April 2012, Vol 5, No 2 by The Oncology Pharmacist

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APRIL 2012

www.TheOncologyPharmacist.com

VOL 5, NO 2

SUPPORTIVE CARE

CANCER CENTER PROFILE

What’s New in Antiemetic Arthur G. James Cancer Hospital, Ohio State University Control? NCCN Attendees Reminded to Follow the Guidelines The Role of the Oncology Pharmacist

By Caroline Helwick

he Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital (OSUCCC– James), located in Columbus, Ohio, is 1 of only 41 centers in the United States designated by the National Cancer Institute (NCI) as a Comprehensive Cancer Center. The OSUCCC– James program is part of Ohio State University and is affiliated with the Ohio State University Wexner Medical Center, one of the largest medical centers in the country. Established in 1973, the OSUCCC–James is the Midwest’s first and Ohio’s only freestanding cancer hospital. OSUCCC–James is 1 of 5 centers in the country approved by the NCI to conduct The Arthur G. James Cancer Hospital, part of the both phase 1 and phase 2 Ohio State University Wexner Medical Center. clinical trials for new antiPhoto courtesy the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. cancer drugs. Ali McBride, PharmD, MS, BCPS, is a specialty practice pharmacist at OSUCCC–James. He answered our questions about the field of oncology and the role of the oncology pharmacist. Continued on page 11

ncology pharmacists should “use guidelines, in combination with the knowledge of their patients and their institution’s formulary, to make the best treatment decisions” regarding antiemetic control, Sally Yowell Barbour, PharmD, Director of Oncology Pharmacy Programs at Duke University Medical Center, told attendees at the

2012 Pharmacy Program held in Hollywood, Florida, during the 17th Annual Conference of the National Comprehensive Cancer Network (NCCN). “Chemotherapy-related nausea and vomiting [CINV] remains a concern despite recent advances. While the 5HT3 antagonists and the NK-1 antagoContinued on page 7

THE PATIENT’S VOICE

The Good Pharmacist By MMA

harmacists and their support staff make the world go round, at least my world outside of the hospital. They are the ones who tell me which pills and injections to take, and when. They put the labels on the orangish pill bottles with the white safety caps that serve as a back-up to their written and spoken instructions. In short, I consider them and the prescriptions they fill as a kind of lifeline between my inpatient and outpatient lives.

Of course, I have met good pharmacists and bad ones. Some pharmacists inspire confidence with their specialized knowledge of medicine. Others make me think that as long as I can pay, they do not really care what pills I pop. Fortunately, I have met more good than bad ones. So, how do I, as a patient, define “good”? I have developed the following list of my top 5 criteria. A good pharmacist: 1. Introduces himself/herself to me and Continued on page 10

NEWS BRIEFS

CYP2D6 Genotyping Fails to Predict Effectiveness of Tamoxifen By Alice Goodman

ccording to 2 large breast cancer trials, CYP2D6 genotyping was not predictive of the effectiveness of tamoxifen in postmenopausal women. Thus, the results of these studies are not generalizable to premenopausal women. CYP2D6 genotyping has been a focus

INSIDE Complimentary Ce

.........

Considerations in Multiple Myeloma— Ask the Experts: Newly Diagnosed Patients Basal Cell CarCinoma

of research interest, but studies have been inconclusive as to the value of testing. In theory, certain CYP2D6 genotypes and phenotypes would be associated with breast cancer outcomes on treatment with tamoxifen; that is, tamoxifen would be less effective in Continued on page 8

....

Vismodegib: A New Treatment Option for Basal Cell Carcinoma ColoreCtal CanCer

.......

Survival Benefit of Oxaliplatin Confirmed Regorafenib for Previously Treated mCRC

supportive Care . . . . . . . . . . . .

Many Febrile Neutropenia Patients Can Be Treated at Home

Koeller’s Corner Shooting from the Hip Oncology Is a Small World Page 27

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NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION

Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint RESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

AT 12 WEEKS (AFTER 4 CYCLES) Single-agent VELCADE® (bortezomib)

53% 51%

43% 42%

11% 12%

7% 8% ORR Primary Endpoint

SC (n=148) IV (n=74)

ORR

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety. *INDICATIONS: VELCADE 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. †

Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1

VELCADE IMPORTANT SAFETY INFORMATION 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

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IN ALL INDICATIONS*

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IV GRADE ≥3

SC (n=147) IV (n=74)

16% ALL GRADES

38% 53% ▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness ▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED ▼ 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 next page. For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com Reference: 1. 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(5):431-440.

2:35 PM

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Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell 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.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, 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 (bortezomib) 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.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). 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. VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0017a 03/12

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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

APril 2012 I VOl 5, NO 2

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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

Managing Editor Kristen Olafson kristen@greenhillhc.com

his issue of The Oncology Pharmacist (TOP) covers a range of issues—from the persistence of “chemo brain” to a report on the specifics of vismodegib, a recently approved agent for the treatment of basal cell carcinoma in adults with locally advanced or metastatic disease who are not candidates for surgery or radiotherapy. We also tell you about some of the news coming out of the American Society of Clinical Oncology Gastrointestinal Symposium and the National Comprehensive Cancer Network annual conference. In The Patient’s Voice article, MMA offers her definition of a “good pharmacist,” giving us all insight into how our actions as healthcare providers are perceived by patients. We hope to provide you with more perspectives from MMA as she journeys through her cancer treatment,

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: 732-992-1891 Fax: 732-656-7938

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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, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. 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.

APril 2012 I VOl 5, NO 2

which at this point includes a stem cell transplant in the near future. MMA would like to remain anonymous, but we welcome her contributions to TOP. In his Shooting From the Hip column, Jim Koeller tells us about the small world of oncology and makes it clear that he is a very happy Texan! We encourage you to visit our Web site, www. TheOncologyPharmacist.com. Please answer this month’s Reader Poll about antiemetic control and let us know what your patients are saying. Also, tell us your thoughts about The Patient’s Voice—we want to hear your reactions to MMA’s experience. And, as always, let us know what topics you want to see covered in TOP. We want to hear from you, and we appreciate your feedback. ●

Noteworthy Numbers

241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831

™

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

Because skin is the largest organ in the body, is it not surprising that skin cancer is the most common of all cancers. Melanoma, the most deadly skin cancer, is caused by overexposure to ultraviolet radiation. So with spring in the air and summer right around the corner, let us dig deeper into the statistics surrounding this fatal disease.

Melanoma accounts for about 4% of all skin cancer cases but 79% of all skin cancer deaths. It is currently the seventh most common cancer in American women and the sixth most common cancer in American men. Incidence rates have been on the rise for the past 30 years. It is estimated there will be 76,250 new cases of melanoma in the US this year. Melanoma has a wide age distribution. There is an increase in occurrence with age, and rates are highest among those in their 80s. Melanoma is not uncommon among those younger than age 30. In fact, it is the

second most common cancer in women between the ages of 20 and 35 and the leading cause of cancer death in women aged 25 to 30. The primary risk factor for developing melanoma is race, with rates 10 times higher for whites than blacks. The lifetime risk of a melanoma diagnosis is about 2% (1 in 50) for whites, 0.5% (1 in 200) for Hispanics, and 0.1% (1 in 1000) for blacks. From 2004 to 2008, 68 years of age was the median age at death for patients with melanoma. The disease is expected to cause approximately 9180

deaths during 2012 (6060 men and 3120 women). If melanoma is discovered early enough, the chance of survival is high. Fiveyear survival rates range from 97% for stage IA down to 15% for stage IV melanoma. In order to prevent this deadly disease, the American Cancer Society encourages everyone to “Slip! Slop! Slap!...and Wrap!” • Slip on a shirt • Slop on sunscreen • Slap on a hat • Wrap on sunglasses Sources: w w w. m e l a n o m a c e n t e r. o rg / b a s i c s / index.html; www.cancer.org/Cancer/Skin C a n c e r- M e l a n o m a / D e t a i l e d G u i d e / melanoma-skin-cancer-key-statistics; seer.cancer.gov/statfacts/html/melan.html.

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Supportive Care What’s New in Antiemetic Control? Continued from cover nists reduce vomiting, nausea continues to be a persistent problem for our patients,” she said. “There will always be patients, no matter what we do, who still have problems.” Patient risk factors drive the choice of prophylaxis and dose, she said. Young age (<50), female gender, no or minimal prior history of alcohol use, and prior CINV are the key patient-related factors. Treatment-related risk factors are the use of moderate to high emetogenic chemotherapy agents or regimens and moderate to high drug doses. Practical Considerations in Selecting Treatment “Guidelines are good for recommendations, but they focus on single-day chemotherapy,” Barbour noted. “For multiday chemotherapy, there is little guidance.” The recommendation is to give appropriate prophylactic therapy for the expected emetogenicity on each day of chemotherapy administration and to continue delayed prophylaxis alone for 2 to 3 days after chemotherapy is completed, if indicated. With multiday chemotherapy, it is not clear whether one should follow the same once-per-cycle dosing of palonosetron that is used in single-day chemotherapy regimens. “There is no right answer,” she said. The other often-asked question is whether all 5-HT3 antagonists are equal. The American Society of Clinical Oncology (ASCO) and NCCN have stated that palonosetron is the preferred agent: ASCO recommends this for moderately emetogenic regimens only, while NCCN recommends it for highly and moderately emetogenic regimens. The decision to make palonosetron the preferred agent was based on multiple noninferiority studies that found equivalency, though the inclusion of corticosteroids varied in these studies, and this may have affected outcomes, she cautioned. The differences between the 2012 NCCN Guidelines and the current ASCO Guidelines for highly emetogenic prophylaxis are shown in the Table. With regard to the question of equivalency between intravenous (IV) and oral agents, she said that at equivalent doses their efficacy should also be equal. “Agents are often chosen based on cost and what is preferred at your institution,” she said. “At Duke we tend to use all IV antiemetics, though some oncologists use oral if no pharmacist is on hand. The nurses find oral drugs easier.” She added that single-dose IV fosaprepitant (150 mg IV day 1) had

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Table Antiemetic Guidelines: High Emetic Risk Emetogenic Risk Category

NCCN* (v.1.2012)

ASCO

High

Acute (day 1): 5-HT3 antagonist (NCCN lists palonosetron as preferred) plus corticosteroid plus NK-1 antagonist Delayed (days 2-4): Corticosteroid plus NK-1 antagonist

Adriamycin/ Acute and delayed: as above cyclophosphamide regimens

Acute: as above Delayed: NK-1 antagonist

*± lorazepam 0.5 to 2 mg PO or IV every 4 to 6 hours; ± H2 blocker or proton pump inhibitor.

“taken over” at her center as a substitute for a 3-day oral regimen, and the staff has found this very helpful. Support for the drug comes from a large randomized double-blind active-control, noninferiority study of 2322 patients on cisplatin who received aprepitant 125 mg on day 1, 80 mg on

and this has improved tolerability of the IV agents, she added. Key Principles of Antiemetic Control Barbour reiterated the key principles of good antiemetic prophylaxis and control:

“There will always be patients, no matter what we do, who still have problems.” —Sally Yowell Barbour, PharmD

day 2, and 80 mg on day 3, or IV fosaprepitant 150 mg on day 1.1 Antiemetic protection was similar between the regimens; both were effective in almost three-quarters of patients. To prevent infusion site pain with the NK-1 antagonists, her nurses increase the volume of normal saline,

• Schedule agents to cover the duration of risk of CINV, and to prevent delayed episodes • Consider oral and IV antiemetics to have equivalent efficacy; choice is based on cost and patient factors • Consider the toxicity of the antiemetics

• Match the antiemetic potency to the emetogenic potential of the chemotherapy; in multidrug regimens, base choice on the agent with highest risk • Combine agents with different mechanisms of action and individualize the regimen • Choose antiemetics based on emetic risk of treatment, prior experience with antiemetics, and patient risk factors • Consider other nonchemotherapy-related causes of nausea and vomiting To prevent or treat breakthrough or refractory CINV, the provider should follow up each chemotherapy cycle for the patient’s response to the prophylaxis and the need for escalation, and take into account other patient-specific factors that may contribute to risk, she said. ● Reference 1. Grunberg S, Chua D, Maru A, et al. Single-dose fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with cisplatin therapy: randomized, double-blind study protocol—EASE. J Clin Oncol. 2011;29:1495-1501.

