www.mlicme.org/P12029.html. Upon completion of theevaluation and scoring 70% or better on the posttest, you will immediatelyreceive your certificate online. If you do not achieve a score of 70% or bet-ter on the posttest, you will be asked to take it again. Please retain a copyof the certificate for your records.

For questions regarding the accreditation of this activity, please contactMedical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

Estimated time to complete activity: 1.0 hourDate of initial release: December 12, 2012Valid for CME/CPE/CE credit through: December 12, 2013

SCAN HERE to Download the PDF or Apply for Credit.

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Web browser, and select “Download”• Visit the app store for your smartphone

New evidence is beginning to emerge, however, to suggest that earlier use of bisphosphonates may be warranted.

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www.TheOncologyPharmacist.com DECEMBER 2012 I VOL 5, NO 8 33

CONTINUING EDUCATION

more accurate assessment of a patient’s condition. If individuals have anysymptoms, but have a negative skeletal survey, we conduct an MRI exami-nation, per current recommendations.7 In patients who have a solitary plas-macytoma or a single lytic lesion, we perform an MRI of the spine and pelvisto ensure that they do not have additional lytic disease. There is evidencethat the presence of focal lesions on MRI may indicate a patient with MM—even one who is otherwise asymptomatic—is at risk for rapid progressionand poor prognosis.8,9 Such patients probably should receive therapy.Fluorodeoxyglucose positron-emission tomography scanning combined withcomputed tomography (CT) is an excellent method for examining bone10;however, it can be very expensive and therefore cannot be used routinely. InEurope, clinicians are utilizing total-body CT scans with lower doses of radi-ation. This may eventually become a more standard practice here in theUnited States.

What is your approach to treating bone disease in patients withsevere renal dysfunction?

In patients with very severe renal failure at diagnosis, we use antimyelomatherapy to improve renal function prior to initiating a bisphosphonate.Bortezomib-based therapy has been used successfully to reverse renal failurein patients with MM; 59% of patients will exhibit an improvement in renalfunction within a median of 11 days (range, 8-41 days), with 2 of 9 dialysis-dependent individuals becoming dialysis-independent.11 The InternationalMyeloma Working Group recommends bortezomib plus high-dose dexam-ethasone to accelerate the reversal of renal impairment.12 Bortezomib mayimprove renal impairment by reducing inflammation through the inhibitionof nuclear factor kappa B (NF-�B), a transcription factor with proinflamma-tory effects in the compromised kidney.13

Unfortunately, some patients remain permanently on dialysis despite theuse of effective novel agents. Although pamidronate and zoledronic acidare not recommended for patients with creatinine clearance (CrCl) <30mL/min, I think whenever possible, these individuals should receive bisphos -phonate therapy to alleviate the pain associated with bone disease and tominimize the risk of pathologic fractures. In rare cases, in which patientshave very poor performance status and rapidly progressing disease afterfrontline therapy, we may be unable to administer bisphosphonates for thepurpose of preventing SREs. However, these agents may still be helpful innormalizing calcium levels in patients who are hypercalcemic.

What is the latest evidence regarding the potential of novel agentsto enhance bone health in patients with MM?

Several antimyeloma agents may have secondary pro-bone effects, partic-ularly proteasome inhibitors and immunomodulatory drugs (Figure).14

Mounting evidence suggests that the proteasome inhibitors bortezomib andcarfilzomib have bone anabolic effects. In other words, they are able to buildbone.15-18 These effects have been observed preclinically; clinically, the roleof proteasome inhibition in bone formation requires further study. Proteasome inhibitors stimulate bone formation by their enhancement

of osteoblast differentiation. In a clinical study, Giuliani and colleaguesdemonstrated that in human osteoblast progenitor cells, bortezomib stimu-lated bone nodule formation.16 These researchers, who administered bor -tezomib as monotherapy to 21 relapsed or previously treated patients withMM, reported that individuals who responded to bortezomib in terms oftheir myeloma also showed an increase in the number of osteoblasts permm2 of bone tissue. Patients who responded to bortezomib also exhibitedan increase in the number of Runx2/Cbfa1-positive osteoblastic cells;Runx2/Cbfa1 is an osteoblast transcription factor regulated by BMP-2.These signs of enhanced osteoblast activity were not observed in nonrespond -ers to bortezomib.

Terpos and colleagues reported that bortezomib use reduced patients’serum levels of dickkopf-1 (DKK-1), thus countering the ability of DKK-1to inhibit the Wnt signaling pathway to suppress osteoblast differentiation.18

Their study results also demonstrated a decrease in receptor activator of NF-�B ligand (RANKL) with bortezomib, indicating a reduction in osteoclastactivity. Together, reduction in DKK-1 and RANKL indicates a normaliza-tion of bone remodeling with bortezomib in patients with relapsed MM. Thecaveat with current data is that, for the most part, patients who demonstrat-ed an increase in bone formation markers also showed an antitumorresponse to bortezomib. This makes it unclear if bone formation is the resultof an effect on osteoblast differentiation or is simply an added benefit ofantimyeloma activity. Only one study to date has demonstrated enhancedbone formation markers regardless of whether a patient’s myeloma respond-ed to bortezomib.19

The immunomodulatory agents lenalidomide, thalidomide, and poma-lidomide also appear to have beneficial effects on bone. These drugs havebeen shown to inhibit osteoclast formation and bone remodeling markers inpatients with MM.20-22 Breitkreutz and colleagues examined the osteoclast

Figure. Bortezomib and lenalidomide in the treatment ofmyeloma-related bone disease.14

Reprinted with permission.

Bzb indicates bortezomib; BMP-2, bone morphogenetic protein-2; MSCs, mesenchymal stromalcells; OAFs, osteoclast-activating factors; OCL, osteoclast; Runx2; runt-related transcription factor 2.

In patients with very severe renal failure at diagnosis,we use antimyeloma therapy to improve renal function prior to initiating a bisphosphonate.

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CONSIDERATIONS IN MULTIPLE MYELOMA

effects of lenalidomide compared with bortezomib, reporting that lenalido-mide reduced levels of RANKL in the serum and bone marrow stromal cellsof patients with MM.20 Anderson and colleagues reported that immunomod-ulators inhibit osteoclastogenesis by diverting osteoclast precursors awayfrom their osteoclast cell lineage toward a granulocytic lineage—a uniquemechanism of action mediated by downregulation of the PU.1 transcriptionfactor.22 Osteoclast inhibition appears to be a class effect of immunomodu-lators. This seems to be more evident with lenalidomide and pomalidomidethan with thalidomide.20-22

Denosumab, a fully humanized monoclonal antibody, is currently ap -proved only for the prevention of SREs in patients with bone metastasesfrom solid tumors.23 However, this novel agent is currently being evaluatedfor potential benefits in patients with MM in a phase 3 trial. RANKLis overexpressed in MM and triggers increased osteoclast activity.15 Deno -sumab inhibits RANKL, and therefore has potent inhibitory effects on thedifferentiation, activity, and survival of osteoclasts,24 although it has notbeen shown to augment bone formation. In clinical trials,25 markers of bothbone resorption and bone formation are reduced with denosumab treatmentin patients with metastatic bone disease, just as they are in trials of bisphos -phonates.26 This is consistent with the suppression of bone remodeling—asless bone is resorbed during treatment, less bone needs to be made.26

ConclusionBone disease is a major morbidity factor in patients with MM, and the asso-

ciated skeletal complications can result in significant morbidity. Bisphos -phonates remain the standard of care for the treatment of myeloma-relatedbone disease, and have been shown to consistently reduce the incidence ofSREs. However, new molecular targets of cell cross-talk in myeloma bone mar-row are currently under investigation, and new drugs are being explored inpreclinical and clinical trials. It is hoped that results from these studies willexpand our armamentarium of treatment options for patients with MM. �

References1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinicalpractice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

2. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recom-mendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol. 2009;20:1303-1317.

