August 2012, Vol 5, No 5 by The Oncology Pharmacist

AUgUst 2012

www.theOncologyPharmacist.com

VOl 5, NO 5

CANCER CENTER PROFILE

BREAST CANCER

University of Arizona Cancer Center

T-DM1 in Metastatic Breast Cancer

The Expanding Role of the Oncology Pharmacist By Alice Goodman

It’s Just the Beginning for an Exciting New Class of Agents By Caroline Helwick

he biggest newsmaker at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) was a compound whose name and actions sound practically missilelike: T-DM1. Because of its highly targeted and potent effect that spares surrounding

healthy tissue, T-DM1 not only has potent antitumor effects but is also very well tolerated. Trastuzumab emtansine (T-DM1) is part of an emerging class of drugs called antibody-drug conjugates (ADCs) that link a monoclonal antibody (in this case, Continued on page 4

RENAL CELL CARCINOMA

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

Quality of Life Drives Patient Preference for Metastatic Renal Cell Carcinoma Drug

Photo courtesy of the University of Arizona Cancer Center.

By Wayne Kuznar

he University of Arizona Cancer Center (UACC) in Tucson is 1 of 41 National Cancer Institute (NCI)-designated comprehensive cancer centers in the United States. Called a “high-performing” center by US News & World Report, the center has 29 beds on 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

Continued on page 7

he surprising results of a randomized trial on patient preference for one cancer therapy over another show that patient-reported quality-of-life (QOL) differences influence treatment preference far more than physicians had imagined, suggested researchers at the 2012 Annual Meeting of the American

Society of Clinical Oncology, held in Chicago, Illinois. In a double-blind, crossover trial, 169 patients with metastatic renal cell carcinoma (mRCC) were randomized 1:1 to 10 weeks of 800 mg of pazopanib or 50 mg of sunitinib as first-line cancer treatment; after a 2-week washout period, Continued on page 25

CONFERENCE NEWS: MASCC

Advances in Supportive Care By Alice Goodman

t the recent 2012 symposium of the Multinational Association of Supportive Care in Cancer (MASCC), held in New York City, experts discussed a wide range of topics related to management of treatmentinduced side effects. Below are some highlights from the MASCC annual symposium.

Management of Febrile Neutropenia Advances over the past few decades have led to reduced morbidity and mortality from chemotherapy-induced febrile neutropenia (FN). FN was once considered fatal, but in the modern era, mortality is about 5% and FN-related

INSIDE Drug Shortage

oral onColytiCS

Exploring the Drug Shortage Crisis . . . . . . . . . . . . . . . . . . 14

Updates on Oral Chemotherapy Adherence—Where Are We Today?

Quantifying the Drug Shortage: One Center’s Experience . . . . . . . . . . . . . . . . . . . . . . 15

ConferenCe newS: aSCo 2012

Complimentary Ce

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Considerations in Multiple Myeloma—Ask the Experts: Maintenance Settings

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Olanzapine Effective Antiemetic for Breakthrough CINV . . . . . . . . . . 26 Duloxetine in Peripheral Neuropathy . . . . . . . . . . . . . . . . . . . . . 26 Ginseng Improves CancerRelated Fatigue . . . . . . . . . . . . . . . . . 27

IV R FO AND D S ON E V OU TI O R NE TRA P AP UTA INIS C M B SU AD

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 Information INDICATION VELCADE is indicated for the treatment of patients with multiple myeloma.

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

Breast Cancer

trastuzumab) to a cytotoxic agent (in this case, a potent antimicrotubule agent DM1 [a derivative of maytansine]). “First and foremost, the design of an ADC centers on the selection of an antigen that is tumor specific and accessible to antibody binding at the

tumor cell,” explained Howard A. Burris III, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee. T-DM1, with its ability to bind HER2 with the same affinity as trastuzumab, maintains the activity of trastuzumab in addition to providing

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.

intracellular delivery of the antimicrotubule agent DM1. Presumably, the binding of T-DM1 to HER2 receptors leads to receptor internalization, followed by lysosomal degradation. Activated DM1 is then released from the lysosome into the cellular cytoplasm, which inhibits microtubule

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

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Photo © ASCO/Todd Buchanan 2012.

T-DM1 in Metastatic Breast Cancer Continued from cover

Kimberly L. Blackwell, MD, at the ASCO 2012 Annual Meeting.

assembly and causes cell death, Burris explained at an educational session on ADCs. Potent cytotoxic agents are necessary for maximizing the role of the drug conjugates, a requirement that maytansine fills; however, its toxicity was prohibitive. Researchers recently improved the therapeutic index through conjugation with trastuzumab, leading to the development of its derivative, DM1. The in vitro cytotoxicity of DM1 is 10 to 200 times greater than that of taxanes. The compound also requires a highly stable linker: heterobifunctional reagent, Nsuccinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC).

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. EMILIA Shows the Drug’s Potential At the ASCO plenary session, investigators reported early results of the international phase 3 EMILIA study of TDM1 in metastatic breast cancer patients (Abstract LBA1). In a population of 991 advanced or metastatic patients who had already received trastuzumab and taxanes, treatment with T-DM1 was associated with an approximately 30% increase in progression-free survival (PFS) compared Continued on page 8

AUGUST 2012 I VOL 5, NO 5

www.TheOncologyPharmacist.com

Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Oklahoma University College of Pharmacy Tulsa, OK

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

ASSOCIATE EDITOR-IN-CHIEF

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN

Jim Koeller, MS

Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA

John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Burt Zweigenhaft, BS

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

BioPharma Partners LLC New York, NY

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

USC/Norris Cancer Hospital Los Angeles, CA

OncologyPharmacist.net Warwick, RI

Laura Boehnke Michaud, PharmD, BCOP, FASHP

John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

Marlo Blazer, PharmD, BCOP

The University of Texas MD Anderson Cancer Center Houston, TX

James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

www.TheOncologyPharmacist.com

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

AUGUST 2012 I VOL 5, NO 5

From the Editors PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Director, Client Services Joe Chanley joe@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com

Patrick Medina, PharmD, BCOP Editor-in-Chief

n this issue of The Oncology Pharmacist (TOP), we continue our coverage of the news from the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). Some of the most exciting news involves trastuzumab emtansine (T-DM1), part of an emerging class of targeted agents called antibody-drug conjugates. The promising early results have excited many healthcare professionals, and we at TOP will be following the results of the clinical trials involving TDM1. The drug shortage situation was also addressed at ASCO, and we report on the experience of a New York cancer center where “about 10% of the patients…treated had an actual change in treatment,” according to one of the researchers who presented the results of the study.

Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino Production Manager Stephanie Laudien Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Jackie Luma Circulation Department circulation@greenhillhc.com Editorial Contact: Telephone: 732-656-7935 Fax: 732-656-7938

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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.

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. BPA Worldwide membership applied for April 2011.

This issue starts our coverage of the Multinational Association of Supportive Care in Cancer International Symposium, held in July in New York City. Our coverage includes acknowledgment that diarrhea is a problematic side effect for patients even in the era of molecularly targeted treatments. Betty Chan, PharmD, BCOP, provides an update of oral chemotherapy adherence and notes the lack of a “gold standard” definition of adherence. Be sure to visit the TOP Web site at www.TheOncologyPharmacist.com to view the table that accompanies her article. The table summarizes information about lab monitoring, common side effects, and instructions for patient education for some targeted oral chemotherapy agents. ●

Noteworthy Numbers

1249 South River Road, Suite 202A Cranbury, NJ 08512

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

AUGUST 2012 I VOL 5, NO 5

In 2012, an estimated 73,510 adults in the United States (55,600 men and 17,910 women) will be diagnosed with bladder cancer. Approximately 14,880 deaths (10,510 men and 4370 women) will occur from this disease. Bladder cancer rarely occurs in patients under the age of 40 years. In fact, about 9 out of 10 people with this cancer are older than 55, and the average age at the time of diagnosis is 73 years. A man’s chance of developing bladder cancer during his lifetime is about 1 in 26. A woman’s chance of being diagnosed with this cancer is about 1 in 86.

Whites are diagnosed with bladder cancer almost twice as often as blacks, and Hispanics have an even lower incidence rate than blacks. About half of those diagnosed with bladder cancer have nonmuscle-invasive/ superficial urothelial carcinoma, and the 5-year survival rate is 98%. Approximately 35% of bladder cancer patients have a tumor that is invasive but has not yet spread outside the bladder. The 5-year survival rate for these patients is 75%. For the more than 500,000 people in the United States who are survivors of this cancer, the American

Urological Association recommends patient assessment every 3 months in the first 2 years after initial diagnosis followed by every 6 months for the subsequent 2 to 3 years, and then annually thereafter. Sources www.cancer.org/Cancer/BladderCancer/ DetailedGuide/bladder-cancer-what-iscancer; www.cancer.net/patient/Cancer+ Types/Bladder+Cancer?sectionTitle=Statis tics; www.auanet.org/content/guidelinesand-quality-care/clinical-guidelines/ main-reports/bladcan07/chapter1.pdf.

For the Record In the June issue of The Oncology Pharmacist, the improvement in overall survival (OS) and radiographic progression-free survival (PFS) data presented in the Androgen Blockers Score Big in Prostate Cancer news brief was incorrect. With respect to enzalutamide, the improvement in OS is 4.8 and the improvement in PFS is 5.4 compared with placebo. We apologize for the error.

