Special Issue May 2012, VOL 5, NO 4 by The Oncology Nurse

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MAY 2012

www.TheOncologyNurse.com

VOL 5, NO 4

ANNUAL REVIEW ISSUE

A Look at Recent Advances in Cancer Care Lymphomas Brentuximab Vedotin for the Treatment of Relapsed/Refractory Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma

Lymphoma Image Source: Dr. Lance Liotta Laboratory

Colleen Erb, MSN, CRNP, ACNP-BC, AOCNP Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC

Multiple Myeloma Managing Bortezomib Therapy in Patients With Multiple Myeloma Linda Caldwell, RN, MS; Cass Hammond, RN, MSN, CRNP; Kathleen Colson, RN, BSN, BS

Prostate Cancer Metastatic Castrate-Resistant Prostate Cancer—Treatment Overview Shari L. Black, MAN, CNP

Prostate Cancer Image Source: Otis Brawley (Photographer)

Hematologic Malignancies Myelofibrosis—A Myeloproliferative Neoplasm Catherine Bishop, DNP, NP, AOCNP

Supportive Care Prevention and Treatment of Thromboembolism in Patients With Cancer Aaron D. Dush, PharmD, CACP

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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.

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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

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

MSN, CRNP

CS, FNP

Avid Education Partners, LLC Sharpsburg, MD

Mayo Clinic Rochester, MN

Northern Michigan University Independent Oncology & Palliative Care Consultant Marquette, MI

Elizabeth Bilotti,

Shannon Hazen, RN, BSN, OCN

Melinda Oberleitner, RN,

Karla Wilson, RN,

RN, MSN, APRN, BC, OCN

Novant Health Presbyterian Cancer Center Charlotte, NC

DNS, APRN, CNS

City of Hope National Medical Center Duarte, CA

Patricia Irouer Hughes, RN, MSN,

Jayshree Shah, NP

DNP, NP, AOCNP Lansdowne, VA

BSN, OCN

Beth Faiman, PhD(c), MSN, APRNBC, AOCN Cleveland Clinic Taussig Cancer Institute Cleveland, OH

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop,

College of Nursing and Allied Health Professions University of Louisiana Lafayette, LA

Piedmont Healthcare Rex, GA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Gary Shelton,

NP, MSN, ACNP-C

AOCN, LNC

University of Southern California Norris Cancer Center & Hospital Los Angeles, CA

MSN, NP, ANP-BC, AOCNP

Fox Chase Cancer Center Philadelphia, PA

Wendy DiSalvo, DNP, APRN, AOCN Genentech New London, NH

Denice Economou, RN, MN, CNS, AOCN

MSN, FNP-C, CPON

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

Nutrition Karen Connelly, RD, CSO

NYU Clinical Cancer Center New York, NY

Somerset Medical Center Somerville, NJ

Sandra E. Kurtin,

Lori Stover, RN,

RN, MS, AOCN, ANP-C

BSN

Patient Advocate Peg Ford

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ovarian Cancer Advocacy Alliance Coronado, CA

Joseph D. Tariman, PhD,

Social Work Carolyn Messner,

APRN, BC

DSW, MSW, LCSW-R, BCD

Arizona Cancer Center Tucson, AZ

Ann McNeill, MSN, RN, NP-C, OCN

City of Hope National Medical Center Duarte, CA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Northwestern University Myeloma Program Chicago, IL

Constance Engelking, RN,

Kena C. Miller, RN, MSN, FNP

Jacqueline Marie Toia, RN, MS, DNP

MS, CNS, OCN

Roswell Park Cancer Institute Buffalo, NY

Northwestern University Myeloma Program Chicago, IL

The CHE Consulting Group, Inc. Mt. Kisco, NY

PhD, RN, AOCN

CancerCare New York, NY

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS BioPharma Partners LLC New York, NY

Amy Ford, RN,

Patricia Molinelli,

BSN, OCN

MS, RN, APN-C, AOCNS

Quintiles Dallas, TX

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCN

Isabell Castellano, RN

Somerset Medical Center Somerville, NJ

Saratoga, CA

Bristol-Myers Squibb Children’s Hospital Robert Wood Johnson University Hospital New Brunswick, NJ