3. Morgan GJ, Davies FE, Gregory WM, et al; National Cancer Research Institute HaematologicalOncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clo-dronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet.2010;376:1989-1999.

4. Morgan GJ, Child JA, Gregory WM, et al; National Cancer Research Institute HaematologicalOncology Clinical Studies Group. Effects of zoledronic acid versus clodronic acid on skeletalmorbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondaryoutcomes from a randomised controlled trial. Lancet Oncol. 2011;12:743-752.

5. Morgan GJ, Davies F, Gregory W, et al. Defining the biological subgroup of multiple myelomapatients which benefits maximally from the overall survival (OS) benefit associated with treat-ment with zoledronic acid (ZOL). J Clin Oncol. 2011;29(suppl). Abstract 8083.

6. D’Arena G, Gobbi PG, Broglia C, et al; Multiple Myeloma Working Group; Gisl (GruppoItaliano Studio Linfomi) Cooperative Group. Pamidronate versus observation in asymptomaticmyeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma. 2011;52:771-775.

7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines™).Multiple Myeloma. Version 1.2013. www.nccn.org. Accessed October 17,2012.

8. Hillengass J, Fechtner K, Weber M-A, et al. Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma. J ClinOncol. 2010;28:1606-1610.

9. Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diag-nostic and clinical implications. J Clin Oncol. 2007;25:1121-1128.

10. Bredella MA, Steinbach L, Caputo G, Segall G, Hawkins R. Value of FDG PET in the assess-ment of patients with multiple myeloma. AJR Am J Roentgenol. 2005;184:1199-1204.

11. Dimopoulos MA, Roussou M, Gavriatopoulou M, et al. Reversibility of renal impairment inpatients with multiple myeloma treated with bortezomib-based regimens: identification of pre-dictive factors. Clin Lymphoma Myeloma. 2009;9:302-306.

12. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiplemyeloma: a consensus statement on behalf of the International Myeloma Working Group. J ClinOncol. 2010;28:4976-4984.

13. Ludwig H, Drach J, Graf H, Lang A, Meran JG. Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica. 2007;92:1411-1414.

14. Roodman GD. Bone building with bortezomib. J Clin Invest. 2008;118:462-464.15. Roodman GD. Skeletal imaging and management of bone disease. Hematology. 2008:313-319.16. Giuliani N, Morandi F, Tagliaferri S, et al. The proteasome inhibitor bortezomib affects osteo -blast differentiation in vitro and in vivo in multiple myeloma patients. Blood. 2007;110:334-338.

17. Hurchla MA, Garcia-Gomez A, Hornick MC, et al. The epoxyketone-based proteasomeinhibitors carfilzomib and orally bioavailable oprozomib have anti-resorptive and bone-anabolicactivity in addition to anti-myeloma effects. Leukemia. 2012 Jul 5. doi: 10.1038/leu.2012.183.

18. Terpos E, Heath DJ, Rahemtulla A, et al. Bortezomib reduces serum dickkopf-1 and receptoractivator of nuclear factor-�B ligand concentrations and normalizes indices of bone remodelingin patients with relapsed multiple myeloma. Br J Haematol. 2006;135:688-692.

19. Delforge M, Terpos E, Richardson PG, et al. Fewer bone disease events, improvement in boneremodeling, and evidence of bone healing with bortezomib plus melphalan-prednisone vs. mel-phalan-prednisone in the phase III VISTA trial in multiple myeloma. Eur J Haematol. 2011;86:372-384.

20. Breitkreutz I, Raab MS, Vallet S, et al. Lenalidomide inhibits osteoclastogenesis, survival factorsand bone-remodeling markers in multiple myeloma. Leukemia. 2008;22:1925-1932.

21. Bolzoni M, Abeltino M, Storti P, et al. The immunomodulatory drugs lenalidomide and poma-lidomide inhibit multiple myeloma-induced osteoclast formation and RANKL/OPG ratio inmyeloma microenvironment targeting the expression or adhesion molecules. Blood (ASHAnnual Meeting Abstracts). 2010;116. Abstract 448.

22. Anderson G, Gries M, Kurihara N, et al. Thalidomide derivative CC-4047 inhibits osteoclastformation by down-regulation of PU.1. Blood. 2006;107:3098-3105.

23. Xgeva [package insert]. Thousand Oaks, CA: Amgen Inc; 2010.24. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausalosteoporosis. Biologics. 2008;2:645-653.

25. Eastell R, Christiansen C, Grauer A, et al. Effects of denosumab on bone turnover markers inpostmenopausal osteoporosis. J Bone Miner Res. 2011;26:530-537.

26. Berenson JR, Lichtenstein A, Porter L, et al; Myeloma Aredia Study Group. Efficacy ofpamidronate in reducing skeletal events in patients with advanced multiple myeloma. N Engl JMed. 1996;334:488-493.

This is consistent with the suppression of bone remodeling—as less bone is resorbed during treatment, less bone needs to be made.

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CONTINUING EDUCATION

Pharmacologic Issues in the Managementof Myeloma-Related Bone Disease

IntroductionBisphosphonate therapy has become an essential component of

treatment for patients with multiple myeloma (MM). Although zole-

dronic acid and pamidronate are highly effective for preventing and

reducing skeletal-related events (SREs), these intravenously adminis-

tered agents may cause adverse events (AEs) that require careful

monitoring throughout the course of therapy. Consideration of pa -

tient comorbidities, such as renal dysfunction, prior to the initiation of

bisphosphonate therapy is critical, as this influences the choice of

agent, as well as the dose and schedule of administration. In this arti-

cle, Raj Duggal, PharmD, BCOP, discusses these key pharmacologic

issues related to the management of myeloma-related bone disease.

Which factors influence the choice of intravenous (IV) bisphospho-nate therapy for patients with myeloma-related bone disease?

Bisphosphonate therapy has an established role in the treatment of patientswith active MM and identified lytic lesions or compression fractures of thespine due to osteopenia.1,2 In the United States, both zoledronic acid andpamidronate are approved by the US Food and Drug Administration (FDA) todecrease bone destruction from osteolytic lesions and minimize SREs in thesepatients.1-4 In clinical practice, zoledronic acid and pamidronate, which are typ-ically administered every 3 to 4 weeks, are considered basically equivalent interms of skeletal protection and pain control.1,2 Therefore, drug selection is dic-tated by patient-specific factors and the healthcare team’s preference.1,5

Infusion time and baseline renal function are 2 major considerations in theselection of bisphosphonate therapy for patients with MM.1 Zoledronic acidis often recommended for patients with a creatinine clearance (CrCl) >30mL/min, as this drug can safely be infused over �15 minutes compared withthe prolonged 2-hour infusion of pamidronate.1,3,4 For patients with an esti-mated CrCl <30 mL/min or serum creatinine (SCr) >3 mg/dL, shorter infu-sion times with zoledronic acid are not recommended, and the infusion timeof pamidronate should be extended to 4 to 6 hours to minimize drug toxicity.1

There is no level of renal dysfunction resulting in absolute contraindicationfor pamidronate therapy.4

In a recent Cochrane review meta-analysis, no statistical difference wasfound regarding the incidence of AEs (including hypocalcemia and renaldysfunction) when comparing bisphosphonates.2 Both pamidronate and zole-dronic acid are associated with osteonecrosis of the jaw (ONJ); the incidenceof this AE rises with increased drug exposure (dose and duration).1-4

Guidelines published by the American Society of Clinical Oncology(ASCO)1 and the National Comprehensive Cancer Network6 cite a signifi-cantly higher incidence of ONJ with zoledronic acid compared with

pamidronate found in a single, prospective study, but this is not supported inthe recent Cochrane review.2

Clinicians at our institution tend to select zoledronic acid as the preferredbisphosphonate, given the advantage of shorter infusion times for patientswith adequate renal function. Pamidronate is typically reserved for patientswith poor renal function at baseline.

