August 2012, Vol 5, No 5

AUgUst 2012 www.theOncologyPharmacist.com VOl 5, NO 5

The University of Arizona Cancer Center (UACC) in Tucson is 1of 41 National Cancer Institute (NCI)-designated comprehen-sive cancer centers in the United States. Called a “high-per-

forming” center by US News & World Report, the center has 29 bedson a dedicated oncology wing, plus beds in surgery, gynecology,and pediatric units. The total number of beds in the facility is 487. UACC has 2 outpatient clinics: UACC North Campus is for

clinic/office visits, infusions, and Mohs surgery; and UACC Orange

CANCER CENTER PROFILE

Continued on page 7

Drug Shortage

Exploring the Drug

Shortage Crisis . . . . . . . . . . . . . . . . . . 14Quantifying the Drug

Shortage: One Center’s

Experience . . . . . . . . . . . . . . . . . . . . . . 15Complimentary Ce . . . . . . . . . 16Considerations in Multiple

Myeloma—Ask the Experts:

Maintenance Settings

oral onColytiCS . . . . . . . . . . . 24Updates on Oral ChemotherapyAdherence—Where Are We Today?

ConferenCe newS: aSCo 2012

Olanzapine Effective Antiemetic

for Breakthrough CINV . . . . . . . . . . 26Duloxetine in Peripheral

Neuropathy . . . . . . . . . . . . . . . . . . . . . 26Ginseng Improves Cancer-

Related Fatigue . . . . . . . . . . . . . . . . . 27

I N S I D E

At the recent 2012 symposium ofthe Multinational As sociationof Supportive Care in Cancer

(MASCC), held in New York City,experts discussed a wide range of topicsrelated to management of treatment-induced side effects. Below are somehighlights from the MASCC annual symposium.

Management of FebrileNeutropeniaAdvances over the past few decadeshave led to reduced morbidity and mor-tality from chemotherapy-induced fe -brile neutropenia (FN). FN was onceconsidered fatal, but in the modern era,mortality is about 5% and FN-related

CONFERENCE NEWS: MASCC

Advances in SupportiveCare By Alice Goodman

The biggest newsmaker at the 2012Annual Meeting of the AmericanSociety of Clinical Oncology

(ASCO) was a compound whose nameand actions sound practically missilelike:T-DM1. Because of its highly targetedand potent effect that spares surrounding

healthy tissue, T-DM1 not only haspotent antitumor effects but is also verywell tolerated.Trastuzumab emtansine (T-DM1) is

part of an emerging class of drugs calledantibody-drug conjugates (ADCs) thatlink a monoclonal antibody (in this case,

BREAST CANCER

T-DM1 in Metastatic BreastCancerIt’s Just the Beginning for an Exciting New Class

of Agents

By Caroline Helwick

Continued on page 4

Continued on page 9

Continued on page 25

RENAL CELL CARCINOMA

Quality of Life Drives PatientPreference for Metastatic RenalCell Carcinoma DrugBy Wayne Kuznar

The surprising results of a random-ized trial on patient preference forone cancer therapy over another

show that patient-reported quality-of-life(QOL) differences influence treatmentpreference far more than physicians hadimagined, suggested researchers at the2012 Annual Meeting of the American

Society of Clinical Oncology, held inChicago, Illinois.In a double-blind, crossover trial, 169

patients with metastatic renal cell carci-noma (mRCC) were randomized 1:1 to10 weeks of 800 mg of pazopanib or 50mg of sunitinib as first-line cancer treat-ment; after a 2-week washout period,

©2012 Green Hill Healthcare Communications, LLC

Daniel Butcher, Outpatient Oncology Pharmacy Supervisor, and Susan Vande Geest, Clinical StaffPharmacist, at the University of Arizona Cancer Center.

Photo courtesy of the University of Arizona Cancer Center.

University of Arizona CancerCenterThe Expanding Role of the Oncology Pharmacist

By Alice Goodman

APPROVED FO

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SUBCUTANEO

US AND IV

ADMINISTRAT

ION

w

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1

VELCADEHCP.COM

If you define value as an overall survival advantage:VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE

At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; 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 $1,471 per 3.5-mg vial as of January 2012

Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

VELCADE Indication and Important Safety InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment

Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated

Closely monitor patients with risk factors for, or existing heart disease

Acute diffuse infiltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement

Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus

Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONSMost commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

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

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233).

*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed.

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.

V

1 6 5:28 PM

trastuzumab) to a cytotoxic agent (inthis case, a potent antimicrotubuleagent DM1 [a derivative of maytan-sine]).“First and foremost, the design of an

ADC centers on the selection of anantigen that is tumor specific andaccessible to antibody binding at the

tumor cell,” explained Howard A.Burris III, MD, of the Sarah CannonResearch Institute in Nashville,Tennessee.T-DM1, with its ability to bind

HER2 with the same affinity astrastuzumab, maintains the activity oftrastuzumab in addition to providing

intracellular delivery of the antimicro-tubule agent DM1. Presumably, thebinding of T-DM1 to HER2 receptorsleads to receptor internalization, fol-lowed by lysosomal degradation.Activated DM1 is then released fromthe lysosome into the cellular cyto-plasm, which inhibits microtubule

assembly and causes cell death, Burrisexplained at an educational session onADCs.Potent cytotoxic agents are necessary

for maximizing the role of the drug con-jugates, a requirement that maytansinefills; however, its toxicity was prohibi-tive. Researchers recently im proved thetherapeutic index through conjugationwith trastuzumab, leading to the devel-opment of its derivative, DM1. The invitro cytotoxicity of DM1 is 10 to 200times greater than that of taxanes. Thecompound also requires a highly stablelinker: heterobifunctional reagent, N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

EMILIA Shows the Drug’s PotentialAt the ASCO plenary session, investi-gators reported early results of the inter-national phase 3 EMILIA study of T-DM1 in metastatic breast cancerpatients (Abstract LBA1).In a population of 991 advanced or

metastatic patients who had alreadyreceived trastuzumab and taxanes, treat-ment with T-DM1 was associated withan approximately 30% increase in pro-gression-free survival (PFS) compared

www.TheOncologyPharmacist.com4 AUGUST 2012 I VOL 5, NO 5

Breast Cancer

Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE 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 to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. 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 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% 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 benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 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, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).In the phase 3 VELCADE + melphalan and prednisone study 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 events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).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 events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) 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. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.USE IN SPECIFIC POPULATIONS:Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0095 6/12

T-DM1, with its ability to

bind HER2 with the same

affinity as trastuzumab,

maintains the activity

of trastuzumab in

addition to providing

intracellular delivery

of the antimicrotubule

agent DM1.

T-DM1 in Metastatic Breast Cancer Continued from cover

Continued on page 8

Kimberly L. Blackwell, MD, at theASCO 2012 Annual Meeting.

Photo © ASCO/Todd Buchanan 2012.

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,BSBioPharma Partners LLCNew York, 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 AUGUST 2012 I VOL 5, NO 5 5

PUBLISHING STAFF

Senior Vice President, Sales & MarketingPhilip Pawelko

[email protected]

PublisherJohn W. Hennessy

[email protected]

Director, Client ServicesJoe Chanley

[email protected]

Editorial DirectorKristin Siyahian

[email protected]

Managing EditorKristen Olafson

[email protected]

Quality Control DirectorBarbara Marino

Production ManagerStephanie Laudien

Business ManagerBlanche Marchitto

[email protected]

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Circulation [email protected]

Editorial Contact:Telephone: 732-656-7935

Fax: 732-656-7938

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 AUGUST 2012 I VOL 5, NO 5 www.TheOncologyPharmacist.com

In this issue of The Oncology Pharmacist (TOP), wecontinue our coverage of the news from the 2012Annual Meeting of the American Society of Clinical

Oncology (ASCO). Some of the most exciting newsinvolves trastuzumab emtansine (T-DM1), part of anemerging class of targeted agents called antibody-drugconjugates. The promising early results have excitedmany healthcare professionals, and we at TOP will befollowing the results of the clinical trials involving T-DM1. The drug shortage situation was also addressed atASCO, and we report on the experience of a New Yorkcancer center where “about 10% of the patients…treat-ed had an actual change in treatment,” according to oneof the researchers who presented the results of the study.

This issue starts our coverage of the MultinationalAssociation of Supportive Care in Cancer InternationalSymposium, held in July in New York City. Our coverageincludes acknowledgment that diarrhea is a problematicside effect for patients even in the era of molecularly tar-geted treatments.Betty Chan, PharmD, BCOP, provides an update of oral

chemotherapy adherence and notes the lack of a “goldstandard” definition of adherence. Be sure to visit theTOP Web site at www.TheOncologyPharmacist.com toview the table that accompanies her article. The tablesummarizes information about lab monitoring, commonside effects, and instructions for patient education forsome targeted oral chemotherapy agents. �

From the Editors

Patrick Medina, PharmD, BCOPEditor-in-Chief

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

Noteworthy Numbers

In 2012, an estimated73,510 adults in the UnitedStates (55,600 men and17,910 women) will bediagnosed with bladdercancer. Approximately14,880 deaths (10,510 menand 4370 women) willoccur from this disease.

Bladder cancer rarelyoccurs in patients underthe age of 40 years. In fact,about 9 out of 10 peoplewith this cancer are olderthan 55, and the averageage at the time of diagnosisis 73 years.

A man’s chance of devel-oping bladder cancer during his lifetime isabout 1 in 26. A woman’schance of being diag-nosed with this cancer isabout 1 in 86.

Whites are diagnosed withbladder cancer almosttwice as often as blacks,and Hispanics have aneven lower incidence ratethan blacks.

About half of those diag-nosed with bladder cancerhave nonmuscle-invasive/superficial urothelial carcinoma, and the 5-year survival rate is 98%.

Approximately 35% of blad-der cancer patients have atumor that is invasive buthas not yet spread outsidethe bladder. The 5-year sur-vival rate for these patientsis 75%.

For the more than 500,000people in the United Stateswho are survivors of thiscancer, the American

Urological Association rec-ommends patient assess-ment every 3 months in thefirst 2 years after initialdiagnosis followed by every6 months for the subse-quent 2 to 3 years, and thenannually thereafter.

Sourceswww.cancer.org/Cancer/BladderCancer/DetailedGuide/bladder-cancer-what-is-cancer; www.cancer.net/patient/Cancer+Types/Bladder+Cancer?sectionTitle=Statistics; www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/bladcan07/chapter1.pdf.

For the RecordIn the June issue of The OncologyPharmacist, the im provement in overallsurvival (OS) and radiographic progres-sion-free survival (PFS) data presented inthe Androgen Blockers Score Big inProstate Cancer news brief was incor-rect. With respect to enzalutamide, theimprovement in OS is 4.8 and theimprovement in PFS is 5.4 comparedwith placebo. We apologize for the error.

Although the rates of bladder cancer incidence and bladder cancer deaths have been fairly stable over the

past 20 years, the disease is still just as serious and deadly. In an effort to learn more about it, let’s take

a closer look at bladder cancer, the fourth most common cancer diagnosed in men.

AUGUST 2012 I VOL 5, NO 5 7www.TheOncologyPharmacist.com

Cancer Center Profile

Grove Campus offers clinic/office visits,infusions, and radiation oncology.Surgery and radiation oncology servicesare also offered at the UniversityCampus hospital center. In the fiscal year of 2011, 8560

patients were treated at UACC forsolid tumor, soft tissue, and skin andblood cancers. UACC is best knownfor its specialties: lymphoma, skin can-cer and melanoma, gastrointestinalcancer, gynecologic cancer, and breastcancer. UACC encompasses 11 multi-disciplinary clinics for major diseasesites, as well as a separate clinic forhigh-risk cancer genetics.Research is a major focus at UACC.

Currently, more than 200 clinical trialsare open for enrollment at UACC.These include: • Study to determine if ursodeoxy-cholic acid (a natural bile acid) canreverse the cellular damage ofBarrett’s esophagus.

• Research to see if taking high-dosevitamin D (cholecalciferol) twice aweek for 8 to 9 weeks prevents skincancer in people with sun damageand low levels of vitamin D.