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Cancer Center Profile University of Arizona Cancer Center Continued from cover Grove Campus offers clinic/office visits, infusions, and radiation oncology. Surgery and radiation oncology services are also offered at the University Campus hospital center. In the fiscal year of 2011, 8560 patients were treated at UACC for solid tumor, soft tissue, and skin and blood cancers. UACC is best known for its specialties: lymphoma, skin cancer and melanoma, gastrointestinal cancer, gynecologic cancer, and breast cancer. UACC encompasses 11 multidisciplinary clinics for major disease sites, as well as a separate clinic for high-risk cancer genetics. Research is a major focus at UACC. Currently, more than 200 clinical trials are open for enrollment at UACC. These include: • Study to determine if ursodeoxycholic acid (a natural bile acid) can reverse the cellular damage of Barrett’s esophagus. • Research to see if taking high-dose vitamin D (cholecalciferol) twice a week for 8 to 9 weeks prevents skin cancer in people with sun damage and low levels of vitamin D. • Study in breast cancer patients or women at high risk who are taking tamoxifen to determine if a supplement called diindolylmethane (DIM) can reduce risk of cancer recurrence. • I-SPY2 breast cancer trial, which is a collaborative study to obtain genetic and biological markers from individual patients’ tumors to screen several promising treatments simultaneously. UACC is affiliated with St. Joseph’s Hospital and Medical Center in Phoenix, and the Cancer Centers of Northern Arizona Healthcare in Sedona. UACC’s research facility has 73 laboratories and about 300 researchers drawn from the University of Arizona and other institutions. The Oncology Pharmacist interviewed Daniel Butcher, PharmD, Outpatient Oncology Pharmacy Supervisor, at the University of Arizona Cancer Center to get his perspective on the role of the oncology pharmacist at his institution.

What approach does the University of Arizona Cancer Center take to treat people with cancer? Daniel Butcher (DB): We are an NCIdesignated comprehensive cancer center that employs experts in all related fields. We use a multidisciplinary approach for each patient to identify the best treatment options. How does your approach translate to better outcomes for your patients?

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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.

DB: The multidisciplinary approach is based on the recognition that a diagnosis of cancer has physical and psychological ramifications. With our pool of experts, we are well equipped to address the entire disease spectrum and to help with healing. We provide active supportive care for treatment-related and diseaserelated side effects as well as for healing, with psychological and family support.

How has the role of the oncology pharmacist changed over the past 5 years? DB: It is exciting to see that the oncology pharmacist is needed more now than ever before. Our role has expanded significantly from compounding and dispensing drugs to helping manage patients with complex diseases and therapies. I firmly believe that oncology

“Our role has expanded significantly from compounding and dispensing drugs to helping manage patients with complex diseases and therapies.” —Daniel Butcher, PharmD

What are you excited about in the field of oncology? DB: Research. Since we are an NCI-designated comprehensive cancer center, a lot of studies are being conducted at our site. Trying to keep up with current studies can be daunting. It is rewarding to watch agents that we have studied make it to the marketplace; for example, nab-paclitaxel (Abraxane) and ipilimumab, an immunotherapy for melanoma. We can have disappointing results as well. Initially, we had the impression that CVAX would be an effective treatment for melanoma, but then the trial was halted because results were not promising.

pharmacists can ease the burden on our providers by implementing collaborative practice agreements that allow us to apply our specialized knowledge. This can have a financial impact. New therapies are extremely expensive and I believe we can guide appropriate use of these therapies to improve outcomes for patients.

What inspired you to become an oncology pharmacist? DB: When I was in pharmacy school, I became interested in oncology drugs. I found the biology fascinating, including the prepharmacy courses about DNA and RNA and the biological underpin-

nings of cancer. My job as an oncology pharmacist is an extension of that. One in 4 deaths in the US are due to cancer. I felt I had the necessary qualifications to help cancer patients.

What advice would you give to oncology pharmacists just entering the field? DB: Oncology can be overwhelming and the work environment is complex. One piece of advice is not to be afraid to ask questions. You are working with patients at the most stressful time in their lives and the work can be emotionally taxing. Be sure to have a planned outlet to process your work experiences in a positive manner. You will see the full range of emotions with your patients, like an emotional roller coaster. You will need a good support system to provide balance. Learn from your patients. They are a valuable educational resource on a daily basis. Your clinical experience with patients is as important as reading journals. If you were not an oncology pharmacist, what would you be doing? DB: The quality that attracted me to oncology is an interest in how things work. I think I would be a mechanical engineer or a nuclear physicist. When I was a kid, I would take apart appliances and other household items to see how they worked, and I always managed to put them back together in working order. ●

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Breast Cancer 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 Duke University, Winston-Salem, North Carolina. Louis Weiner, MD, director of the

Georgetown-Lombardi Comprehensive Cancer Center in Washington, DC, the invited discussant of the study, commented, “Stated simply, T-DM1 really works in this patient population. It is an important new weapon in the therapeutic armamentarium for breast cancer.” Patients received intravenous T-

DM1 or capecitabine plus lapatinib every 3 weeks until disease progression. Those getting T-DM1 had a median PFS of 9.6 months, compared with 6.4 months for those on capecitabine/lapatinib. This represented a 35% reduction in the risk of progression (P <.0001), Blackwell reported.

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YOUR QUESTIONS ANSWERED

™

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine

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

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University

really works in this patient population. It is an in the therapeutic

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

armamentarium for breast cancer.” —Louis Weiner, MD

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.

ALL NEW CONTENT FOR 2012 Accreditation These 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.

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“Stated simply, T-DM1

important new weapon

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.

Median overall survival was not reached with T-DM1, and was 23.3 months with standard treatment, for a 38% reduction in mortality risk (P = .0005). This did not, however, meet the prespecified threshold for statistical significance for this end point at the first analysis. Nevertheless, after 2 years, 65.4% of the T-DM1 patients were alive, compared with 47.5% of the conventionally treated group. “There is an apparent survival benefit with T-DM1,” Blackwell said. It is expected that further analyses will show a survival difference. Tolerability was far better with T-DM1 as well. Dose reductions were required for 16.3% 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 typically observed with the chemotherapy regimen were not seen.

The Future of T-DM1 Additional trials are now being conducted to evaluate T-DM1 as first-line treatment, including 2 randomized multicenter phase 3 trials of the drug in earlier lines of therapy. The MARIANNE trial is comparing the efficacy and safety of T-DM1 alone and in combination with pertuzumab—another drug with striking activity in breast cancer when combined with trastuzumab. The experimental combination will be compared with the standard trastuzumab/taxane regimen, Burris noted. Burris concluded, “T-DM1 meets the criteria for a successful ADC by combining the targeted effect of trastuzumab with the cytotoxic potency of DM1 using a stable linker and minimizing systemic toxicity. In addition, other tumor histologies, such as gastrointestinal cancers that are HER2-positive, may be sensitive to this agent.…An aggressive portfolio of phase 2 and 3 clinical trials will help determine the role of T-DM1 in earlier lines of therapy or with combination of other targeted agents.” ●

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Conference News: MASCC Advances in Supportive Care Continued from cover morbidity is about 20% to 30%. Complications can include hypotension, respiratory failure, intensive care unit admission, and confusion. The MASCC scoring system for FN and the use of granulocyte colonystimulating factor (G-CSF) for prevention of FN in high-risk patients are the most important advances over the past 2 or 3 decades, explained Jean Klastersky, MD, Institut Jules Bordet, Université Libre de Bruxelles, Belgium. “Mortality and morbidity are greatly reduced, and therapies are simpler, less toxic, and appropriately delineated according to patients’ risk status,” Klastersky told the audience. “Despite this progress, numerous challenges remain in patients at high risk, and further study is needed to define the optimal use of G-CSF.” “Even a 5% mortality rate is too high,” he continued. “Some of the patients who die are young and treated with curative therapy.” Treating an episode of FN is expensive, with much of the direct treatment costs driven by G-CSF. The mean cost of treating 1 episode of FN is $7700 for outpatients, and $15,231 for inpatients. “The cost is reduced by 50% if you can treat on an outpatient basis,” he said. The MASCC scoring index, developed in 2000, enables risk stratification of patients who develop FN. A score >21 predicts a low risk of complications (ie, <5%). These patients can be treated with oral antibiotics as outpatients. Prerequisites for oral antibiotic therapy include: (1) low risk on MASCC scoring index, (2) feasibility of oral antibiotics, and (3) 24-hour hospitalization period for observation. The rates of mortality and complications are higher in patients with a MASCC index score <15 versus >21. Mortality from gram-negative bacteremia is 43% in patients with a MASCC score <15, Klastersky noted. “A low MASCC score predicts for severe sepsis. We need protocolized approaches for patients with FN and poor MASCC score. Some of these patients are kept too long in the emergency department—for several hours— without antibiotics. We should be more aggressive in selecting patients at high risk,” he continued. The possibility of preventing FN with G-CSF has moved the field forward. Prophylactic use of G-CSF can decrease the incidence by about 50% and reduce mortality as well. The management algorithm for G-CSF is based on economic considerations, Klastersky noted, and now it is given when the risk of FN is >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 and mortality as high-risk patients, and studies show that low-risk patients derive a similar benefit from G-CSF. Klastersky suggested expanding criteria

for use of G-CSF as primary prophylaxis and exploring the possibility of shorter schedules for this expensive therapy. Scrambler Therapy for Chemotherapy-Induced Peripheral Neuropathy Current treatments for chemothera-

py-induced peripheral neuropathy (CIPN) are suboptimal, according to Charles Loprinzi, MD, Mayo Clinic, Rochester, Minnesota. Drugs such as duloxetine, venlafaxine, and gabapentin are sometimes used off label and are not universally effective. Continued on page 10

Announcing: J-code for YERVOY™ (ipilimumab) J9228 Indication YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.1

Replaces J9999, J3490, J3590, and C9284.