What bisphosphonate dosing adjustments are necessary forcomorbidities such as renal impairment?

The primary dose adjustment for bisphosphonate therapy is based on renalfunction.1,3,4 Patients with MM are at risk for renal dysfunction at baselineand during treatment, due to kidney damage from monoclonal light chains,hypercalcemia, hyperuricemia, dehydration, and nephrotoxic pharmacologicagents (including bisphosphonates).2,3,7 Careful consideration of baselinerenal function must occur prior to initiating bisphosphonate therapy in thesepatients (see Tables 1 and 2 for initial dosing recommendations).1,3,4 Once apatient is started on bisphosphonate therapy, ASCO guidelines recommendrechecking SCr levels prior to each subsequent dose.1 Treatment should bewithheld for deterioration in renal function, which is defined as an increasein SCr by �0.5 mg/dL if normal at baseline, or �1 mg/dL if abnormal at base-line. Therapy may be restarted at the previously prescribed dose once the SCrhas returned to within 10% of baseline.1,3,4

Another method of monitoring patients for renal dysfunction involvesperiodic assessments (every 3-6 months) for unexplained albumin spilling

Raj Duggal, PharmD, BCOPOncology Clinical PharmacistIU Simon Cancer CenterIndianapolis, IN

Table 1. Suggested Initial Dosing of Zoledronic Acid Based onRenal Function1,3

Zoledronic DoseCreatinine Clearance (infused over 15 minutes)

>60 mL/min 4 mg

50-60 mL/min 3.5 mg

40-49 mL/min 3.3 mg

30-39 mL/min 3 mg

<30 mL/min Avoid use

Table 2. Suggested Initial Dosing of Pamidronate Based onRenal Function1,4

Serum Creatinine Creatinine Clearance Pamidronate Dose

<3 mg/dL >30 mL/min 90 mg over 2 hours

>3 mg/dL <30 mL/min 90 mg over 4-6 hoursa

Albuminurea

>500 mg/24 hours (unexplained) Hold dose until returns to baselineRestart at 90 mg over �4 hours

aConsider reducing initial dose of pamidronate for baseline renal impairment.

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www.TheOncologyPharmacist.com36 DECEMBER 2012 I VOL 5, NO 8

CONSIDERATIONS IN MULTIPLE MYELOMA

into the urine. If there is >500 mg of albumin in the urine measured over 24hours, IV bisphosphonate therapy should be withheld until the level of pro-teinuria returns to baseline. Pamidronate therapy may be reinstituted with aprolonged infusion time (over �4 hours).1,4

ASCO guidelines also recommend periodic monitoring of serum calcium,electrolytes, phosphate, magnesium, and hematocrit/hemoglobin, althoughno specific frequency is given, due to a lack of supportive evidence.1

Commonly, clinicians draw serum calcium levels prior to each dose of bis-phosphonate therapy to monitor for additional drug toxicity and potentially,disease progression.2,3,6 Doses can be delayed for hypocalcemia at the discre-tion of the healthcare team. As long as hypercalcemia is not present, calciumand vitamin D supplementation can be instituted safely to minimize the riskof hypocalcemia.3,4

ONJ is a major concern for patients receiving bisphosphonate therapy, asit can cause significant morbidity.8 Prior to initiating therapy, a routine clin-ical dental exam is recommended, and dental procedures, including extrac-tions, should ideally be completed prior to initiation of therapy. Once thera-py has begun, regular dental exams should be scheduled depending ontreatment- and patient-specific risk factors, such as oral health, bisphospho-nate dose, and duration of therapy. Some clinicians may consider delayingthe dose of bisphosphonate if a dental procedure is scheduled, but no clearrecommendations have been established.1,3,4

How do you decide how long to keep patients on bisphosphonatetherapy?

The optimal duration for bisphosphonate therapy is currently unknown.ASCO guidelines currently recommend monthly bisphosphonate therapy for2 years for patients with active lytic lesions or spinal compression related toosteopenia.1,3,4 After the initial course of therapy, the healthcare team mustdecide whether therapy should be continued on an individualized basis. Iftherapy is stopped, it should be restarted upon relapse with development ofadditional SREs.1

Guidelines published by the European Myeloma Network similarly rec-ommend monthly bisphosphonate therapy for 2 years.8 After this initial

therapy, in those patients who have achieved remission and have stable dis-ease, bisphosphonates can be discontinued. For some individuals, it may bebeneficial to continue bisphosphonate therapy beyond 2 years, at a reduceddose and frequency. However, the panel noted that there is no hard data tosupport this approach.Recently, the Medical Research Council Myeloma IX trial provided evi-

dence that suggests maintenance bisphosphonate therapy might have a moresignificant clinical benefit.9 In this study, subjects were randomized to IVzoledronic acid (4 mg every 3-4 weeks during induction chemotherapy, thenevery 4 weeks thereafter) or oral clodronate (1600 mg/day). In this popula-tion of newly diagnosed MM patients, an overall survival advantage wasnoted with zoledronic acid compared with clodronate. Many study partici-pants received bisphosphonate therapy longer than the 2-year recommenda-tion, so it is possible that this prolonged therapy may have contributed to thedecreased SREs and increased survival times. Due to the study’s small samplesize, additional trials need to be completed to confirm this advantage.9

ConclusionBisphosphonate use has been shown to prevent, reduce, and delay SREs in

MM. Although these agents have an established role in the management ofthe disease, additional evaluations are needed to clarify the optimal durationof therapy, identify candidates for maintenance therapy longer than 2 years,and observe and report on toxicities noted with this extended treatment reg-imen.1,2,9 The successful use of bisphosphonates requires careful assessment ofpatients prior to and during therapy, diligent monitoring for AEs, and a thor-ough understanding of dosing and administration guidelines that will pro-mote optimal clinical outcomes. �

References1. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinicalpractice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

2. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a networkmeta-analysis. Coch Database Syst Rev. 2012;5:CD003188.

3. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 20124. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; May 2012.5. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid com-pared with pamidronate disodium in the treatment of skeletal complications in patients withadvanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter,comparative trial. Cancer. 2003;98:1735-1744.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCNGuidelines™). Multiple Myeloma. Version 1.2013. www.nccn.org. Accessed October 31, 2012.

7. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiplemyeloma: a consensus statement on behalf of the International Myeloma Working Group.J Clin Oncol. 2010;28:4976-4984.

8. Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: rec-ommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol.2009;20:1303-1317.

9. Morgan GJ, Davies FE, Gregory WM, et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the MedicalResearch Council Myeloma IX trial. Blood. 2012;119:5374-5383.

If there is >500 mg of albumin in the urine measured over 24 hours, IV bisphosphonate therapy should be withheld until the level of proteinuria returns to baseline.

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DECEMBER 2012 I VOL 5, NO 8 37www.TheOncologyPharmacist.com

CONTINUING EDUCATION

Nursing Considerations in MyelomaPatients with Skeletal Complications

IntroductionSustaining skeletal integrity and preventing disability are essential

goals of long-term multiple myeloma (MM) care. Achieving these

goals requires pharmacologic therapy with intravenous (IV) bisphos-

phonates, along with strategies to protect mobility and decrease

pain. In this article, Lori Case, RN, BSN, OCN, discusses important con-

siderations in the administration and monitoring of bisphosphonate

therapy, including the prevention and management of osteonecro-

sis of the jaw (ONJ) and other adverse events (AEs). She also summa-

rizes best practices in surgical, physical, and educational interven-

tions that can be used to support bone health in patients with

myeloma.