Reader Poll Do patients talk with you about antiemetic control? r Yes r No

To answer this question and tell us what your patients are saying, please log on to

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News Briefs CYP2D6 Genotyping Fails to Predict Effectiveness... Continued from cover poor and intermediate metabolizers of endoxifen (a metabolite of tamoxifen) and more effective in extensive metabolizers of endoxifen. The 2 studies—ATAC and BIG 1-98—were published in the Journal of the National Cancer Institute (JNCI)

online on March 6, 2012. ATAC was a prospective clinical trial that compared effectiveness and safety of the aromatase inhibitor anastrozole versus tamoxifen in postmenopausal women with hormone receptor–positive earlystage breast cancer. Tumor samples from

1203 women were genotyped for CYP2D6. At a median follow-up of 10 years, no significant associations were found in the tamoxifen-treated group between the CYP2D6 genotype for poor metabolizers versus extensive metabolizers for distant recurrence or for any recur-

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rence. As might be expected, no associations were found between the CYP2D6 genotype and recurrence in the patients who received anastrozole. BIG 1-98 randomized postmenopausal women with hormone-sensitive, operable, invasive breast cancer to 5 years of treatment with tamoxifen monotherapy versus letrozole monotherapy. The findings were similar to those of ATAC, with no significant association found between CYP2D6 metabolism phenotypes and breast cancer–free interval in women treated with tamoxifen. The authors of BIG 1-98 also studied new-onset or worsening hot flushes during the first 2 years of tamoxifen therapy. They wrote, the results “suggest that CYP2D6 testing is not justified to determine whether tamoxifen should be given to postmenopausal women, nor to withhold treatment with an aromatase inhibitor. The presence or absence of hot flushes should not be used in the clinical setting to estimate tamoxifen efficacy.”

NO SHORTAGE OF COMMITMENT.

In an accompanying editorial in the same issue of JNCI, Catherine M. Kelly, MD, and Kathleen I. Pritchard, MD, wrote: “The fact that these two studies confirm each other suggests that this matter has likely been laid to rest.” They noted that the findings suggest that the vast industry of CYP2D genotype testing was premature, that patients underwent additional and unnecessary tests and charges related to genotyping, and that therapy was adjusted according to genotyping test results without firm evidence. Both editorial writers wrote that the lessons learned from these 2 large trials include the need for large confirmatory studies of therapeutic agents and biomarkers. Results of ATAC and BIG 1-98 illustrate that laboratory observations that raise hypotheses must be independently validated in order to guide clinical practice. ●

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News Briefs

“Chemo Brain” Can Persist for 2 Decades

©iStockphoto.com/AnsonLu

he term “chemo brain” was coined to describe mild cognitive problems in cancer patients attributed to chemotherapy. Although minor chemotherapy-induced memory and cognitive impairments have been described previously, a case-cohort study suggests that these effects can persist more than 20 years posttherapy. The authors state that chemo brain effects are subtle compared with women who never had chemotherapy, but it’s possible that these effects place people at greater risk for cognitive decline associated with aging. A partial explanation for chemo brain may be that chemotherapy penetrates the blood-brain barrier, killing healthy brain cells, or that chemotherapy affects the immune system or is proinflammatory. The study, published online in February in the Journal of Clinical Oncology (Koppelmans V, Breteler MM, Boogerd W, et al) included 196 breast cancer survivors treated with adjuvant CMF (cyclophosphamide, methotrexate, and fluorouracil) who were tested with a series of cognitive and memory tests. Ages were from 50 to 80 years, the mean number of chemotherapy cycles was 6, and the mean interval since chemotherapy was 21 years. Scores on speed processing, word, memory, and general cognitive functioning tests were compared with scores of a population-based sample of 1509 women who did not undergo cancer treatment and were participants in a larger long-term study.

Someone in a demanding job might notice these changes in cognition, but someone who is not working and has a more relaxed lifestyle may not.

Women treated with chemotherapy scored significantly lower on tests of immediate and delayed verbal memory, processing speed, executive function, and psychomotor speed than the reference group and similarly on the other 10 tests included in the study. The inter-

group differences were small. On word learning tests, women who had chemotherapy had an average score of 24.3 of 45 compared with 25.5 in the control group. Senior author Sanne Schagen, MD, Netherlands Cancer Institute,

Amsterdam, the Netherlands, said that these differences might or might not be apparent, depending on the specific tasks involved in people’s daily lives. Someone in a demanding job might notice these changes in cognition, but someone who is not working and has a more relaxed lifestyle may not. One limitation of this study is that CMF is an older chemotherapy regimen no longer considered a standard of care. However, Dr Schagen noted that more modern drugs would probably cause the same effects. Other limitations include the inability to prove cause and effect between chemotherapy and cognitive changes, which may be an effect of breast cancer itself. Also, baseline mental function was not assessed prior to chemotherapy. The study does not imply that women with breast cancer should not undergo chemotherapy. Rather, the implication is that patients and physicians should be aware of the potential cognitive effects of chemotherapy and seek help if these problems interfere with daily function. The effects documented in this study do not appear to be serious cognitive impairment or even mild cognitive impairment, but patients are scoring slightly lower on tests of memory and thinking, explained neuropsychologist Barbara Collins, PhD, Ottawa Hospital, Ontario, Canada, who was not involved in this study. ● —AG

Tumors More Heterogeneous Than Previously Recognized

esearchers have documented diverse genetic changes in different parts of the same primary tumor, suggesting that individual tumors harbor a complexity of genetic changes that has not been well appreciated (Gerlinger M, Rowan AJ, Horswell S, et al. N Engl J Med. 2012;366:883-892). This discovery has implications for personalized medicine directed at genetic changes identified in 1 biopsy of a primary tumor. “Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor biopsy samples and may present challenges to personalized medicine and biomarker development,” wrote the authors. They noted that the extent of intratumoral heterogeneity is what was striking and surprising in this study. The small study found more genetic differences than genetic similarities

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between biopsies taken from different parts of the same tumor. The authors also found differences in genetic changes between the primary tumor and local as well as distant metastases. The fact that

metastases when they develop in addition to primary tumor biopsies. The study analyzed cancer genomics in biopsy samples of a total of 30 biopsies from 4 primary tumors. Genomic

The small study found more genetic differences than genetic similarities between biopsies taken from different parts of the same tumor.

the primary tumor has different genetic characteristics than metastases from that tumor has been documented in breast cancer, and there is currently a movement to recommend biopsies of

analysis revealed that 26 of the 30 biopsies had different genetic expressions. The authors identified 118 different genetic mutations. About 40 were found in all the biopsies from the

primary tumor and the metastases (ubiquitous mutations), and 53 mutations were shared. Twenty-five mutations were found only in a single biopsy (“private mutations”). Furthermore, gene expression signatures associated with a good prognosis and also those associated with a poor prognosis were seen in different sites of the same primary tumor. Likening the genetic changes to a trunk and branches of a tree, the authors said that some genetic changes were seen early in the “trunk,” while others evolved over time into different “branches.” In an accompanying editorial, Dan Longo, MD, deputy editor of the New England Journal of Medicine, wrote that these observations suggest that it is probably “too simple” to direct therapy according to genetic tumor markers due to the heterogeneity observed within a single tumor. ● —AG

APril 2012 I VOl 5, NO 2

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News Briefs

GIST Outside GI Tract Has Poor Prognosis

rimary gastrointestinal stromal tumor (GIST) sited outside the gastrointestinal (GI) tract carries a poorer prognosis than primary GIST within the GI tract, according to a study presented at the recent ASCO GI Symposium in January 2012. Lead investigator of the study, Mary L. Guye, MD, surgical oncologist at the City of Hope Medical Center in Duarte, California, noted that these results suggest that GIST location should be factored into risk stratification. The reasons are unknown for the poorer prognosis in

GIST sited outside the GI tract, she said, noting that molecular analysis is needed to investigate the biology of

Extra-GI tumors were still associated with almost a 30% increase in mortality. these less common GISTs to help determine why they carry a worse prognosis.

The study included 2591 patients from a SEER (Surveillance, Epidemiology, and End Results) database from 1996-2008 who underwent primary surgery for GIST. Primary tumors were located outside the GI tract (omentum, mesentery, retroperitoneum, or another location) in 10% of cases. Patients with intra-GI and extra-GI primary tumors were of similar ages and racial distribution. For the group with extra-GI primary tumors, 5-year survival was 62% versus 70% for those with tumors located within the GI tract. Median overall sur-

vival was 105 months for extra-GI tumors versus 120 months for those with tumors in the GI tract (P = .002). Tumors sited outside the GI tract tended to be larger than 10 cm, have more advanced regional or distant disease, and were more likely to be treated with radiation therapy. In a multivariate analysis adjusting for these confounding factors, the findings remained the same. Extra-GI tumors were still associated with almost a 30% increase in mortality (P = .03). One limitation of the study is that the SEER registry does not include data on mitotic rate or on systemic medical therapies patients were taking. ● —AG

The Patient’s Voice The Good Pharmacist Continued from cover tells me what he/she studied. For example, recently at the end of a hospital stay, a pharmacist came into my room just before I went home. She told me her name and explained to me that she had specialized knowledge in oncology medicines. I felt really confident that she knew what she was doing. 2. Reviews my list of medicines with me in detail, mentioning both the formal name of the medicine, the name of the medicine that may be replacing it, when I should take it, how much I should take, and what time of day I should take it. He/she gives me this information both orally and on an orderly written sheet that I can see during the conversation. This auditory-visual combination from a specialized pharmacist makes me really believe that I will know how and when to take my medicines once I am on my own at home. 3. Asks me if I have any questions and answers them, politely. I need a

chance to process all the information I am being given. Oftentimes, my list of medicines includes up to 18 prescriptions, some of which I need to take twice a day, others once a day, others only as needed, and yet others for a

know that the pharmacist really wants me to understand. And the polite part? Well, no patient (or anyone else) wants to be treated as a bother or as being stupid. So, even though I am sure that some of the fantastically pre-

Fortunately for me and for all the other patients of the world, I can vouch that most pharmacists are really good. specified number of days. So even when the pharmacists take the time to go over the list medicine by medicine, sometimes I am left uncertain about a detail or need clarification. When the pharmacist asks me if I have any questions—or answers my questions even when we are in the process of going over the list—I feel empowered. I

pared pharmacists probably have thought my simple questions rather, well, silly, they have never let on (even when I have asked—alright, asked twice—when I have to take a pill despite having it written down and being told verbally already). They have always answered my questions professionally, even gleefully in some cases!

Reader Poll Results

Should everyone be required to purchase health insurance?

n the February issue, we published an editorial from the Wall Street Journal about the requirement under the federal 2010 Patient Protection and Affordable Care Act that everyone have health insurance. This aspect of the act is scheduled to take effect in 2014, but there are legal challenges working their way through the courts.

We asked our online reading community about this subject, and here are the results: • 61% said people should be required to purchase health insurance • 39% didn’t think people should be required to purchase health insurance

Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 7 for details.

www.TheOncologyPharmacist.com 10

April 2012 I VOl 5, NO 2

4. Writes on the prescription label what medicine is a substitution for what other medicine. I have no idea if this is a legal requirement, but honestly, I only recognize the names of medicines that my nurses, the pharmacist, or a doctor mentions to me. I have no idea about the fancy or official names of medicines. So, when the label tells me through a brightly colored sticker on the bottle that some 16-letter medicine is actually a substitute for a 5-letter one I have heard mentioned by my medical personnel, I get it! 5. Acts as if he/she has time to attend to me. After I pick up my prescription at the window and am asked or directed to ask questions of the pharmacist, I need to perceive that he/she is paying attention to me, not trying to fill the next prescription or be preoccupied with some other issue behind the counter (even when he/she really is). This may require some acting on the pharmacist’s part, especially at retail outlets where more than a dozen patients may be waiting for the same attention. But, hey, I am finally at the front of the line after a 30-minute wait and deserve to have my questions answered completely and calmly. Admittedly, I do not know all the duties of a pharmacist. I am not privy to all the behind-the-scenes preparation of prescriptions. I do not boast a great understanding of all the years of education it takes to become a pharmacist. My perspective stems only from my face-to-face contact with those in the profession. Fortunately for me and for all the other patients of the world, I can vouch that most pharmacists are really good. ● MMA is undergoing treatment for cancer. She wishes to use her initials.

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Cancer Center Profile Arthur G. James Cancer Hospital, Ohio State University Continued from cover What are you excited about right now in the field of oncology? Ali McBride (AM): Oncology is a practice that continues to grow and is everchanging, as we enter onto a path of genomic-based research and molecularly targeted therapies. New therapies are hitting the market for prostate cancer, breast cancer, and leukemia. We are seeing promising molecular therapies in chronic lymphocytic leukemia and acute lymphoblastic leukemia. The introduction of new therapies in myelofibrosis has opened the door to this field, in which no therapies showed much promise just a decade ago.

practitioners today is finding a focus. Oncology is a field of diversity, as you may be working in specific disease states that require intense learning and years of devotion. In some cases your face may be buried in the grindstone, and it will be up to you to realize the process of oncology practice. Once that happens, you will be able to make not just small patient changes for your practice, you will be able to guide larger changes in the practice of pharmacy.