• Study in breast cancer patients orwomen at high risk who are takingtamoxifen to determine if a sup-plement called diindolylmethane(DIM) can reduce risk of cancerre currence.

• I-SPY2 breast cancer trial, which isa collaborative study to obtaingenetic and biological markers fromindividual patients’ tumors to screenseveral promising treatments simul-taneously.

UACC is affiliated with St. Joseph’sHospital and Medical Center inPhoenix, and the Cancer Centers of Northern Arizona Healthcare inSedona. UACC’s research facility has73 laboratories and about 300 re -searchers drawn from the University ofArizona and other institutions.

The Oncology Pharmacist interviewedDaniel Butcher, PharmD, OutpatientOncology Pharmacy Supervisor, at theUniversity of Arizona Cancer Center toget his perspective on the role of theoncology pharmacist at his institution.

What approach does the Universityof Arizona Cancer Center take totreat people with cancer?Daniel Butcher (DB): We are an NCI-designated comprehensive cancer cen-ter that employs experts in all relatedfields. We use a multidisciplinary ap -proach for each patient to identify thebest treatment options.

How does your approach translateto better outcomes for yourpatients?

DB: The multidisciplinary approach isbased on the recognition that a diagnosisof cancer has physical and psychologicalramifications. With our pool of experts,we are well equipped to address theentire disease spectrum and to help withhealing. We provide active supportivecare for treatment-related and disease-related side effects as well as for healing,with psychological and family support.

What are you excited about in thefield of oncology?DB: Research. Since we are an NCI-des-ignated comprehensive cancer center,a lot of studies are being conducted atour site. Trying to keep up with currentstudies can be daunting. It is rewardingto watch agents that we have studiedmake it to the marketplace; for exam-ple, nab-paclitaxel (Abraxane) andipilimumab, an immunotherapy formelanoma. We can have disappointingresults as well. Initially, we had theimpression that CVAX would be aneffective treatment for melanoma, butthen the trial was halted becauseresults were not promising.

How has the role of the oncologypharmacist changed over the past 5 years?DB: It is exciting to see that the oncol-ogy pharmacist is needed more nowthan ever before. Our role has expand-ed significantly from compounding anddispensing drugs to helping managepatients with complex diseases andtherapies. I firmly believe that oncology

pharmacists can ease the burden on ourproviders by implementing collaborativepractice agreements that allow us toapply our specialized knowledge.This can have a financial impact. New

therapies are extremely expensive and Ibelieve we can guide appropriate use ofthese therapies to improve outcomes forpatients.

What inspired you to become anoncology pharmacist?DB: When I was in pharmacy school, Ibecame interested in oncology drugs. Ifound the biology fascinating, includingthe prepharmacy courses about DNAand RNA and the biological underpin-

nings of cancer. My job as an oncologypharmacist is an extension of that. Onein 4 deaths in the US are due to cancer.I felt I had the necessary qualifications tohelp cancer patients.

What advice would you give to oncology pharmacists just entering the field?DB: Oncology can be overwhelmingand the work environment is complex.One piece of advice is not to be afraid to ask questions. You are working withpatients at the most stressful time in theirlives and the work can be emotionallytaxing. Be sure to have a planned out-let to process your work experiences ina positive manner. You will see the fullrange of emotions with your patients,like an emotional roller coaster. Youwill need a good support system to pro-vide balance. Learn from your patients.They are a valuable educational re -source on a daily basis. Your clinicalexperience with patients is as impor-tant as reading journals.

If you were not an oncology pharma-cist, what would you be doing?DB: The quality that attracted me tooncology is an interest in how thingswork. I think I would be a mechanicalengineer or a nuclear physicist. WhenI was a kid, I would take apart appli-ances and other household items to seehow they worked, and I always man-aged to put them back together inworking order. �

University of Arizona Cancer Center Continued from cover

Jerrelee Hollings, Pharmacist; Daniel Butcher, Outpatient Oncology Pharmacy Supervisor; and Amy Smith, Pharmacy Technician (left to right), at the University of Arizona Cancer Center.Photo courtesy of the University of Arizona Cancer Center.

“Our role has expanded significantly from

compounding and dispensing drugs to helping manage

patients with complex diseases and therapies.”

—Daniel Butcher, PharmD

T-DM1 in Metastatic Breast Cancer Continued from page 4

with a standard treatment regimen.“For patients facing metastatic

breast cancer, this is a breakthrough,”said lead author Kimberly L. Blackwell,MD, of Duke Cancer Institute at DukeUniversity, Winston-Salem, NorthCarolina.Louis Weiner, MD, director of the

Georgetown-Lombardi Comp rehen siveCancer Center in Washington, DC, theinvited discussant of the study, com-mented, “Stated simply, T-DM1 reallyworks in this patient population. It is animportant new weapon in the therapeu-tic armamentarium for breast cancer.”Patients received intravenous T-

DM1 or capecitabine plus lapatinibevery 3 weeks until disease progression.Those getting T-DM1 had a medianPFS of 9.6 months, compared with 6.4months for those on capecitabine/lapa-tinib. This represented a 35% reduc-tion in the risk of progression (P <.0001), Blackwell reported.

Median overall survival was notreached with T-DM1, and was 23.3months with standard treatment, for a38% reduction in mortality risk (P = .0005). This did not, however,meet the prespecified threshold for sta-tistical significance for this end pointat the first analysis.Nevertheless, after 2 years, 65.4% of

the T-DM1 patients were alive, com-pared with 47.5% of the conventionallytreated group. “There is an apparent sur-vival benefit with T-DM1,” Blackwellsaid. It is expected that further analyseswill show a survival difference.Tolerability was far better with T-DM1

as well. Dose reductions were required for16.3% of this arm, compared with 53.4%for capecitabine and 27.3% for lapatinib.With T-DM1, the diarrhea, vomiting,hand–foot syndrome, and alopecia typi-cally observed with the chemotherapyregimen were not seen.

The Future of T-DM1Additional trials are now being conduct-ed to evaluate T-DM1 as first-line treat-ment, including 2 randomized multicen-ter phase 3 trials of the drug in earlierlines of therapy. The MARIANNE trialis comparing the efficacy and safety of T-DM1 alone and in combination withpertuzumab—another drug with strikingactivity in breast cancer when combinedwith trastuzumab. The experimentalcombination will be compared with thestandard trastuzumab/taxane regimen,Burris noted.Burris concluded, “T-DM1 meets the

criteria for a successful ADC by combin-ing the targeted effect of trastuzumabwith the cytotoxic potency of DM1 usinga stable linker and minimizing systemictoxicity. In addition, other tumor his-tologies, such as gastrointestinal cancersthat are HER2-positive, may be sensitiveto this agent.…An aggressive portfolio ofphase 2 and 3 clinical trials will helpdetermine the role of T-DM1 in earlierlines of therapy or with combination ofother targeted agents.” �

“Stated simply, T-DM1

really works in this patient

population. It is an

important new weapon

in the therapeutic

armamentarium for

breast cancer.”

—Louis Weiner, MD

�� 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

�� ™

��

Topics include:• Mantle Cell Lymphoma• Follicular Lymphoma

�� ™

��

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

COEAsize61512AskExperts

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.

� ��

Breast Cancer


morbidity is about 20% to 30%.Complications can include hypoten-sion, respiratory failure, intensive careunit admission, and confusion.The MASCC scoring system for FN

and the use of granulocyte colony-stimulating factor (G-CSF) for preven-tion of FN in high-risk patients are the most important advances over the past 2 or 3 decades, explained JeanKlastersky, MD, Institut Jules Bordet,Université Libre de Bruxelles,Belgium.“Mortality and morbidity are greatly

reduced, and therapies are simpler, lesstoxic, and appropriately delineatedaccording to patients’ risk status,”Klastersky told the audience. “Despitethis progress, numerous challengesremain in patients at high risk, and fur-ther study is needed to define the opti-mal use of G-CSF.”“Even a 5% mortality rate is too

high,” he continued. “Some of thepatients who die are young and treatedwith curative therapy.” Treating an episode of FN is expen-

sive, with much of the direct treatmentcosts driven by G-CSF. The mean costof treating 1 episode of FN is $7700 foroutpatients, and $15,231 for inpatients.“The cost is reduced by 50% if you cantreat on an outpatient basis,” he said. The MASCC scoring index, devel-

oped in 2000, enables risk stratificationof patients who develop FN. A score>21 predicts a low risk of complica-tions (ie, <5%). These patients can betreated with oral antibiotics as outpa-tients. Prerequisites for oral antibiotictherapy include: (1) low risk onMASCC scoring index, (2) feasibilityof oral antibiotics, and (3) 24-hourhospitalization period for observation. The rates of mortality and complica-

tions are higher in patients with aMASCC index score <15 versus >21.Mortality from gram-negative bac-teremia is 43% in patients with aMASCC score <15, Klastersky noted. “A low MASCC score predicts for

severe sepsis. We need protocolizedapproaches for patients with FN andpoor MASCC score. Some of thesepatients are kept too long in the emer-gency department—for several hours—without antibiotics. We should be moreaggressive in selecting patients at highrisk,” he continued. The possibility of preventing FN with

G-CSF has moved the field forward.Prophylactic use of G-CSF can decreasethe incidence by about 50% and reducemortality as well. The managementalgorithm for G-CSF is based on eco-nomic considerations, Klastersky noted,and now it is given when the risk of FNis >20%. “I take issue with the fact that if the

risk is >10%, G-CSF is not advised.This is not based on clinical science.”Low-risk patients who develop FN

have similar rates of complications andmortality as high-risk patients, andstudies show that low-risk patientsderive a similar benefit from G-CSF.Klastersky suggested expanding criteria

for use of G-CSF as primary prophylax-is and exploring the possibility of short-er schedules for this expensive therapy.

Scrambler Therapy forChemotherapy-Induced Peripheral Neuropathy Current treatments for chemothera-

py-induced peripheral neuropathy(CIPN) are suboptimal, according toCharles Loprinzi, MD, Mayo Clinic,Rochester, Minnesota. Drugs such asduloxetine, venlafaxine, and gabapentinare sometimes used off label and are notuniversally effective.

Pub:

IndicationYERVOY (ipilimumab) is indicated for the treatmentof unresectable or metastatic melanoma.1

REFERENCES 1. YERVOY (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011.2. Alpha-numeric HCPCS. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/HCPCSReleaseCodeSets/Downloads/12anweb.zip. Accessed November 1, 2011.

Please see Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions, continued on the following pages.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose.Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Important Safety Information

Announcing: J-code for YERVOY™ (ipilimumab) J9228

The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agentsmake no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide speci� c directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the speci� c insurer requirements.

aReplaces J9999, J3490, J3590, and C9284.

Access Support™, the Bristol-Myers Squibb Oncology reimbursement services program, offers patient assistance support, bene� ts investigation, prior authorization support and appeals assistance. Program counselors are available Monday through Friday, from 8:00 A.M. to 8:00 P.M. ET at 1-800-861-0048, to support the oncology of� ces’ reimbursement services needs of their insured and uninsured patients. You can also � nd information online at www.bmsaccesssupport.com

ProductDescription

50-mg/10 mL (5 mg/mL),single-use vial of YERVOY


NDC Number

10-digit 0003-2327-11 0003-2328-22

11-digit 00003-2327-11 00003-2328-22


Replaces J9999, J3490, J3590, and C9284.

12:22 PM

Conference News: MASCC


Advances in Supportive Care Continued from cover

Continued on page 10

A recent study presented at the 2012Annual Meeting of the AmericanSociety of Clinical Oncology showedthat duloxetine reduced pain associ-ated with CIPN by 30% in about one-third of patients. Although thisreduction was clinically meaningfulaccording to the authors, about two-

thirds of patients did not get better.Venlafaxine and gabapentin are usedoff label based on anecdotal evidence.Loprinzi said that scrambler therapy

“may offer a glimmer of hope” in thissetting. A previous pilot study foundthat scrambler therapy reduced painscores by 59% in 52 patients with neu-

ropathic pain (Smith TJ, et al. J PainSymptom Manage. 2010;40(6):883-891).“At first I was skeptical about using

scrambler therapy for CIPN, but I amencouraged by results of a pilot study atour institution,” he told listeners.Scrambler therapy uses a device to

treat pain via noninvasive cutaneous

electrostimulation, substituting “pain”messages with “nonpain” messages; thedevice generates 16 different current pat-terns to stimulate nerve action potentials. At MASCC, Deirdre R. Pachman,

MD, Mayo Clinic, reported experiencewith scrambler therapy in the first 11patients with CIPN-related pain: 8 were



Pub:

Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.