How do you monitor and manage the renal AEs associated with IVbisphosphonate therapy?

For patients with MM, we have 2 choices for IV bisphosphonate therapy:zoledronic acid and pamidronate. Although generally well tolerated, theseagents can cause kidney function to deteriorate.1,2 Therefore, one concern isthe safe administration of bisphosphonate therapy in patients with renalinsufficiency. In the case of zoledronic acid, dosage must be reduced from thestandard dose of 4 mg for patients whose baseline creatinine clearance(CrCl) is <60 mL/min; use of this drug in patients with severe renal impair-ment is not recommended.1 In addition, zoledronic acid should always beadministered over 15 minutes or longer, to prevent any renal issues that mayarise during the infusion process.1

With pamidronate, caution is advised in patients with marked renalimpairment (serum creatinine [SCr] >3.0 mg/dL).2 Treatment should bewithheld in the event of renal deterioration, which can be defined as anincrease in SCr of �0.5 mg/dL in patients with normal baseline creatinine or�1 mg/dL in patients with an abnormal baseline.2 Doses can generally beresumed when SCr levels return to within 10% of baseline value.Pamidronate dose can be reduced from the standard 90 mg when the SCrlevel is >3.0 mg/dL or the estimated CrCl is <30 mL/min.3 This drug is usu-ally administered over 4 hours, but the infusion time can be increased to 6hours or longer to minimize renal risk.3

A best practice before and during bisphosphonate therapy is frequent mon-itoring of renal function. Prior to each infusion, we check SCr in order to prop-erly dose the bisphosphonate. We also conduct a panel of serum chemistries atleast once every 3 to 4 months. This assessment evaluates potential metaboliceffects of bisphosphonates—hypophosphatemia, hypokalemia, and hypomag-nesemia. If we do discover any abnormalities, we can replace the levels withoral supplementation.

How do you manage the flu-like symptoms that may occur follow-ing a bisphosphonate infusion?

Some patients experience fever, chills, flushing, and body aches resultingfrom a bisphosphonate infusion.1,2 For instance, with zoledronic acid andpamidronate at standard doses, approximately 44% and 33% of patients,respectively, report fever.1,2 We inform our patients that they may experiencethese flu-like symptoms during therapy, so that they are not caught off-guard.We also encourage them to call the clinic if any of these AEs occur. Typically,we recommend acetaminophen to manage mild-to-moderate flu-like symp-toms; use of this medication was reported effective for this indication in a2012 study.4 We do not recommend nonsteroidal anti-inflammatory drugs forMM patients because of the potential for renal toxicity.

For patients with severe flu-like symptoms, we have also utilized dexa -methasone at very low doses. Since many patients are receiving a steroid aspart of antimyeloma therapy, we will try to have them coordinate their week-ly dose on the same day that they are scheduled for their bisphosphonatetreatment, which may prevent or minimize flu-like symptoms.

What strategies do you use to reduce the risk of ONJ related to IVbisphosphonate therapy?

At baseline and at every visit, we look inside the mouth for ulcers, bumps,or protrusions. If individuals wear dentures, we ask them to remove theseappliances so we can closely examine the gums; we also try to ascertainwhether dentures are fitting well. Poorly fitting dentures are a risk factor forONJ, as are invasive dental procedures such as extractions.5 Evidence alsosuggests that periodontal disease may increase the risk of ONJ.6 Thesepotential risk factors can be addressed by ensuring that all patients receive athorough dental checkup and cleaning, and take care of any extractions,dental implants, or other invasive procedures before they start bisphospho-nate therapy.3,7

We educate our patients to continue twice-yearly checkups and cleanings,and to inform their dentists of any and all treatments they are receiving. Ifan invasive dental procedure is recommended during bisphosphonate thera-py, we ask that the dentist call our office before scheduling the procedure, todiscuss risks and benefits. We encourage our patients to call us every timethey are planning to go to the dentist, to reiterate the importance of avoidingspecific procedures.

Prevention of ONJ is critical, because once it occurs, healing—if it hap-pens at all—is a slow process.8,9 We send some patients with ONJ to our oralsurgeon for assessment. The surgeon may be able to smooth jagged boneedges and make the area more comfortable. We prescribe chlorhexidine

Lori Case, RN, BSN, OCNNurse CoordinatorIU Simon Cancer CenterIndianapolis, IN

Poorly fitting dentures are a risk factor for ONJ, as are invasive dental procedures such as extractions.

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www.TheOncologyPharmacist.com38 DECEMBER 2012 I VOL 5, NO 8

CONSIDERATIONS IN MULTIPLE MYELOMA

mouthwash to keep the area clean, and we use antibiotics for infection.7 Datasuggest that combining antibiotic therapy with oral surgery (eg, curettage,sequestrectomy) may be the most effective approach to ONJ, especially ifaugmented with a novel treatment called O2 hyperbaric/ozonotherapy, whichlocally increases the oxygen content of blood (Figure 1a and 1b). However,even the best available interventions fail to resolve ONJ fully in a significantproportion of patients.9

In addition to bisphosphonate therapy, what strategies can beused to prevent or minimize skeletal-related events (SREs)?

Nonpharmacologic management to prevent SREs and to minimize theirpain and impact on function must be highly individualized. The first thingfor nurses to do is to speak with the physicians about limitations and inter-ventions appropriate to the patient. Taking into consideration the individ-ual’s health status, level of pain, location of osteolytic lesions, and psycho -social profile, we can devise a plan that may include some or all of thefollowing: weight-bearing exercises; strength training; kyphoplasty10,11; phys-ical therapy; localized, palliative radiation therapy; nutritional counselingand calcium/vitamin D supplementation; reduction of alcohol and caffeine(which interfere with calcium and vitamin D absorption); elimination ofcontact sports; and a home-health intervention to minimize the risk of falls. We conduct yearly skeletal surveys in our patients, and will often adjust our

nonpharmacologic recommendations based on the results. Patients need to beeducated about their bone health. An annual skeletal survey can help illus-trate any skeletal changes that have occurred. If there are no changes, it canhelp them to see that therapy is working to prevent further bone damage.

ConclusionWhole-patient care in MM requires a commitment to bone health. Nurses

play a pivotal role in supportive therapy, including careful administration ofbisphosphonates, prevention and control of treatment-related AEs, and indi-vidualized nonpharmacologic regimens to protect against SREs, reduce pain,and maintain function. All of these work together to provide the best possi-ble quality of life for patients. �

References1. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; February 2011.2. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; April 2011.3. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinicalpractice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

4. Wark JD, Bensen W, Recknor C, et al. Treatment with acetaminophen/paracetamol or ibupro-fen alleviates post-dose symptoms related to intravenous infusion with zoledronic acid 5 mg.Osteoporos Int. 2012;23:503-512.

5. Kyrgidis A, Arora A, Lyroudia K, Antoniades K. Root canal therapy for the prevention ofosteonecrosis of the jaws: an evidence-based clinical update. Aust Endod J. 2010;36:130-136.

6. American Association of Oral and Maxillofacial Surgeons Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaws. American Association of Oral and Maxillofacial Surgeons;2006. http://www.aaoms.org/docs/position_papers/osteonecrosis.pdf. Accessed December 4, 2012.

7. Shannon J, Shannon J, Modelevsky S, Grippo AA. Bisphosphonates and osteonecrosis of thejaw. J Am Geriatr Soc. 2011;59:2350-2355.