Product Description

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

200-mg/40 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

The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide specific 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 specific insurer requirements. Access Support™, the Bristol-Myers Squibb Oncology reimbursement services program, offers patient assistance support, benefits 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 offices’ reimbursement services needs of their insured and uninsured patients. You can also find information online at www.bmsaccesssupport.com

Important Safety Information 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.

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

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Conference News: MASCC Advances in Supportive Care Continued from page 9 A recent study presented at the 2012 Annual Meeting of the American Society of Clinical Oncology showed that duloxetine reduced pain associated with CIPN by 30% in about onethird of patients. Although this reduction was clinically meaningful according to the authors, about two-

thirds of patients did not get better. Venlafaxine and gabapentin are used off label based on anecdotal evidence. Loprinzi said that scrambler therapy “may offer a glimmer of hope” in this setting. A previous pilot study found that scrambler therapy reduced pain scores by 59% in 52 patients with neu-

ropathic pain (Smith TJ, et al. J Pain Symptom Manage. 2010;40(6):883-891). “At first I was skeptical about using scrambler therapy for CIPN, but I am encouraged by results of a pilot study at our institution,” he told listeners. Scrambler therapy uses a device to treat pain via noninvasive cutaneous

electrostimulation, substituting “pain” messages with “nonpain” messages; the device generates 16 different current patterns to stimulate nerve action potentials. At MASCC, Deirdre R. Pachman, MD, Mayo Clinic, reported experience with scrambler therapy in the first 11 patients with CIPN-related pain: 8 were

Important Safety Information (cont) Recommended Dose Modifications Withhold 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: t Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day t Failure to complete full treatment course within 16 weeks from administration of first dose t 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: t 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 t 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 t Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immunemediated enterocolitis following inadequate response to corticosteroids t 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 t 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 t 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: t 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% t 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) t 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 t 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 t Withhold YERVOY in patients with Grade 2 hepatotoxicity Immune-mediated Dermatitis: t 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 t There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis t 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 t 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

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

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Conference News: MASCC women, and 3 were men; mean age was 57 years; patients had been exposed to various chemotherapy regimens; and the majority of patients had symptoms for more than 2 years. After 10 days of treatment, scrambler therapy decreased the average daily CIPN score (measuring pain, numbness, and tingling) as well as the worst daily CIPN score for these symp-

After 10 days of treatment, scrambler therapy decreased the average daily CIPN score (measuring pain, numbness, and tingling). toms. Numbness was decreased by about 30% over 10 days, and pain and tingling were reduced by about 40%.

Loprinzi and colleagues plan to conduct a prospective, placebo-controlled trial to confirm these findings.

Control of Grade 1 Diarrhea Important In the molecularly targeted therapy era, severe diarrhea continues to be a problematic side effect and accounts for increased resource utilization if not controlled. “If grade 1 diarrhea is not appropriately treated, diarrhea can quickly spiral Continued on page 12

Important Safety Information (cont) t 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: t 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 t Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported t 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 t 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: t 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 insufficiency, hypogonadism, and hypothyroidism – 6 of the 9 patients were hospitalized for severe endocrinopathies t Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome t Median time to onset of moderate to severe immunemediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY t 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 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 t 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: t In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia t 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 t Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions t Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy Pregnancy & Nursing: t YERVOY is classified 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 benefit justifies the potential risk to the fetus t 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 t 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: t 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%)

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Conference News: MASCC Advances in Supportive Care Continued from page 11 down to grades 2, 3, and 4 and risk of hospitalization and death,â&#x20AC;? Lowell Anthony, MD, Louisiana State University School of Medicine, New Orleans, told supportive care experts at MASCC. â&#x20AC;&#x153;Only you can really prevent the spiral of diarrhea.â&#x20AC;? Conventional chemotherapy agents,

such as fluorouracil (5-FU), irinotecan, paclitaxel, and epirubicin, cause diarrhea. With good supportive care, these drugs can be used in clinical practice. â&#x20AC;&#x153;Even giving 5-FU via different routes is still associated with 10% to 20% severe diarrhea. An incidence of >20% is not acceptable,â&#x20AC;? he said.

Targeted agents, including bevacizumab, epidermal growth factor receptor inhibitors, sunitinib, and sorafenib, have an additive risk of diarrhea when combined with chemotherapy. â&#x20AC;&#x153;The only good news is that the rate of grades 3 and 4 diarrhea [with these agents] is under 10%, but they increase the rates of grades

YERVOYâ&#x201E;˘ (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (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 3â&#x20AC;&#x201C;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 1.6â&#x20AC;&#x201C;13.4) and 6.3 weeks (range 0.3â&#x20AC;&#x201C;18.9) after the initiation of YERVOY for patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3â&#x20AC;&#x201C;5 enterocolitis were treated with high-dose (â&#x2030;Ľ40 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 3â&#x20AC;&#x201C;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 3â&#x20AC;&#x201C;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 biopsyproven hepatitis to characterize the clinical course of this event.

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-BarrĂŠ 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-BarrĂŠ 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-BarrĂŠ-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 3â&#x20AC;&#x201C;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 Cushingâ&#x20AC;&#x2122;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 immunemediated 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]

Permanently discontinue YERVOY in patients with Grade 3â&#x20AC;&#x201C;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]

ADVERSE REACTIONS

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 3â&#x20AC;&#x201C;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.

AUGUST 2012 I VOL 5, NO 5

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).

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.

Immune-mediated Dermatitis

1 and 2 diarrhea,â&#x20AC;? Anthony stated. â&#x20AC;&#x153;In general we donâ&#x20AC;&#x2122;t stop treatment with targeted therapy for grades 1 and 2 diarrhea. These rates are much lower than what we see with irinotecan.â&#x20AC;? Bortezomib causes diarrhea (all grades) in about 45% of patients. Lapatinib causes grades 1 to 3 diarrhea in up to 64% of

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

t *NNVOF NFEJBUFE FOUFSPDPMJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE IFQBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE EFSNBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE OFVSPQBUIJFT [see Warnings and Precautions].

t *NNVOF NFEJBUFE FOEPDSJOPQBUIJFT [see Warnings and Precautions].

t 0 UIFS JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT JODMVEJOH PDVMBS NBOJGFTUBUJPOT [see Warnings and Precautions].

Pub:

www.TheOncologyPharmacist.com

Conference News: MASCC patients. Vandetanib causes grades 1 to 4 diarrhea in 56% of patients with thyroid cancer. Cabozantinib, used to treat solid tumors, causes grades 1 to 4 diarrhea in 57% of patients. Regorafenib, an investigational oral multikinase inhibitor, caused grades 1 to 4 diarrhea in 32% of patients with colorectal cancer, but more data are needed to establish risk. â&#x20AC;&#x153;We are dealing with diarrhea in the context of other side effects caused by

It is important to establish the diagnosis and etiology of diarrhea in cancer patients.

small molecule inhibitors; for example, peripheral neuropathy with bortezomib; QTc prolongation with dasatinib; rash, diarrhea, fatigue, conjunc-

tivitis with erlotinib; rash, loss of appetite, interstitial lung disease with gefitinib; rash, weight gain, edema with imatinib; hypertension, heart fail-

Clinical Trials Experience

Immunogenicity

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.

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.

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 (â&#x2030;Ľ5%) 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 3â&#x20AC;&#x201C;5 events. Table 1:

Percentage (%) of YERVOY 3 mg/kg n=131

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a

DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy

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.

Patientsa

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

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 â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), offspring lacking CTLA-4 were born apparently healthy, but died within 3â&#x20AC;&#x201C;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

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:

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.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

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.

Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

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

Get involved: have you ever wanted to write an article for TOP?