Recommended Dose Modifi cationsWithhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following:

Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day

Failure to complete full treatment course within 16 weeks from administration of � rst dose

Severe or life-threatening adverse reactions, including any of the following– Colitis with abdominal pain, fever, ileus, or peritoneal

signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation

– AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN

– Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations

– Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis

– Severe immune-mediated reactions involving any organ system

– Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy

Immune-mediated Enterocolitis: In the pivotal Phase 3 study in YERVOY-treated patients,

severe, life-threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients

Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis

In� iximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid

tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients

Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent)

Immune-mediated Hepatitis: In the pivotal Phase 3 study in YERVOY-treated patients,

severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4%

13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2)

Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution

Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids

Withhold YERVOY in patients with Grade 2 hepatotoxicityImmune-mediated Dermatitis: In the pivotal Phase 3 study in YERVOY-treated patients,

severe, life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients

– 1 (0.2%) patient died as a result of toxic epidermal necrolysis

– 1 additional patient required hospitalization for severe dermatitis

There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis

Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identi� ed, signs or symptoms of dermatitis should be considered immune-mediated

Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms

Important Safety Information (cont)

Advances in Supportive Care Continued from page 9



731US11AB18323 TRIM 7.25" x 9.75" Pub:

© 2012 Bristol-Myers Squibb Company 731US11AB18323 06/12 Printed in USA YERVOY is a trademark of Bristol-Myers Squibb Company.

Please see brief summary of Full Prescribing Information, including Boxed WARNING regarding immune-mediated adverse reactions, on the following spread.

Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week

Immune-mediated Neuropathies: In the pivotal Phase 3 study in YERVOY-treated patients, 1

case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported

Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes

Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities)

Immune-mediated Endocrinopathies: In the pivotal Phase 3 study in YERVOY-treated

patients, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients

– All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insuf� ciency, hypogonadism, and hypothyroidism

– 6 of the 9 patients were hospitalized for severe endocrinopathies

Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insuf� ciency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome

Median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insuf� ciency (including adrenal crisis), and hyper- or hypothyroidism

– Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspeci� c symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identi� ed, signs or symptoms should be considered immune-mediated

– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland

Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations:

In the pivotal Phase 3 study in YERVOY-treated patients, clinically signi� cant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia

Across the clinical development program for YERVOY, immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis

Permanently discontinue YERVOY for clinically signi� cant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions

Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy

Pregnancy & Nursing: YERVOY is classi� ed as pregnancy category C. There are

no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential bene� t justi� es the potential risk to the fetus

Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus

It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY

Common Adverse Reactions: The most common adverse reactions (≥5%) in patients

who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%)

Important Safety Information (cont)

12:22 PM

women, and 3 were men; mean age was57 years; patients had been exposed tovarious chemotherapy regimens; and themajority of patients had symptoms formore than 2 years.After 10 days of treatment, scram-

bler therapy decreased the averagedaily CIPN score (measuring pain,numbness, and tingling) as well as theworst daily CIPN score for these symp-

toms. Numbness was decreased byabout 30% over 10 days, and pain andtingling were reduced by about 40%.

Loprinzi and colleagues plan to con-duct a prospective, placebo-controlledtrial to confirm these findings.

Control of Grade 1 DiarrheaImportantIn the molecularly targeted therapyera, severe diarrhea continues to be aproblematic side effect and accountsfor increased resource utilization if notcontrolled.“If grade 1 diarrhea is not appropriate-

ly treated, diarrhea can quickly spiralContinued on page 12

After 10 days of treatment, scrambler therapy

decreased the average daily CIPN score

(measuring pain, numbness, and tingling).

down to grades 2, 3, and 4 and risk ofhospitalization and death,” LowellAnthony, MD, Louisiana State Uni -versity School of Medicine, NewOrleans, told supportive care experts atMASCC. “Only you can really preventthe spiral of diarrhea.” Conventional chemotherapy agents,

such as fluorouracil (5-FU), irinotecan,paclitaxel, and epirubicin, cause diar-rhea. With good supportive care, thesedrugs can be used in clinical practice. “Even giving 5-FU via different routes

is still associated with 10% to 20% severediarrhea. An incidence of >20% is notacceptable,” he said.

Targeted agents, including bevacizu -mab, epidermal growth factor receptorinhibitors, sunitinib, and sorafenib, havean additive risk of diarrhea when com-bined with chemotherapy. “The onlygood news is that the rate of grades 3 and4 diarrhea [with these agents] is under10%, but they increase the rates of grades

1 and 2 diarrhea,” Anthony stated. “Ingeneral we don’t stop treatment with tar-geted therapy for grades 1 and 2 diarrhea.These rates are much lower than whatwe see with irinotecan.”Bortezomib causes diarrhea (all grades)

in about 45% of patients. Lapatinib caus-es grades 1 to 3 diarrhea in up to 64% of



YERVOY™ (ipilimumab) Injection, for intravenous infusion

Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: IMMUNE-MEDIATED ADVERSE REACTIONSYERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY.

Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information]

Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions]

INDICATIONS AND USAGE

YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.

CONTRAINDICATIONS

None.

WARNINGS AND PRECAUTIONS

YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning]

Immune-mediated Enterocolitis

In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3–5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis.

The median time to onset was 7.4 weeks (range 1.6–13.4) and 6.3 weeks (range 0.3–18.9) after the initiation of YERVOY for patients with Grade 3–5 enterocolitis and with Grade 2 enterocolitis, respectively.

Twenty-nine patients (85%) with Grade 3–5 enterocolitis were treated with high-dose (≥40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids.

Of the 34 patients with Grade 3–5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve.

Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients.

Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Hepatitis

In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3–5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsy-proven hepatitis to characterize the clinical course of this event.

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Permanently discontinue YERVOY in patients with Grade 3–5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Dermatitis

In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).

Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks.

Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement.

Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information]

For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week.

Immune-mediated Neuropathies

In Study 1, one case of fatal Guillain-Barré syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported.

Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information]

Immune-mediated Endocrinopathies

In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3–4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushing’s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY.

Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13).

Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated.

Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations

The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia.

Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune-mediated adverse reactions.

Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

[see Warnings and Precautions].






G

Pub:

Advances in Supportive Care Continued from page 11

patients. Vandetanib causes grades 1 to 4diarrhea in 56% of patients with thyroidcancer. Cabozantinib, used to treat solidtumors, causes grades 1 to 4 diarrhea in57% of patients. Regorafenib, an investi-gational oral multikinase inhibitor,caused grades 1 to 4 diarrhea in 32% ofpatients with colorectal cancer, but moredata are needed to establish risk.“We are dealing with diarrhea in the

context of other side effects caused by

small molecule inhibitors; for example,peripheral neuropathy with bortez -omib; QTc prolongation with dasa-tinib; rash, diarrhea, fatigue, conjunc-

tivitis with erlotinib; rash, loss ofappetite, interstitial lung disease withgefitinib; rash, weight gain, edemawith imatinib; hypertension, heart fail-

ure syndrome with sorafenib and suni-tinib,” Anthony explained.In clinical practice, diarrhea and its

sequelae involve increased resource util -ization, he continued. It is important toestablish the diagnosis and etiology ofdiarrhea in cancer patients. Factors toconsider in assessing risk of diarrheainclude prior chemotherapy and priorpelvic radiation, performance status,response to prior cycle of chemothera-py, increased age, and female gender. Guidelines suggest 3 drugs: lo -

peramide, opium derivatives, andoctreotide. Grades 1 and 2 uncompli-cated diarrhea should be managed withadequate fluids, and the BRAT(bananas, rice, applesauce, and toast)diet. Grades 3 and 4 diarrhea mayrequire hospitalization, antibiotics,octreotide, and fluids.With tyrosine kinase inhibitor

(TKI)-induced diarrhea, dosing adjust-ment is not usually needed for grades 1and 2 diarrhea; dose reduction andintravenous fluids should be used totreat grades 3 and 4.“We will never see a clinical trial of

treating TKI-induced diarrhea. Treat -ment will be based on expert opinion,”Anthony said.Studies are now evaluating probiotics

and aluminum silicates for treatment ofdiarrhea. In Europe, glucagon-like pep-tide-2 is being studied in this setting, butthese drugs cannot be used for chronicdiarrhea, Anthony reported. �



Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients.

The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis.

Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3–5 events.

Table 1: Selected Adverse Reactions in Study 1

Percentage (%) of Patientsa

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100

n=380

gp100 n=132

System Organ Class/ Preferred Term

Any Grade

Grade3–5

Any Grade

Grade3–5

Any Grade

Grade 3–5

Gastrointestinal Disorders Diarrhea ColitisSkin and Subcutaneous Tissue Disorders Pruritus RashGeneral Disorders and Administration Site Conditions Fatigue

328

3129

41

55

02

7

375

2125

34

43

<12

5

202

118

31

10

00

3

a Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1.

Table 2: Severe to Fatal Immune-mediated Adverse Reactions in Study 1

Percentage (%) of Patients

YERVOY3 mg/kgn=131

YERVOY3 mg/kg+gp100

n=380

Any Immune-mediated Adverse ReactionEnterocolitisa,b

Hepatotoxicitya

Dermatitisa

Neuropathya

Endocrinopathy Hypopituitarism Adrenal insufficiencyOther Pneumonitis Meningitis Nephritis Eosinophiliac

Pericarditisa,c

157121440

00110

12723

<1111

<1<100

<1

a Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established.

Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction.

Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

Immunogenicity

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab).

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information]

In genetically engineered mice in which the gene for CTLA-4 has been deleted (a “knockout mouse”), offspring lacking CTLA-4 were born apparently healthy, but died within 3–4 weeks due to multi-organ infiltration and damage by lymphocytes.

Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Nursing Mothers

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.

Pediatric Use

Safety and effectiveness of YERVOY have not been established in pediatric patients.

Geriatric Use

Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years).

Renal Impairment

No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

Hepatic Impairment

No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information]

OVERDOSAGE

There is no information on overdosage with YERVOY.

PATIENT COUNSELING INFORMATION

See MEDICATION GUIDE in Full Prescribing Information.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1281558A2 IP-B0001A-03-11 Issued: March 2011

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The drug shortage crisis is easing,but an actual solution to theproblem is still elusive, accord-

ing to participants in a press briefingthat addressed the issue at the 2012Annual Meeting of the AmericanSociety of Clinical Oncology (ASCO)held in Chicago, Illinois.Richard Schilsky, MD, chair of

ASCO’s government relations commit-tee and an oncologist at the Universityof Chicago, indicated, “Patient care hasbeen threatened in many cases. But thegood news is that the frequency of drugshortages is beginning to decline.” In the past 2 years, 22 oncology

drugs were, or still are, in short supply,mostly generic injectables. “They areirreplaceable when there are noacceptable substitutes,” Schilsky point-ed out. “We are not exactly sure whena generic drug will suddenly go out ofsupply, and this creates a tremendousamount of uncertainty, anxiety, anddifficulty in planning.” Sandra Kweder, MD, deputy director

of the Office of New Drugs at the US Food and Drug Admin istration(FDA), said she was primarily con-cerned about the patients. “This isabout people being able to get treat-ments they need, when they needthem. This situation is not acceptable.”

FDA HypervigilantKweder said that prevention of short-ages is the FDA’s “absolute priority,”and a priority of Congress and theadministration.In the past 6 months, more than 150

drug shortages have been avertedthrough early notification by manufac-turers. “These drugs have not appearedon the list of shortages,” she noted. “Butthings can change quickly. Early notifi-cation is the key….Our staff is vigilant,and we work under extraordinary condi-tions to pull out the stops every day toprevent shortages and address those thatare occurring.”However, the early notification sys-

tem is voluntary, and the FDA cannotmandate that companies up their pro-

duction, she acknowledged. “One thingthe FDA cannot do is tell a companythey must make a drug.”But it can work with companies to

“ferret out problems” and resolve manu-facturing and drug quality issues, whichaccount for most shortages. “Theseissues are not minor,” she said.The FDA helps companies ramp up

production for new or “relaunched”products and uses “regulatory discre-tion” to help companies import drugs,she stated.Thanks to such efforts, she noted that

cytarabine, doxorubicin, liposomal dox-orubicin, mitomycin, daunorubicin, and5-fluorouracil are currently meetingdemands. Methotrexate continues to becarefully monitored, although a resolu-tion is expected soon.