How has the role of the oncology pharmacist changed over the past 5 years? AM: Oncology pharmacists have been changing with the advent of translational medicine. Twenty years ago, the face of pharmacy was focused on conventional chemotherapy, consisting of vinca alkaloids, anthracyclines, nitrogen mustards, and numerous other agents. Since that time the face of pharmacy has moved with science as therapies have become focused on cell signaling processes, molecular markers, and gene variants. The development of these new therapies has also brought cytogenetic and pharmacogenomics data to the forefront, as oncology pharmacists are able to help determine the appropriate therapies for numerous mutations in disease states, including breast and colorectal cancer, myelodysplastic syndrome, leukemia, and lymphoma. What inspired you to become an oncology pharmacist? AM: My inspiration to enter hematology/oncology practice actually stemmed from my work as a scientist before I entered pharmacy school. I graduated from Purdue University with a BS and MS in neurobiology and physiology and biochemistry and decided to focus on cell adhesion and protein signaling research. The areas I focused on included tyrosine and serine/threonine kinase inhibitors in the cell signaling process as well as drug resistance proteins upregulated in cancer cells. Going to pharmacy school at the University of Arizona and training at Moffitt Cancer Center for my PGY-2 residency allowed me to combine my basic science background with clinical application in oncology. The combination of these 2 fields has helped me keep abreast of the new changes in chemotherapy as we continue to move forward to molecular-based therapy regimens. Any advice for new pharmacists? AM: I think the toughest issue for new

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If you weren’t a pharmacist, what would you be doing? AM: If I were not a pharmacist, I would most likely have entered a trade profession after college. My father is a transmission mechanic and, having been associated with cars for so long, this would have been my natural progression into the field. This is in no correlation to the widely heralded novel Zen and the Art of Motorcycle Maintenance but rather an analogy to the constant work and erudition mechanics in the

field have to update themselves on in terms of new transmission systems, electronic interfaces, and diagnostic criteria for individual makes and models of cars. The constant work that is needed to maintain the level of competency is hard, and the required tools are expensive. However, there is nothing more amazing to watch than a transmission mechanic breaking down every part in the transmission casing and then rebuilding it without extra pieces to be found. ●

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TOP_April 2012_v3_TOP 4/21/12 8:33 PM Page 12

CONTINUING EDUCATION APRIL 2012 • VOLUME 5 • NUMBER 1

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Newly Diagnosed Patients 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

Project Manager Elizabeth S. Cohen liz@coexm.com

Copyeditor Dana Delibovi

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 first issue, experts from Winship Cancer Institute of Emory University answer questions pertaining to the management of newly diagnosed patients.

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, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

Quality Control Director Barbara Marino

Web Coordinator Jose Valentin

Business Manager Blanche Marchitto

FACULTY Leonard T. Heffner, Jr., MD Associate Professor of Hematology and Oncology and Internal Medicine Emory University Clinical Director of the Myeloma Program at Winship Cancer Institute of Emory University, Atlanta, GA

Melanie Watson, RN, OCN Oncology Certified Registered Nurse Myeloma Team/BMT Winship Cancer Institute Emory University Atlanta, GA

Minal Surati, PharmD Clinical Pharmacy Specialist Department of Hematology and Medical Oncology Emory University Hospital/ Winship Cancer Institute Atlanta, GA

Executive Administrator Jackie Luma

Circulation Department circulation@greenhillhc.com Center of Excellence Media, LLC 241 Forsgate Drive Suite 205B Monroe Township, NJ 08831

April 2012 I VOl 5, NO 2

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

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

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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: • Use diagnostic and staging criteria to distinguish active multiple myeloma (MM) from smoldering MM and monoclonal gammopathy of undetermined significance • Determine appropriate treatment for newly diagnosed MM based on patient- and disease-related characteristics and the riskbenefit profile of available agents and combinations • Apply evidence-based strategies to prevent and/or manage common comorbidities in patients with 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/P12025.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 04689999-12-012-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, 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 PI on a study for Pfizer.

Faculty Disclosures *Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. Leonard T. Heffner, Jr., MD, has nothing to disclose. Melanie Watson, RN, OCN, has nothing to disclose. *Minal Surati, PharmD, has nothing to disclose. 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: April 16, 2012 Valid for CME/CE credit through: April 16, 2013

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Evolving Concepts in the Management of Newly Diagnosed Multiple Myeloma Leonard T. Heffner, Jr., MD Associate Professor of Hematology and Oncology and Internal Medicine, Emory University Clinical Director of the Myeloma Program at Winship Cancer Institute of Emory University, Atlanta, GA

Introduction The management of multiple myeloma (MM) is rapidly changing. New prognostic systems based on clinical and biologic features, such as cytogenetic abnormalities, continue to be developed and refined. Novel agents designed to interrupt myeloma growth and survival pathways have also entered the clinical arena, leading to improved response rates, survival, and quality of life. A major challenge is to define the optimal use of these new tools and therapies in order to significantly impact the natural history of disease. In this article, Leonard T. Heffner, Jr., MD, answers questions related to the diagnosis, staging, and initial management of patients with MM, and offers insights on his institution’s approach to aligning patient- and disease-characteristics with the most appropriate treatments to optimize care.

monoclonal (M) protein in serum and <10% of bone marrow plasma cells (BMPCs), but they do not have end-organ damage. In SMM, the clinical and laboratory findings are the same as MGUS except that the serum Mprotein is 3 g/dL and/or the BMPCs are 10%. Symptomatic MM is determined by the presence of 10% BMPCs, serum or urinary M-protein, and evidence of end-organ damage; specifically, hypercalcemia, renal insufficiency, anemia, or bone lesions (Table 1).1-4 Overall, the risk of MGUS progressing to MM is about 1% per year.2 However, the risk of progression for SMM is considerably higher; approximately 10% per year in the first 5 years.2 Risk factors for progression in SMM include: plasma cell mass including M-protein size and the percentage of BMPCs, abnormal free light chain (FLC) ratio, proportion of phenotypically abnormal BMPC, and presence of magnetic resonance imaging (MRI) abnormalities2 (Table 2). Patients with SMM who have an FLC ratio of either <0.125 or >8 have an increased risk for progression to symptomatic myeloma, and this risk is independent of the risk defined by the percentage of BMPCs or size of the M-protein spike.2,5 Should patients with high-risk SMM be observed or treated?

What criteria are used to distinguish smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) from active myeloma?

MGUS and SMM are asymptomatic, and each carries a considerably different potential for progression to MM. Patients with MGUS have <3 g/dL

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The current standard of care for asymptomatic SMM is observation.6 However, we do know that a large majority of high-risk patients will evolve into symptomatic myeloma that requires treatment. Clinical trials are ongoing to assess whether the progression of SMM can be delayed or halted with early treatment. One such study is the Eastern Cooperative Oncology Group

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Table 1. Diagnostic Criteria for Specific Plasma Cell Disorders1-4

Table 2. Risk Factors for Progression in Smoldering Multiple Myeloma5

Monoclonal gammopathy of undetermined significance (MGUS) All 3 criteria must be met: • Serum monoclonal protein <3 g/dL • Clonal bone marrow plasma cells <10% • Absence of end-organ damage (such as CRAB criteria) that can be attributed to the plasma cell proliferative disorder

Higher plasma cell mass (including monoclonal-protein size and percentage of BMPCs) Abnormal free light chain ratio Abnormal immunophenotype and immunoparesis (95% of BMPCs with abnormal phenotype; decrease in 1-2 uninvolved immunoglobulins)

Smoldering multiple myeloma (SMM) (also referred to as asymptomatic multiple myeloma)

Evolving pattern (progressive increase in the serum monoclonal-protein value, eg, increase in monclonal-protein level in each of the first 2 follow-up visits)

Both criteria must be met: • Serum monoclonal protein (IgG or IgA) 3 g/dL and/or clonal bone marrow plasma cells 10% • Absence of end-organ damage (such as CRAB criteria) that can be attributed to the plasma cell proliferative disorder

Presence of MRI abnormalities (especially a focal pattern on spinal MRI) BMPCs indicates bone marrow plasma cells; MRI, magnetic resonance imaging.

Multiple myeloma (MM) All 3 criteria must be met, except as noted: • Clonal bone marrow plasma cells 10% • Presence of serum and/or urinary monoclonal protein (except in patients with true nonsecretory MM) • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (specifically CRAB): Calcium elevation: serum calcium 11.5 mg/dL or Renal insufficiency: serum creatinine >2 mg/dL Anemia: hemoglobin >2 g/dL below lower limit of normal or value <10 g/dL Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures

(ECOG) E3A06 phase 2/3 trial, which is comparing the progression-free survival of patients with high-risk SMM treated with lenalidomide or observation.7 Lenalidomide was chosen because of its clinical activity in MM, as well as the fact that it can be administered orally and is generally well tolerated. Thirty-four patients were enrolled in the phase 2 portion of the trial and were treated with lenalidomide 25 mg/day on days 1 to 21 of a 28-day cycle for 6 cycles in the absence of disease progression or unacceptable toxicity. Following a 6-month hold for safety analysis of the phase 2 data, the phase 3 portion of the trial, in which 370 patients will be randomized to either lenalidomide or observation, will begin enrollment. I think this is an exciting trial because we are trying to move back the clock a little rather than wait until a patient with SMM has become symptomatic. It will be interesting to see whether the natural history of the disease can be influenced with early treatment, especially in a population that has a fairly high risk of eventually requiring therapy. How have staging criteria for MM evolved over time?

First published in 1975, the Durie-Salmon (DS) staging system was the method clinicians commonly relied on for staging MM for more than 25 years. This system assessed myeloma tumor burden, and based stages I, II, and III on serum M-spike, hemoglobin, calcium level, and number of bone lesions. Subclassifications A and B reflected the degree of kidney involvement, as measured by creatinine level.8 The DS staging system provided a framework by which clinicians could communicate clearly with each other regarding the extent of the disease. Unfortunately, there were drawbacks to this system. Many found it to be too complex, and there were problems in terms of evaluating lytic bone lesions accurately. To address these issues, investigators proposed a new method of staging called the International Staging System (ISS). This system includes an assessment of beta-2-microglobulin (ß2M) and serum

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albumin levels, which were shown in a multi-variant analysis to be the 2 important prognostic factors in myeloma.9 Patients with stage I disease have a ß2M level <3.5 mg/L and albumin level 3.5 g/dL (median survival 62 months) compared with stage III with ß2M 5.5 mg/L (median survival 29 months) and stage II (not meeting criteria for either stage I or III) (median survival 44 months).9 Because ß2M and serum albumin are easily obtainable parameters, the ISS has superseded the DS staging system and is now widely accepted as the standard of care for staging MM. What role does cytogenetic testing play in the prognosis and treatment of newly diagnosed patients with MM?

The use of cytogenetic testing to help identify myeloma patients with highrisk disease continues to evolve as we learn more about the biology of the disease. Conventional metaphase karyotyping is one modality for assessing risk, but it is not as informative as we would like because myeloma cells proliferate poorly in vitro.10 This method of analysis is useful, however, for the screening of hyper- and hypodiploidy and cytogenetic abnormalities such as deletion of chromosome 13 [del(13q)].4,11 Fluorescence in situ hybridization (FISH), on the other hand, analyzes cells in mitotic interphase, which allows better identification of certain chromosomal abnormalities.11 In particular, it is instrumental in screening for del(13q), deletion of the short arm of chromosome 17 [del(17p)], translocations involving chromosomes 4, 11, 14, and 16 [t(4;14), t(11;14), and t(14;16)], and 1q21 amplification.4,11 Abnormalities indicative of poorer prognosis in myeloma include del(17p), t(4;14), and t(14;16).10,12,13 Interestingly, del(13q), once considered a high-risk characteristic, is no longer thought to indicate a poor prognosis if it occurs independently of other cytogenetic abnormalities.10,14 At diagnosis, metaphase karyotyping and FISH results are certainly very important to obtain and use in treatment planning, but they must be considered in the context of other features of a patient’s condition, such as age, stage of disease, extent of bone disease and renal function, and comorbidities. In addition, there is still a question as to how best to incorporate results into a patient’s course of therapy because cytogenetic abnormalities continue to evolve over time.14,15 At our institution, we retest cytogenetics prior to transplantation to determine whether a patient’s risk status has changed in any way. Clinical evidence suggests that bortezomib and lenalidomide may have particular value in the context of certain high-risk cytogenetics.13,16-19 Whenever possible, we treat newly diagnosed myeloma patients with regimens that contain one or both of these agents. In addition to cytogenetic abnormalities, gene expression profiling (GEP) signatures are now being identified, including a 70-gene profile from the

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University of Arkansas20 and a 15-gene profile by the Intergroupe Francophone du Myélome.21 Although these 2 profiles do not share any common genes, GEP has the potential to be a useful tool for risk-stratifying patients and determining optimal therapy, and investigation in this area continues. For example, GEP signatures are being utilized in the ECOG E3A06 trial for SMM,7 to help identify patients who are going to have higher or lower risk of progression.

Figure. Best responses to RVD for the treated population and the phase 2 population.19

100

100%

How do you determine the appropriate treatment for newly diagnosed MM?

What advances have been made to help clinicians assess bone disease in MM?

74% 67%

Patients (%)

For transplant-eligible patients, the approach we typically use is frontline treatment with a combination of lenalidomide, bortezomib, and dexamethasone (RVD). In a phase 1/2 study in newly diagnosed patients, this combination was shown to have favorable tolerability, and resulted in a partial response or better rate of 100%, with a 74% rate of very good partial response or better in the phase 2 population (Figure).19 The study included subgroup analyses of patients with high-risk cytogenetics, which showed that response to RVD was unaffected by cytogenetic abnormalities. This finding suggested that RVD may overcome high-risk cytogenetics, but was not definitive because of the small sample size of patients with these abnormalities. We almost always use this combination, whether the risk is standard or high, unless the patient has plasma cell leukemia or another medical condition that would require a different approach to treatment. RVD is also being used more frequently in the nontransplant setting, as long as patients can tolerate these agents. If RVD is too aggressive, we consider regimens using melphalan and prednisone combined one of the novel agents bortezomib, lenalidomide, or thalidomide. If we can find a clinical trial that would suit the needs of transplant-ineligible patients better, we may offer that to them.