There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *OGPSN QBUJFOUT PG UIF QPUFOUJBM SJTL PG JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT t "EWJTF QBUJFOUT UP SFBE UIF :&370: .FEJDBUJPO (VJEF CFGPSF FBDI :&370: JOGVTJPO t "EWJTF XPNFO UIBU :&370: NBZ DBVTF GFUBM IBSN t "EWJTF OVSTJOH NPUIFST OPU UP CSFBTU GFFE XIJMF UBLJOH :&370:

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

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

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.

ure syndrome with sorafenib and sunitinib,â&#x20AC;? Anthony explained. In clinical practice, diarrhea and its sequelae involve increased resource utilization, he continued. It is important to establish the diagnosis and etiology of diarrhea in cancer patients. Factors to consider in assessing risk of diarrhea include prior chemotherapy and prior pelvic radiation, performance status, response to prior cycle of chemotherapy, increased age, and female gender. Guidelines suggest 3 drugs: lo peramide, opium derivatives, and octreotide. Grades 1 and 2 uncomplicated diarrhea should be managed with adequate fluids, and the BRAT (bananas, rice, applesauce, and toast) diet. Grades 3 and 4 diarrhea may require hospitalization, antibiotics, octreotide, and fluids. With tyrosine kinase inhibitor (TKI)-induced diarrhea, dosing adjustment is not usually needed for grades 1 and 2 diarrhea; dose reduction and intravenous fluids should be used to treat grades 3 and 4. â&#x20AC;&#x153;We will never see a clinical trial of treating TKI-induced diarrhea. Treatment will be based on expert opinion,â&#x20AC;? Anthony said. Studies are now evaluating probiotics and aluminum silicates for treatment of diarrhea. In Europe, glucagon-like peptide-2 is being studied in this setting, but these drugs cannot be used for chronic diarrhea, Anthony reported. â&#x2014;?

1281558A2

IP-B0001A-03-11

Issued: March 2011

Weâ&#x20AC;&#x2122;re interested in articles about the everyday issues that affect pharmacistsâ&#x20AC;&#x201D; everything from chemotherapy safe handling to supportive care for patients to challenging cases. Contact editorial@greenhillhc.com for information.

TRIM 7.25" x 9.75"

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AUGUST 2012 I VOL 5, NO 5

Drug Shortage

Exploring the Drug Shortage Crisis By Caroline Helwick

he drug shortage crisis is easing, but an actual solution to the problem is still elusive, according to participants in a press briefing that addressed the issue at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) held in Chicago, Illinois. Richard Schilsky, MD, chair of ASCO’s government relations committee and an oncologist at the University of Chicago, indicated, “Patient care has been threatened in many cases. But the good news is that the frequency of drug shortages is beginning to decline.” In the past 2 years, 22 oncology drugs were, or still are, in short supply, mostly generic injectables. “They are irreplaceable when there are no acceptable substitutes,” Schilsky pointed out. “We are not exactly sure when a generic drug will suddenly go out of supply, and this creates a tremendous amount of uncertainty, anxiety, and difficulty in planning.” Sandra Kweder, MD, deputy director of the Office of New Drugs at the US Food and Drug Administration (FDA), said she was primarily concerned about the patients. “This is about people being able to get treatments they need, when they need them. This situation is not acceptable.” FDA Hypervigilant Kweder said that prevention of shortages is the FDA’s “absolute priority,” and a priority of Congress and the administration. In the past 6 months, more than 150

drug shortages have been averted through early notification by manufacturers. “These drugs have not appeared on the list of shortages,” she noted. “But things can change quickly. Early notification is the key….Our staff is vigilant, and we work under extraordinary conditions to pull out the stops every day to prevent shortages and address those that are occurring.” However, the early notification system is voluntary, and the FDA cannot mandate that companies up their pro-

they believe it will enable a more timely review of their applications, and a faster time getting their drugs to market.” —Richard Schilsky, MD

duction, she acknowledged. “One thing the FDA cannot do is tell a company they must make a drug.” But it can work with companies to “ferret out problems” and resolve manufacturing and drug quality issues, which account for most shortages. “These issues are not minor,” she said. The FDA helps companies ramp up production for new or “relaunched” products and uses “regulatory discretion” to help companies import drugs, she stated. Thanks to such efforts, she noted that

Are you confident that the FDA actions and the recent congressional legislation will resolve the drug shortage issue? r Yes r No

Go to www.TheOncologyPharmacist.com to cast your vote and add your comments. Please tell us what you think about the efforts to resolve the drug shortage issue.

AUGUST 2012 I VOL 5, NO 5

User Fee Legislation, Economic Incentives “ASCO believes a permanent solution will require congressional legislation,” Schilsky said. Progress has been made. On May 30,

“Industry is very willing to pay these fees because

Reader Poll

cytarabine, doxorubicin, liposomal doxorubicin, mitomycin, daunorubicin, and 5-fluorouracil are currently meeting demands. Methotrexate continues to be carefully monitored, although a resolution is expected soon.

the Prescription Drug User Fee Act (PDUFA) reauthorization legislation passed the United States Senate as the FDA Safety and Innovation Act (S 3187), and the companion bill passed the United States House of Representatives as the FDA Reform Act (HR 5651). The next step was to reconcile the differences between the 2 versions, both of which contained a proposed user fee program for generic drugs and biosimilars and language on drug shortages. The program will allow the FDA to collect user fees from industry to help fund the agency’s timely review of applications. On June 18, the United States Congress released a reconciled version of the reauthorization bill, which was presented again to the House of Representatives and Senate. The House passed the final version on June 20 and the Senate passed it on June 26. President Barack Obama signed the bill on July 9, 2012. The PDUFA legislation will bring in an additional $1.5 billion to the FDA, which is expected to reduce the review time for a new drug application from the current 30 months to 10 months or less. “This is a huge step forward in getting manufacturers into the game,” said Schilsky. “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.” The FDA “user fee” legislation that was passed by Congress, however, does not contain an enforcement mecha-

nism that carries penalties for not reporting. “ASCO has concerns that if there is no teeth in that legislation, companies may decide not to report,” Schilsky said. “On the Hill, there is not much receptivity to putting that in the legislation.” “We also feel that Congress should consider making economic incentives for companies to stay in the market for these lower-cost drugs,” he added. “And that the provisions addressing drug shortages also apply to biologics, which at the moment are branded but will eventually be generic.” Would economic incentives encourage production of generics? The fact that virtually all shortages so far have been generics “speaks to the economic and business model,” Schilsky acknowledged. “These drugs have the smallest profit margins, but it’s hard to connect the dots on this.…The generic drug industry is thriving. Yes, they have manufacturing problems and yes, periodically plants go down, but it’s not like the economics of the situation is driving them out of business. Economic issues may be contributing to the shortage, but not at such a fundamental level that companies are folding their tents and going away.” Could New Drugs Be Affected? While the shortages to date have been almost restricted to generics, it appears possible that even supplies of the newest drugs may fall short of the demand. News of the FDA’s approval of pertuzumab (Perjeta) for HER2-positive metastatic breast cancer was welcomed, but in its announcement, Genentech, the manufacturer, disclosed that production issues could affect the drug’s long-term supply. “We expect to meet demand for Perjeta following today’s FDA approval,” said spokesperson Patrick Y. Yang, PhD, head of technical operations. “We recently identified a cell growth issue that might affect our future supply of the medicine. We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it.” In her FDA announcement of the drug’s approval, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said, “Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply.” ●

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Drug Shortage

Quantifying the Drug Shortage: One Center’s Experience

t one New York medical center, half of the cancer patients required drugs that were considered in short supply in 2010 and 2011, and 10% were forced to receive an alternative, according to a study presented at the 2012 ASCO Annual Meeting (Abstract 6114). While the investigators hope that this did not compromise efficacy, about one-third of the time the physicians felt the substitute was inferior, said Daniel J. Becker, MD, of St. Luke’sRoosevelt and Beth Israel Medical Center, New York, who led the study presented at ASCO. Becker reported that drugs considered in shortage were used for 51% of patients in 2010, and this increased significantly to 64% in 2011. “When the shortage reached critical levels, about 10% of the patients we treated had an actual change in treatment mandated by the shortage,” he told The Oncology Pharmacist. The researchers reviewed pharmacy records for drug shortages, defined as supply issues that affect how the pharmacy prepares or dispenses a drug product or influences patient care when prescribers must use an alternative agent, and examined records of outpatients who received chemotherapy from April 2010 to September 2010 (n = 335) and from April 2011 to September 2011 (n = 379). They also surveyed physicians about the efficacy and toxicity of the alternative regimen used during the shortage. The percentage of drugs in shortage increased from 30% in 2010 to 50% in 2011, and the percentage of patients treated with a shortage drug increased from 51% to 65%. Most of the shortages occurred in breast cancer patients (48%), followed by gynecologic cancer patients (26%). Of the 235 patients in the subgroup examined in August/September 2011 (when shortages peaked), 23 (9.8%) experienced a change in therapy, he reported. No substitutions occurred in 2010. Three medications were unavailable at St. Luke’s-Roosevelt: paclitaxel (74%), liposomal doxorubicin (22%), and 5-fluorouracil (4%). Leucovorin was also in short supply, but the consequences were difficult to track for this project, since most patients continued to receive the drug in reduced dosages, Becker said. As a substitute for paclitaxel, the use of docetaxel increased by 80%, while paclitaxel decreased by 69% during the most critical period. The estimated

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cost of a single treatment with paclitaxel for the average patient was $47, versus $858 for docetaxel, a 1704% increase, Becker pointed out. “When we surveyed treating physicians about the change in therapy, we found that they considered the alternative regimen inferior to the standard reg-

imen in 30% of patients and thought the alternative regimen was more toxic in around 35%,” Becker said. Today, he added, “Many drugs are still in shortage, but few affect care on a daily basis. There is definitely progress, though there is still vulnerability.” ●

Daniel J. Becker, MD

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace09 TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.

STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the 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 OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in 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 to patients

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

FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA

E. Shelley Hwang, MD, MPH Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC

Kathy D. Miller, MD Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.