User Fee Legislation, EconomicIncentives“ASCO believes a permanent solutionwill require congressional legislation,”Schilsky said.Progress has been made. On May 30,

the Prescription Drug User Fee Act(PDUFA) reauthorization legislationpassed the United States Senate as the FDA Safety and Innovation Act (S 3187), and the companion billpassed the United States House ofRep resentatives as the FDA ReformAct (HR 5651). The next step was toreconcile the differences between the 2versions, both of which contained aproposed user fee program for genericdrugs and biosimilars and language ondrug shortages. The program will allowthe FDA to collect user fees fromindustry to help fund the agency’stimely review of applications. On June18, the United States Congressreleased a reconciled version of thereauthorization bill, which was pre-sented again to the House of Rep -resentatives and Senate. The Housepassed the final version on June 20 andthe Senate passed it on June 26.President Barack Obama signed thebill on July 9, 2012.The PDUFA legislation will bring in

an additional $1.5 billion to the FDA,which is expected to reduce the reviewtime for a new drug application fromthe current 30 months to 10 months orless. “This is a huge step forward in get-ting manufacturers into the game,” saidSchilsky. “Industry is very willing topay these fees because they believe itwill enable a more timely review oftheir applications, and a faster timegetting their drugs to market.”The FDA “user fee” legislation that

was passed by Congress, however, doesnot contain an enforcement mecha-

nism that carries penalties for notreporting. “ASCO has concerns that ifthere is no teeth in that legislation,companies may decide not to report,”Schilsky said. “On the Hill, there is notmuch receptivity to putting that in thelegislation.”“We also feel that Congress should

consider making economic incentivesfor companies to stay in the market forthese lower-cost drugs,” he added.“And that the provisions addressingdrug shortages also apply to biologics,which at the moment are branded butwill eventually be generic.”Would economic incentives en cour-

age production of generics? The factthat virtually all shortages so far havebeen generics “speaks to the economicand business model,” Schilsky acknowl-edged. “These drugs have the smallestprofit margins, but it’s hard to connectthe dots on this.…The generic drugindustry is thriving. Yes, they havemanufacturing problems and yes, peri-odically plants go down, but it’s notlike the economics of the situation isdriving them out of business. Economicissues may be contributing to the short-age, but not at such a fundamentallevel that companies are folding theirtents and going away.”

Could New Drugs Be Affected?While the shortages to date have beenalmost restricted to generics, it appearspossible that even supplies of the newestdrugs may fall short of the demand.News of the FDA’s approval of per-

tuzumab (Perjeta) for HER2-positivemetastatic breast cancer was welcomed,but in its announcement, Genentech,the manufacturer, disclosed that pro-duction issues could affect the drug’slong-term supply.“We expect to meet demand for

Perjeta following today’s FDA ap -proval,” said spokesperson Patrick Y.Yang, PhD, head of technical opera-tions. “We recently identified a cellgrowth issue that might affect our futuresupply of the medicine. We take thisvery seriously and are working with theFDA to ensure a consistent manufactur-ing process that maintains drug supplyfor the people who need it.”In her FDA announcement of the

drug’s approval, Janet Woodcock, MD,director of the FDA’s Center for DrugEvaluation and Research, said, “Giventhe need for additional treatments formetastatic breast cancer, we made thedecision to approve this drug today andnot to delay its availability to patientspending resolution of the productionissues relating to future supply.” �

Drug Shortage


Exploring the Drug Shortage CrisisBy Caroline Helwick

“Industry is very willing to pay these fees because

they believe it will enable a more timely review

of their applications, and a faster time getting

their drugs to market.”

—Richard Schilsky, MD

Reader PollAre you confident that the FDA actions and the recent

congressional legislation will resolve the drug shortage issue? r Yesr No

Go to www.TheOncologyPharmacist.com to cast your vote and add your comments.

Please tell us what you think about theefforts to resolve the drug shortage issue.

At one New York medical center,half of the cancer patientsrequired drugs that were consid-

ered in short supply in 2010 and 2011,and 10% were forced to receive an alter-native, according to a study presented atthe 2012 ASCO Annual Meeting(Abstract 6114).While the investigators hope that

this did not compromise efficacy, aboutone-third of the time the physiciansfelt the substitute was inferior, saidDaniel J. Becker, MD, of St. Luke’s-Roosevelt and Beth Israel MedicalCenter, New York, who led the studypresented at ASCO.Becker reported that drugs considered

in shortage were used for 51% of patientsin 2010, and this increased significantlyto 64% in 2011.“When the shortage reached critical

levels, about 10% of the patients wetreated had an actual change in treat-ment mandated by the shortage,” hetold The Oncology Pharmacist. The researchers reviewed pharmacy

records for drug shortages, defined assupply issues that affect how the phar-macy prepares or dispenses a drug prod-uct or influences patient care whenprescribers must use an alternativeagent, and examined records of outpa-tients who received chemotherapyfrom April 2010 to September 2010 (n = 335) and from April 2011 toSeptember 2011 (n = 379). They alsosurveyed physicians about the efficacyand toxicity of the alternative regimenused during the shortage.The percentage of drugs in shortage

increased from 30% in 2010 to 50% in2011, and the percentage of patientstreated with a shortage drug increasedfrom 51% to 65%. Most of the short-ages occurred in breast cancer patients(48%), followed by gynecologic cancerpatients (26%).Of the 235 patients in the subgroup

examined in August/September 2011(when shortages peaked), 23 (9.8%)experienced a change in therapy, hereported. No substitutions occurred in2010.Three medications were unavailable

at St. Luke’s-Roosevelt: paclitaxel(74%), liposomal doxorubicin (22%),and 5-fluorouracil (4%). Leucovorinwas also in short supply, but the conse-quences were difficult to track for thisproject, since most patients continuedto receive the drug in reduced dosages,Becker said.As a substitute for paclitaxel, the use

of docetaxel increased by 80%, whilepaclitaxel decreased by 69% during themost critical period. The estimated

cost of a single treatment with pacli-taxel for the average patient was $47,versus $858 for docetaxel, a 1704%increase, Becker pointed out.“When we surveyed treating physi-

cians about the change in therapy, wefound that they considered the alterna-tive regimen inferior to the standard reg-

imen in 30% of patients and thought thealternative regimen was more toxic inaround 35%,” Becker said.Today, he added, “Many drugs

are still in shortage, but few affectcare on a daily basis. There is defi-nitely progress, though there is stillvulnerability.” �

Drug Shortage


Quantifying the Drug Shortage: One Center’s Experience

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.

��

� � �� Daniel J. Becker, MD

CONTINUING EDUCATION

CONSIDERATIONS inMultiple Myeloma™5th Annual

ASK THE EXPERTS: Maintenance Settings

Amrita Y. Krishnan, MD, FACPDirector, Multiple Myeloma ProgramAssociate Director, Medical Educationand Training Department of Hematology/HCTCity of Hope Cancer CenterDuarte, CA

Christina Boeckman, RN, ANP-C,AOCNPNurse PractitionerDepartment of Hematology/HCTCity of Hope Cancer CenterDuarte, CA

Sepideh Shayani, PharmD, BCOPClinical Manager, Pharmacy ServicesDepartment of Pharmaceutical ServicesCity of Hope Cancer CenterDuarte, CA

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

PUBLISHING STAFF

President & CEOBrian F. Tyburski

Chief Operating OfficerPam Rattananont Ferris

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Linda M. Ritter, [email protected]

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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 second issue, experts from City of Hope CancerCenter answer questions pertaining to the management of patients in the maintenance 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

JULY 2012 • VOLUME 5 • NUMBER 2

� ��


CONSIDERATIONS IN MULTIPLE MYELOMA

IntroductionDespite the development of more effective induction regimens

and the increased use of autologous stem cell transplant (ASCT), most

patients with multiple myeloma (MM) eventually relapse and suc-

cumb to progressive disease. Novel agents that have demonstrated

good clinical activity in the frontline and relapsed settings continue to

be evaluated as maintenance therapy, with the goal of delaying

relapse and extending survival. However, important questions related

to the use of these therapies remain unresolved. In this article, Amrita

Y. Krishnan, MD, FACP, shares her insight on recent clinical data and

ongoing issues in the maintenance setting for myeloma.

When do you consider maintenance therapy for your patientswith MM?

I am most likely to recommend maintenance for patients with high-riskcytogenetics and for those who do not achieve a complete response (CR)after ASCT. Unfavorable cytogenetics in both transplant and nontransplantcandidates portend a high risk of relapse or disease progression. In addition,an important objective posttransplant is CR or at least very good partial

response, as this has been correlated with improved overall survival (OS).1,2

Maintenance therapy with novel agents can contribute to these treatmentgoals, especially in patients who do not achieve a CR with transplant alone. I am less likely to use maintenance in standard-risk patients who achieve

CR, because of concern that the risk of continued drug treatment may out-weigh benefit in this population. Of course, there are always exceptions, andthe approach to therapy must be individualized to the patient. Many questionsremain on the optimal use of maintenance therapy, because we do not yethave unequivocal evidence that it prolongs OS in specific MM subgroups.3,4

What evidence has influenced your approach to maintenancetherapy?

In patients with high-risk cytogenetics who exhibit the translocationt(4;14), I tend to use bortezomib. The HOVON-65/GMMG-HD4 trialshowed a benefit in progression-free survival (PFS) in patients with t(4;14)who received this agent as maintenance. There is controversy, however,because HOVON-65/GMMG-HD4 did not prove that it was the mainte-nance that produced this clinical benefit, since patients received bortezomibduring induction as well in one arm of the study, whereas the other arm didnot receive bortezomib during induction or maintenance (Figure).5

There has also been debate regarding the efficacy of bortezomib mainte-nance in patients with deletion 17p (del[17p]). A study by Avet-Loiseau andcolleagues reported that bortezomib-based therapy could not overcome thischromosomal abnormality. However, patients in this trial received bortez -omib short-term (4 cycles) with no maintenance.6 Results of HOVON-

Recent Advances and Ongoing Controversiesin the Maintenance Setting

Amrita Y. Krishnan, MD, FACPDirector, Multiple Myeloma ProgramAssociate Director, Medical Education and Training, Department of Hematology/HCTCity of Hope Cancer Center, Duarte, CA

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

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

Educational ObjectivesUpon completion of this activity, the participant will be able to:• Describe recent advances in maintenance therapy that can po -

tentially prolong survival and improve quality of life in patientswith MM

• Identify specific patient- and disease-related factors that may im -pact the choice of maintenance therapy in MM

• Review recent safety and efficacy data on novel agents used in themaintenance setting for MM

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

Instructions for Credit

There is no fee for this activity. To receive credit after reading this CME/CEactivity in its entirety, participants must complete the pretest, posttest, andevaluation. The pretest, posttest, and evaluation can be completed onlineat www.mlicme.org/P12026.html. Upon completion of the evaluationand scoring 70% or better on the posttest, you will immediately receiveyour certificate online. If you do not achieve a score of 70% or better onthe posttest, you will be asked to take it again. Please retain a copy of theCertificate for your records.

For questions regarding the accreditation of this activity, please contactMLI at 609-333-1693 or [email protected].

Physician Credit DesignationThe Medical Learning Institute, Inc. (MLI) designates this enduringmaterial for a maximum of 1.25 AMA PRA Category 1 Credits™.Physicians should claim only the credit commensurate with the extentof their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of theAccreditation Council for Continuing Medical Education (ACCME)

through the joint sponsorship of the Medical Learning Institute, Inc.and the Center of Excellence Media, LLC. The Medical LearningInstitute, Inc. is accredited by the ACCME to provide continuing med-ical education for physicians.