PR VGPR CR/nCR

57%

39%

Best Responses in All Patients (n=66)

Best Responses in Phase 2 Patients (n=35)

CR/nCR indicates complete response/near-complete response; PR, partial response; VGPR, very good partial response; RVD, lenalidomide/bortezomib/dexamethasone.

sion. We also repeat bone assessments by PET or MRI after a course of therapy. For transplant-eligible patients, this is done prior to transplant to document the degree of response to treatment. For transplant-ineligible patients, this practice helps us to determine whether we should continue with the current approach to therapy. Conclusion

In the most recent consensus guidelines from the International Myeloma Working Group, the bone survey is still the gold standard for assessing myeloma bone disease.22 However, there is a movement among many cancer centers to make more frequent use of MRI and positron emission tomography/computed tomography (PET/CT) scans.4,23 Fortunately, Medicare now allows coverage of PET/CT scans for myeloma. At our institution, we consider each patient’s case on an individual basis. In general, we still conduct a bone survey. If results are negative, we will typically do an MRI of the spine and pelvis, as this procedure can pick up abnormalities even if a plain film is negative in symptomatic patients.22 The use of PET scans is clearly important, because they can detect not only bone-based disease, but also extramedullary disease.22,24

The use of PET scans is clearly important, because they can detect not only bone-based disease, but also extramedullary disease.

For patients with oligosecretory or nonsecretory disease who do not have laboratory parameters to monitor outside of a bone marrow examination, and particularly for patients with extramedullary plasmacytomas, we use PET scans to monitor them and to document whether they are in remis-

Progress in the diagnosis and treatment of MM has been tremendous over the past 10 to 15 years and continues to move forward. We are going to continue to see new drugs come along that will no doubt result in even more progress. In this last decade alone, we have been able to take the novel agents thalidomide, lenalidomide, and bortezomib, and utilize them in numerous combinations and schedules. In addition to the continued research to find an approach to cure, I think the future of myeloma may be in going back to the precursor diseases. I believe MGUS and SMM are where we are ultimately going to learn why these plasma cell dyscrasias progress to myeloma. ◆ References 1. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9. 2. Kyle RA, Durie BG, Rajkumar SV, et al. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010:24:11211127. 3. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haem. 2003;121:749-757. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple myeloma. Version 1.2012. www.nccn.org/professionals/physician_gls/pdf/ myeloma.pdf. Accessed March 18, 2012. 5. Blade J, Dimopoulos M, Rosinol L, et al. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol. 2010;28:690-697. 6. Dispenzieri A, Kyle RA, Katzmann JA, et al. Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood. 2008;111:785-789. 7. Lenalidomide or observation in treating patients with asymptomatic high-risk smoldering multiple

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Improving Patient Outcomes in Newly Diagnosed Multiple Myeloma Oncology Certified Registered Nurse/Myeloma Team/BMT Winship Cancer Institute, Emory University Atlanta, GA

Introduction At the time of diagnosis, patients with multiple myeloma (MM) may present with numerous disease-related symptoms. Each of these complications requires supportive care, and providing that care demands a high degree of individualization. In many cases, one symptom can influence the management of another. For example, renal insufficiency may impact the administration of bisphosphonates used to protect bone health. In addition, specific agents used to treat myeloma may produce confounding symptoms, such as neurotoxicity in a patient already experiencing disease-related bone pain. In this article, Melanie Watson, RN, OCN, discusses her center’s evidence-based approach to providing symptom relief for patients with newly diagnosed myeloma.

What is the nurse’s role in the assessment and management of patients with MM who present with hypercalcemia?

Elevated calcium is a relatively common laboratory finding in patients newly diagnosed with MM (Figure).1 The incidence of hypercalcemia— defined as a very high serum calcium ( 11 mg/dL)—is approximately 13%; however, an additional 15% of patients present with calcium levels of 10.2 mg/dL to 10.9 mg/dL.1 When we conduct an initial work-up on a patient, a finding of hypercalcemia prompts us to take necessary steps to minimize this complication. Intervention becomes especially urgent if the patient reports potential symptoms of hypercalcemia, such as emesis, weakness, and confusion. Immediate hydration is essential, and many patients will also require bisphosphonate therapy. In some instances, it is necessary to prescribe antiemetic agents for patients who are experiencing hypercalcemia-related nausea and vomiting. At our center, we treat hypercalcemia if the serum calcium level is 10.5 mg/dL. We also initiate treatment if serum calcium is only borderline high, but serum albumin is low, as the serum calcium should be corrected based on the serum albumin. Some patients present with very mild hypercalcemia (10.5 mg/dL with a low albumin); our approach with these patients is to treat with intravenous (IV) hydration only, and then routinely check their calcium levels. For all other patients, we control hypercalcemia with hydration plus bisphosphonate therapy (zoledronic acid or pamidronate). If zoledronic acid is used, it is given as a single IV dose of 4 mg infused over 15 to 30 minutes. This is followed by a second 4-mg dose given at a minimum of 7 days, if necessary.2 Pamidronate dosing of 60 mg to 90 mg, infused over 2 to 4 hours, is dependent on the level of albumin-corrected serum calcium as well as a patient’s renal function.3 Treatment with bisphosphonate therapy generally results in rapid resolution of hypercalcemia.

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Renal insufficiency is also prevalent in newly diagnosed patients with MM. What role do nurses play in the evaluation, monitoring, and supportive care of this complication?

Approximately 19% of patients with MM present with a serum creatinine 2 mg/dL at the time of diagnosis (Figure). Renal dysfunction may be exacerbated by hypercalcemia, but even after serum calcium levels have stabilized, we still have to contend with myeloma-related renal tubular pathology.4 The presence of renal insufficiency sometimes signals that the patient has light-chain myeloma, which has been correlated with elevated creatinine.1 Circulating monoclonal immunoglobulin free light chains can clog up renal tubules; myeloma kidney is characterized by light-chain cast nephropathy.4 Laboratory testing for serum creatinine, creatinine clearance, and serum and urine protein electrophoresis are critical in the initial work-up of patients with MM. Nurses are primarily responsible for the evaluation of any symptom patterns related to impaired renal function, such as elevated blood pressure, changes in urination, and fatigue. It is important to remember, however, that a patient may have renal insufficiency in the absence of any physical signs or symptoms. Following initial assessment, we keep a close watch on renal function and check laboratory results at every visit, which during frontline treatment may be several times a week. We also encourage patients to drink between 2 and 3 L of fluid a day to stay hydrated. It is imperative to obtain a list of every drug the patient is taking, to ensure that none of them are renally toxic—this includes over-the-counter (OTC) medications. We strongly advise patients to avoid the use of OTC or prescribed nonsteroidal anti-inflammatory drugs (NSAIDs), which can have adverse renal effects. We also remind them to report any changes in their urine (eg, output, frequency, appearance, presence of blood).

Figure. Incidence of anemia, renal dysfunction, and hypercalcemia in newly diagnosed patients with MM (N=1027).1

50 40

Patients (%)

Melanie Watson, RN, OCN

35%

30 19%

13% 10 0 Hemoglobin 10 g/dL

Creatinine 2 mg/dL

Calcium 11 mg/dL

MM indicates multiple myeloma.

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Table 1. Suggested Lenalidomide Dose Reductions for Renal Impairment7 Degree of Renal Dysfunction Moderate

Renal Function (Cockcroft-Gault CrCl) 30-60 mL/min

Dose for MM 10 mg orally every 24 hours

Severe (not requiring dialysis)

<30 mL/min

15 mg orally every 48 hours

End-stage renal disease (requiring dialysis)

<30 mL/min

5 mg orally once dailya

CrCl indicates creatinine clearance; MM, multiple myeloma. a Doses that fall on dialysis days should be given after dialysis.

Table 2. Bortezomib Dose Modifications Based on Severity of Peripheral Neuropathy10 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.

A small subset of patients with myeloma-related renal insufficiency will require dialysis. In many cases, this need for dialysis is reversible with effective antimyeloma treatment. Reducing the myeloma burden as quickly as possible is the key to getting patients off dialysis. Our induction therapy for newly diagnosed patients with significant renal dysfunction—certainly in the transplant-eligible group but also in many nontransplant candidates— is the combination of bortezomib, thalidomide, and dexamethasone (VTD).5 The inclusion of novel agents in this regimen offers a benefit to patients with renal insufficiency.6 Current consensus suggests that treatment with bortezomib plus dexamethasone provides optimal therapy to reverse renal dysfunction in myeloma. Lenalidomide is also effective in reversing renal insufficiency if given at doses appropriately reduced on the basis of renal function (Table 1).6,7

The severity of renal impairment affects our selection of bisphosphonate therapy to protect against skeletal-related events.

The severity of renal impairment affects our selection of bisphosphonate therapy to protect against skeletal-related events (SREs), since this class of drugs is excreted via the kidney and can therefore produce renal toxicity. At our institution, we use zoledronic acid for patients with a baseline crea-

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Table 3. Selected Outcomes in Cancer Patientsa with Vertebral Compression Fractures Treated with Balloon Kyphoplasty vs Nonsurgical Management12 Outcome Variable at 1 Month of Follow-Up

Kyphoplasty (n=70)

Nonsurgical Management (n=64)b

P Value

Mean change from baseline in RDQc score (primary endpoint; improvement = decline in score)

-8.3 points

+0.1 points

<.0001

Change in medication utilization (% change in the incidence of use)

-44.7

-2.3

<.001

Overall incidence of adverse events (% of patients)

37.1

29.7

Not reported

32% of patients in the kyphoplasty group and 44% of patients in the nonsurgical management group had a diagnosis of MM. b Analgesics, bed rest, bracing, physiotherapy, rehabilitation programs, walking aids, radiation treatment, and other antitumor therapy at the discretion of treating physicians. Patients receiving kyphoplasty were allowed to receive these treatments as well, in addition to their surgery, if needed. c RDQ indicates back-specific functional status measured by the Roland-Morris disability questionnaire.

tinine clearance of 30 mL/min, dose-adjusted as creatinine clearances from >60 mL/min to 30 mL/min.2 This is given as a 30-minute infusion, which, in our experience, tends to be gentler on the kidney than the standard 15-minute infusion. If creatinine clearance is below 30 mL/min we use pamidronate, although the pharmacokinetic data on its use in such instances is limited.3 In addition to initiating bisphosphonate therapy, what other supportive care strategies are necessary for patients with myelomarelated bone disease?

Approximately 80% of patients with MM present with SREs, which typically manifest as osteolytic lesions or fractures.1 Therefore, bisphosphonate therapy is a mainstay of bone support in MM. From a nursing perspective, ongoing patient education about bisphosphonate use is critical to help patients remain on this effective therapy. The most important educational intervention is in the area of dental hygiene, since osteonecrosis of the jaw (ONJ) is a rare but very serious adverse effect of bisphosphonate therapy, for which there is no satisfactory intervention.8 For example, zoledronic acid was shown in the Medical Research Council Myeloma IX study to reduce SREs and improve overall survival compared with clodronic acid, but it also produced a higher rate of ONJ than clodronic acid.9 We require a dental exam before we start a bisphosphonate for SRE prevention. We repeatedly inform patients that they should have no invasive dental procedures that disturb the bone while being treated with bisphosphonates. We tell patients, “If it’s above the gum line, it’s fine. If it’s below the gum line, it’s not.” If an invasive procedure becomes necessary, we need to know in advance. We hold the bisphosphonate therapy for 2 months before and 2 months after any invasive dental procedure. Treatment of bone pain is another critical aspect of supportive care. Nurses have always held a leadership role in the management of pain, and it takes all of our skill and insight to effectively treat the complexities of

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pain associated with MM. The first step is always an assessment based on the patient’s self-reported level of pain, using both qualitative inventories and a quantitative scale such as the 1-10 visual analog scale. Pain assessment should be frequent and routine, not only to determine severity, but also to help distinguish between bone pain and neurotoxicity that may be associated with the use of specific novel agents.7,10 We recently switched from IV to subcutaneous (SC) bortezomib in certain regimens, because SC dosing appears to significantly reduce the risk of bortezomib-induced peripheral neuropathy (BIPN).11 For patients who receive bortezomib as an IV infusion, dose reductions can be implemented to prevent irreversible nerve damage and ensure optimal benefits of treatment (Table 2).10 BIPN typically improves following implementation of these recommendations or resolves following treatment discontinuation.

As a nurse, I feel I have done my job well when a patient demonstrates an understanding of their disease and feels comfortable calling me to report a new symptom or potential complication.