Sharon S. Gentry,

Ellen A. Neylon,

Connie Visovsky,

Jeanne Westphal, RN

RN, MSN, AOCN

MSN, FNP, CCRP, OCN

RN, PhD, APRN

Meeker County Memorial Hospital Litchfield, MN

Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

www.TheOncologyNurse.com

Columbia University Medical Center Center for Lymphoid Malignancies New York, NY

University of South Florida College of Nursing Tampa, FL

May 2012 I VOL 5, NO 4

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About the Editor 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 Managing Editor Kristen Olafson kristen@greenhillhc.com Quality Control Director Barbara Marino

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

Production Manager Stephanie Laudien

ll of us here at The Oncology Nurse-APN/PA (TON) are pleased to announce that our editor-in-chief, Beth Faiman, was the recipient of the 2012 Oncology

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

Nursing Society (ONS) Excellence in Medical Oncology Award. She was honored during the opening ceremonies at the ONS 37th Annual Congress, held in New Orleans, Louisiana. The award recognizes accomplishments in the advancement of nursing knowledge within hematology and medical oncology. Beth clearly met the criteria, as an active author, educator, mentor, and researcher in the field. She is currently an Adult Nurse Practitioner in the Multiple Myeloma Program at the Taussig Cancer Institute of the Cleveland Clinic. Beth commented on receiving the award, “Every day I am inspired by nurses, patients, caregivers, and members of the healthcare team. It is truly an honor to win this prestigious award and represent each and every

nurse who is as deserving of this honor as I am.” She added that dealing with her patients’ problems is especially important to her. “Being recognized as recipient of the 2012 ONS Excellence in Medical Oncology Award will allow me to achieve one of many goals, which is to become a nurse researcher with a focus on cancer symptom management. My education enables me to conduct research and investigation into my patients’ problems,” she said. “I aspire to become a nurse researcher in the Cancer Institute. Many supportive treatments will go uninvestigated due to a lack of researchers. I am the fortunate recipient of NIH funding to continue my education and achieve my goal.” Congratulations, Beth! You are truly deserving of this recognition. ●

About This Issue

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241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831 The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print); ISSN 1944-9801 (online) is published 11 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 Nurse-APN/PA® 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 Nurse-APN/PA®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: kristin@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 Nurse-APN/PA® 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 Nurse-APN/PA® 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.

his month’s Fourth Annual Review Issue of The Oncology Nurse-APN/PA (TON) highlights some of the advances in cancer care over the past year. While this issue presents several of the most noteworthy developments, we could only scratch the surface of all that has happened in the world of oncology. One needs only to look at the total number of abstracts presented at the American Society of Hematology and the American Society of Clinical Oncology annual meetings to know how much potentially practice-changing research is in the pipeline. Some of these developments have been presented in previous issues while others will be featured in upcoming issues as researchers release updated data from ongoing studies. Although each issue of TON features articles that illustrate how rapidly practices are changing—everything from the expanding use of oral oncolyt-

Visit our Web site to vote for the recipient of the second annual Oncology Nurse Excellence award.

ics to the increasing role of personalized medicine in oncology—this issue in particular points out how important it is for oncology nurses to be aware of all these advances, both for themselves and for their patients. Newer therapies bring about changes to daily practice, and informed nurses can better help their patients understand these treatments. As we did in last month’s issue, we present the 4 finalists for the second annual Oncology Nurse Excellence award. The 4 finalists—Darcie Deaver, MSN, NP-C; Wendy Miano, RN,

MSN, DNP, DN; Patricia (Patti) Palmer, RN, MS, AOCN; and Deborah Thompson, BSN, ONC— were selected from among the many nominations we received. The outstanding contributions of each finalist are representative of all the accomplishments of those who are part of the oncology nursing profession. If you haven’t already done so, go to www.TheOncologyNurse.com/award to vote for your choice as the recipient of the Oncology Nurse Excellence award. The winner will be announced in the June issue. ●

Visit our user-friendly Web site www.TheOncologyNurse.com In addition to Web-only exclusives, news coverage, journal articles, contests, and polling questions, you’ll have the opportunity to earn Continuing Education credits at NO CHARGE by participating in a number of activities offered!