Registered Nurse DesignationMedical Learning Institute, Inc. (MLI).Provider approved by the California Board of Registered Nursing,Provider Number 15106, for 1.25 contact hours.

Registered Pharmacy DesignationMedical Learning Institute, Inc. (MLI) is accredited by the Accredi -tation Council for Pharmacy Education (ACPE) as a provider of

continuing pharmacy education. Completion of this activity provides for1.25 contact hours (0.125 CEUs) of continuing education credit. Theuniversal activity number for this activity is 0468-9999-12-024-H01-P.

DisclosuresBefore the activity, all faculty and anyone who is in a position to havecontrol over the content of this activity and their spouse/life partner willdisclose the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcaregoods/services to be discussed during their presentation(s): honoraria,expenses, grants, consulting roles, speakers’ bureau membership, stockownership, or other special relationships. Presenters will inform partici-pants of any off-label discussions. All identified conflicts of interest arethoroughly vetted by MLI for fair balance, scientific objectivity of studiesmentioned in the materials or used as the basis for content, and appropri-ateness 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 dis-closed that her spouse is investigator on a study for Agenix and Lilly;on the data monitoring committee for Infinity; and on the data moni-toring committee and 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.

*Amrita Y. Krishnan, MD, FACP, is a consultant for CelgeneCorporation, and is on the speakers’ bureau for Celgene Corporation,Genentech, and Millennium: The Takeda Oncology Company.Christina Boeckman, RN, ANP-C, AOCNP, has nothing to disclose.*Sepideh Shayani, PharmD, BCOP, is on the advisory board forGenzyme.

*Content will include non–FDA-approved uses.

The associates of Medical Learning Institute, Inc., the accreditedprovider for this activity, and Center of Excellence Media, LLC, donot have any financial relationships or relationships to products ordevices with any commercial interest related to the content of thisCME/CE activity for any amount during the past 12 months.

Disclaimer The information provided in this CME/CE activity is for continuingeducation purposes only and is not meant to substitute for the inde-pendent medical judgment of a healthcare provider relative to diag-nostic and treatment options of a specific patient’s medical condition.Recommendations for the use of particular therapeutic agents are based onthe best available scientific evidence and current clinical guidelines. No biastowards or promotion for any agent discussed in this program should beinferred.

Agenda: 1.25 hoursArticles/Commentaries: 60 minutesEvaluation/Posttest: 15 minutes

Date of original release: July 12, 2012Valid for CME/CE credit through: July 12, 2013

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65/GMMG-HD4 suggested a benefit with bortezomib-based induction plusmaintenance,5 as did data from the Total Therapy 3 trial.7 In addition, arecent study by Neben and colleagues reported that patients with del(17p)who received bortezomib before and after ASCT had a median PFS of 26.2months compared with 12.0 months for patients who did not receive bor -tezomib (P=.024), with 3-year OS rates of 69% and 17%, respectively(P=.028).8 The results of this trial are changing the landscape of treatmentfor patients with del(17p).For patients with a partial response after ASCT, I generally use lenalido-

mide maintenance, based on results from the CALGB 100104 and IFM2005-02 trials.9,10 CALGB 100104 compared single-agent lenalidomidemaintenance with placebo in patients with stable disease or better (includingpatients who achieved CR) following ASCT. This study demonstrated signif-icantly longer time to progression and improved survival in the lenalidomidearm versus the placebo arm (Table).9 IFM 2005-02 also compared single-agent lenalidomide maintenance with placebo post-ASCT (after 2 courses oflenalidomide consolidation in both arms).10 In this study, lenalidomide main-tenance improved median PFS to 41 months versus 23 months with placebo(P<.001), with benefit across cytogenetic subgroups. Three-year and 4-yearOS rates were comparable in the lenalidomide versus placebo groups: 80%versus 84% (3-year) and 73% versus 75% (4-year), respectively. Recent data from the RV-MM-PI-209 trial add further support to the use

of lenalidomide maintenance after consolidation.11 Patients received induc-tion with lenalidomide and low-dose dexamethasone, followed by either

melphalan, prednisone, and lenalidomide (MPR) ± lenalidomide mainte-nance or melphalan/ASCT ± lenalidomide maintenance. A comparison ofall patients given lenalidomide maintenance (after either MPR or ASCT)versus all patients receiving no maintenance showed that maintenanceincreased PFS but not OS. The recent MM-015 trial evaluated lenalidomidemaintenance in older, transplant-ineligible patients with myeloma. Theinvestigators of this study reported that lenalidomide after initial therapywith MPR significantly extended PFS compared with melphalan plus pred-nisone alone or MPR without maintenance.12

Thalidomide is not used preferentially for maintenance in the UnitedStates, largely due to data showing a high incidence of serious adverseevents, reduced quality of life, and potentially poorer outcomes in del(17p)patients.13-15 In Europe, however, thalidomide is used more often, because ofregulatory limitations on other novel drugs such as lenalidomide.

What are some of the key concerns in using maintenance therapy?

The first concern is risk versus benefit. Are we seeing enough clinicalbenefit to justify the toxicity and added expense of maintenance therapy?Certainly, data suggest benefits in response and PFS when maintenance isused, but a consistent benefit in OS has not been shown.3-8

Adverse events are also an important consideration. With bortezomibmaintenance, grade 3 or 4 peripheral neuropathy may be treatment-limit-ing.3,5 With lenalidomide, trials have reported an increased risk of secondprimary malignancies with maintenance therapy.9,10,12,16 In CALGB 100104,for example, second cancers were reported in 8% of patients receivinglenalidomide maintenance versus 3% of patients receiving placebo duringapproximately 3 years of follow-up.9 The investigators of this study haveindicated that they will continue to assess risk factors for development ofsecond primary cancers with further follow-up. Factors such as cost andinsurance coverage may also affect the choice of maintenance therapy.These issues can influence patient preference, which we always consider.

How long should patients remain on maintenance therapy withnovel agents?

Currently, there is no consensus regarding the optimal duration of main-tenance therapy for myeloma. In HOVON-65/GMMG-HD4, patientsreceived bortezomib maintenance for 2 years.5 In CALGB 100104, lenalido-mide maintenance was given until progression.9 The investigators in theIFM 2005-02 trial planned to use lenalidomide until progression but stoppedtherapy once secondary malignancies arose.10 In the ongoing phase 3 multi-center BMT CTN 0702 trial, we plan to give lenalidomide maintenancetherapy for 3 years.17

However, many questions remain unresolved. What is the optimal dura-tion of lenalidomide therapy to improve PFS and possibly OS? Since bor -tezomib-related neuropathy may shorten maintenance time, can we reducethe incidence and severity of this toxicity and extend the duration of timethat patients can stay on maintenance by using subcutaneous bortezomib18

or an alternate proteasome inhibitor such as carfilzomib or MLN9708?19-22

Hopefully, emerging clinical data and ongoing research will better definethe role of novel agents in the maintenance setting and provide answers tothese questions. �

References1. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response

is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dosetherapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009;27:5720-5726.

Figure. Efficacy results at 36 months of follow-up in the HOVON-65/GMMG-HD4 trial.5

Pati

ents

(%

)

80

70

60

50

40

30

20

10

0

HDT/ASCT indicates high-dose therapy/autologous stem cell transplant; OS, overall survival; PAD,bortezomib, doxorubicin, dexamethasone; PFS, progression-free survival; VAD, vincristine, doxoru-bicin, dexamethasone.

All pts t(4;14) del(17p) All pts t(4;14) del(17p)

PFS OS

VAD + HDT/ASCT + thalidomidemaintenancePAD + HDT/ASCT + bortezomibmaintenance

Table. Efficacy Results at a Median Follow-up of 34 months inthe CALGB 100104 Trial9

LenalidomideMaintenance Placebo P Value

Median TTP 46 months 27 months <.001

3-Year PFS rate 66% 39% —(95% CI, 59-73) (95% CI, 33-48)

3-Year OS rate 88% 80% —(95 CI, 84-93) (95 CI, 74-86)

OS indicates overall survival; PFS, progression-free survival; TTP, time to progression.

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2. Harousseau J-L, Attal M, Avet-Loiseau H. The role of complete response in multiple myeloma.Blood. 2009;114:3139-3146.

3. Ludwig H, Duries BGM, McCarthy P, et al. IMWG consensus on maintenance therapy in multi-ple myeloma. Blood. 2012;119:3003-3015.

4. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clashof philosophies. Blood. 2011;118:3205-3211.

5. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4 randomizedphase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed byhigh-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients withnewly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts).2010;116:Abstract 40.

6. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improvesoutcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J ClinOncol. 2010;28:4630-4634.

7. Shaughnessey JD, Zhou Y, Haessler J, et al. TP53 deletion is not an adverse feature in multiplemyeloma treated with total therapy 3. Br J Haematol. 2009;147:347-351.

8. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologousstem cell transplantation improves outcome in multiple myeloma patients with deletion 17p.Blood. 2012;119:940-948.

9. McCarthy PL, Owzar K, Hofmeister CG, et al. Lenalidomide after stem-cell transplantation formultiple myeloma. N Engl J Med. 2012;366:1770-1781.

10. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplan-tation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.

11. Cavallo F, Hardan I, Gay F, et al. Lenalidomide maintenance significantly reduces the risk of pro-gression in newly diagnosed young multiple myeloma patients enrolled in RV-MM-PI-209 trial.Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012;Amsterdam, Netherlands.

12. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-ineligi-ble newly diagnosed multiple myeloma: update on patients aged 65-75 years enrolled in MM-015.Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012;Amsterdam, Netherlands.

13. Hicks LK, Haynes AE, Reece DE, et al. A meta-analysis and systematic review of thalidomide

for patients with previously untreated multiple myeloma. Cancer Treat Rev. 2008;34:442-452.14. Morgan GJ, Jackson GH, Davies FE, et al. Maintenance thalidomide may improve progression

free but not overall survival: results from the Myeloma IX maintenance randomisation. Blood(ASH Annual Meeting Abstracts). 2008;112:Abstract 656.

15. Stewart AK, Trudel S, Bahlis NJ, et al. A randomized phase III trial of thalidomide and pred-nisone as maintenance therapy following autologous stem cell transplantation (ASCT) inpatients with multiple (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual MeetingAbstracts). 2010;116:Abstract 39.

16. Delforge M, Dimopoulos M, Adam Z, et al. Safety profile and management in MM-015 compar-ing lenalidomide-melphalan-prednisone followed by lenalidomide maintenance (MPR-R) withMP and MPR in newly diagnosed multiple myeloma (NDMM). Presented at: 17th AnnualCongress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands.

17. Stem cell transplant with lenalidomide maintenance in patients with multiple myeloma (BMTCTN 0702). ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01109004.Updated March 28, 2012. Accessed June 30, 2012.

18. 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.

19. Jakubowiak AJ, Griffith KA, Dytfeld D, et al. Stringent complete response (sCR) in patients (pts)with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide(LEN), and dexamethasone (DEX). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8011.

20. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oralproteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myelo-ma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8017.

21. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigational pro-teasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) withpreviously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO AnnualMeeting Abstracts). 2012;30(suppl):Abstract 8033.

22. Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral proteasomeinhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): a phase Istudy. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8034.

IntroductionAlong with the clinical benefits seen with maintenance regimens for

multiple myeloma (MM), new challenges have arisen, due to the

increased risk of adverse events associated with prolonged use of ther-

apy. As a member of the cancer care team, it is the nurse’s responsi-

bility to anticipate which toxicities and complications are likely to

occur, to employ the necessary interventions, and to counsel patients

accordingly. In this article, Christina Boeckman, RN, ANP-C, AOCNP,

discusses effective nursing strategies in the maintenance setting, and

shares her perspectives on preventing and managing common

adverse events related to the use of novel agents.

Which patient-related factors need to be considered in the main-tenance setting?