Opioid treatment is often necessary for myeloma-associated bone pain, which was reported by 58% of patients at the time of diagnosis in one study.1 Since we cannot prescribe NSAIDs to myeloma patients, we rely on opioid analgesics to control pain. When we give these medications, we always put patients on a bowel regimen that includes dietary and hydration support and a stool softener, as opioids can cause significant constipation. We try not to use radiation therapy for pain; we only radiate for severe pain that has not responded to other interventions, including analgesic medication, physical therapy (PT), and surgery. Patients sometimes do not understand why PT can help with bone pain, so we explain that improving muscle strength around a bone may improve pain control and function. Compression fracture of the spine is one of the more common SREs in myeloma patients.1 In our weekly clinic, a spine specialist is available to evaluate individuals with back pain. If necessary, patients may undergo kyphoplasty, which has been shown to be effective in treating vertebral compression fractures in patients with MM or bone metastasis from solid tumors (Table 3).12 The specialist may also recommend a steroid injection into the back to relieve the pain. Finally, we advise patients to take the necessary steps to protect themselves from trauma. The last thing they need is an injury to bone. We urge them to avoid risky sports and counsel them to evaluate their homes for hazards such as slippery rugs and broken steps. What supportive care strategies are necessary for managing anemia in patients with MM?

Anemia is a common finding among newly diagnosed MM patients (Figure).1 This condition may also occur at later points in the clinical course of the disease and can be an adverse effect of specific agents. We take a dual approach to combat anemia, using effective antimyeloma therapy and transfusions. Controlling a patient’s disease is the best way to manage anemia over the long term. We order blood transfusions whenever a patient’s hematocrit drops to about 25% to 27%. Hematocrit 25% signals that a transfusion is appropriate; 26% to 27%, in the presence of anemia symptoms, also indicates a need for transfusion.6

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We rarely use erythropoietins to treat anemia, as most of our patients are receiving therapies that may elevate risk of thrombosis, such as thalidomide or lenalidomide, combined with dexamethasone.13 In addition, erythropoietins can increase thromboembolic risk.13,14 We therefore do not want to augment risk of thrombosis by adding an erythropoietin to the mix. In rare instances, we may opt for erythropoietin support of anemia in heavily treated patients who are far into the clinical course and have already received multiple transfusions and anticoagulant therapy. It is important to provide ongoing education to patients regarding the signs and symptoms of anemia, which can include shortness of breath or extreme fatigue. We describe how hemoglobin in red blood cells carries oxygen throughout the body, so that they understand why we must frequently check their counts and recommend transfusions. Patients often call us and say, “I’ve been extremely tired over the past couple of days. I wonder if I need a transfusion.” When this occurs, we have them come in to the clinic so that we can assess their blood cell counts, and we often find that these patients are correct and do need to be transfused. To be effective in providing prompt and appropriate supportive care, nurses must listen attentively to their patients’ concerns. Most patients can sense subtle changes in their bodies, and our education is designed to contribute to that knowledge. As a nurse, I feel I have done my job well when a patient demonstrates an understanding of their disease and feels comfortable calling me to report a new symptom or potential complication. Good communication between nurses and patients is the cornerstone for providing the best possible supportive care. Conclusion

MM is an incurable hematologic malignancy that attacks the body in many ways, resulting in renal dysfunction, hypercalcemia, SREs, and anemia. It is imperative that patients are carefully screened for these complications at the time of diagnosis and throughout the course of the disease. Proactive nursing measures are the key to reducing the impact and severity of these symptoms, which in turn will help patients remain on therapy and achieve the best possible outcomes. ◆ References 1. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33. 2. Zometa® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. February 2011. 3. Aredia® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008. 4. Hutchison CA, Batuman V, Behrens J, et al. The pathogenesis and diagnosis of acute kidney injury in multiple myeloma. Nat Rev Nephrol. 2011;8:43-51. 5. Kaufman JL, Nooka A, Vrana M, et al. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010;116:3143-3151. 6. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:4976-4984. 7. Revlimid® [package insert]. Summit, NJ: Celegene Corporation. October 2010. 8. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients: clinical features and risk factors. J Clin Oncol. 2006;24:945-952. 9. Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010;376:1989-1999. 10. Velcade® [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc. December 2010. 11. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 12. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12:225-235. 13. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 14. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008;111:25-41.

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Pharmacologic Considerations in Newly Diagnosed Multiple Myeloma Minal Surati, PharmD Clinical Pharmacy Specialist Department of Hematology and Medical Oncology Emory University Hospital/Winship Cancer Institute Atlanta, GA

Introduction Symptom patterns in patients with newly diagnosed multiple myeloma (MM) can influence the approach to both antimyeloma therapy and supportive care. The core “CRAB” symptoms (hypercalcemia, renal insufficiency, anemia, or bone lesions) may require interventions, such as transfusions for anemia or bisphosphonates for hypercalcemia; renal dysfunction may influence drug selection and dosing. Complicating the clinical picture are several additional factors: drug-drug interactions; medical comorbidities; the adverse events associated with treatments for MM; and the inherent, myeloma-related risks of fracture and venous thromboembolism (VTE). In this article, Minal Surati, PharmD, describes the key role of pharmacy in identifying and clarifying the needs of each patient, to personalize drug choices and dosing strategies.

Symptomatic MM is defined by the presence of CRAB symptoms, which identify end-organ involvement. As a pharmacy professional, what is your role in minimizing these symptoms in newly diagnosed patients?

Our priority as pharmacists is to counsel patients regarding their treatment regimen and assess the interaction of agents, whether it be with other drugs or with a patient’s comorbid conditions.1 When a patient newly diagnosed with MM presents with CRAB symptoms, we evaluate the drugs he or she takes for preexisting conditions in the context of the proposed treatment regimen, in an effort to discover and manage any problematic interactions. For example, a newly diagnosed, elderly woman may present with renal insufficiency and bone lesions attributable to MM, but may also have a history of diabetes, controlled with oral metformin, and osteoporosis treated with the oral bisphosphonate, ibandronate. Oral ibandronate and metformin do not interact.2 However, the risk of lactic acidosis, a rare but serious complication of metformin, is elevated in patients with renal insufficiency and older age.3 Antimyeloma regimens that include steroids such as dexamethasone or prednisone may interfere with glycemic control.3 Intravenous (IV) bisphosphonate therapy for MM should replace oral ibandronate; if the patient’s creatinine clearance is <30 mL/min, IV pamidronate rather than IV zoledronic acid would be the recommended agent.4,5 It is important to stress that medication therapy management provided by a pharmacist is not a one-time event. Patients are assessed prior to each cycle of chemotherapy or IV bisphosphonate treatment, to ensure medications are adjusted appropriately based on changes in renal function, anemia, calcium levels, etc, that may have occurred since their last visit.

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We have found that patients often research their disease state and therapies through various means such as the internet or discussions with other patients, family, and friends. This is encouraged to promote knowledge and support throughout their treatment. However, with the increasing trend of holistic and alternative health movements, patients may begin taking overthe-counter (OTC) supplements or herbal medications without discussing it with their providers. For example, I recently consulted with a myeloma patient who was taking 21 different supplements. Pharmacists must check for herbal and synthetic supplements—especially high-dose vitamins, which can affect the efficacy of chemotherapy treatment or exacerbate a patient’s disease. For example, if a newly diagnosed patient with hypercalcemia is taking excess calcium OTC, we need to address this issue. After discussing the situation with the team, we inform the patient of the appropriate calcium supplementation strategy. This may include discontinuation of the supplement, decreasing the dose, or replacing it with a simple multivitamin. Our fundamental approach to the symptom of anemia in MM is to provide effective antimyeloma treatment, which should elevate and stabilize red blood cell counts.6 We do provide transfusions if necessary,6 when the hemoglobin is <10 g/dL or hematocrit is <25%. Given the fact that many of our patients’ treatments include thalidomide or lenalidomide, we seldom use erythropoietins to treat chronic anemia. Both thalidomide and lenalidomide can put patients at an increased risk of developing a VTE. The addition of erythropoietins would further increase this risk,7,8 therefore, we do not use these agents concurrently. This is a cautious interpretation of guidance from the American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO), which also warns against the use of an erythropoietin in combination with lenalidomide or thalidomide plus corticosteroids.7

It is important to stress that medication therapy management provided by a pharmacist is not a one-time event.

Myeloma-related bone disease tends to be very painful, as is peripheral neuropathy (PN) that may result from bortezomib or immunomodulators used in the treatment of MM.9-11 Since we increasingly use the RVD regimen (lenalidomide, bortezomib, and dexamethasone) in newly diagnosed patients (Figure),12 we monitor closely for PN. Working with pain assessments provided by the nursing staff, the pharmacist plays a key role in developing a rational plan for pharmacologic management of nociceptive and neuropathic pain in the myeloma patient. We rely on opioid medication, typically oxycodone or morphine, for bone pain, which requires us to be very cautious about opioid adverse effects. One must distinguish between opioid tolerance, a natural physiological response to these drugs, and opioid addiction, which has psychological ramifications.13 In our practice, we avoid the use of both acetaminophen and nonsteroidal antiinflammatory drugs since these agents may affect liver and/or kidney func-

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CONTINUING EDUCATION

Figure. Common adverse events with RVD in newly diagnosed patients with MM (N=66).12

Table. Disease-Related and Comorbid Thromboembolic Risk Factors in Patients with Myeloma8 Risk Factors

Specific Examples

Related to the disease and treatment

Myeloma itself Hyperviscosity Therapies: erythropoietins, immunomodulators, high-dose dexamethasone, doxorubicin, multiagent chemotherapy

Related to comorbidities

History of venous thromboembolism Obesity Heart disease/atrial fibrillation Chronic renal disease Diabetes Infection Immobilization Surgery/anesthesia Trauma Central venous catheter or pacemaker Clotting disorders

100

Overall Grade 3

90 80

80%

Patients (%)

64% 61%

60 50

45%

44%

36%

35% 32%

32%

30 20 10 3%

y ath rop eu yn

e gu ati

sor Sen

n on ain ma tio ati de ep ipa am scl be nst squ Mu Lim Co e d sh/ Ra

3% 0%

ea rrh Dia

sea au

thy pa uro Ne

MM indicates multiple myeloma; RVD, lenalidomide, bortezomib, and dexamethasone.

tion, as well as mask fevers, which can deprive us of a warning sign for infection in our frequently neutropenic patients. To a large extent, opioid therapy is very helpful with neuropathic pain.14 However, additional agents such as gabapentin or pregabalin can be useful as well. Other therapies that may also be used are alpha lipoic acid, L-carnitine, folic acid, and B complex vitamins. What strategies can be used for the prevention of infection in patients with MM?

Many newly diagnosed MM patients experience a disease-related increase in infection risk; extensive disease, poor renal function, and compromise to plasma cells can produce poor health status. Add to that the risks of therapy, such as viral reactivation and neutropenia, and the result is a significant potential for infection. At our center, we ensure that every individual receives basic preventive care. Patients receive vaccines, including seasonal flu vaccine and, if not up-to-date, pneumococcal vaccine. Bortezomib use can increase the risk of herpes zoster reactivation,15 therefore, if a patient receives this agent as part of the treatment regimen, we always include antiviral prophylaxis with acyclovir or another drug in its class. Pneumocystis carinii pneumonia (PCP) is always a concern in patients receiving high-dose steroids. If a steroid is part of the patientâ&#x20AC;&#x2122;s treatment regimen, we will begin prophylaxis for PCP. With regard to the use of prophylactic antibiotics and antifungals, we are selective and commensurate with recommendations from the National Comprehensive Cancer Network.16 We simply do not want to add the adverse events of antimicrobial agents if not necessary. From my perspective, education is an extremely important aspect regarding infection control. When counseling patients for the first time, I typically ask if they have a history of herpes viral infections, cold sores, or zoster. If they report recurrent zoster infections, this would prompt me to consider the use of valacyclovir, if acyclovir has previously not been effective. Bisphosphonates are a mainstay of therapy for myeloma-related bone disease, but their use can be complicated by certain CRAB symptoms. What is your approach to bisphosphonate use in patients with renal dysfunction or hypercalcemia?

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The bisphosphonate we use the majority of the time is IV zoledronic acid, administered monthly for 2 years, then every 2 to 6 months, depending on the patientâ&#x20AC;&#x2122;s status at that time. An advantage of zoledronic acid is a relatively short IV infusion time of at least 15 minutes.4,17 Zoledronic acid also produced favorable outcomes in the recent Medical Research Council Myeloma IX study.18 However, this bisphosphonate must be dose-adjusted downward in increments, ranging from 4 mg to 3 mg, as patientsâ&#x20AC;&#x2122; baseline creatinine clearance falls from a normal value (>60 mL/min) to 30 mL/min; zoledronic acid is not recommended in patients with severe renal insufficiency (creatinine clearance <30 mL/min).4,17 Although the prescribing information for zoledronic acid suggests that the criterion for dose adjustment is the baseline creatinine clearance, we assess serum creatinine and calculate clearance at each visit and adjust the dose accordingly. We will also infuse zoledronic acid over 30 minutes rather than 15 minutes. For patients with significant renal impairment, we often elect to use pamidronate infused over 2 to 4 hours.5,17

When counseling patients for the first time, I typically ask if they have a history of herpes viral infections, cold sores, or zoster. The approach is different, however, when hypercalcemia complicates the clinical picture. A newly diagnosed MM patient presenting with hypercalcemia will receive aggressive, acute treatment with zoledronic acid, which is the preferred bisphosphonate for this condition.19 Per our institutional guidelines, zoledronic acid dosing for hypercalcemia is 4 mg as a single-dose IV infusion over 30 minutes, followed by close monitoring to assess if further treatment is needed. No specific dose adjustment is suggested for patients with renal impairment. Similarly, if a patient with renal impairment is receiving zoledronic acid monthly, and we detect the emergence of hypercalcemia, we will administer a 1-time, full 4-mg dose, rather than adjusting the dose for renal dysfunction. There are situations in which a switch from zoledronic acid to pamidronate may be necessary. We look for trends in serum creatinine and

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CONSIDERATIONS IN MULTIPLE MYELOMA

creatinine clearance with our patients, and if we notice a trend toward worsening renal insufficiency, with serum creatinine rising, we may discontinue the zoledronic acid and begin pamidronate, with the infusion rate at the slower end of the recommended time.17 How do you reduce the risk of disease- or treatment-related VTE in newly diagnosed patients?