BPA Worldwide membership applied for April 2011.

May 2012 I VOL 5, NO 4

www.TheOncologyNurse.com

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020-300046-02 Rev 1 (3-2012)

TON_May2012_v7_TON 5/18/12 3:32 PM Page 8

News Briefs

Pazopanib Potential Treatment for Refractory Urothelial Cancer By Alice Goodman

azopanib, an angiogenesis inhibitor, achieved meaningful responses in about threequarters of patients with refractory urothelial cancer in preliminary clinical trial results presented at a press briefing during the 2012 Annual Meeting of the American Association for Cancer Research (AACR) in Chicago, Illinois. According to lead author of the study, Andrea Necchi, MD, Instituto Nazionale dei Tumori, Milan, Italy, this is the first targeted therapy to demonstrate meaningful clinical activity in patients with refractory urothelial cancer. He called the 76% rate of disease stabilization “remarkable,” noting that data on other efficacy outcomes are needed in the future. The study also provided some new information on interleukin-8 (IL-8) levels as a potential biomarker for response. Elevated levels of IL8, as well as rising IL-8 levels during the first 4 weeks of pazopanib treatment, were associated with tumor progression and shorter overall survival. These data need to be confirmed in further trials.

Five-year overall survival of metastatic urothelial cancer is about 10% to 15%.

Although targeted therapies are theoretically attractive in bladder cancers, thus

far no beneficial strategies have been identified until this trial.

TREANDA® is her chemo.

This is her therapy.

“Our biomarker analysis clearly pointed out the role of rising levels of circulating interleukin-8 as an early and potentially practicechanging indicator of tumor resistance and poor survival.” —Andrea Necchi, MD

“Our data indicate that pazopanib seems to be a legitimate drug in this disease. Most interestingly, our biomarker analysis clearly pointed out the role of rising levels of circulating interleukin-8 as an early and potentially practice-changing indicator of tumor resistance and poor survival,” he said, as reported in a news release from AACR. Second-line therapies thus far have been disappointing in advanced urothelial cancer, which has a poor prognosis. Median overall survival is about 4 to 5 months.

May 2012 I VOL 5, NO 4

www.TheOncologyNurse.com

TON_May2012_v7_TON 5/18/12 3:32 PM Page 9

News Briefs The phase 2, open-label, proof-ofconcept study enrolled 41 patients with advanced or metastatic urothelial cancer. Fifty percent progressed on secondline therapy. Patients received daily

pazopanib 800 mg once a day until development of disease progression or unacceptable toxicity, or withdrawal. According to RECIST criteria (for tumor shrinkage), objective responses

were seen in 7 patients and stable disease in 24 patients (total disease stabilization, 31 out of 41 patients: 76%). Median progression-free survival (PFS) was 2.6 months and median

overall survival was 4.7 months. At 2 months, 61% of patients were free of progression, and durable PFS was seen in 10% of patients at a median followup of 19 months. â&#x2014;?

Single-agent TREANDA tripled median PFS in patients with CLL* 42%!.$! IS INDICATED FOR THE TREATMENT OF PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA #,, %FlCACY RELATIVE TO lRST LINE THERAPIES OTHER THAN CHLORAMBUCIL HAS NOT BEEN ESTABLISHED

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

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

s 42%!.$! HAS AN ESTABLISHED SAFETY PROlLE

6 months

s )N THE PIVOTAL PHASE TRIAL OF PATIENTS WITH #,, THE MOST common non-hematologic adverse reactions (frequency â&#x2030;Ľ WERE PYREXIA NAUSEA AND VOMITING N 4HE MOST COMMON HEMATOLOGIC abnormalities (frequency â&#x2030;Ľ WERE ANEMIA THROMBOCYTOPENIA NEUTROPENIA

LYMPHOPENIA AND LEUKOPENIA N

median PFS

P<.0001 HRâ&#x20AC; =0.27 (95% CIâ&#x20AC;Ą: 0.17, 0.43)

s 42%!.$! WAS COMPARED WITH CHLORAMBUCIL IN A randomized, open-label, phase 3 trial in treatment-naĂŻve PATIENTS WITH "INET STAGE " OR # 2AI STAGES ) )6 #,, WHO REQUIRED TREATMENT . 0ATIENTS WERE SCHEDULED TO RECEIVE EITHER 42%!.$! MG M2 intravenously on $AYS AND N OR CHLORAMBUCIL MG KG ORALLY ON $AYS AND N OF A DAY TREATMENT CYCLE

up to 6 cycles

20 25 Months

*TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â&#x20AC; HR=hazard ratio. â&#x20AC;Ą CI=confidence interval.