Age, comorbidities, and performance status must all be considered when apatient is scheduled to receive maintenance therapy. Elderly MM patientsfrequently have age-related comorbid conditions that can make managingtheir disease especially challenging.1 These individuals are more likely to

have organ dysfunction (eg, cardiovascular disease, renal impairment) anddiabetes, and are more prone to infection and deep vein thrombosis.1 It is cru-cial to take these factors into account when determining an effective man-agement plan. It is also important to know which agents were used duringprevious lines of therapy, how patients tolerated these medications, andwhether they are experiencing any residual adverse events. In some cases, itmay be necessary to avoid the use of specific agents due to preexisting comor-bidities or cumulative toxicities. A patient’s overall performance status should also be evaluated prior to

and during maintenance therapy. Nurses must assess whether an individual isable to perform activities of daily living, such as preparing meals, eating,bathing, and dressing. The goal is to achieve a balance between providingeffective therapy and maintaining good quality of life.

What strategies do you use to minimize peripheral neuropathy (PN)in patients receiving bortezomib as maintenance therapy?

Neuropathy is a well-known adverse event associated with the use of novelagents such as bortezomib and thalidomide.2 Symptoms may include tran-sient numbness and tingling, paresthesias, and muscle cramping or weakness,or in severe cases, burning pain, organ dysfunction, and paralysis.2 High ratesof thalidomide-induced PN have been observed during maintenance thera-py.2-4 If treatment with this agent is not interrupted quickly, symptoms maybecome irreversible.5 As a result, thalidomide is being used less frequently asmaintenance. Bortezomib-induced PN, on the other hand, is generallyreversible with dose reduction and treatment discontinuation.2 We have

Improving Patient Outcomes DuringMaintenance Therapy

Christina Boeckman, RN, ANP-C, AOCNPNurse PractitionerDepartment of Hematology/HCT, City of Hope Cancer CenterDuarte, CA

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recently seen an increase in the use of bortezomib in the maintenance set-ting, and nurses need to be familiar with its toxicity profile and recommendedsupportive care strategies.Assessing PN prior to the start of maintenance and throughout the course

of therapy is essential.2,5 Verbal and nonverbal questionnaires and pain scalesare helpful for these assessments. When patients come to our center for treat-ment, I ask them if they are experiencing any numbness and tingling in theirhands and feet, ringing in their ears, neuropathic pain, or cramping. I alsodetermine if they are having trouble with everyday tasks, such as buttoningtheir shirts or writing with a pen. Patients must understand the importanceof reporting signs and symptoms of PN as soon as they occur, so that theappropriate interventions can be initiated. When bortezomib-related PN develops, the goal is to alleviate symptoms

and prevent progression.2 This can be accomplished through recommendeddose modifications based on the degree of neurotoxicity (Table).5,6 For exam-ple, if a patient develops grade 3 PN while on bortezomib, we typically holdtreatment until symptoms resolve, and then reinitiate therapy at a lower doseand schedule. For patients who have neuropathic pain, we prescribe opioidswhen necessary; the use of nonsteroidal anti-inflammatory drugs is not advis-able due to the likelihood of myeloma-related renal dysfunction. Additionalmedications that may be used in the treatment of PN symptoms includegabapentin, pregabalin, duloxetine hydrochloride, and tricyclic antidepres-sants.2 We usually recommend that patients start taking B complex vitamins,folic acid, and alpha lipoic acid, as long as they are not contraindicated withother medications.

How do you assess and treat hematologic toxicities related to lena -lidomide therapy in the maintenance setting?

Hematologic toxicities are commonly associated with the use of lenalido-mide.7 To effectively manage these adverse events, it is important for myelo-ma patients to have their blood counts monitored regularly, with the mostfrequent monitoring performed early in their treatment cycles. We seepatients at least every 2 weeks during the first and second cycles of mainte-nance to assess how they are responding to treatment and to evaluate theneed to make dose or schedule adjustments based on their counts. Dependingon their performance status and laboratory results, we may lessen the frequen-cy of these evaluations to once per month. When platelet counts fall to <30,000/mcL, we may need to temporarily

discontinue lenalidomide. Treatment can usually be resumed when plateletcounts return to 30,000/mcL, but it may be necessary to restart them at areduced dose.7,8 We usually do not initiate transfusion unless platelet countsdecline to <20,000/mcL. If the patient’s absolute neutrophil count (ANC) is<1000/mcL, lenalidomide treatment should also be halted until counts returnto baseline. In some cases, we may initiate granulocyte colony-stimulatingfactor if a patient’s ANC remains low for an extended period of time.Patients also need to be evaluated for bleeding, bruising, dyspnea, fatigue,

and infection, and should be educated on how to monitor for these signs andsymptoms at home. We tell them to notify us immediately if they experiencebleeding that does not stop, frequent bruising, or fever. It is important toinstruct patients on effective strategies for infection control, including rou-tine hand washing and the avoidance of crowds, when their blood counts arelow. If patients develop signs of infection, we may also need to hold lenalido-mide treatment until symptoms resolve.

What is the nurse’s role in helping patients continue with mainte-nance therapy?

Prior to the initiation of maintenance, it is important to discuss with patientsboth the risks and benefits of prolonged therapy with novel agents. Some indi-viduals do not understand why they need to undergo further treatment if theyhave responded well to initial chemotherapy and/or transplantation. It isimportant to remind these patients that continued use of effective agents mayhelp to delay relapse and disease progression. Although patients will typicallybe familiar with the toxicity profiles of agents they have already received duringfrontline therapy, we review this information again prior to the start of main-tenance. We also inform patients about the increased risk for secondary malig-nancies related to prolonged duration of therapy, and encourage them to bediligent about routine health screenings, including mammograms and colon -oscopies. We ensure them that we will also monitor for secondary malignanciesthrough laboratory tests and other procedures.To provide optimal care, nurses must consider patient preferences as well as

psychosocial factors in the maintenance setting. Some individuals would ratherreceive oral lenalidomide, so they do not have to travel back and forth to the cen-ter every week for treatment. If we determine that a patient can be compliantwith an oral regimen, and they do not have comorbidities or other characteristicsthat would preclude the use of lenalidomide, we will most likely use this therapy.For other patients, intravenous or subcutaneous bortezomib may be preferential,based on patient- or disease-related factors. Regardless of which type of therapy isprescribed during maintenance, oncology nurses play an important role inimproving patient outcomes by establishing good communication with patients,carefully monitoring for signs and symptoms of toxicities, and being prepared toinitiate effective supportive care strategies when needed. �

References1. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of ther-

apy or sequencing. Hematology Am Soc Hematol Educ Program. 2009:566-577.2. Tariman JD, Love G, McCullagh E, Sandifer S; IMF Nurse Leadership Board. Peripheral neu-

ropathy associated with novel therapies in patients with multiple myeloma: consensus state-ment of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):29-36.

3. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves sur-vival in patients with multiple myeloma. Blood. 2006;108:3289-3294.

4. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation formultiple myeloma. N Engl J Med. 2006;354:1021-1030.

5. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for mul-tiple myeloma: background and practical recommendations. Haematologica. 2010;95:311-319.

6. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals; January 2012.7. Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression

associated with novel therapies in patients with multiple myeloma: consensus statement of theIMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20.

8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; October 2010.

Table. Bortezomib Dose Modifications Based on Severity ofPeripheral Neuropathy5,6

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)

Grading based on NCI Common Toxicity Criteria CTCAE V 3.0.

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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Dosing and Administration of Novel Agents in the Maintenance Setting

IntroductionOver the past decade, maintenance therapy has become an

increasingly important component of treatment for patients with mul-

tiple myeloma (MM). Recent evidence has shown that newer target-

ed agents, such as bortezomib and lenalidomide, have the potential

to extend duration of response following frontline therapy, and are

generally better tolerated and more effective than older, conven-

tional therapies used for this indication. In this article, Sepideh

Shayani, PharmD, BCOP, discusses recent advances in the mainte-

nance setting, and answers questions related to the administration of

novel agents.

Has a standard dose and schedule been established for bortez -omib as maintenance therapy?

To date, a standard dose and schedule has yet to be established for bortez -omib maintenance; however, data from recent clinical trials can be helpful inguiding therapeutic decisions. As in the frontline and relapsed/refractory set-tings, it is essential to strike a balance between efficacy and safety when usingnovel agents as maintenance, especially since patients will be on therapy foran extended period of time.In the phase 3 HOVON-65/GMMG-HD4 trial, transplant-eligible pa -

tients with MM were randomly assigned to induction therapy with vin-cristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxoru-bicin, and dexamethasone (PAD).1 This was followed by high-dosemelphalan and autologous stem cell transplant (ASCT). Patients started onVAD received thalidomide maintenance at a dose of 50 mg/day for 2 years(arm A) and those randomized to PAD received bortezomib maintenance ata dose of 1.3 mg/m2 biweekly for 2 years (arm B).In this trial, progression-free survival (PFS) was lower with VAD/

ASCT/thalidomide compared with PAD/ASCT/bortezomib (42% vs 46% at36 months, P=.047). Overall survival was significantly higher in arm B(P=.048). A total of 67% of patients in arm A and 57% in arm B startedmaintenance therapy, and 64% and 47% of those patients, respectively, wentoff protocol due to various factors (Table 1). Grade 3/4 peripheral neuropathy(PN) was observed in 7% of patients in arm A and 16% of patients in arm B.In the phase 3 GIMEMA trial, patients with MM were randomized to nine

6-week cycles of induction with bortezomib, melphalan, prednisone, andthalidomide (VMPT) followed by 2 years of maintenance with bortezomib(1.3 mg/m2 every 14 days) plus thalidomide (50 mg/day) (VT) or to nine6-week cycles of VMP induction without maintenance.2 Early in this trial,which enrolled patients who were not eligible for transplant due to advanced

age or comorbidities, the schedule of bortezomib (1.3 mg/m2) used for induc-tion was reduced from twice weekly to once weekly. In addition, both theVMPT and VMP schedules were changed to nine 5-week cycles. Results showed a benefit with VMPT/VT compared with VMP alone, in

terms of complete response rates (38% vs 24%; P<.001), PFS (56% vs 41%,P=.008), and time to next treatment. Importantly, the once-weekly scheduleof bortezomib lowered discontinuation rates and prolonged time on therapy.This finding has important clinical implications, especially for the treatmentof older patients who may have difficulty tolerating a standard regimen. Theschedule adjustment used in this study also significantly reduced the inci-dence of severe sensory PN from 16% to 3% (P<.001).

Both of these maintenance trials reported encouraging clinical activitywith bortezomib. In GIMEMA, once-weekly dosing was more tolerable thantwice-weekly dosing, but maintained good clinical activity.2 In this trial,bortezomib maintenance administered bimonthly also appeared to be aneffective strategy. Investigators continue to evaluate various bortezomib dos-ing and schedule protocols. Hopefully, data from new trials will help to deter-mine a standard of care. In the meantime, following established dosingadjustment guidelines for bortezomib3,4 to reduce toxicities such as PN isessential to ensure optimal outcomes. Additionally, subcutaneous adminis-tration of bortezomib may improve the adverse event profile associated withthis agent. In a recent trial of relapsed/refractory MM, this mode of adminis-tration resulted in similar overall response rates but significantly less PN thantraditional intravenous dosing.5 The increased tolerability seen with subcuta-neous bortezomib in this population of patients may translate to the mainte-nance setting.

What dosing and administration schedules are being used forlenalidomide as maintenance?

In the phase 3 IFM 2005-02 trial, patients with MM who had single ordouble ASCT were treated with 2 cycles of consolidation with lenalidomide(25 mg/day, days 1-21) followed by placebo or lenalidomide maintenance(given at 10 mg/day for the first 3 months and increased to 15 mg/day if tol-erated).6 Treatment was continued until disease progression or development

Sepideh Shayani, PharmD, BCOPClinical Manager, Pharmacy ServicesDepartment of Pharmaceutical ServicesCity of Hope Cancer CenterDuarte, CA

Table 1. Discontinuation Rates in the Maintenance Phase of theHOVON-65/GMMG-HD4 Trial1

Toxicity Progression Other Overall

Thalidomide 31% 31% 2% 64%

Bortezomib 9% 29% 9% 47%

It is essential to strike a balance between efficacy and safety when using novel agents as maintenance, especially since patients will be on therapy for an extended period of time.