We ensure that all patients with thromboembolic risk factors, specifically those receiving thalidomide- or lenalidomide-containing regimens, receive VTE prophylaxis.8 Clinicians should be aware of the increased risk of VTE in the MM population—typically older patients with a disease that exacerbates thrombosis8—regardless of therapy (Table). Many patients present with a history of VTE, or with comorbidities that can increase the risk of thrombus formation. Numerous patients may already be taking warfarin or low-molecularweight heparin, which we continue as their VTE prophylaxis. Conclusion

It is vitally important for all members of the interdisciplinary cancer care team to understand the complexity of MM. Symptoms of the disease, including hypercalcemia, renal insufficiency, anemia, and bone disease, will influence not only which therapies can be used, but the dose and duration of treatment. Myeloma-related complications may change over time, as the disease responds to treatment or progresses. In addition, drug-drug interactions have the potential to cause clinical emergencies, which require immediate interventions. The pharmacist plays a key role in identifying these complex relationships, counseling patients, and monitoring responses to various therapies to ensure optimal clinical outcomes. ◆

References 1. Tam-McDevitt J. Polypharmacy, aging, and cancer. Oncology (Williston Park). 2008;22:10521055. 2. Boniva® [package insert]. South San Francisco, CA: Genentech USA, Inc. January 2011. 3. Glucophage® [package insert]. Princeton, NJ: Bristol-Myers Squibb Company. January 2009. 4. Zometa® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. February 2011. 5. Aredia® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008. 6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Cancer- and chemotherapy-induced anemia. Version 2.2012. www.nccn.org/professionals/physician_gls/pdf/anemia.pdf. Accessed March 26, 2012. 7. Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood. 2008;111:25-41. 8. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 9. Velcade® [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc. December 2010. 10. Thalomid® [package insert]. Summit, NJ: Celegene Corporation. August 2010. 11. Revlimid® [package insert]. Summit, NJ: Celegene Corporation. October 2010. 12. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679686. 13. Jan SA. Introduction: landscape of opioid dependence. J Manag Care Pharm. 2010;16(suppl 1b):S4-S8. 14. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132:237-251. 15. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 16. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prevention and treatment of cancer-related infections. Version 2.2011. www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Accessed March 26, 2012. 17. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472. 18. Morgan GJ, Child JA, Gregory WM, et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol. 2011;12:743-752. 19. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple myeloma. Version 1.2012. www.nccn.org/professionals/physician_ gls/pdf/myeloma.pdf. Accessed March 15, 2012.

Evolving Concepts in the Management of Newly Diagnosed Multiple Myeloma Continued from page 15 myeloma. NCT01169337. http://clinicaltrials.gov/ct2/show/NCT01169337?term= E3A06&rank=1. Accessed March 27, 2012. 8. Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36:842-854. 9. Griepp PR, San Miguel J, Durie BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412-3420. 10. Avet-Loiseau H, Attal M, Moreau P, et al. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007;109:3489-3495. 11. Fonseca R, Barlogie B, Bataille R, et al. Genetics and cytogenetics of multiple myeloma: a workshop report. Cancer Res. 2004;64:1546-1558. 12. Fonseca R, Blood E, Rue M, et al. Clinical and biologic implications of recurrent genomic aberrations in myeloma. Blood. 2003;101:4569-4575. 13. mSMART. Mayo Stratification for Myeloma and Risk-adapted Therapy. Newly diagnosed myeloma. http://msmart.org/newly%20diagnosed%20myeloma.pdf. Accessed March 28, 2012. 14. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009;23:2210-2221. 15. Munshi NC, Anderson KC, Bergsagel L, et al. Consensus recommendations for risk stratification in multiple myeloma: report of the international Myeloma Workshop Consensus Panel 2. Blood. 2011;117:4696-4700. 16. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085.

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17. 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. 18. Klein U, Jauch A, Hielscher T, et al. Chromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple myeloma treated with lenalidomide and dexamethasone. Cancer. 2011;117:2136-2144. 19. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 20. Shaughnessy JF Jr, Zhan F, Burington B, et al. A validated gene expression signature of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood. 2007;109:2276-2284. 21. Decaux O, Lode L, Magrangeas F, et al. Intergoupe Francophone du Myelome. Prediction of survival in multiple myeloma based on gene expression profiles reveals cell cycle and chromosomal instability signatures in high-risk patients and hyperdiploid signatures in low-risk patients: a study of the Intergroupe Francophone du Myelome. J Clin Oncol. 2008;26:4798-4805. 22. Dimopoulos M, Terpos E, Comenzo RL, et al. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple myeloma. Leukemia. 2009;23:1545-1556. 23. Durie BGM. The role of anatomic and functional staging in myeloma: description of Durie/Salmon plus staging system. Eur J Cancer. 2006;42:1539-1543. 24. Zamagni E, Patriarca F, Nanni C, et al. Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation. Blood. 2011;118:5989-5995.

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Basal Cell Carcinoma

Vismodegib: A New Treatment Option for Basal Cell Carcinoma By Rhonda Williams

asal cell carcinoma (BCC) and squamous cell carcinoma (SCC), commonly referred to as nonmelanoma skin cancers (NMSCs), are the most common types of cancers in the United States. These 2 cancers account for approximately 2 million cases of skin cancer annually.1 BCC is approximately 4 to 5 times more common than SCC.2 Although rarely metastatic, BCC and SCC can cause substantial local destruction involving extensive areas of soft tissue, cartilage, and bone, as well as disfigurement. It is estimated that the cost of treating these NMSCs in the Medicare population exceeds $400 million annually.3

The Management of BCC The goal of primary treatment for BCC of the skin is curing the tumor. Surgical approaches are the most common treatment and offer the most effective method for achieving cure for this condition; however, considerations related to preserving function; preservation, restoration, or physical appearance; and patient preference all may lead to the choice of radiation therapy as the primary treatment to achieve optimal overall results.4 For patients who have low-risk, superficial BCC, or for those in whom surgery or radiation is contraindicated or unfeasible, topical therapies or vigorous cryotherapy may be considered, although the cure rate with these options may be lower. In addition, for patients at high risk for multiple primary skin tumors, increased surveillance and prophylactic measures may be indicated.4 Postoperative radiation has been widely accepted as a valuable approach for high-risk patients to reduce the rate of recurrence. Adjuvant radiotherapy is recommended by the National Comprehensive Cancer Network panel for any NMSC that shows evidence of substantial perineural involvement; that is, involvement of more than a few small or large nerves.4 All patients with BCC of the trunk and extremities who have undergone lymph node dissection should be considered for adjuvant radiation therapy; despite resection followed by radiation therapy, patients at high risk often experience locoregional recurrence and distant metastasis. The behavior of cutaneous BCC is characteristically indolent, but it rarely metastasizes to distant areas. When the disease does metastasize to distant sites, systemic therapy is indicated.4

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Table 1 Objective Response Rate With Vismodegib: Efficacy in Evaluable Patients6 Metastatic BCC (n = 33)

Locally Advanced BCC (n = 63)

10 (30.3)

27 (42.9)

15.6-48.2

30.5-56.0

0 (0)

13 (20.6)

Partial response

10 (30.3)

14 (22.2)

Median response duration, months

7.6

5.6-nonestimable

5.7-9.7

Response Objective response rate, N (%)* 95% CI Complete response

95% CI

*Confirmed by independent review facility. BCC indicates basal cell carcinoma; CI, confidence interval.

A New Treatment Option for Advanced Disease Extensive research has led to advances in the understanding of the genetics of NMSCs.5 Among these advances, an understanding of the role of the sonic hedgehog pathway has played a pivotal role in understanding the pathogenesis of BCCs. We now know that mutations in PTCH, the patched gene located on chromosome 9q that codes for the sonic hedgehog receptor, are the underlying cause of nevoid BCC syndrome. These mutations are also common in sporadic BCCs. In addition, specific mutations in the tumor suppressor gene p53 appear to be involved in the development of NMSCs.5

The ORR was 30.3% in patients with metastatic BCC and 42.9% in patients with locally advanced BCC.

On January 30, 2012, the FDA approved vismodegib (Erivedge), a hedgehog pathway inhibitor, for the treatment of BCC in adults with locally advanced or metastatic disease who are not candidates for surgery or radiotherapy. The FDA used its priority review process for the approval of vismodegib; this approval was based on the results of an international, open-label, single-arm trial that evaluated the efficacy and safety of vis-

modegib in 104 patients with locally advanced or metastatic BCC. The approval of vismodegib represents the first approved therapy for patients with locally advanced or metastatic BCC whose disease is not amenable to surgery or radiation therapy, which are the standard treatments for this serious condition. In addition, vismodegib’s oral formulation may be viewed as more convenient for patients and may increase patient adherence to therapy. Some type of assistance program may be necessary to increase patients’ ability to obtain the drug. Clinical Pharmacology and Pharmacokinetics Vismodegib binds to and inhibits smoothened, a transmembrane protein involved in hedgehog signal transduction.6 Vismodegib is eliminated via multiple pathways, but it is predominantly excreted unchanged. Inhibition of the cytochrome (CY) P450 is not predicted to alter vismodegib’s systemic exposure, because steady-state plasma concentrations of vismodegib were observed in patients enrolled in vismodegib’s clinical trials who were being treated concomitantly with CYP3A4 inducers or CYP3A4 inhibitors.6 The results of in vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein; therefore, when vismodegib is coadministered with drugs that inhibit Pglycoprotein, such as clarithromycin, erythromycin, and azithromycin, systemic exposure to vismodegib and the incidence of adverse events may be increased.6 Drugs that alter the pH of the upper gastrointestinal tract may alter the sol-

ubility of vismodegib and reduce its bioavailability, but no formal studies have been conducted to evaluate the effect of gastric pH-altering drugs on the systemic exposure of vismodegib. Therefore, if vismodegib is coadministered with proton pump inhibitors, H2receptor antagonists, or antacids, the systemic exposure of vismodegib may be decreased, and the effect of vismodegib on efficacy is unknown.6 The single-dose bioavailability of vismodegib is 31.8%. The systemic exposure of vismodegib is not affected by food; therefore, vismodegib may be taken with or without food. The volume of distribution of vismodegib ranges from 16.4 L to 26.6 L. The plasma protein binding of the drug in patients is >99%. The primary route of elimination of vismodegib and its metabolites is hepatic, with 82% of the dose administered recovered in the feces and 4.4% recovered in urine. The vismodegib estimated elimination halflife is 4 days after continuous oncedaily dosing and 12 days after administration of a single dose.6 Clinical Trial Evidence and Efficacy The efficacy and safety of vismodegib was evaluated in an international, singlearm, open-label trial of 104 patients with metastatic BCC (n = 33) or with locally advanced BCC (n = 71). Enrolled patients with locally advanced BCC had to have lesions that recurred after radiotherapy, unless radiotherapy was contraindicated or inappropriate (ie, Gorlin syndrome, limitations because of the location of the tumor), or in cases where the lesion was unresectable or when surgical resection would result in substantial deformity. Patients received vismodegib 150 mg/day orally until disease progression or unacceptable toxicity occurred. The primary efficacy outcome of this study was determination of objective response rate (ORR), which was assessed by an independent review facility. In the cohort of patients with metastatic BCC, tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.0. In the cohort of patients with locally advanced BCC, evaluation of tumor response included measurement of externally assessable tumor (including scarring) and assessment for ulceration in photographs, radiographic assessment of target lesions when appropriate, and tumor biopsy.6 Of the 104 patients enrolled in this study, 96 patients were evaluable for

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Basal Cell Carcinoma ORR: 33 patients in the metastatic BCC cohort and 63 patients in the locally advanced BCC cohort. The median age of all patients evaluable for efficacy was 62 years; 46% of patients were aged ≥65 years. Of the patients in the metastatic BCC cohort, 97% of patients had received previous therapies, including surgery (97%), radiotherapy (58%), and systemic therapies (30%). Among the patients with locally advanced BCC, 94% had previous therapies, including surgery (89%), radiotherapy (27%), and systemic/topical therapies (11%).6 The ORR was 30.3% in patients with metastatic BCC and 42.9% in patients with locally advanced BCC. There were no complete responses in the metastatic BCC cohort compared with 20.6% of patients in the locally advanced BCC cohort who had a complete response. The median duration of response in the metastatic and the locally advanced BCC cohorts was 7.6 months.6 Table 1 outlines the response rates in both cohorts.