8. Badros A, Terpos E, Katodritou E, et al. Natural history of osteonecrosis of the jaw in patientswith multiple myeloma. J Clin Oncol. 2008;26:5904-5909.

9. Andriani A, Petrucci MT, Caravita T, et al; on behalf of GIMEMA. Evolution of bisphospho-nate-related osteonecrosis of the jaw in patients with multiple myeloma and Waldenstrom’smacroglobulinema: a retrospective multicentric study [published online ahead of print March23, 2012]. Blood Cancer J. doi:10.1038/bcj.2012.9.

10. Berenson J, Pflugmacher R, Jarzem P, et al; for the Cancer Patient Fracture Evaluation (CAFE)Investigators. Balloon kyphoplasty versus non-surgical fracture management for treatment ofpainful vertebral body compression fractures in patients with cancer: a multicentre, randomisedcontrolled trial. Lancet Oncol. 2011;12:225-235.

11. Kristinsson SY, Minter AR, Korde N, Tan E, Landgren O. Bone disease in multiple myelomaand precursor disease: novel diagnostic approaches and implications on clinical management.Expert Rev Mol Diagn. 2011;11:593-603.

Figure 1a and b. Efficacy of treatments for ONJ (N=53).9

Patients (%)

80

70

60

50

40

30

20

10

0

*Concomitant O2 hyperbaric/ozonotherapy was used in 16 patients who also received antibiotics and curettage and in 12 patients who also received antibiotics and sequestrectomy. This group of patients isincluded in the data in Figure 1a.

ONJ indicates osteonecrosis of the jaw.

Antibiotics Alone Antibiotics + Antibiotics +(n=19) Curettage (n=22) Sequestrectomy

(n=12)

Resolution of ONJ

Improvement in ONJ

No change/progression in ONJ

10.5%

52.6%

36.9%

45.5%40.9%

13.6%

66.6%

16.7% 16.7%

Patients (%)

80

70

60

50

40

30

20

10

0With O2 Therapy Without O2 Therapy

(n=27) (n=26)

Resolution of ONJ

Improvement in ONJ

No change/progression in ONJ

44.4%48.2%

7.4%

30.8% 30.8%

38.4%

a. Antibiotics vs antibiotics + oral surgery b. Concomitant O2 hyperbaric/ozonotherapy* vs no concomitant O2 hyperbaric/ozonotherapy

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DECEMBER 2012 I VOL 5, NO 8 39www.TheOncologyPharmacist.com

www.TheOncologyPharmacist.com40 DECEMBER 2012 I VOL 5, NO 8

Conference News: ESMO

Highlights From the european Society for medical Oncology 2012 CongressBy Alice Goodman

Adding bevacizumab to chemo therapyregimens improved response rates andprogression-free survival (PFS) in pa-tients with platinum-resistant recurrentovarian cancer, according to an ex-ploratory analysis of the phase 3 AURE-LIA trial (Abstract LBA26).1 The studydesign allowed treatment with 1 of 3chemo therapy regimens (weekly pacli-taxel, pegylated liposomal doxorubicin[PLD], or topotecan). Bevacizumab improved PFS in the

overall analysis of the trial (poolingdata from the 3 different regimens).Median PFS was 10.4 months for beva-cizumab plus chemotherapy versus 3.9months for chemotherapy alone.“Bevacizumab combined with chemo -

therapy should be considered a newstandard option for platinum-resistant

recurrent ovarian cancer,” stated leadauthor Andres M. Poveda, MD,Fundación Instituto Valenciano deOncología, Valencia, Spain. The exploratory analysis looked at

each of the 3 regimens and found that

weekly paclitaxel plus bevacizumab hadsuperior results. As stated above, medi-an PFS was 10.4 months when beva-cizumab was added to weekly paclitaxel

versus 3.9 months for weekly paclitaxelalone. In the PLD cohort, median PFSwas 5.4 months versus 3.4 months, respectively. In the topotecan cohort,median PFS was 5.8 months versus 2.1months, respectively.

AURELIA randomized 361 patientswith platinum-resistant recurrent ovar-ian cancer treated with up to 2 prioranticancer regimens to chemotherapy

alone or chemotherapy plus bevacizu - mab. The chemotherapy regimen wasthe investigator’s choice among the 3regimens. Treatment was continueduntil unacceptable toxicity or progres-sive disease occurred.Overall response rates (ORRs) were

superior with the addition of bevacizu -mab, with the highest response ratesobserved in the weekly paclitaxel co-hort: 51.7% versus 28.8% for chemo -therapy alone. ORR was 18.3% and7.9%, respectively, for the PLD cohortand 22.8% and 3.3%, respectively, forthe topotecan cohort. No significant differences in toxicity

were observed, with the exception ofmore peripheral neuropathy in the week-ly paclitaxel cohort and more hand-footsyndrome in the PLD cohort.

Overall response rates were superior with the

addition of bevacizumab, with the highest response

rates observed in the weekly paclitaxel cohort.

Bevacizumab Plus Chemotherapy extends Survival in Platinum-Resistant Ovarian Cancer

Oncology experts from all over the globe arrived in Vienna, Austria, to attend the Euro pean Society for Medical Oncology (ESMO)

2012 Congress. Attendance broke all records, with 16,394 delegates, many of them from outside of Europe: 1116 from the United

States, 539 from Japan, 479 from China, 292 from Argentina, and 258 from Brazil. Following are some highlights from the

Presidential Symposia and papers proffered at the meeting.

Standard of Care for Soft Tissue CarcinomaSingle-agent doxorubicin remains thestandard of care as first-line treatmentfor unresectable or metastatic soft tis-sue sarcomas, according to results of a phase 3 trial conducted by EORTCand presented at the PresidentialSymposium during the ESMO 2012Congress (Abstract LBA7).2,3 Thisstudy is the latest in a string of trials at-

tempting to improve outcomes withdoxorubicin by adding other agents. Soft-tissue sarcomas are a heteroge-

neous group of tumors that are relative-ly rare. Overall incidence is approxi-mately 5 per 100,000, said Winette van der Graaf, MD, University ofNijmegen, the Netherlands. The com-plexity of the tumor types and the rela-

tive rarity of the tumors have made itchallenging to conduct clinical trials,she added. This study compared doxorubicin to

doxorubicin/ifosfamide plus growth fac-tor support in 455 patients aged 18 to60 years with locally advanced ormetastatic soft tissue sarcomas. Thisstudy used a higher dose of ifosfamide

(10 g/m2 over 4 days with growth factorsupport) than previous studies that eval-uated this combination.Treatment was continued every 3

weeks for a maximum of 6 cycles or untilthe development of progressive disease.At a median follow-up of 56 months,there was no significant difference be-tween the 2 treatment arms in overallsurvival (OS). Median OS was 14.3months with the combination of doxoru-bicin/ifosfamide versus 12.8 months withdoxorubicin alone; OS at 1 year was 60%and 51% for the 2 arms, respectively.Doxorubicin/ifosfamide achieved alonger progression-free survival: 7.4months versus 4.6 months, respectively(P = .003), and higher overall responserates—26.5% versus 13.6%, re spective-ly—but this came with a host of in-creased toxicity.Based on these results, van der Graaf

said that single-agent doxorubicin shouldremain the standard of care in the pallia-tive setting. The combination might beuseful for selected patients 60 years andyounger with large tumors.