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of intolerance. After a median follow-up of 2 years postrandomization tomaintenance, there was a significant improvement in PFS in the lenalido-mide arm (41 months vs 23 months, P<.001). The rates of grade 3/4 PN weresimilar in both groups. Grade 3/4 hematologic events were reported in 58%of patients on lenalidomide versus 23% on placebo, but these were manage-able with dose adjustments (down to 5 mg/day). The incidence of second pri-mary cancers was higher in the lenalidomide arm (3.1 vs 1.2 per 100 patient-years, P=.002). Overall, 21% of patients in the lenalidomide arm and 15% inthe placebo arm discontinued therapy due to toxicity.6

The phase 3 MM-015 trial randomized elderly, transplant-ineligible MMpatients to 9 cycles of melphalan, prednisone, and lenalidomide followed bylenalidomide maintenance (MPR-R), or to 9 cycles of MPR or MP withoutmaintenance.7,8 In this study, the scheduled dose of lenalidomide (duringinduction and maintenance) was 10 mg/day, given on days 1 to 21. Patientscould receive maintenance until disease progression or development of intol-erance. After a median follow-up of 27 months, PFS was significantly longerwith lenalidomide maintenance (31 vs 14 vs 13 months for MPR-R, MPR,and MP, respectively; MPR-R vs MP, P<.001).The most common adverse events were hematologic; these occurred more

frequently in patients who received lenalidomide. Grades 3 and 4 hemato-logic toxicities in this study are shown in Table 2. However, during themaintenance phase of MPR-R, the incidence of new or worsening toxicitieswas low. Discontinuation due to adverse events in the MPR-R, MPR, andMP arms was observed in 16%, 14%, and 5%, respectively. These rates werehigher in patients >75 years of age than in those 65 to 75 years of age, as wasthe need for dose reductions. Incidence of second primary malignancies waslow, corresponding to 3.04, 2.57, and 0.98 per 100 patient-years for MPR-R,MPR, and MP, respectively.8

BMT CTN-0702, a new phase 3 multicenter trial, will evaluate the safety

and efficacy of lenalidomide maintenance in 3 cohorts of patients.9 FollowingASCT, participants will proceed to either second transplant, consolidationwith lenalidomide, dexamethasone, and bortezomib (RVD), or maintenancewith lenalidomide. Patients undergoing second transplant and consolidationwill also receive maintenance therapy, which will start at 10 mg/day for 3months and increase to 15 mg/day. We are seeing RVD used more frequentlyas induction therapy in MM, so data from this study should be relevant toclinical practice.

What strategies are important to ensure optimal outcomes in themaintenance setting?

Certainly, it is important to consider safety and efficacy data from recentstudies in the decision-making process. Beyond that, factors such as conven-ience, cost, reimbursement, and, of course, toxicity profiles of specific agentsmust be considered so that therapy can be tailored to a patient’s needs. Thetreatment landscape for MM is constantly evolving; therefore, cliniciansmust also stay informed of new agents that are being investigated in clinicaltrials. For example, early data from phase 1/2 trials were recently released onthe use of the oral proteasome inhibitor MLN9708 in MM. In both newlydiagnosed and relapsed/refractory patients, treatment with this agent resultedin encouraging response rates with good tolerability, especially low rates ofPN.10,11 Based on these results, phase 3 trials are under way to further evaluatethe safety and efficacy of this agent in myeloma. �

References1. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4 randomized

phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed byhigh-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patientswith newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts).2010;116:Abstract 40.

2. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide fol-lowed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J ClinOncol. 2010;28:5101-5109.

3. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for mul-tiple myeloma: background and practical recommendations. Haematologica. 2010;95:311-319.

4. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals; January 2012.5. 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.

6. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell trans-plantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.

7. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diag-nosed multiple myeloma. N Engl J Med. 2012;366:1759-1769.

8. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-inel-igible newly diagnosed multiple myeloma: update on patients aged 65-75 years enrolled inMM-015. Presented at: 17th Annual Congress of the European Hematology Association; June14-17, 2012; Amsterdam, Netherlands.

9. ClinicalTrials.gov Web site. Stem cell transplant with lenalidomide maintenance in patientswith multiple myeloma (BMT CTN 0702). http://clinicaltrials.gov/ct2/show/NCT01109004.Updated March 28, 2012. Accessed July 3, 2012.

10. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigationaloral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiplemyeloma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8017.

11. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigationalproteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts)with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCOAnnual Meeting Abstracts). 2012;30(suppl):Abstract 8033.

Table 2. Select Grades 3 and 4 Hematologic Toxicities in theMM-015 Trial8

MP MPR MPR-R(Gr 3/4) (Gr 3/4) (Gr 3/4)

Neutropenia (%) 29/8 64/32 67/35

Thrombocytopenia (%) 12/4 38/12 35/11

Anemia (%) 14/1 26/3 24/3

MP indicates melphalan plus prednisone; MPR, melphalan, prednisone, lenalidomide;MPR-R, melphalan, prednisone, lenalidomide plus lenalidomide maintenance.

We are seeing RVD used more frequently as induction therapy in MM, so data from this studyshould be relevant to clinical practice.

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Oral Oncolytics

For the past few years, much atten-tion has been given to the develop-ment and US Food and Drug

Administration (FDA) approval of tar-geted oral chemotherapy agents. As ourknowledge of cancer and its molecularbiology increases, many targeted oralchemotherapy agents have become avail-able for use in clinical practice. Theemergence of oral chemotherapy agentshas provided alternative treatmentoptions and allowed patients to receivecancer treatment in the convenience oftheir home. While there are many advan-tages to oral chemotherapy treatment,there are also many safety concerns. Ashealthcare professionals, we must educatepatients and their caregivers on the use of these oral chemotherapy agents.Education should include but not be lim-ited to: (1) what side effects to expect(both acute and chronic); (2) how tomonitor, assess, and manage these sideeffects (are there over-the-counter prod-ucts that can be safely used to help mini-mize these side effects, and which sideeffects warrant immediate medical atten-tion); (3) what to do for missed doses(take as soon as remembered, or skip doseuntil next scheduled dose); (4) what todo if patients are not able to swallow(should dose be crushed or do we haveany information); (5) what precautionsto take in the safe handling of these oralchemo therapy agents (storage informa-tion, and proper disposal of these agents);and (6) the importance of oral adherenceand compliance to these medications toprovide effective treatment (do patientsand their caregivers fully understand thetreatment schedule, as it can be compli-cated to follow, etc). With the emergence of oral chemo -

therapy, adherence to oral chemotherapytreatment has become a concern formany healthcare professionals. In 2009,

the American Society of ClinicalOncology and the Oncology NursingSociety (ONS) published a practiceguideline on chemotherapy administra-tion safety standards,1 focusing on the 7domains of the chemotherapy adminis-tration process, which include the follow-ing: (1) review of clinical informationand selection of a treatment regimen; (2)treatment planning and informed con-sent; (3) ordering of treatment and pre-scription writing; (4) drug preparation;(5) assessment of treatment compliance;(6) administration and monitoring oftreatment; and (7) assessment of responseand toxicity monitoring. The guidelineindicates that adherence to standards for

safe chemotherapy administrationshould be the goal of all healthcareproviders in any oncology care settings,both inpatient and outpatient. Since itspublication, the safety standards haveprovided a framework for best practicethroughout the oncology practice arena,and many of these domains are tasksthat pharmacists can assist in providing.On June 14-15, 2011, the National

Coalition for Cancer Survivorship inpartnership with the National As -sociation of Social Workers, the ONS,and the Association of Oncology SocialWork sponsored an oral chemotherapyadherence train-the-trainer conferencein Washington, DC. Representatives in -cluded teams of 1 pharmacist, nurse, andsocial worker each from 11 medical cen-ters. Our medical center was privileged tobe one of the team participants. Topicsdiscussed at the conference included: (1)addressing oral chemotherapy adherence

through multidisciplinary teams; (2) stateof the science: adherence to oralchemotherapeutic agents; (3) barriers toadherence; and (4) motivational inter-viewing/active listening to promote oralchemotherapy adherence. Breakout dis-cussions were used to further identify bar-riers to successful adherence, tools andapproaches that might address these bar-riers, and how barriers to adherence canbest be resolved using a multidisciplinaryteam approach. At the conclusion of theconference, each of the team participantswas given the task of developing plans toimprove oral chemotherapy adherence intheir own institution practice settingsand community.

What was interesting for me to learnwas that there is no “gold standard” defi-nition of adherence, as most literatureexamining and evaluating oral adherenceoffers its own definition of adherence.2While nonadherence to oral chemother-apy agents is an important concern, over-adherence to oral chemotherapy agents isalso a major concern, as it poses a risk forincreases in unwanted side effects anddrug toxicities, something I am seeingmore frequently at our institution. Asmany oral chemotherapy agents haverestricted REMS (risk evaluation andmitigation strategies) distribution accessand require an FDA-approved medica-tion guide with dispensing, we must befamiliar with the use of oral chemothera-py agents and be able to provide educa-tion to other healthcare professionals,patients, and their caregivers. See theTable that accompanies the online ver-sion of this article for a summary of some

targeted oral chemotherapy agents withinformation on lab monitoring, commonside effects, and instructions for patienteducation.3-16While our own institution is collabora-

tively developing a plan of action toimprove oral chemotherapy adherence atour practice setting, some of you havealready implemented a program at yourinstitution. I ask that you continue toshare your developmental process andyour success with us through publicationsor at the Hematology Oncology Phar -m acy As sociation annual conference. �

References1. Jacobson JO, Polovich M, McNiff KK, et al. AmericanSociety of Clinical Oncology/Oncology Nursing Societychemotherapy administration safety standards. J ClinOncol. 2009;27:5469-5475.2. Given BA, Spoelstra SL, Grant M. The challenges oforal agents as antineoplastic treatments. Semin OncolNurs. 2011;27:93-103.3. Lam MS. Extemporaneous compounding of oral liquiddosage formulations and alternative drug delivery meth-ods for anticancer drugs. Pharmacotherapy. 2011;31:164-192.4.Crizotinib (Xalkori) full prescribing information [pack-age insert]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202570s000lbl.pdf. Accessed September8, 2011.5. Vemurafenib (Zelboraf) full prescribing information.http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf. Accessed September 8, 2011.6. Abiraterone (Zytiga) full prescribing information.http://www.zytiga.com/pdf/prescribing_information.pdf.Accessed September 8, 2011.7. Vandetanib (Caprelsa) full prescribing information.http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022405s000lbl.pdf. Accessed September 9, 2011.8. Sorafenib (Nexavar) full prescribing information.http://www.nexavar.com/html/download/Nexavar_PI.pdf.Accessed September 9, 2011.9. Sunitinib (Sutent) full prescribing information.http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021938s009lbl.pdf. Accessed September 10, 2011.10. Pazopanib (Votrient) full prescribing information.http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022465s002lbl.pdf. Accessed September 10, 2011.11. Everolimus (Afinitor) full prescribing information.http://www.pharma.us.novartis.com/product/pi/pdf/afinitor.pdf. Accessed September 20, 2011.12. Lapatinib (Tykerb) full prescribing information.http://us.gsk.com/products/assets/us_tykerb.pdf. AccessedSeptember 23, 2011.13. Lenalidomide (Revlimid) full prescribing informa-tion. http://www.revlimid.com/pdf/REVLIMID_PI.pdf.Accessed September 20, 2011.14.Thalidomide (Thalomid) full prescribing information.http://www.revlimid.com/docs/Revlimid-Full-PI.pdf.Accessed September 20, 2011.15. Erlotinib (Tarceva) full prescribing information.http://www.gene.com/gene/products/information/pdf/tarceva-prescribing.pdf. Accessed September 23, 2011.16. Capecitabine (Xeloda) full prescribing information.http://www.gene.com/gene/products/information/xeloda/pdf/pi.pdf. Accessed September 23, 2011.

Updates on Oral ChemotherapyAdherence—Where Are We Today?By Betty M. Chan, PharmD, BCOPUSC/Norris Cancer Hospital, Los Angeles, California

While there are many advantages to oral

chemotherapy treatment, there are also many safety

concerns. As healthcare professionals, we must

educate patients and their caregivers on the use of

these oral chemotherapy agents.