ACCREDITATION Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation 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 does not 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 Manager Certification. Case Managers number 790005057.

AUGUST 2012 I VOL 5, NO 5

CONTINUING EDUCATION JULY 2012 • VOLUME 5 • NUMBER 2

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Maintenance Settings LETTER PUBLISHING STAFF President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Director, Medical & Scientific Services Linda M. Ritter, PhD linda@coexm.com

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

Director, Production and Manufacturing Alaina Pede

FROM THE

EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). This is due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinical investigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria for diagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management of comorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regarding the application and interpretation of recent clinical advances. In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently asked questions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questions are answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowledge, and professional experience regarding evidence-based care. In this second issue, experts from City of Hope Cancer Center answer questions pertaining to the management of patients in the maintenance setting.

Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Director, Creative and Design Robyn Jacobs

FACULTY

Quality Control Director Barbara Marino

Web Coordinator Jose Valentin

Business Manager Blanche Marchitto

Amrita Y. Krishnan, MD, FACP Director, Multiple Myeloma Program Associate Director, Medical Education and Training Department of Hematology/HCT City of Hope Cancer Center Duarte, CA

Christina Boeckman, RN, ANP-C, AOCNP Nurse Practitioner Department of Hematology/HCT City of Hope Cancer Center Duarte, CA

Sepideh Shayani, PharmD, BCOP Clinical Manager, Pharmacy Services Department of Pharmaceutical Services City of Hope Cancer Center Duarte, CA

Executive Administrator Jackie Luma

Circulation Department circulation@greenhillhc.com

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

Center of Excellence Media, LLC 241 Forsgate Drive Suite 205B Monroe Township, NJ 08831 This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC.

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www.TheOncologyPharmacist.com

CONSIDERATIONS IN MULTIPLE MYELOMA Sponsor This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Educational Objectives Upon completion of this activity, the participant will be able to: • Describe recent advances in maintenance therapy that can potentially prolong survival and improve quality of life in patients with MM • Identify specific patient- and disease-related factors that may impact the choice of maintenance therapy in MM • Review recent safety and efficacy data on novel agents used in the maintenance setting for MM Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12026.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records. For questions regarding the accreditation of this activity, please contact MLI at 609-333-1693 or cgusack@mlicme.org. Physician Credit Designation The Medical Learning Institute, Inc. (MLI) designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME)

through the joint sponsorship of the Medical Learning Institute, Inc. and the Center of Excellence Media, LLC. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute, Inc. (MLI). Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours. Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.25 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-12-024-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by MLI for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Planners’ and Managers’ Disclosures Dana 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 disclosed that her spouse is investigator on a study for Agenix and Lilly; on the data monitoring committee for Infinity; and on the data monitoring committee and principal investigator on a study for Pfizer.

*Amrita Y. Krishnan, MD, FACP, is a consultant for Celgene Corporation, 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 for Genzyme. *Content will include non–FDA-approved uses. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Agenda: 1.25 hours Articles/Commentaries: 60 minutes Evaluation/Posttest: 15 minutes Date of original release: July 12, 2012 Valid for CME/CE credit through: July 12, 2013

Faculty Disclosures *Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx.

Recent Advances and Ongoing Controversies in the Maintenance Setting Amrita Y. Krishnan, MD, FACP Director, Multiple Myeloma Program Associate Director, Medical Education and Training, Department of Hematology/HCT City of Hope Cancer Center, Duarte, CA

Introduction Despite 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-

response, as this has been correlated with improved overall survival (OS).1,2 Maintenance therapy with novel agents can contribute to these treatment goals, 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 outweigh benefit in this population. Of course, there are always exceptions, and the approach to therapy must be individualized to the patient. Many questions remain on the optimal use of maintenance therapy, because we do not yet have unequivocal evidence that it prolongs OS in specific MM subgroups.3,4

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

What evidence has influenced your approach to maintenance therapy?

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 patients with MM?

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

www.TheOncologyPharmacist.com

In patients with high-risk cytogenetics who exhibit the translocation t(4;14), I tend to use bortezomib. The HOVON-65/GMMG-HD4 trial showed 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 maintenance that produced this clinical benefit, since patients received bortezomib during induction as well in one arm of the study, whereas the other arm did not receive bortezomib during induction or maintenance (Figure).5 There has also been debate regarding the efficacy of bortezomib maintenance in patients with deletion 17p (del[17p]). A study by Avet-Loiseau and colleagues reported that bortezomib-based therapy could not overcome this chromosomal abnormality. However, patients in this trial received bortezomib short-term (4 cycles) with no maintenance.6 Results of HOVON-

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Figure. Efficacy results at 36 months of follow-up in the HOVON-65/GMMG-HD4 trial.5 VAD + HDT/ASCT + thalidomide maintenance PAD + HDT/ASCT + bortezomib maintenance

80 70

Patients (%)

60 50 40 30 20 10 0

All pts

t(4;14)

del(17p)

PFS

All pts

t(4;14)

del(17p)

melphalan, prednisone, and lenalidomide (MPR) ± lenalidomide maintenance or melphalan/ASCT ± lenalidomide maintenance. A comparison of all patients given lenalidomide maintenance (after either MPR or ASCT) versus all patients receiving no maintenance showed that maintenance increased PFS but not OS. The recent MM-015 trial evaluated lenalidomide maintenance in older, transplant-ineligible patients with myeloma. The investigators of this study reported that lenalidomide after initial therapy with MPR significantly extended PFS compared with melphalan plus prednisone alone or MPR without maintenance.12 Thalidomide is not used preferentially for maintenance in the United States, largely due to data showing a high incidence of serious adverse events, reduced quality of life, and potentially poorer outcomes in del(17p) patients.13-15 In Europe, however, thalidomide is used more often, because of regulatory limitations on other novel drugs such as lenalidomide. What are some of the key concerns in using maintenance therapy?

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

Table. Efficacy Results at a Median Follow-up of 34 months in the CALGB 100104 Trial9 Lenalidomide Maintenance

Placebo

P Value

46 months

27 months

<.001

3-Year PFS rate

66% (95% CI, 59-73)

39% (95% CI, 33-48)

—

3-Year OS rate

88% (95 CI, 84-93)

80% (95 CI, 74-86)

—

Median TTP

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

65/GMMG-HD4 suggested a benefit with bortezomib-based induction plus maintenance,5 as did data from the Total Therapy 3 trial.7 In addition, a recent study by Neben and colleagues reported that patients with del(17p) who received bortezomib before and after ASCT had a median PFS of 26.2 months compared with 12.0 months for patients who did not receive bortezomib (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 treatment for patients with del(17p). For patients with a partial response after ASCT, I generally use lenalidomide maintenance, based on results from the CALGB 100104 and IFM 2005-02 trials.9,10 CALGB 100104 compared single-agent lenalidomide maintenance with placebo in patients with stable disease or better (including patients who achieved CR) following ASCT. This study demonstrated significantly longer time to progression and improved survival in the lenalidomide arm versus the placebo arm (Table).9 IFM 2005-02 also compared singleagent lenalidomide maintenance with placebo post-ASCT (after 2 courses of lenalidomide consolidation in both arms).10 In this study, lenalidomide maintenance improved median PFS to 41 months versus 23 months with placebo (P<.001), with benefit across cytogenetic subgroups. Three-year and 4-year OS 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 induction with lenalidomide and low-dose dexamethasone, followed by either

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The first concern is risk versus benefit. Are we seeing enough clinical benefit to justify the toxicity and added expense of maintenance therapy? Certainly, data suggest benefits in response and PFS when maintenance is used, but a consistent benefit in OS has not been shown.3-8 Adverse events are also an important consideration. With bortezomib maintenance, grade 3 or 4 peripheral neuropathy may be treatment-limiting.3,5 With lenalidomide, trials have reported an increased risk of second primary malignancies with maintenance therapy.9,10,12,16 In CALGB 100104, for example, second cancers were reported in 8% of patients receiving lenalidomide maintenance versus 3% of patients receiving placebo during approximately 3 years of follow-up.9 The investigators of this study have indicated that they will continue to assess risk factors for development of second primary cancers with further follow-up. Factors such as cost and insurance 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 with novel agents?

Currently, there is no consensus regarding the optimal duration of maintenance therapy for myeloma. In HOVON-65/GMMG-HD4, patients received bortezomib maintenance for 2 years.5 In CALGB 100104, lenalidomide maintenance was given until progression.9 The investigators in the IFM 2005-02 trial planned to use lenalidomide until progression but stopped therapy once secondary malignancies arose.10 In the ongoing phase 3 multicenter BMT CTN 0702 trial, we plan to give lenalidomide maintenance therapy for 3 years.17 However, many questions remain unresolved. What is the optimal duration of lenalidomide therapy to improve PFS and possibly OS? Since bortezomib-related neuropathy may shorten maintenance time, can we reduce the incidence and severity of this toxicity and extend the duration of time that 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 define the role of novel agents in the maintenance setting and provide answers to these questions. ◆ References 1. 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-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009;27:5720-5726.

www.TheOncologyPharmacist.com

CONSIDERATIONS IN MULTIPLE MYELOMA

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 multiple myeloma. Blood. 2012;119:3003-3015. 4. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011;118:3205-3211. 5. 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 by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly 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 improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634. 7. Shaughnessey JD, Zhou Y, Haessler J, et al. TP53 deletion is not an adverse feature in multiple myeloma 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 autologous stem 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 for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 10. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation 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 progression 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-ineligible 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 prednisone as maintenance therapy following autologous stem cell transplantation (ASCT) in patients with multiple (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 39. 16. Delforge M, Dimopoulos M, Adam Z, et al. Safety profile and management in MM-015 comparing lenalidomide-melphalan-prednisone followed by lenalidomide maintenance (MPR-R) with MP and MPR in newly diagnosed multiple myeloma (NDMM). Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands. 17. Stem cell transplant with lenalidomide maintenance in patients with multiple myeloma (BMT CTN 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 of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. 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 oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (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 proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8033. 22. Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): a phase I study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8034.