���� ���������� �������� � ������ ����

SECOND ANNUAL CONFERENCE

July 26-28, 2013Hyatt Regency La Jolla • at Aventine

3777 La Jolla Village Drive • San Diego, California

��

• Melanoma• Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma• Squamous Cell Carcinoma • Merkel Cell Carcinoma

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DECEMBER 2012 I VOL 5, NO 8 41www.TheOncologyPharmacist.com

Conference News: ESMO

T-DM1, an antibody-drug conjugatelinking trastuzumab to potent chemo -therapy, extended survival, comparedwith lapatinib plus capecitabine, in ad-vanced HER2+ breast cancer in an updated analysis from the phase 3 EMILIA trial (Abstract LBA12).4At a median follow-up of about 20

months, T-DM1 reduced the risk ofdying by 32%, with a 6-month differencefavoring T-DM1. Median overall sur-vival (OS) (death from any cause) was30.9 months for T-DM1 versus 25.1months for lapatinib plus capecitabine(P <.0001).

Lead author Sunil Verma, MD,Sunnybrook Odette Cancer Centre,Toronto, Ontario, Canada, predictedthat T-DM1 would be an importanttreatment option for unresectable locallyadvanced or metastatic breast cancer. EMILIA was conducted at 213 sites in

26 countries. The study randomized 991patients with HER2+ advanced breastcancer who had been treated withtrastuzumab and a taxane in a 1:1 ratio toT-DM1 or lapatinib plus capecitabine. Final progression-free survival (PFS),

presented earlier at the 2012 AnnualMeeting of the American Society ofClinical Oncology, showed median PFSof 9.6 months with T-DM1 versus 6.4months with lapatinib plus capecitabine,a 35% reduction in the risk of progres-sion favoring T-DM1 (P <.0001).The OS data presented at ESMO were

from the second interim analysis, with adata cutoff of July 31, 2012, when morethan 50% of targeted survival events hadoccurred. Final OS data are expected in2014.Grade 3 or higher adverse events oc-

curred more frequently with lapatinibplus capecitabine: 57% versus 41% for T-DM1. Patients in the T-DM1 arm hada higher incidence of thrombocytopeniaand increased serum aminotransferaselevels, whereas those treated with lapa-tinib plus capecitabine had higher ratesof diarrhea, nausea, vomiting, and hand-foot syndrome. The rates of cardiac dys-function were very low and similar inboth treatment arms.

T-DM1 extended survival,

compared with lapatinib

plus capecitabine, in

advanced HER2+

breast cancer.

T-Dm1 SurvivalBenefit Confirmedin Advanced HeR2+Breast Cancer

������������

����*���������������3:00 pm - 7:00 pm Registration

5:30 pm - 7:30 pm Welcome Reception and Exhibits

�����������������7:00 am - 8:00 am Symposium/Product Theater

8:00 am - 11:45 am General Session I• Welcome to the Second Annual Conference of the Global Biomarkers Consortium—Setting the Stage for the Meeting

• Personalized Medicine in Oncology: The Future Is Now• Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies

• Biomarker-Defined Populations• Taking Stock of Molecular Oncology Biomarkers: Genomics, Proteomics,Imaging, Bioinformatics• Solid Tumors• Hematologic Malignancies• The Value Proposition of Real-Time Genomic Testing The Payer Perspective The Provider Perspective• Panel Discussion: The Value Proposition of Real-Time Genomic Testing• Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm General Session II • Molecular Subtyping of Solid Tumors• Molecular Subtyping of Hematologic Malignancies• Case Studies: Optimal Value-Based Use of Molecular Biomarkers in

Oncology: The Expert’s Perspective on How I Treat My Patients • NSCLC• Breast Cancer• Melanoma• Colorectal Cancer and Other GI Malignancies• Prostate Cancer• Multiple Myeloma• Leukemia• Lymphoma• MDS/Myelofibrosis

• Panel Discussion: Management Controversies and Accepted Guidelinesfor the Personalized Management of Solid Tumors and Hematologic Malignancies

4:30 pm - 6:30 pm Meet the Experts/Networking/Exhibits

���������������7:00 am - 8:00 am Symposium/Product Theater

8:00 am - 11:45 am General Session III• Review of Saturday’s Presentations and Preview of Today• Impact of Cancer Genomics on Advances in Cancer Therapy • Recent and Late-Breaking Clinical Trial Data

• Solid Tumors• Hematologic Malignancies

• Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care

• Tumor Board: Challenging Cases in Managing Solid Tumors (attendee-contributed cases)

• Tumor Board: Challenging Cases in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm General Session IV • Keynote Lecture: Making Personalized Medicine a Reality: The Realization

of Genomic Medicine• The Future of Personalized Medicine: A Systems Biology Approach

• Cost-Effective Technologies That Can Drive Therapeutic Decision Making• Panel Discussion: Can We Afford PMO? A Value-Based Analysis

• Practical Considerations in Incorporating PMO into Everyday Cinical Management

• Reimbursement Challenges: Guidence from a Payer• Closing Remarks

3:00 pm Departures

��������������The only global meeting dedicated to advancing the understanding of value and clinical impactof biomarker research in oncology. Guided by the expertise of leaders in this field, participants willreceive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

�����������This meeting will be directed toward medical oncologists and hematologists, pathologists, geneti-cists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, andgenetic counselors involved in the management of patients with solid tumors or hematologic ma-lignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

��������This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media,LLC, and Core Principle Solutions, LLC.

� ����������������������The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1Credits™. Physicians should claim only the credit commensurate with the extent oftheir participation in the activity. This activity has been planned and implemented in accordancewith the Essential Areas and policies of the Accreditation Council for Continuing Medical Educa-tion through the joint sponsorship of the Medical Learning Institute Inc and the Center of ExcellenceMedia, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Con-tinuing Medical Education to provide continuing medical education for physicians.

���������������������Medical Learning Institute IncProvider approved by the California Board of Registered Nursing, Provider Number 15106, for12.5 contact hours.

�������� ����������������The Medical Learning Institute Inc is accredited by the Accreditation Council for Phar-macy Education as a provider of continuing pharmacy education. Completion of thisknowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing

pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

����������������Upon completion of this activity, the participant will be able to:

• Assess emerging data and recent advances in the discovery of molecular biomarkers andtheir impact on the treatment of patients with solid tumors or hematologic malignancies

• Discuss the role of molecular biomarkers in designing personalized therapy for patients withsolid tumors or hematologic malignancies

• Outline the practical aspects of integrating molecular biomarkers into everyday clinicalpractice in the treatment of patients with cancer

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CONFERENCE REGISTRATIONEARLY BIRD

REGISTRATION NOW OPEN!

www.globalbiomarkersconsortium.com$125.00 until December 31, 2012

Professor Rob Coleman, MBBS, MD, FRCPYorkshire Cancer Research Professor of Medical OncologyDirector, Sheffield Cancer Research CentreAssociate Director, National Institute for Health Research Cancer Research NetworkDepartment of Oncology, Weston Park HospitalSheffield, United Kingdom

Jorge E. Cortes, MDChair, CML and AML SectionsD.B. Lane Cancer Research Distinguished Professor for Leukemia ResearchDepartment of Leukemia, Division of Cancer MedicineThe University of Texas MD Anderson Cancer CenterHouston, TX

*Agenda is subject to change.

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MEDICINE IN ONCOLOGY ��

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�����������������������������Grant requests are currently being reviewed by numerous supporters. Support will be acknowl-edged prior to the start of the educational activities.

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ANNUAL CONFERENCE

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Initiative Improves Pain Control in Several Countries The major barriers to implementing ad-equate pain control for cancer patientson a global scale are restrictive govern-ment regulations and lack of access tosupplies of morphine. Individual coun-tries may lack morphine suppliers, andregulations in countries where mor-phine is available may prevent doctorsfrom prescribing doses strong enough toalleviate pain and suffering.