Table 2 Adverse Reactions Occurring in ≥10% of Patients With Advanced BCC6

Safety Profile When vismodegib monotherapy was administered at daily oral doses of ≥150 mg in 4 open-label, uncontrolled, dose-ranging or fixed singledose clinical trials enrolling a total of 138 patients with advanced BCC, the most common adverse reactions (≥10% of patients) included muscle spasms, alopecia, dysgeusia, and others, as shown in Table 2. Furthermore, 3 of 10 premenopausal women developed amenorrhea while being treated with vismodegib. In addition, treatment-emergent grade 3 laboratory abnormalities were observed in 11 patients in clinical trials; 6 (4%) patients experienced hyponatremia, 2 (1%) patients experienced hypokalemia, and azotemia was reported in 3 (2%) patients.6 The safety and effectiveness of vismodegib has not been established in patients with renal or hepatic impairment. In addition, clinical trials of vismodegib did not include sufficient numbers of patients aged ≥65 years to establish whether this patient population responded differently to vismo degib than younger patients. The safety and effectiveness of vismodegib have not been established in pediatric patients.6 Warnings and Precautions Associated With Vismodegib

Black Box Warning: Embryo-Fetal Death and Severe Birth Defects Vismodegib can result in severe birth defects or embryo-fetal death. Vismodegib is embryotoxic and teratogenic in animals. Teratogenic effects with this medication included severe

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MedDRA Preferred Term

All Patients With Advanced BCC (N = 138) All grades,* N (%)

Grade 3, N (%)

Grade 4, N (%)

42 (30.4)

1 (0.7)

–

Diarrhea

40 (29)

1 (0.7)

–

Constipation

29 (21)

–

19 (13.8)

–

55 (39.9)

7 (5.1)

1 (0.7)

62 (44.9)

10 (7.2)

–

35 (25.4)

3 (2.2)

–

Gastrointestinal disorders Nausea

Vomiting

General disorders and administration site conditions Fatigue Investigations Weight loss Metabolism and nutrition disorders Decreased appetite

Musculoskeletal and connective tissue disorders Muscle spasms

99 (71.7)

5 (3.6)

–

Arthralgias

22 (15.9)

1 (0.7)

–

Dysgeusia

76 (55.1)

–

Ageusia

15 (10.9)

–

88 (63.8)

–

Nervous system disorders

Skin and subcutaneous disorders Alopecia

*Grading according to NCI-CTCAE v3.0. BCC indicates basal cell carcinoma; MedDRA, Medical Dictionary for Regulatory Activities; NCI-CTCAE v3.0, National Cancer Institute Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0.

midline defects, missing digits, and other irreversible malformation. In rats at maternal exposures lower than human exposures of the recommended dose (150 mg/day), vismodegib was teratogenic, embryotoxic, and fetotoxic. Malformations in rats included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardation and variations were also observed. Pregnancy status should be verified before initiation of treatment with vismodegib. Both male and female patients should be made aware of these risks. Female patients should be advised of the need for contraception, and male patients should be advised of the potential risk to the fetus of vismodegib exposure through semen. Patients should be advised to notify their healthcare provider immediately if they suspect that they or their female partner may be pregnant. Patients exposed to vismodegib during pregnancy, either directly or through seminal fluid, should be encouraged to participate in the vismodegib pregnancy pharmacovigilance program.6

Blood Donation Patients should be advised not to donate blood or blood products while receiving vismodegib and for at least 7

months after the last dose of vismodegib is received.6 Dosing The recommended dose of vismodegib is 150 mg orally once daily until evidence of disease progression exists or until unacceptable toxicity is noted. If a dose of vismodegib is missed, the dose should not be made up. Dosing should resume with the next scheduled dose.6 Vismodegib may be taken with or without food. The capsule should be taken whole and not be opened or crushed. Vismodegib is not available at local drugstores and is only distributed through specialty pharmacies. Conclusion Vismodegib, a hedgehog pathway inhibitor, was approved by the FDA earlier this year for the treatment of BCC in adults with locally advanced or metastatic disease who are not candidates for surgery or radiotherapy. This approval, which was done under the FDA’s priority review process, was based on the results of an international, open-label, single-arm trial that evaluated the efficacy and safety of vismodegib in 104 patients with locally advanced or metastatic BCC.

Vismodegib is the first FDA-approved agent for the treatment of this serious condition. Although BCC is usually curable if lesions are contained to a small area of skin, in rare cases the lesions can become disfiguring, invade surrounding tissue, and/or metastasize. In these instances of advanced BCC, the disease cannot be effectively managed with surgery or radiation, the standard treatments for this common skin cancer. This recent approval of vismodegib fills a gap and an unmet need in the treatment paradigm of this serious condition. ● References 1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. www.cancer.org/acs/groups/content/@epidemiology surveilance/documents/document/acspc-029771.pdf. Accessed February 17, 2012. 2. Miller SJ, Alam M, Andersen J, et al. Basal cell and squamous cell skin cancers. J Natl Compr Cancer Netw. 2010;8:836-864. 3. Mudigonda T, Pearce DJ, Yentzer BA, et al. The economic impact of non-melanoma skin cancer: a review. J Natl Compr Canc Netw. 2010;8:888-896. 4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Basal Cell and Squamous Cell Skin Cancers. Version 1.2012. www.nccn.org/professionals/physi cian_gls/pdf/nmsc.pdf. Accessed February 3, 2012. 5. Benjamin CL, Melnikova VO, Ananthaswamy HN. P53 protein and pathogenesis of melanoma and nonmelanoma skin cancer. Adv Exp Med Biol. 2008; 624:265-282. 6. Erivedge [prescribing information]. South San Francisco, CA: Genentech, Inc; 2012.

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Colorectal Cancer

Survival Benefit of Oxaliplatin Confirmed By Alice Goodman

pdated analysis of disease-free survival (DFS) in the NO16968 trial confirms a survival benefit with the addition of oxaliplatin in adjuvant treatment of stage III colorectal cancer. The study compared XELOX (capecitabine plus oxaliplatin) versus bolus 5-fluorouracil/leucovorin (5-FU/LV) in 1886 patients with resected stage III colon cancer, and the updated analysis was based on a median follow-up of 7 years. “After this study and overall experience with more than 5000 patients, oxaliplatin should now be considered standard treatment for stage III colon cancer,” stated lead author HansJoachim Schmoll, MD, University Clinic Halle in Germany, who presented these findings at the American Society of Clinical Oncology Gastrointestinal Symposium held in San Francisco, California. An earlier analysis of the study with median follow-up of 4.75 years demonstrated a significant DFS advantage for XELOX over 5-FU/LV (hazard ratio [HR], 0.80; P = .0045), but no significant difference was seen between the 2 arms for overall survival (OS). The updated analysis, with median follow-

up of 7 years (minimum follow-up of 6.6 years), showed that OS was significantly better for the XELOX arm: 73% versus 67%, respectively (HR, 0.83, P = .0367). DFS, the primary end point, also significantly favored XELOX with longer follow-up: 63% versus 56%, respectively (HR, 0.80; P = .0038).

“After this study and overall experience with more than 5000 patients, oxaliplatin should now be considered standard treatment for stage III colon cancer.” —Hans-Joachim Schmoll, MD Patients were randomized to adjuvant treatment with XELOX versus bolus 5FU/LV for a total of 6 months. Both arms were well balanced at baseline for sex, age, ECOG performance status, carcinoembryonic antigen level, and lymph node classification.

Commenting on the DFS and OS curves for both arms, Dr Schmoll said that the curves remain separated after 7 years. The death rate was 26% in the XELOX arm compared with 30% in the 5-FU/LV arm. This difference was mainly driven by excess deaths from colon cancer in the control arm: 20% for XELOX and 26% for 5-FU/LV. The number of deaths due to other cancers, treatment, or unrelated deaths was similar in the 2 arms. Dr Schmoll commented that chemotherapy in the current era is more effective, prolonging the time until curves start to separate compared with earlier trials; it takes longer to demonstrate the true benefit of oxaliplatin with modern chemotherapy. He said that in future trials, longer followup is needed for DFS and OS. A multivariate analysis for prognositic factors confirmed the treatment effect of XELOX (HR, 0.84; P = .047). Subgroup analysis showed no major difference in DFS and OS, with all subgroups favoring XELOX, with 2 exceptions: black American ethnicity and laparoscopic surgery favored the control arm. “These are very small numbers of patients, and the confidence

Regorafenib for Previously Treated mCRC

he multitargeted kinase inhibitor regorafenib improved overall survival (OS) and progression-free survival (PFS) and achieved superior disease control in patients with metastatic colorectal cancer (mCRC) who progressed on all standard therapy. These results of the international, phase 3, randomized, double-blind, placebo-controlled, multicenter CORRECT trial were presented at the American Society of Clinical Oncology Gastrointestinal Symposium in San Francisco, California. “Regorafenib increases overall survival versus placebo in patients with mCRC who have exhausted other treatment options. This is the first small-molecule multikinase inhibitor with proof of efficacy in colorectal cancer, and it is a potential new standard of care in this patient population,” stated Axel Grothey, MD, Mayo Clinic, Rochester, Minnesota. Each year there are 1,234,000 new CRC cases diagnosed and 608,000 CRC deaths. The vast majority of patients with mCRC require palliative care because there are no good options after progression on all standard treatments. “There is a rationale for multitargeted therapy in this setting. Regorafenib is a

April 2012 I VOl 5, NO 2

multikinase inhibitor, and phase 1 studies suggested that regorafenib has a high disease control rate of about 74%,” he told listeners. CORRECT randomized patients 2:1 to regorafenib 160 mg/day (3 weeks on and 1 week off) plus best supportive care (BSC) versus placebo and BSC. The study enrolled 760 patients with mCRC who progressed within 3 months of standard therapy (fluoropyridine, oxaliplatin, irinotecan, bevacizumab, cetuximab). Baseline disease characteristics were well balanced between treatment arms. About 55% to 60% had KRAS mutations, around 60% had received at least 4 lines of prior therapy, and every patient had been exposed to prior bevacizumab. “There are no specific therapies for patients with KRAS mutations,” he commented. Regorafenib improved OS from 5.0 to 6.4 months (P = .0052). “This represents a 23% reduction of death events, which I perceive as clinically meaningful,” Dr Grothey said. The trial was stopped when the primary OS end point was met. The PFS curve showed that the median difference in PFS between the 2 arms, although highly significant, does not

explain the difference in survival between the 2 arms, he continued. Median PFS was 1.9 months in the regorafenib arm versus 1.7 months in the placebo group (P <.000001).

“Regorafenib increases overall survival versus placebo in patients with metastatic colorectal cancer who have exhausted other treatment options.” —Axel Grothey, MD

“The results suggest that regorafenib exerts its effect on disease control. There was a higher incidence of stable disease with regorafenib (43%) versus 14.9% with BSC alone,” Dr Grothey said. The rate of disease control (response plus stable disease) was 44.8% for regorafenib versus

intervals are wide. This is a chance finding,” Dr Schmoll stated. Now 3 randomized stage III trials (MOSAIC, NSABP CO-7, and NO16968) with about 5000 patients and a median follow-up of 6 to 8 years demonstrate a clear benefit for oxaliplatin, Dr Schmoll said. About 22% of patients in the NO16968 trial were aged 70 and older, and in these patients the magnitude of the survival benefit of oxaliplatin was somewhat less than in younger patients. A translational research program for this trial is under way. “This is the most important part of the program,” Dr Schmoll stated. Formal discussant of this trial, Gail Eckhardt, MD, University of Colorado at Denver, said, “Many trials show that the addition of oxaliplatin demonstrates improvement in DFS in stage III patients. Toxicity is an important determinant going forward. Diarrhea and hand-foot syndrome are concerning toxicities with oxaliplatin-containing regimens. We can assume the regimens [studied in this trial] are equivalent, and we need to move forward with integration of new agents. In stage III patients we need better predictive markers for response to oxaliplatin and ways to minimize toxicity.” She also said that the optimal duration of oxaliplatin therapy remains to be defined. ●

15.2% for BSC alone (P <.000001). Subgroup analyses are currently being conducted. Preliminary results show that KRAS wild-type and KRAS mutant tumors had similar benefit. Further subgroup analyses will be presented at future meetings. Side effects of any grade with a frequency of ≥10% in the regorafenib arm included hand-foot skin reaction, fatigue, hypertension, diarrhea, rash, anorexia, mucositis, thrombocytopenia, fever, nausea, bleeding, voice changes, and weight loss. Grade 3 side effects with ≥5% frequency were handfoot skin reaction (16.6%), fatigue (9.2%), hypertension (7.2%), diarrhea (7%), and rash (5.8%). Toxicities were manageable with dose delays and adjustments. Only 8.2% of the regorafenib group discontinued treatment due to side effects. Dr Grothey was asked to speculate why these results with regorafenib were so much better than those of studies of other multikinase inhibitors in mCRC. He said that “a promiscuous drug” like regorafenib may be needed in this setting and may be best used as a single agent when patients have had prior treatments. Previous studies evaluated use of multitargeted kinase inhibitors in combination with chemotherapy, not as a single agent, he noted. ● —AG

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Gastroesophageal Cancer

Late Effects of Treatment Common in Gastroesophageal Cancer Survivors

atients with gastric or gastro esophageal cancer commonly experience long-term complications from treatment that compromise their quality of life (QOL), according to self-reported answers to an Internetbased survey questionnaire. Difficulty swallowing appears to be universal, and other problems range from dry mouth and taste changes to cardiovascular disease, according to a study presented at the 2012 American Society of Clinical Oncology Gastrointestinal Symposium held in San Francisco, California. “Survivors…unanimously and voluntarily report significant health problems after treatment for gastroesophageal cancers. The data reported here are important for designing future studies of QOL, as well as patient counseling and comprehensive survivor care,” stated lead

author James M. Metz, MD, Department of Radiation Oncology at University of Pennsylvania’s Abramson Cancer Center, Philadelphia, Pennsylvania.