Improving Patient Outcomes During Maintenance Therapy Christina Boeckman, RN, ANP-C, AOCNP Nurse Practitioner Department of Hematology/HCT, City of Hope Cancer Center Duarte, CA

Introduction Along 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 therapy. As a member of the cancer care team, it is the nurseâ&#x20AC;&#x2122;s responsibility to anticipate which toxicities and complications are likely to occur, to employ the necessary interventions, and to counsel patients

have organ dysfunction (eg, cardiovascular disease, renal impairment) and diabetes, and are more prone to infection and deep vein thrombosis.1 It is crucial to take these factors into account when determining an effective management plan. It is also important to know which agents were used during previous lines of therapy, how patients tolerated these medications, and whether they are experiencing any residual adverse events. In some cases, it may be necessary to avoid the use of specific agents due to preexisting comorbidities or cumulative toxicities. A patientâ&#x20AC;&#x2122;s overall performance status should also be evaluated prior to and during maintenance therapy. Nurses must assess whether an individual is able to perform activities of daily living, such as preparing meals, eating, bathing, and dressing. The goal is to achieve a balance between providing effective therapy and maintaining good quality of life.

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

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

adverse events related to the use of novel agents.

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

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

www.TheOncologyPharmacist.com

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

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Table. Bortezomib Dose Modifications Based on Severity of Peripheral Neuropathy5,6 Severity of Peripheral Neuropathy

Modification of Dose and Regimen

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

No action

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

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

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

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

Grade 4 (permanent sensory loss that interferes with function)

Discontinue bortezomib

Grading based on NCI Common Toxicity Criteria CTCAE V 3.0.

recently seen an increase in the use of bortezomib in the maintenance setting, and nurses need to be familiar with its toxicity profile and recommended supportive 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 scales are helpful for these assessments. When patients come to our center for treatment, I ask them if they are experiencing any numbness and tingling in their hands and feet, ringing in their ears, neuropathic pain, or cramping. I also determine if they are having trouble with everyday tasks, such as buttoning their shirts or writing with a pen. Patients must understand the importance of reporting signs and symptoms of PN as soon as they occur, so that the appropriate interventions can be initiated. When bortezomib-related PN develops, the goal is to alleviate symptoms and prevent progression.2 This can be accomplished through recommended dose modifications based on the degree of neurotoxicity (Table).5,6 For example, if a patient develops grade 3 PN while on bortezomib, we typically hold treatment until symptoms resolve, and then reinitiate therapy at a lower dose and schedule. For patients who have neuropathic pain, we prescribe opioids when necessary; the use of nonsteroidal anti-inflammatory drugs is not advisable due to the likelihood of myeloma-related renal dysfunction. Additional medications that may be used in the treatment of PN symptoms include gabapentin, pregabalin, duloxetine hydrochloride, and tricyclic antidepressants.2 We usually recommend that patients start taking B complex vitamins, folic acid, and alpha lipoic acid, as long as they are not contraindicated with other medications. How do you assess and treat hematologic toxicities related to lenalidomide therapy in the maintenance setting?

discontinue lenalidomide. Treatment can usually be resumed when platelet counts return to 30,000/mcL, but it may be necessary to restart them at a reduced dose.7,8 We usually do not initiate transfusion unless platelet counts decline to <20,000/mcL. If the patient’s absolute neutrophil count (ANC) is <1000/mcL, lenalidomide treatment should also be halted until counts return to baseline. In some cases, we may initiate granulocyte colony-stimulating factor 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 and symptoms at home. We tell them to notify us immediately if they experience bleeding that does not stop, frequent bruising, or fever. It is important to instruct patients on effective strategies for infection control, including routine hand washing and the avoidance of crowds, when their blood counts are low. If patients develop signs of infection, we may also need to hold lenalidomide treatment until symptoms resolve. What is the nurse’s role in helping patients continue with maintenance therapy?

Prior to the initiation of maintenance, it is important to discuss with patients both the risks and benefits of prolonged therapy with novel agents. Some individuals do not understand why they need to undergo further treatment if they have responded well to initial chemotherapy and/or transplantation. It is important to remind these patients that continued use of effective agents may help to delay relapse and disease progression. Although patients will typically be familiar with the toxicity profiles of agents they have already received during frontline therapy, we review this information again prior to the start of maintenance. We also inform patients about the increased risk for secondary malignancies related to prolonged duration of therapy, and encourage them to be diligent about routine health screenings, including mammograms and colonoscopies. We ensure them that we will also monitor for secondary malignancies through 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 rather receive oral lenalidomide, so they do not have to travel back and forth to the center every week for treatment. If we determine that a patient can be compliant with an oral regimen, and they do not have comorbidities or other characteristics that 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 is prescribed during maintenance, oncology nurses play an important role in improving patient outcomes by establishing good communication with patients, carefully monitoring for signs and symptoms of toxicities, and being prepared to initiate effective supportive care strategies when needed. ◆ References

Hematologic toxicities are commonly associated with the use of lenalidomide.7 To effectively manage these adverse events, it is important for myeloma patients to have their blood counts monitored regularly, with the most frequent monitoring performed early in their treatment cycles. We see patients at least every 2 weeks during the first and second cycles of maintenance to assess how they are responding to treatment and to evaluate the need to make dose or schedule adjustments based on their counts. Depending on their performance status and laboratory results, we may lessen the frequency of these evaluations to once per month. When platelet counts fall to <30,000/mcL, we may need to temporarily

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1. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of therapy 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 neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement 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 survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 4. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple 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 multiple 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 the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; October 2010.

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CONSIDERATIONS IN MULTIPLE MYELOMA

Dosing and Administration of Novel Agents in the Maintenance Setting Sepideh Shayani, PharmD, BCOP Clinical Manager, Pharmacy Services Department of Pharmaceutical Services City of Hope Cancer Center Duarte, CA

Introduction Over the past decade, maintenance therapy has become an increasingly important component of treatment for patients with multiple myeloma (MM). Recent evidence has shown that newer target-

age or comorbidities, the schedule of bortezomib (1.3 mg/m2) used for induction was reduced from twice weekly to once weekly. In addition, both the VMPT 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 schedule of bortezomib lowered discontinuation rates and prolonged time on therapy. This finding has important clinical implications, especially for the treatment of older patients who may have difficulty tolerating a standard regimen. The schedule adjustment used in this study also significantly reduced the incidence of severe sensory PN from 16% to 3% (P<.001).

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, conventional therapies used for this indication. In this article, Sepideh Shayani, PharmD, BCOP, discusses recent advances in the maintenance setting, and answers questions related to the administration of

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.

novel agents.

Has a standard dose and schedule been established for bortezomib as maintenance therapy?

To date, a standard dose and schedule has yet to be established for bortezomib maintenance; however, data from recent clinical trials can be helpful in guiding therapeutic decisions. As in the frontline and relapsed/refractory settings, 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. In the phase 3 HOVON-65/GMMG-HD4 trial, transplant-eligible patients with MM were randomly assigned to induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD).1 This was followed by high-dose melphalan and autologous stem cell transplant (ASCT). Patients started on VAD received thalidomide maintenance at a dose of 50 mg/day for 2 years (arm A) and those randomized to PAD received bortezomib maintenance at a 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% at 36 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 started maintenance therapy, and 64% and 47% of those patients, respectively, went off 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, and thalidomide (VMPT) followed by 2 years of maintenance with bortezomib (1.3 mg/m2 every 14 days) plus thalidomide (50 mg/day) (VT) or to nine 6-week cycles of VMP induction without maintenance.2 Early in this trial, which enrolled patients who were not eligible for transplant due to advanced

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Both of these maintenance trials reported encouraging clinical activity with bortezomib. In GIMEMA, once-weekly dosing was more tolerable than twice-weekly dosing, but maintained good clinical activity.2 In this trial, bortezomib maintenance administered bimonthly also appeared to be an effective strategy. Investigators continue to evaluate various bortezomib dosing and schedule protocols. Hopefully, data from new trials will help to determine a standard of care. In the meantime, following established dosing adjustment guidelines for bortezomib3,4 to reduce toxicities such as PN is essential to ensure optimal outcomes. Additionally, subcutaneous administration of bortezomib may improve the adverse event profile associated with this agent. In a recent trial of relapsed/refractory MM, this mode of administration resulted in similar overall response rates but significantly less PN than traditional intravenous dosing.5 The increased tolerability seen with subcutaneous bortezomib in this population of patients may translate to the maintenance setting. What dosing and administration schedules are being used for lenalidomide as maintenance?