Although a number of internationalorganizations have made strong state-ments hoping to address the problem ofinadequate pain control in cancer pa-tients, this has not led to widespread re-form in allowing access to standard care,said Kathleen Foley, MD, MemorialSloan-Kettering Cancer Center in NewYork City, at the ESMO 2012 Congress.5These organizations include the Council

of Europe, International NarcoticsControl Board, United Nations, WorldHealth Or g a nization, Commission onNarcotic Drugs, and Human RightsWatch, among others.Foley believes that the problems are

solvable, but mainly on a country-by-country basis. She reported success storiesfor programs funded by the International

Continued on page 42

www.TheOncologyPharmacist.com42 DECEMBER 2012 I VOL 5, NO 8

Conference News: ESMO

Continued from page 41

Initiative Improves Pain Control in Several Countries

Palliative Care Initiative. The modelfor these programs is to identify a “na-tional champion” for cancer pain con-trol within a country, perform a needsassessment, hold a stakeholders meet-ing, develop task forces, and then for-mulate a palliative care concept for

that country. So far, this has been donein 20 countries. “We use international documents with

symbolic language to guide this policy ata country level. These passionate cham-pions are driving this movement withineach country,” she told listeners.

In 2012, the International PalliativeCare Initiative funded fellowships inIndia, Bangladesh, Sri Lanka, Albania,Kyrgyzstan, and Ukraine. Fellows workat the University of Wisconsin inMadison to learn the model describedabove.

Success Stories In Romania, 35-year-old restrictive poli-cies were changed. Now there are no lim-its on daily morphine dose or patient di-agnosis. “Past policies were burdensomefor patients, and physicians, and these arenew beginnings,” Foley said.In Colombia, a new palliative care law

was passed in 2009, and as a result of thatlaw, each district of the country has 1pharmacy that can provide opioids 24hours a day.In Guatemala, efforts are ongoing to

bring a morphine supply from GuatemalaCity to rural areas and to provide furthereducation to legislators, physicians, andpatients.“It’s hard to believe, but in 2012, the

first injectable morphine prescriptionwas written in Guatemala, at a hospitalwhere bone marrow transplant is avail-able,” she said. In Nigeria, the government is now sup-

portive of getting cancer patients accessto pain control. In Serbia, a pain policyfellow is working with the government,which has adopted a pain policy statingthat opioids are essential for pain relief.In Armenia, a policy is in place, but asupplier still needs to be found. “Uganda is a great success story,”

she continued. The initiative created astrategic health plan, added liquid mor-phine to the essential list, adopted newguidelines, and authorized prescriptionby nurses. Seventy-nine providers havebeen trained.“We argue that no country should be

allowed to enter the EU [EuropeanUnion] unless they have opioids and apain policy for cancer care. The solutionis to identify champions at a country leveland work with them. We can do this,”Foley said. l

References1. Poveda A, Selle F, Hilpert F, et al. Weekly paclitaxel,pegylated liposomal doxorubicin or topotecan ± beva-cizumab in platinum-resistant recurrent ovarian cancer:analysis by chemotherapy cohort in the GCIG AURELIArandomised phase III trial. Presented at: European Societyfor Medical Oncology 2012 Congress; September 30,2012; Vienna, Austria. Abstract LBA26.2. van der Graaf W. Successful targeting of VEGFR in softtissue sarcomas. Presented at: European Society forMedical Oncology 2012 Congress; September 30, 2012;Vienna, Austria.3. van der Graaf WTA, Judson I, Verweij J, et al. Resultsof a randomised phase III trial (EORTC 62012) of singleagent doxorubicin versus doxorubicin plus ifosfamide asfirst line chemotherapy for patients with advanced ormetastatic soft tissue sarcoma: a survival study by theEORTC Soft Tissue and Bone Sarcoma Group. Presentedat: European Society for Medical Oncology 2012Congress; October 1, 2012; Vienna, Austria. AbstractLBA7.4. Verma S, Miles D, Gianni L, et al. Updated overall sur-vival results from EMILIA, a phase 3 study of trastuzumabemtansine (T-DM1) vs. capecitabine (X) and lapatinib(L) in HER2-positive locally advanced or metastaticbreast cancer (MBC). Presented at: European Society forMedical Oncology Congress; October 1, 2012; Vienna,Austria. Abstract LBA12.5. Foley K. A global policy approach to freedom from cancer pain. Presented at: European Society for MedicalOncology 2012 Congress; September 29, 2012; Vienna,Austria.

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CONQUERING THECANCER CARECONT I NUUM™

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A 6-part series

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Cancer is an illness associated with substantialphysical, emotional, social, and financial ram-ifications for affected individuals and their

families. In a significant number of cases, the diagnosisof cancer is either preceded by a periodof gradual, nonspecific symptoms ordiscovered by routine screening, andindividuals are then thrust into awhirlwind of diagnostic testing, in-vasive procedures, and complicatedtreatments with very little warning oropportunity to assimilate their circum-stances. Frequently, a multidisciplinaryapproach to treatment is necessary, re-quiring patients to engage with numer-ous medical teams comprising severaldifferent specialties, often in differentlocations. Many patients have beenrelatively healthy prior to the cancer event and there-fore are not sophisticated consumers of medical ser-vices. Consequently, it is incumbent on healthcareprofessionals to be able to facilitate patients’ transitioninto care in order to minimize their distress and maxi-mize their clinical outcomes.Challenges exist beyond the initial diagnosis and

treatment period as well. According to the NationalCancer Institute (NCI), more than 12 million individ-uals in the United States are living with a history of

cancer.1 More than half are living well beyond 5 yearsafter diagnosis. Women comprise a majority of long-term survivors due to the favorable outcomes withbreast, cervical, and uterine cancers.2 The number of

people living with a history of canceris projected to grow considerably overthe next 20 years for 2 major reasons.First, the number of Americans overage 65 is predicted to double betweenthe years 2000 and 2030.3 Conse-quently, as a disease primarily of olderadults, cancer will also increase. Sec-ond, as the effectiveness of cancertreatments improves, the number ofpatients cured of the disease will in-crease, and an even larger percentagewill be living longer with the diseasewhile receiving multiple “lines” of

therapy (first-line, second-line, etc) over time. Theoverall demand for oncology services is expected to in-crease by 48% by 2020, while the supply of oncologistswill increase by only 14% based on current patterns.4

These statistics underscore the need for a wide varietyof health professionals and other support personnel toplay a part in enabling each and every patient to re-ceive quality care that addresses all of their needsthroughout the continuum of the illness. Patients de-fine quality of care based on their ability to5:

Challenges Patients Face in Cancer Care:Implications for the Healthcare TeamLea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University

Lea Ann Hansen,PharmD, BCOP

CONQUERING THECANCER CARECONT I NUUM™

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The past decade has seen a dramatic upsurge inthe utilization of specialty pharmacies for alltypes of therapeutic modalities, including

those for cancer. The cost of cancer care may rise from

about $125 billion in 2010 to $207 bil-lion by the end of the decade. By thattime, specialty drugs are predicted toaccount for 2 of every 5 pharmacy dol-lars spent.1 The purpose of this articleis to explain the evolution of the spe-cialty pharmacy and the functions itcan serve in the treatment of cancerand to discuss the potential benefitsand challenges of the system from thepoint of view of the patient.