Single-agent TREANDA produced a 74% ORRÂ§ in patients with indolent B-cell NHL that had progressed 42%!.$! IS INDICATED FOR THE TREATMENT OF PATIENTS WITH INDOLENT " CELL NON (ODGKIN S LYMPHOMA .(, THAT HAS PROGRESSED DURING OR WITHIN MONTHS OF TREATMENT WITH RITUXIMAB OR A RITUXIMAB CONTAINING REGIMEN s 42%!.$! WAS EVALUATED IN A SINGLE ARM PIVOTAL STUDY OF PATIENTS WITH INDOLENT " CELL .(, THAT HAD PROGRESSED during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled TO RECEIVE 42%!.$! MG M2 ON $AYS AND OF A 21-day treatment cycle, up to 8 cycles

ORRÂ§: INDOLENT B-CELL NHL THAT HAS PROGRESSED

57%

PR (n=57)

74%

Total ORR (95% CI: 64.3, 82.3)

17%

CR/CRu (n=17)

s 42%!.$! HAS AN ESTABLISHED SAFETY PROlLE

s )N SINGLE ARM STUDIES OF PATIENTS WITH INDOLENT " CELL .(, THAT HAD PROGRESSED . THE MOST COMMON non-hematologic adverse reactions (frequency â&#x2030;Ľ30%) WERE NAUSEA FATIGUE VOMITING

DIARRHEA AND PYREXIA . 4HE MOST common hematologic abnormalities (frequency â&#x2030;Ľ WERE LYMPHOPENIA LEUKOPENIA ANEMIA (88%), neutropenia (86%), and thrombocytopenia (86%)

100

Patients responding (%) Â§

Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for complete response (CR) would be scored as partial response (PR). Bone marrow sample lengths were not required to be â&#x2030;Ľ20 mm.

Important Safety Information s 3ERIOUS ADVERSE REACTIONS INCLUDING MYELOSUPPRESSION INFECTIONS INFUSION REACTIONS AND ANAPHYLAXIS TUMOR LYSIS SYNDROME SKIN REACTIONS INCLUDING 3*3 4%.

OTHER MALIGNANCIES AND EXTRAVASATION HAVE BEEN ASSOCIATED WITH 42%!.$! 3OME REACTIONS SUCH AS MYELOSUPPRESSION INFECTIONS AND 3*3 4%. WHEN 42%!.$! WAS ADMINISTERED CONCOMITANTLY WITH ALLOPURINOL AND OTHER MEDICATIONS KNOWN TO CAUSE 3*3 4%. HAVE BEEN FATAL 0ATIENTS SHOULD BE MONITORED CLOSELY FOR THESE REACTIONS AND TREATED PROMPTLY IF ANY OCCUR s !DVERSE REACTIONS MAY REQUIRE INTERVENTIONS SUCH AS DECREASING THE DOSE OF 42%!.$! OR WITHHOLDING OR DELAYING TREATMENT s 42%!.$! IS CONTRAINDICATED IN PATIENTS WITH A KNOWN HYPERSENSITIVITY TO BENDAMUSTINE OR MANNITOL 7OMEN SHOULD BE ADVISED TO AVOID BECOMING PREGNANT WHILE USING 42%!.$! l

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

Oncology

Built for ActionÂŽ

ÂĽ #EPHALON )NC IS A WHOLLY OWNED SUBSIDIARY OF 4EVA 0HARMACEUTICAL )NDUSTRIES ,TD !LL RIGHTS RESERVED 42% .OVEMBER

www.TheOncologyNurse.com

May 2012 I VOL 5, NO 4

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News Briefs

Luminal A Subtype Breast Cancer: Forgo Radiation?