In the phase 3 IFM 2005-02 trial, patients with MM who had single or double 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 tolerated).6 Treatment was continued until disease progression or development

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

Progression

Other

Overall

Thalidomide

31%

64%

Bortezomib

29%

47%

AUGUST 2012 I VOL 5, NO 5

CONTINUING EDUCATION

Table 2. Select Grades 3 and 4 Hematologic Toxicities in the MM-015 Trial8 MP (Gr 3/4)

MPR (Gr 3/4)

MPR-R (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.

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

We are seeing RVD used more frequently as induction therapy in MM, so data from this study should be relevant to clinical practice. The phase 3 MM-015 trial randomized elderly, transplant-ineligible MM patients to 9 cycles of melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R), or to 9 cycles of MPR or MP without maintenance.7,8 In this study, the scheduled dose of lenalidomide (during induction and maintenance) was 10 mg/day, given on days 1 to 21. Patients could receive maintenance until disease progression or development of intolerance. After a median follow-up of 27 months, PFS was significantly longer with 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 hematologic toxicities in this study are shown in Table 2. However, during the maintenance phase of MPR-R, the incidence of new or worsening toxicities was low. Discontinuation due to adverse events in the MPR-R, MPR, and MP arms was observed in 16%, 14%, and 5%, respectively. These rates were higher in patients >75 years of age than in those 65 to 75 years of age, as was the need for dose reductions. Incidence of second primary malignancies was low, 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

AUGUST 2012 I VOL 5, NO 5

and efficacy of lenalidomide maintenance in 3 cohorts of patients.9 Following ASCT, participants will proceed to either second transplant, consolidation with lenalidomide, dexamethasone, and bortezomib (RVD), or maintenance with lenalidomide. Patients undergoing second transplant and consolidation will also receive maintenance therapy, which will start at 10 mg/day for 3 months and increase to 15 mg/day. We are seeing RVD used more frequently as induction therapy in MM, so data from this study should be relevant to clinical practice. What strategies are important to ensure optimal outcomes in the maintenance setting?

Certainly, it is important to consider safety and efficacy data from recent studies in the decision-making process. Beyond that, factors such as convenience, cost, reimbursement, and, of course, toxicity profiles of specific agents must be considered so that therapy can be tailored to a patientâ&#x20AC;&#x2122;s needs. The treatment landscape for MM is constantly evolving; therefore, clinicians must also stay informed of new agents that are being investigated in clinical trials. For example, early data from phase 1/2 trials were recently released on the use of the oral proteasome inhibitor MLN9708 in MM. In both newly diagnosed and relapsed/refractory patients, treatment with this agent resulted in encouraging response rates with good tolerability, especially low rates of PN.10,11 Based on these results, phase 3 trials are under way to further evaluate the safety and efficacy of this agent in myeloma. â&#x2014;&#x2020;

References 1. 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 by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with 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 followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalanprednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109. 3. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple 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-inferiority study. Lancet Oncol. 2011;12:431-440. 6. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation 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 diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 8. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-ineligible 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. 9. ClinicalTrials.gov Web site. Stem cell transplant with lenalidomide maintenance in patients with 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 investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (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 investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8033.

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Oral Oncolytics

Updates on Oral Chemotherapy Adherence—Where Are We Today? By Betty M. Chan, PharmD, BCOP USC/Norris Cancer Hospital, Los Angeles, California

or the past few years, much attention has been given to the development and US Food and Drug Administration (FDA) approval of targeted oral chemotherapy agents. As our knowledge of cancer and its molecular biology increases, many targeted oral chemotherapy agents have become available for use in clinical practice. The emergence of oral chemotherapy agents has provided alternative treatment options and allowed patients to receive cancer treatment in the convenience of their home. 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. Education should include but not be limited to: (1) what side effects to expect (both acute and chronic); (2) how to monitor, assess, and manage these side effects (are there over-the-counter products that can be safely used to help minimize these side effects, and which side effects warrant immediate medical attention); (3) what to do for missed doses (take as soon as remembered, or skip dose until next scheduled dose); (4) what to do if patients are not able to swallow (should dose be crushed or do we have any information); (5) what precautions to take in the safe handling of these oral chemotherapy agents (storage information, and proper disposal of these agents); and (6) the importance of oral adherence and compliance to these medications to provide effective treatment (do patients and their caregivers fully understand the treatment schedule, as it can be complicated to follow, etc). With the emergence of oral chemotherapy, adherence to oral chemotherapy treatment has become a concern for many healthcare professionals. In 2009,

the American Society of Clinical Oncology and the Oncology Nursing Society (ONS) published a practice guideline on chemotherapy administration safety standards,1 focusing on the 7 domains of the chemotherapy administration process, which include the following: (1) review of clinical information and selection of a treatment regimen; (2) treatment planning and informed consent; (3) ordering of treatment and prescription writing; (4) drug preparation; (5) assessment of treatment compliance; (6) administration and monitoring of treatment; and (7) assessment of response and toxicity monitoring. The guideline indicates that adherence to standards for

through multidisciplinary teams; (2) state of the science: adherence to oral chemotherapeutic agents; (3) barriers to adherence; and (4) motivational interviewing/active listening to promote oral chemotherapy adherence. Breakout discussions were used to further identify barriers to successful adherence, tools and approaches that might address these barriers, and how barriers to adherence can best be resolved using a multidisciplinary team approach. At the conclusion of the conference, each of the team participants was given the task of developing plans to improve oral chemotherapy adherence in their own institution practice settings and community.

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. safe chemotherapy administration should be the goal of all healthcare providers in any oncology care settings, both inpatient and outpatient. Since its publication, the safety standards have provided a framework for best practice throughout the oncology practice arena, and many of these domains are tasks that pharmacists can assist in providing. On June 14-15, 2011, the National Coalition for Cancer Survivorship in partnership with the National Association of Social Workers, the ONS, and the Association of Oncology Social Work sponsored an oral chemotherapy adherence train-the-trainer conference in Washington, DC. Representatives included teams of 1 pharmacist, nurse, and social worker each from 11 medical centers. Our medical center was privileged to be one of the team participants. Topics discussed at the conference included: (1) addressing oral chemotherapy adherence

What was interesting for me to learn was that there is no “gold standard” definition of adherence, as most literature examining and evaluating oral adherence offers its own definition of adherence.2 While nonadherence to oral chemotherapy agents is an important concern, overadherence to oral chemotherapy agents is also a major concern, as it poses a risk for increases in unwanted side effects and drug toxicities, something I am seeing more frequently at our institution. As many oral chemotherapy agents have restricted REMS (risk evaluation and mitigation strategies) distribution access and require an FDA-approved medication guide with dispensing, we must be familiar with the use of oral chemotherapy agents and be able to provide education to other healthcare professionals, patients, and their caregivers. See the Table that accompanies the online version of this article for a summary of some

targeted oral chemotherapy agents with information on lab monitoring, common side effects, and instructions for patient education.3-16 While our own institution is collaboratively developing a plan of action to improve oral chemotherapy adherence at our practice setting, some of you have already implemented a program at your institution. I ask that you continue to share your developmental process and your success with us through publications or at the Hematology Oncology Pharmacy Association annual conference. ● References 1. Jacobson JO, Polovich M, McNiff KK, et al. American Society of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards. J Clin Oncol. 2009;27:5469-5475. 2. Given BA, Spoelstra SL, Grant M. The challenges of oral agents as antineoplastic treatments. Semin Oncol Nurs. 2011;27:93-103. 3. Lam MS. Extemporaneous compounding of oral liquid dosage formulations and alternative drug delivery methods for anticancer drugs. Pharmacotherapy. 2011;31:164192. 4. Crizotinib (Xalkori) full prescribing information [package insert]. http://www.accessdata.fda.gov/drugsatfda_ docs/label/2011/202570s000lbl.pdf. Accessed September 8, 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/afini tor.pdf. Accessed September 20, 2011. 12. Lapatinib (Tykerb) full prescribing information. http://us.gsk.com/products/assets/us_tykerb.pdf. Accessed September 23, 2011. 13. Lenalidomide (Revlimid) full prescribing information. 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/tarc eva-prescribing.pdf. Accessed September 23, 2011. 16. Capecitabine (Xeloda) full prescribing information. http://www.gene.com/gene/products/information/xelo da/pdf/pi.pdf. Accessed September 23, 2011.

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.

AUGUST 2012 I VOL 5, NO 5

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Renal Cell Carcinoma Quality of Life Drives Patient Preference... Continued from cover

patients received 10 weeks of the alternate treatment. The primary end point was patient preference, measured at 22 weeks. Because patients with mRCC receive therapies for many months or even years, the team assessed whether the drug toxicity would be significant enough to make patients want to continue treatment with either drug or to switch therapy. A total of 126 patients completed a preference questionnaire. In the primary analysis, 70% of the patients preferred pazopanib, 22% preferred sunitinib, and 8% cited no preference. After adjustments for a modest sequence effect, the difference in preference was 49% in favor of pazopanib. All other analyses showed a significant preference for pazopanib.