To see the Table that accompanies this article, go to www.TheOncologyPharmacist.com

The Table provides a summary of lab monitoring, side effects, and patient education on targeted oral chemotherapy agents. Information is provided for crizotinib, vemurafenib, abiraterone, vandetanib, sorafenib, sunitinib, pazopanib, everolimus,

lapatinib, thalidomide, lenalidomide, erlotinib, and capecitabine.

patients received 10 weeks of the alter-nate treatment. The primary end pointwas patient preference, measured at 22weeks. Because patients with mRCC re -

ceive therapies for many months oreven years, the team assessed whetherthe drug toxicity would be significantenough to make patients want to con-tinue treatment with either drug or toswitch therapy.A total of 126 patients completed a

preference questionnaire. In the pri-mary analysis, 70% of the patients pre-ferred pazopanib, 22% preferred suni-tinib, and 8% cited no preference.After adjustments for a modestsequence effect, the difference in pref-erence was 49% in favor of pazopanib.All other analyses showed a significantpreference for pazopanib.

The most common reasons givenfor pazopanib preference were betterQOL and less fatigue. Patients takingpazopanib had fewer dose reductionsthan those taking sunitinib (13% vs20%, respectively) and fewer treat-ment interruptions (6% vs 12%).Adverse events were compatible withknown profiles for both drugs.The researchers, led by Bernard J.

Escudier, MD, from the InstitutGustave Roussy, Villejuif, France,said that they expected patients toprefer one drug over the otherbecause of adverse effects, but “wedidn’t ever expect such a big differ-ence between the 2 drugs.”Physicians may perceive toxicity

differences between 2 different thera-pies as relatively minor, but topatients, even low-grade toxicitiesover a long period have a significanteffect on QOL, according to Escudierand colleagues. How patients feelwhen they take a drug over manymonths is not reflected in traditionalreporting of adverse events.A survey on physician therapy

preferences, which was a secondaryend point in this study, showed somedifference in physicians’ drug prefer-ences: 61% preferred pazopanib, 22%preferred sunitinib, and 17% had nopreference.

Patient-reported outcomes are in -creasingly being added to traditionalefficacy outcomes to better under-stand the clinical relevance of differ-ences in drug toxicities, Escudier andcolleagues noted. �

ReferenceEscudier BJ, Porta C, Bono P, et al. Patient preferencebetween pazopanib (Paz) and sunitinib (Sun): results ofa randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carci-noma (mRCC)—PISCES study, NCT 01064310.Presented at: 2012 Annual Meeting of the AmericanSociety of Clinical Oncology; June 2012; Chicago, IL.Abstract CRA4502.

Quality of Life Drives Patient Preference... Continued from cover

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Join us on our journey to realizethe tremendous possibilities ofimproving cancer prevention,diagnosis, and treatment througha new medical model of personalized care.

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Bernard J. Escudier, MD

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Conference News: ASCO 2012

Patients with breakthrough chemo -therapy-induced nausea and vom-iting (CINV) can gain superior

relief from olanzapine (Zyprexa), a drugapproved by the US Food and DrugAdministration as an antipsychotic,compared with standard antiemetic ther-apy with metoclopramide. The resultsfrom this phase 3 study address an impor-tant unmet need for patients who expe -

rience these side effects despite beinggiven standard antiemetic therapy.“Breakthrough CINV usually occurs

on day 2 through 4 after chemotherapy,despite guideline-directed prophylaxis.This study found that olanzapine is sig-nificantly better than metoclopramidein controlling CINV in this group ofpatients,” stated lead author RudolphNavari, MD, PhD, of the University of

Indiana in Indianapolis. Olanzapine achieved superior emesis

control at 72 hours: 71% of those receiv-ing olanzapine had no emesis versus 32%of those treated with metoclopramide (P<.01). Patients treated with olanzapinealso had significantly im proved controlof nausea: 67% of the olanzapine groupversus 24% of the metoclopramide grouphad complete control of nausea (P <.01).

No patient experienced any grade 3 or4 toxicity, and no central nervous systemadverse events were seen in this short-term study comparing the 2 drugs.Olanzapine is known to have severaladverse effects when used as long-termantipsychotic therapy, but Navariemphasized that these effects were notseen with short-term administration ofthe drug.“This is the first study to show a treat-

ment is effective in breakthroughCINV,” Navari stated.

The study included 205 chemother-apy-naive patients receiving highlyemetogenic chemotherapy who weregiven standard drugs to control CINV.Of these, 80 experienced breakthroughCINV on standard therapy and wererandomized 1:1 to olanzapine 10 mgorally daily for 3 days versus metoclo-pramide 10 mg TID for 3 days. Patientswith breakthrough CINV were ob -served for 72 hours and were asked tofill out a daily diary.Incoming American Society of

Clinical Oncology President SandraSwain, MD, said, “This study was areminder that in the era of precisionmedicine, we still need to improve thepatient experience. CINV can be quitelimiting. Patients don’t eat and they canbe tired. Olanzapine is another tool wenow have to treat this side effect.” �

ReferenceNavari RM, Nagy CK, Gray SE. The use of olanzapineversus metoclopramide for the treatment of break-through chemotherapy-induced nausea and vomiting(CINV) in patients receiving highly emetogenicchemotherapy. Presented at: 2012 Annual Meeting ofthe American Society of Clinical Oncology; June 2012;Chicago, IL. Abstract 9064.

Olanzapine Effective Antiemetic for Breakthrough CINVBy Alice Goodman

The antidepressant duloxetine(Cymbalta) appears to reducepainful peripheral neuropathy

associated with taxane- or platinum-based chemotherapy in some, but notall, patients, according to a randomizedphase 3 study presented at the 2012Annual Meeting of the AmericanSociety of Clinical Oncology (ASCO).About one-third of patients treatedwith duloxetine reported at least a 30%or greater reduction in pain scores ver-sus 17% of placebo patients. “Unfortunately, no medication is

completely effective. Duloxetine isn’tperfect and did not work for everypatient in our study, but it was effectivefor a majority of patients. This was thefirst randomized trial to show that anydrug is effective for this terrible pain,”stated lead author Ellen M. LavoieSmith, PhD, assistant professor in theSchool of Nursing at the University ofMichigan in Ann Arbor.Painful peripheral neuropathy, which

affects 20% to 30% of patients treatedwith taxane- or platinum-based chemo -therapy, can be debilitating, interferingwith the ability to perform activities ofdaily living. Thus far, there is no estab-lished effective treatment for this adverseevent, which can persist for years afterchemotherapy is completed.The study randomized 231 patients to

duloxetine followed by placebo versusplacebo followed by duloxetine; 220patients received the initial treatmentwith 187 patients completing the initialtreatment period. All patients reportedhigh levels of pain from peripheral neu-ropathy prior to enrollment. Duloxetine

was given as one 30-mg oral capsule perday for 1 week, followed by 2 capsules perday (60 mg) for 4 more weeks. “The gradual dosing was employed to

reduce the side effects of duloxetine,which can include fatigue, dry mouth,sleepiness, and nausea,” Smith said.

Patients completed the Brief PainInventory–Short Form survey at baselineand then every week. Decrease in painscores was reported by 59% of the dulox-etine-treated patients versus 38% forplacebo. Thirty-three percent of theduloxetine group reported at least a 30%decrease in pain severity, and 21%reported at least a 50% decrease in painseverity. No change in pain score was seen in

30% of the duloxetine group and 34%of placebo patients. Pain was increasedin 11% of those taking duloxetine ver-sus 28% of placebo patients. No differ-ence in duloxetine efficacy was

observed based on the specific neuro-toxic chemotherapy given. “Patients treated with duloxetine

enjoyed a greater decrease in theamount of pain that interfered withgeneral activity, mood, walking, work,enjoyment of life, and social relation-ships,” Smith told listeners. Severe (grade 3) nonhematologic

toxicity was seen in 11% of those whoreceived duloxetine, and 41% reportedmoderate (grade 2) toxicity. Grade 2 orhigher fatigue was the most commonadverse event in the duloxetine-treat-ed patients, reported in 11% versus 3%of placebo patients. Less than 10%experienced fatigue, insomnia, nausea,somnolence, or dizziness.The incidence of adverse events

was lower than in previous trials ofduloxetine for diabetic neuropathy,which Smith attributed to the lowerstarting dose in this trial.Gabapentin has been used off label for

chemotherapy-related peripheral neu-ropathy, but it causes somnolence,explained Hope Rugo, MD, of theUniversity of California San Francisco,who commented on this paper during apress conference. “Duloxetine doesn’thave that side effect, so it could beadvantageous for patients who needtreatment for peripheral neuropathy,”Rugo said. � —AG

ReferenceLavoie Smith EM, Pang H, Cirrincione C, et al.CALGB 170601: a phase III double blind trial ofduloxetine to treat painful chemotherapy-inducedperipheral neuropathy (CIPN). Presented at: 2012Annual Meeting of the American Society ofClinical Oncology; June 2012; Chicago, IL.Abstract CRA9013.

Visit our user-friendly Web sitewww.TheOncologyPharmacist.com

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Duloxetine in Peripheral Neuropathy

Painful peripheral

neuropathy, which affects

20% to 30% of patients

treated with taxane- or

platinum-based

chemotherapy, can

be debilitating.

“This study was a

reminder that in the era

of precision medicine, we

still need to improve the

patient experience.”

—Sandra Swain, MD

Ginseng has significant activityagainst fatigue in adults withcancer, according to a random-

ized trial.1 Eight weeks of treatment withginseng significantly improved fatiguescores by 20% versus 10% for patientstreated with placebo (P = .003). More -over, ginseng was as safe as placebo in thispreliminary trial.Fatigue is almost universally com-

mon in patients treated for cancer, andmany patients continue to experiencefatigue for up to 10 years after theirtreatments are completed, explainedlead author Debra Barton, RN, PhD, ofthe Mayo Clinic Cancer Center inRochester, Minnesota. Erythropoietinhad been used to treat cancer-relatedfatigue, but it is no longer used becauseserious adverse events were found tooutweigh the benefits.

The trial enrolled 364 cancer patientsbeing treated with curative intent at 40sites; all patients reported at least moder-ate fatigue, reflected by a score of 4 orhigher on a 10-point fatigue scale. Othercauses of fatigue were ruled out, includinganemia, pain, and insomnia. Patients received double-blind, ran-

domized assignment to 2000 mg/day ofground Wisconsin ginseng root in theform of 2 capsules or to placebo takenbefore noon for 8 weeks. Mean age was55 years, about 80% were female, andabout 90% were white. About 60%had breast cancer, and about 10% hadcolon cancer.Pain scores improved over the course

of treatment. At 4 weeks, a trend wasseen favoring ginseng, according tochange on the 100-point Multi -dimensional Fatigue Symptom In -ventory score: an improvement of 14.4points was reported with ginseng versusan 8.2 improvement in placebopatients (P = .07). By 8 weeks, scoresimproved by 20 points from baseline inthe ginseng group versus 10.3 pointswith placebo (P = .003).Rates of nausea, diarrhea, and vomit-

ing were quite low and were similar in the2 groups. Insomnia and anxiety werereported less often in the ginseng groupthan in the placebo patients. Grade 3 or4 adverse events were reported in 8% and6% of patients, respectively.

Formal discussant of this trial, KarenM. Mustian, PhD, MPH, of theUniversity of Rochester, New York, com-mended the authors for using well-vali-dated measures of cancer-related fatigue.“Ginseng has no discernible toxicity.This is only the second nutritional sup-plement to show effectiveness in reduc-

ing cancer-related fatigue,” she said. The NCCN guidelines for cancer-

related fatigue recommend psychologicalintervention, physical activity, psycho -stimulants, and steroids.2 Mustian said,“It may be time to recommend specificnutritional supplements, such as ginseng.” � —AG

References1. Barton DL, Liu H, Dakhil SR, et al. Phase III evalua-tion of American ginseng (panax quinquefolius) toimprove cancer-related fatigue: NCCTG trial N07C2.Presented at: 2012 Annual Meeting of the AmericanSociety of Clinical Oncology; June 2012; Chicago, IL.Abstract 9001.2. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology: Cancer-RelatedFatigue. Version 1.2012. http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Accessed June 12, 2012.

Ginseng Improves Cancer-Related Fatigue


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