specific subgroup of women with early-stage breast cancer may be able to avoid adjuvant radiation, according to a presentation

at the 2012 Annual Meeting of the American Association for Cancer Research (AACR) held in Chicago, Illinois. Women with the luminal A

subtype of breast cancer, particularly those older than age 60, had fewer local recurrences at 10 years when treated with tamoxifen alone versus

Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

May 2012 I VOL 5, NO 4

tamoxifen plus radiation therapy in a post hoc analysis of a randomized trial that compared these 2 forms of treatment.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased

TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)

Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53)

13 (7)

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

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TON_May2012_v7_TON 5/18/12 3:32 PM Page 11

News Briefs Senior author of this paper, Fei-Fei Liu, MD, radiologist at Princess Margaret Hospital, senior scientist at the Ontario Cancer Institute, and professor at the University of Toronto,

Canada, cautioned that local radiation therapy is still the standard of care for all other breast cancer subtypes. Liu commented that avoiding radiation therapy in these patients, who

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25

Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased

account for about 25% of all newly diagnosed breast cancer cases in North America, could achieve an estimated $400 million in savings for the healthcare system in the United States.

TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. M D6AE:42==J C64@?DE:EFE6 6249 ,* & G:2= 2D 7@==@HD M >8 ,* & G:2= 55 >$ @7 @?=J Sterile Water for Injection, USP M >8 ,* & G:2= 55 >$ @7 @?=J Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. M D6AE:42==J H:E95C2H E96 G@=F>6 ?66565 7@C E96 C6BF:C65 5@D6 32D65 @? >8 >$ 4@?46?EC2E:@? and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture D9@F=5 36 2 4=62C 2?5 4@=@C=6DD E@ D=:89E=J J6==@H D@=FE:@? M -D6 +E6C:=6 /2E6C 7@C "?;64E:@? -+( for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown E@ 36 4@>A2E:3=6 M (2C6?E6C2= 5CF8 AC@5F4ED D9@F=5 36 :?DA64E65 G:DF2==J 7@C A2CE:4F=2E6 >2EE6C 2?5 discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 50

DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:

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Manufactured by: Pharmachemie B.V. The Netherlands

Manufactured for: Cephalon, Inc. Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2011 Cephalon, Inc., or its affiliates. TRE-2263 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

The luminal A subtype of breast cancer is defined as estrogen receptor–positive, progesterone receptor–positive, HER2-negative, and low Ki-67 (<14%), a proliferation marker. The study was based on molecular subtyping analysis of 304 tumor blocks from 769 women with early T1 or T2, node-negative breast cancer who participated in a randomized controlled trial comparing tamoxifen plus whole-breast radiation therapy versus tamoxifen alone. Using immunohistochemistry, the researchers classified tumors into 6 categories: luminal A, luminal B, luminal-HER2, HER2enriched, basal-like, or triple-negative phenotype nonbasal. Overall, breast cancer recurrence at 10 years was 13.8% with tamoxifen alone compared with 5% for tamoxifen plus breast radiation. The luminal A subtype had the best outcome of any subgroup, with a 10-year risk of local relapse of 8% with tamoxifen alone versus 4.6% with tamoxifen and radiation. Luminal A patients older than age 60 had a 10-year local recurrence rate of 4.3% on tamoxifen alone versus 6% for combined modality therapy. Grade 1/2 luminal A tumors had a similar rate of recurrence regardless of treatment; 4.9% with tamoxifen versus 5.5% with tamoxifen plus radiation. The researchers said that these findings suggest that local breast radiation therapy did not affect the outcome of older patients with the luminal A subtype. By contrast, radiation therapy had a positive impact on other breast cancer subtypes. For example, women with luminal B tumors had a 10-year recurrence rate of 16.1% with tamoxifen alone versus 3.9% with tamoxifen plus radiation therapy. A similar trend was seen for HER2, HER2-enriched, and basal-like tumors, but the numbers in each group were small. These findings have implications for personalized cancer medicine, suggesting that Ki-67 be added to the current standard testing for hormone receptor and HER2 status in newly diagnosed patients with breast cancer. If these data on the luminal subtype A tumors are validated, that would pave the way for discussions with patients with this subtype about the need to undergo radiation therapy in addition to tamoxifen or other adjuvant therapy. In a news release from AACR, Liu was quoted as saying: “This is yet another powerful example of ‘personalized cancer medicine.’ When this information is combined with wellconducted randomized clinical trials, significant advances can be made whereby we can truly start to tailor therapies, based on new molecular markers, which can be introduced into routine clinical practice.” ● —AG