Bernard J. Escudier, MD

The most common reasons given for pazopanib preference were better QOL and less fatigue. Patients taking pazopanib had fewer dose reductions than those taking sunitinib (13% vs 20%, respectively) and fewer treatment interruptions (6% vs 12%). Adverse events were compatible with known profiles for both drugs. The researchers, led by Bernard J. Escudier, MD, from the Institut Gustave Roussy, Villejuif, France, said that they expected patients to prefer one drug over the other because of adverse effects, but “we didn’t ever expect such a big difference between the 2 drugs.” Physicians may perceive toxicity differences between 2 different therapies as relatively minor, but to patients, even low-grade toxicities over a long period have a significant effect on QOL, according to Escudier and colleagues. How patients feel when they take a drug over many months is not reflected in traditional reporting of adverse events. A survey on physician therapy

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preferences, which was a secondary end point in this study, showed some difference in physicians’ drug preferences: 61% preferred pazopanib, 22% preferred sunitinib, and 17% had no preference.

Patient-reported outcomes are increasingly being added to traditional efficacy outcomes to better understand the clinical relevance of differences in drug toxicities, Escudier and colleagues noted. ●

Reference Escudier BJ, Porta C, Bono P, et al. Patient preference between pazopanib (Paz) and sunitinib (Sun): results of a randomized double-blind, placebo-controlled, crossover study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract CRA4502.

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Conference News: ASCO 2012

Olanzapine Effective Antiemetic for Breakthrough CINV By Alice Goodman

atients with breakthrough chemotherapy-induced nausea and vomiting (CINV) can gain superior relief from olanzapine (Zyprexa), a drug approved by the US Food and Drug Administration as an antipsychotic, compared with standard antiemetic therapy with metoclopramide. The results from this phase 3 study address an important unmet need for patients who expe-

rience these side effects despite being given standard antiemetic therapy. “Breakthrough CINV usually occurs on day 2 through 4 after chemotherapy, despite guideline-directed prophylaxis. This study found that olanzapine is significantly better than metoclopramide in controlling CINV in this group of patients,” stated lead author Rudolph Navari, MD, PhD, of the University of

Indiana in Indianapolis. Olanzapine achieved superior emesis control at 72 hours: 71% of those receiving olanzapine had no emesis versus 32% of those treated with metoclopramide (P <.01). Patients treated with olanzapine also had significantly improved control of nausea: 67% of the olanzapine group versus 24% of the metoclopramide group had complete control of nausea (P <.01).

Duloxetine in Peripheral Neuropathy

he antidepressant duloxetine (Cymbalta) appears to reduce painful peripheral neuropathy associated with taxane- or platinumbased chemotherapy in some, but not all, patients, according to a randomized phase 3 study presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). About one-third of patients treated with duloxetine reported at least a 30% or greater reduction in pain scores versus 17% of placebo patients. “Unfortunately, no medication is completely effective. Duloxetine isn’t perfect and did not work for every patient in our study, but it was effective for a majority of patients. This was the first randomized trial to show that any drug is effective for this terrible pain,” stated lead author Ellen M. Lavoie Smith, PhD, assistant professor in the School of Nursing at the University of Michigan in Ann Arbor. Painful peripheral neuropathy, which affects 20% to 30% of patients treated with taxane- or platinum-based chemotherapy, can be debilitating, interfering with the ability to perform activities of daily living. Thus far, there is no established effective treatment for this adverse event, which can persist for years after chemotherapy is completed. The study randomized 231 patients to duloxetine followed by placebo versus placebo followed by duloxetine; 220 patients received the initial treatment with 187 patients completing the initial treatment period. All patients reported high levels of pain from peripheral neuropathy prior to enrollment. Duloxetine

was given as one 30-mg oral capsule per day for 1 week, followed by 2 capsules per day (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.

Painful peripheral neuropathy, which affects 20% to 30% of patients treated with taxane- or platinum-based chemotherapy, can be debilitating.

Patients completed the Brief Pain Inventory–Short Form survey at baseline and then every week. Decrease in pain scores was reported by 59% of the duloxetine-treated patients versus 38% for placebo. Thirty-three percent of the duloxetine group reported at least a 30% decrease in pain severity, and 21% reported at least a 50% decrease in pain severity. No change in pain score was seen in 30% of the duloxetine group and 34% of placebo patients. Pain was increased in 11% of those taking duloxetine versus 28% of placebo patients. No difference in duloxetine efficacy was

No patient experienced any grade 3 or 4 toxicity, and no central nervous system adverse events were seen in this shortterm study comparing the 2 drugs. Olanzapine is known to have several adverse effects when used as long-term antipsychotic therapy, but Navari emphasized that these effects were not seen with short-term administration of the drug. “This is the first study to show a treatment is effective in breakthrough CINV,” Navari stated.

observed based on the specific neurotoxic chemotherapy given. “Patients treated with duloxetine enjoyed a greater decrease in the amount of pain that interfered with general activity, mood, walking, work, enjoyment of life, and social relationships,” Smith told listeners. Severe (grade 3) nonhematologic toxicity was seen in 11% of those who received duloxetine, and 41% reported moderate (grade 2) toxicity. Grade 2 or higher fatigue was the most common adverse event in the duloxetine-treated 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 of duloxetine for diabetic neuropathy, which Smith attributed to the lower starting dose in this trial. Gabapentin has been used off label for chemotherapy-related peripheral neuropathy, but it causes somnolence, explained Hope Rugo, MD, of the University of California San Francisco, who commented on this paper during a press conference. “Duloxetine doesn’t have that side effect, so it could be advantageous for patients who need treatment for peripheral neuropathy,” Rugo said. ● —AG

The study included 205 chemotherapy-naive patients receiving highly emetogenic chemotherapy who were given standard drugs to control CINV. Of these, 80 experienced breakthrough CINV on standard therapy and were randomized 1:1 to olanzapine 10 mg orally daily for 3 days versus metoclopramide 10 mg TID for 3 days. Patients with breakthrough CINV were observed for 72 hours and were asked to fill out a daily diary. Incoming American Society of Clinical Oncology President Sandra Swain, MD, said, “This study was a reminder that in the era of precision medicine, we still need to improve the patient experience. CINV can be quite limiting. Patients don’t eat and they can be tired. Olanzapine is another tool we now have to treat this side effect.” ●

Reference

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

Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 9064.

“This study was a reminder that in the era of precision medicine, we still need to improve the patient experience.” —Sandra Swain, MD

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AUGUST 2012 I VOL 5, NO 5

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Conference News: ASCO 2012

Ginseng Improves Cancer-Related Fatigue

Many patients continue to experience fatigue for up to 10 years after their treatments are completed.

The trial enrolled 364 cancer patients being treated with curative intent at 40 sites; all patients reported at least moderate fatigue, reflected by a score of 4 or higher on a 10-point fatigue scale. Other causes of fatigue were ruled out, including anemia, pain, and insomnia. Patients received double-blind, randomized assignment to 2000 mg/day of ground Wisconsin ginseng root in the form of 2 capsules or to placebo taken before noon for 8 weeks. Mean age was 55 years, about 80% were female, and about 90% were white. About 60% had breast cancer, and about 10% had colon cancer. Pain scores improved over the course of treatment. At 4 weeks, a trend was seen favoring ginseng, according to change on the 100-point Multidimensional Fatigue Symptom Inventory score: an improvement of 14.4 points was reported with ginseng versus an 8.2 improvement in placebo patients (P = .07). By 8 weeks, scores improved by 20 points from baseline in the ginseng group versus 10.3 points with placebo (P = .003). Rates of nausea, diarrhea, and vomiting were quite low and were similar in the 2 groups. Insomnia and anxiety were reported less often in the ginseng group than in the placebo patients. Grade 3 or 4 adverse events were reported in 8% and 6% of patients, respectively.

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Formal discussant of this trial, Karen M. Mustian, PhD, MPH, of the University of Rochester, New York, commended the authors for using well-validated measures of cancer-related fatigue. “Ginseng has no discernible toxicity. This is only the second nutritional supplement to effectiveness in reduc$ ) show "#( ("&%

ing cancer-related fatigue,” she said. The NCCN guidelines for cancerrelated fatigue recommend psychological intervention, physical activity, psychostimulants, and steroids.2 Mustian said, “It may be time to recommend specific nutritional supplements, such as ginseng.” ● —AG

References 1. Barton DL, Liu H, Dakhil SR, et al. Phase III evaluation of American ginseng (panax quinquefolius) to improve cancer-related fatigue: NCCTG trial N07C2. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 9001. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue. Version 1.2012. http://www.nccn.org/profession als/physician_gls/pdf/fatigue.pdf. Accessed June 12, 2012.

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inseng has significant activity against fatigue in adults with cancer, according to a randomized trial.1 Eight weeks of treatment with ginseng significantly improved fatigue scores by 20% versus 10% for patients treated with placebo (P = .003). Moreover, ginseng was as safe as placebo in this preliminary trial. Fatigue is almost universally common in patients treated for cancer, and many patients continue to experience fatigue for up to 10 years after their treatments are completed, explained lead author Debra Barton, RN, PhD, of the Mayo Clinic Cancer Center in Rochester, Minnesota. Erythropoietin had been used to treat cancer-related fatigue, but it is no longer used because serious adverse events were found to outweigh the benefits.

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