The Evolution of SpecialtyDrugs and SpecialtyPharmacyThere is a lack of consensus on the definition of a

specialty drug. The Food and Drug Administration has

not defined the term. Initially, the label was virtually

synonymous with biotechnology products, either pro-

teins produced by recombinant DNA techniques or

monoclonal antibodies produced with cellular hy-

bridomas, but this is no longer the case. The 2007

Medicare Modernization Act defined a specialty drug

as “a part D drug with plan-negotiated prices that ex-

ceed $400 per month.”2 Other health plans may de-

fine specialty drugs differently. In general, they arehigh cost, administered by injectionor infusion, require special handling,or are used for complex diseases thatrequire special monitoring. In on-cology, however, the most commonagents dispensed by a specialty phar-macy provider (SPP) are the newertargeted agents that are adminis-tered orally. After a systematic re-view of the literature, one academicgroup of authors proposed the mostcritical descriptors of a specialtydrug to be3:• High cost (prescriptions cost more than $600 per month)

• Difficult medication delivery, such as— Special handling requiring strict temperature

control— Restricted location for medication preparation

or distribution site— Restricted location for medication adminis-tration

Convenience, Challenges, and Cost Containment:

The Impact of Specialty Pharmacies on

Patient CareLea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University

Lea Ann Hansen,PharmD, BCOP

CONQUERING THECANCER CARECONT I NUUM™

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The predominant

scenario for systemic treatment

of cancer has traditionally involv

ed administra-

tion of intravenous chemother

apy by highly

trained personnel who closely m

onitored the patient.

When these procedures took place i

n an

oncologist’s office or in a hospit

al infu-

sion center, extensive education

of the

patient and family was possible

. More

recently, however, an increasing

ly com-

mon situation involves the use of

one or

more oral medications and self-a

dmin-

istered subcutaneous therapies

in the

home environment. The direct r

espon-

sibility for drug acquisition and

admin-

istration is shifting to the patie

nts and

their social support network, i

f avail-

able. At the present time, more t

han 20

oral medications are FDA appro

ved for

the first-line treatment of cance

r (Table 1). In addition,

a number of other oral agents ar

e used for tumors that

have relapsed or are refractory to

initial treatment. Ac-

cording to the National Compre

hensive Cancer Net-

work, approximately 25% of a

ll compounds in the

oncology research and developm

ent pipeline are admin-

istered orally, so the trend is like

ly to continue.1

With this shift in responsibility co

mes the increased

possibility that anticancer medic

ations may not be ad-

ministered correctly, especially fo

r regimens that require

repeated dosing. Overall estimat

es of adherence to long-

term oral medication regimens r

ange from 17% to 80%,

with an average around 50%.

2-4 A common assumption

that adherence to oral antica

ncer agents would be

higher, due to the severity of

the disease, has been

proven untrue. Studies indica

te the

adherence rates for cancer therap

y are

15% to 97%.5 Nonadherence

has

been associated with worse out

comes

in a number of disease states and

with

increased physician visits, higher

hos-

pitalization rates, longer hospital

stays,

disease worsening, and increased

mor-

tality.6 Approximately one-th

ird to

two-thirds of all medication-r

elated

hospitalizations are due to medic

ation

nonadherence—at a cost of $100

bil-

lion annually.7 The purpose of t

his ar-

ticle is to describe general con

cepts

regarding patient adherence and

the research related to

adherence to cancer treatment.

The incidence, risk fac-

tors, and consequences of this pr

oblem will be reviewed.

The last article in this series wil

l subsequently examine

the best practices for maximizing

adherence and clinical

outcomes.

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Adherence was defined by the W

orld Health Organ-

ization in 2003 as the “extent t

o which a person’s be-

havior, taking medication, fol

lowing a diet, and/or

Impact of Nonadherence to Cancer Therapy

Lea Ann Hansen, PharmD, BCOP

Associate Professor, Virginia Commonwealth University

Lea Ann Hansen,

PharmD, BCOP

CONQUERINGTHE

CANCER CARE

CONT I NUUM™

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The previous installment in this cancer care se-ries examined the growing importance of oraltherapies for the treatment of cancer and the

implications of patient adherence on its success. At thepresent time, more than 20 oral med-ications are approved by the Food andDrug Administration (FDA) for first-line treatment of cancer. A number ofother oral agents are used for tumorsthat have relapsed or are refractory toinitial treatment, and about 25% of theoncology research pipeline consists oforal compounds.1 This is in addition toself-administered subcutaneous thera-pies for the home environment thatare under FDA review. When cancer medications are ad-ministered orally in the home envi-ronment rather than in the clinic or hospital, the rates

of adherence range from 15% to 97%.2 For example,at the end of the first year of treatment with adjuvanthormonal treatment (AHT) for early-stage breast can-cer, only 79% of patients remained on therapy withouta gap exceeding 60 days and 85% without a gap ex-ceeding 180 days. By year 5, only 27% and 29% re-mained without 60- and 180-day gaps, respectively.3In another study of AHT, patients with a medica-

tion possession ratio (MPR) >80% had a statisticallysignificantly higher 10-year survival rate than those

with a lesser MPR (82% vs 78%).4 (MPR is a metricderived from electronic prescription records based onrefill patterns over time, and 80% is an arbitrary cutpoint for adherence used by many investigators.) Thesame study found survival at 10 yearsto be 81% for those who continuedtherapy versus 74% for those whohad discontinued it. Nonadherencehas also been shown to produce sub-stantial detriment in clinical out-comes in chronic myeloid leukemiaand childhood acute lymphoblasticleukemia.5-8 For each of these disor-ders, prolonged oral therapy hasbeen the standard of care for adecade or more. It is likely that neg-ative consequences of nonadherencewith other oral cancer medications

will be documented in the future as their role in ther-apy matures. The purpose of this article is to discussthe results of available research on maximizing adherence and suggest best practices to improve clin-ical outcomes.

� ���������������������������������� �������Direct communication with all patients about their

personal barriers to taking daily therapy for a prolongedperiod is an important aspect to maximizing adher-

Best Practices in Maximizing Adherence to Cancer Therapy

Lea Ann Hansen, PharmD, BCOPAssociate Professor, Virginia Commonwealth University

Lea Ann Hansen,PharmD, BCOP

CONQUERING THECANCER CARECONT I NUUM™

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The publishers of The OncologyNurse-APN/PA, The OncologyPharmacist, and PersonalizedMedicine in Oncology are proud to present our 2nd annualConquering the Cancer CareContinuum series. Upcoming topics include:

• Palliation• Pain management• Hospice care • Treatment planning• Survivorship care• Biosimilars in supportive care

TO VIEW THE SERIES ONLINEPLEASE LOG ON TO:

2ND ANNUAL View the

series online at

TheOncologyPharmacist.com

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BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

Docetaxel Injection, USPFor 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

docetaxel at 100 mg/m2 (5.1)

treatment cycle (8.6)

< 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4)

dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4)

polysorbate 80 (4)

(5.5)

CONTRAINDICATIONS

3

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, www.fda.

gov/medwatch

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

INDICATIONS AND USAGE

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact

at ProductComplaintsPP@hospira.com, or FDA at www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 09/2011

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

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

Oxaliplatin for Injection,

Oxaliplatin Injection,solution for intravenous use

Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONSSee full prescribing information for complete boxed warning.

Anaphylactic reactions to Oxaliplatin have been

administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1)

INDICATIONS AND USAGE

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Hospira

See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling.

Revised: 04/2011

Zydus Hospira

Hospira, Inc. Manufactured for:Hospira, Inc.

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

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045 P12-3707-11.125x14.125-Jul., 12

For more information, contact your

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

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160 mg/16 mL multiple-dose vial

80 mg/8 mL multiple-dose vial

20 mg/2 mL single-dose vial

See Black Box Warning Below

DOCETAXEL INJECTION (10 mg/mL)

2 g/52.6 mL single-dose vial

1 g/26.3 mL single-dose vial

200 mg/5.26 mL single-dose vial

GEMCITABINE INJECTION(38 mg/mL)

50 mg/10 mL single-dose vial

100 mg/20 mL single-dose vial

OXALIPLATIN INJECTION(5 mg/mL)

See Black Box Warning Below

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Docetaxel:WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTIONOxaliplatin:WARNING: ANAPHYLACTIC REACTIONS

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