OncoLink Web site). The tool enables survivors to enter data regarding diagnosis and treatments and provides customized guidelines for future care.

“Survivors…unanimously and voluntarily report significant health problems after treatment for gastroesophageal cancers.” —James M. Metz, MD

The authors of this study utilized an Internet-based tool for creation of survivorship plans (available at www.live strongcareplan.org and through the

Patients who use this tool are asked about late effects associated with specific treatment and answer “yes,” “no,” or “I don’t know.” They are also asked

to score toxicity using World Health Organization criteria. Questions about late effects of treatment were answered by 66 survivors: 80% with esophageal cancer and 20% with gastric cancer. Median age was 55 years. Slightly less than two-thirds were female, and 93% were Caucasian. Average time from diagnosis was 3.8 years. Of the sample, 91% of those with esophageal cancer and 77% of those with gastric cancer underwent surgery; 79% and 85%, respectively, received chemotherapy; and 53% and 31%, respectively, were treated with radiation. Late effects, in descending order from most common to least frequent, were difficulty swallowing (100%), dry mouth/taste changes (60%), cognitive changes (42%), dental changes (40%), tinnitus (36%), cardiovascular disease (35%; hypertension, 21%; hyperlipidemia, 13%; angina, 2%), sexual changes (28%), peripheral neuropathy (24%), and chronic lung disease (14%). ● —AG

Supportive Care

Many Febrile Neutropenia Patients Can Be Treated at Home Cost Savings Are Obvious for Appropriately Selected Patients

utpatient management of febrile neutropenia is appropriate for carefully selected lowrisk patients, according to Ashley Morris Engemann, PharmD, Duke University Medical Center, who spoke at the 2012 Pharmacy Program held in Hollywood, Florida, during the 17th Annual Conference of the National Comprehensive Cancer Network (NCCN). Dr Engemann noted that treating patients at home is clearly the patient’s preference and is cost saving. Risk assessment is the first step, as outpatient management is not appropriate for high-risk patients but can be considered in low-risk patients. Highrisk patients are those with a score <21 on the MASCC (Multinational Association for Supportive Care in Cancer) index, which generally includes patients expected to have prolonged neutropenia (>7 days) or profound neutropenia (absolute neutrophil count ≤100 cells/mm3) following chemotherapy, and those with significant medical comorbidities or hepatic or renal insufficiency.

www.TheOncologyPharmacist.com

“In general, we recommend hospitalization for IV antibiotics in these cases,” she said.

Risk assessment is the first step, as outpatient management is not appropriate for high-risk patients but

The 2012 NCCN Guidelines allow selected low-risk patients who are not already on fluoroquinolone prophylaxis to be considered for initial therapy with oral broad-spectrum antibiotics, most commonly with the following: • Ciprofloxacin 500 mg PO q8h plus amoxicillin/clavulanate 50 mg PO q8h • Ciprofloxacin plus clindamycin if allergic to penicillin While not part of the NCCN Guidelines, there is supporting literature for levofloxacin 750 mg PO daily in selected patients.2

can be considered in low-risk patients.

Low-risk patients (MASCC score ≥21) are anticipated to have a brief (≤7 days) neutropenic period or no or few comorbidities. “These patients may be treated with oral and/or outpatient empirical antibiotic therapy,”1 Dr Engemann said.

Recent Study Supportive but Underpowered Two key studies have evaluated the outpatient treatment of febrile neutropenia.3,4 A study from 2006 identified 178 outpatients who presented to the hospital with a first febrile neutropenia episode and who were deemed to be at low risk for complications.3 They were treated with oral ciprofloxacin and amoxicillin/clavulanate and observed over 24 hours while hospitalized. Of these, 79 subjects (44%) were dis-

By Caroline Helwick

charged early (median hospitalization time of 26 hours), while the other 56% remained hospitalized. No difference in complication rates was observed. Three patients in the early discharge group were readmitted for various reasons. The success rate for outpatient treatment was 96%. In 2011, Talcott and colleagues also reported success with early discharge in a study of 121 patients who developed postchemotherapy fever and neutropenia and were deemed at low risk.4 Patients were either discharged for home treatment (n = 50) or continued on hospital treatment (n = 71) with the same IV antibiotic regimen (penicillin/aminoglycoside combination or ceftazidime alone; imipenem- or aztreContinued on page 26

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Supportive Care Many Febrile Neutropenia Patients Can Be Treated at Home Continued from page 25 onam-based regimen if allergic; vancomycin added at discretion of physician). Oral antibiotic therapy was not standard at the time. “Unfortunately, this study was closed early due to poor accrual so we cannot draw significant conclusions,” Dr Engemann said, “but it showed the feasibility of outpatient treatment.”

The median duration of fever was 3 days; of neutropenia, 4 days; and of febrile neutropenia, 4 days. Subsequent antibiotic changes were more common in hospitalized patients (24% vs 9%; P = .04). Four outpatient episodes (9%) resulted in hospital readmission. Major medical complications occurred in 8% of hospitalized patients and 9% of outpa-

tients. Quality-of-life measures slightly favored the outpatient treatment, but most measures were equivalent. Home Treatment Is Less Expensive “It’s no surprise the cost of home management is much less,” she added. This was confirmed by a study published in 2011 in which investigators collected

direct medical and self-reported indirect costs for 57 inpatient and 35 outpatient episodes (2008 dollars).5 In the hospitalized group versus the home treatment group, mean total charges were 49% higher ($16,341 vs $10,977; P <.01), mean estimated total costs were 30% higher ($10,143 vs $7830; P <.01), and patient/caregiver out-of-pocket costs were higher (mean, $201 vs $74; P <.01). Informal caregivers in both groups reported similar time caring for patients and time lost from work.

Major medical complications occurred in 8% of hospitalized patients and 9% of outpatients.

“Managing patients with myeloma means staying current.”

“The study concluded that home IV antibiotic treatment was less costly than continued inpatient care for carefully selected patients,” Dr Engemann said. “At this point, it’s not known whether oral and IV therapy are equally effective, but we do know that early discharge following evaluation is a strategy we can use and it has cost savings.” ● References

Ira Klein, MD, MBA, FACP

1. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-e93. 2. Freifeld A, Sankaranarayanan J, Ullrich F, et al. Clinical practice patterns of managing low-risk adult febrile neutropenia during cancer chemotherapy in the USA. Support Care Cancer. 2008;16:181-191. 3. Klastersky J, Paesmans M, Georgala A, et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol. 2006;24:4129-4134. 4. Talcott JA, Yeap BY, Clark JA, et al. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial. J Clin Oncol. 2011;29:3977-3983. 5. Hendricks AM, Loggers ET, Talcott JA. Costs of home versus inpatient treatment for fever and neutropenia: analysis of a multicenter randomized trial. J Clin Oncol. 2011;29:3984-3989.

Chief of Staff to the Chief Medical Officer Aetna Hartford, CT

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A recent study showed that people with systemic lupus erythematosus may be at increased risk for potentially viral-related malignancies, especially those cancers associated with the human papilloma virus. —Arthritis Rheum. 2011;63:3032-3037.

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Koeller’s Corner Shooting from the Hip

Oncology Is a Small World

aving just returned from the Hematology/Oncology Phar macy Association (HOPA) meeting, I am reminded of just how small the world of oncology is. Everywhere you turn, you spot someone you know. It’s like homecoming or even a class reunion—you see people you know. The only issue is, after not seeing them for at least a year, how much older everybody looks now. I do admit that oncology pharmacy has come a long way since the early days, and that for as many people as I knew at the meeting, there were many, many more younger folks that I didn’t know. With HOPA membership now over 1500 and HOPA meeting attendance in the high hundreds, not knowing a majority of the attendees is understandable. However, with more than 35 years in the business, and having trained over a hundred plus oncology pharmacists over the years, I usually run into one of my old students, residents, fellows, graduate students, etc, and have to check up on them to see how they are doing. I have always told the people we trained in Texas that once you come out of Texas, you are always part of the family. We won’t forget you and will track your progress throughout your career. The first question I generally ask when catching up with an old acquaintance at these types of meetings is always, Are you still at X (ie, name of practice or institution)? One asks this question knowing that most people do not leave oncology, they just move around a bit. Oncology pharmacists have a tendency not to move around any more than necessary. Family forces roots, and tearing out roots is hard to do, especially with kids in school (they seldom want to leave their friends, and moving them becomes the biggest obstacle). The most common event is a change in job, not location. I often hear friends say, I wouldn’t mind tak-

ing a job with X; however, I don’t want to have to move to take it. However, depending on the job, not moving may not be an option. The question a lot of times is, where would you be willing to move? From my perspective, the list is extremely limited. I’m not sure I could ever go to the Northeast. I mean, have you ever driven in New Jersey or flown into Newark (on time)? For many of us, there is a quality of life that is hard to envision on the East Coast (ie, housing costs, other

with the requisite showing of new pictures of the kids (always nice to see). This usually leads to a short discussion concerning how the kids are doing in school and then veers to sports (all kids are generally involved with something to do with sports, and that includes cheerleading with me—my daughter was a high school cheerleader at one time, so it counts as a sport). For those fortunate enough to have a child in college, the discussion moves to what college, what degree, and then some gener-

It’s not only pharmacist or physician friends and colleagues that it’s nice to catch up with at major meetings, but also our friends in the pharmaceutical industry. The oncology pharmaceutical industry world is actually also relatively small. costs of living, state taxes, etc). I guess the same could be said about California (not that I don’t like to visit, especially the wine country!). Texas to me is the perfect state—no state taxes, relatively inexpensive housing, low cost of living, and most important, guns are OK, in fact, they are encouraged. As leaving Texas would be difficult for me, I can easily see why people don’t want to move unless it’s absolutely necessary (unless you are in the military, because they have to move every bunch of years, generally). At least from an academic standpoint, I can assure you that it is hard to get established faculty to move! We have had several faculty positions open now for some time, and it is difficult for the reasons I mentioned above to get pharmacy people to leave their homes and move somewhere new, even if it is to a good job. The second question always ask is, How is the family? This is generally met

al discourse concerning the cost we parents encounter. All this is actually good stuff. It brings us up to speed on what is happening with friends and colleagues you see infrequently. This to me is always the hidden agenda of attending a national meeting like HOPA—catching up with friends and colleagues. It’s not only pharmacist or physician friends and colleagues that it’s nice to catch up with at major meetings, but also our friends in the pharmaceutical industry. The oncology pharmaceutical industry world is actually also relatively small. Those in the oncology pharmaceutical industry also seem to stay in oncology. However, they seem to move from company to company more frequently than oncology pharmacists move between jobs. So when I see someone from the oncology pharmaceutical industry at a major meeting who I haven’t seen in a while, I also ask if they are still with X (or I quickly glance at

their name badge to see who they are with now). More often than not, they have changed jobs and in many cases are now with a different company. This is because of the large number of corporate mergers or buyouts that have occurred with many of the smaller biotech or oncology companies. With many of the mergers we have seen in the past decade, consolidations occurred, causing layoffs of a variety of oncology folks. However, specialtytrained oncology representatives, marketers, and others have specific skill sets that are needed by companies looking to get into the oncology business or companies looking to expand, so many of those who had been laid off generally pop up at one of these new endeavors. Also, as a new company is formed or a new product is approved, sales forces and other specialists are needed, again causing shifting of these individuals. The other thing I have noticed is that, if you have been in academics as long as I have, many of my peers have left academia for the pharmaceutical industry (actually, many if not most of those I have known over the years have made some form of move to industry). In our business, the pharmaceutical industry has been called “the dark side.” I guess because their job is to sell a specific product (which is FDA approved by the way), and this is somehow sinister, and what we do is somehow more “pure,” they are the dark side. I never actually bought into all that. The industry has a job to do just as we do, simple as that. Most of the people I have met in the pharmaceutical industry are very nice, and many of them have become friends over the years. So, the oncology world is actually a small world, and if you are in the business long enough, there probably will not be an oncology meeting you attend where you will not know someone. ●

Would you like straight-shooter Jim Koeller to address a particular topic? E-mail your ideas to editorial@greenhillhc.com. www.TheOncologyPharmacist.com

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