May 2012 I VOL 5, NO 4

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News Briefs

Radiologists and Medical Oncologists Attend to Fertility Issues in Younger Survivors

ontemporary treatment options have improved survival in cancer patients, making it more important than ever to focus on quality-of-life issues such as fertility in survivors of childbearing age. The majority of radiologists and medical oncologists appear to

appreciate the need for attention to fertility in age-appropriate patients, according to a study published online ahead of print in Practical Radiation Oncology (Gwede C, et al. 2012). The survey found that more than 80% of radiation oncologists and medical oncologists discuss the

impact of treatment on fertility with patients of childbearing age. â&#x20AC;&#x153;These findings are particularly important for radiation oncologists, who may have a unique role in communicating fertility preservation options to their patients, since their patients have daily

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

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

STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141. 2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVES After completion of this activity, participants will be better able to: â&#x20AC;˘ Identify approaches currently available or in development to predict recurrence risk in DCIS patients â&#x20AC;˘ Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer â&#x20AC;˘ Describe the design and findings of the ECOG 5194 validation study â&#x20AC;˘ Apply the 12-gene assay for DCIS into clinical decision-making â&#x20AC;˘ Explain relevant information about the 12-gene DCIS assay and DCIS score to patients

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

FACULTY

fertility should be discussed prior to initiation of cancer treatment with have a first child or an

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

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

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

Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Centerâ&#x20AC;&#x2122;s (ANCC) Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Certification. Case Managers number 790005057.

May 2012 I VOL 5, NO 4

Options for preserving

patients who may want to

ACCREDITATION

interaction with staff and weekly treatment exams with the radiation oncology physician and nurse,â&#x20AC;? stated senior author of this paper, Gwendolyn P. Quinn, PhD, Moffitt Cancer Center, Tampa, Florida. As the authors point out, with successful treatment, survival is increased. In the past, the clinical focus was on keeping patients alive, but now attention has shifted to survival with good quality of life. Chemotherapy, radiotherapy, and surgery can impact fertility. Thus, options for preserving fertility should be discussed prior to initiation of cancer treatment with patients who may want to have a first child or an additional child.

additional child. Unfortunately, previous studies suggested that less than 50% of adult cancer patients of childbearing age are given adequate information about fertility-preserving options prior to cancer treatment, and less than 35% of women stated that they discussed risk of infertility during or after cancer treatment. The present study sought to examine patterns of discussion of fertility preservation and referrals among medical oncologists, radiation oncologists, and surgical oncologists. These professionals were surveyed about whether they â&#x20AC;&#x153;always/often,â&#x20AC;? â&#x20AC;&#x153;sometimes,â&#x20AC;? or â&#x20AC;&#x153;rarely/neverâ&#x20AC;? initiated discussions on the impact of treatment on future fertility. Radiation and medical oncologists were more proactive than surgical oncologists in having fertility discussions with patients; 83% of radiation oncologists and 84% of medical oncologists discussed fertility options with patients â&#x20AC;&#x153;always/ often,â&#x20AC;? compared with only 51% of surgical oncologists. None of the radiation oncologists, 4% of medical oncologists, and 20% of surgical oncologists said they â&#x20AC;&#x153;neverâ&#x20AC;? discussed it with their patients. Surprisingly, in view of the fertility discussion rates, referral rates for fertility preservation among the 3 specialties were similar: 40% of radiologists, 45% of medical oncologists, and 46% of surgical oncologists reported referring patients of childbearing age to fertility specialists â&#x20AC;&#x153;always/often.â&#x20AC;? â&#x2014;? â&#x20AC;&#x201D;AG

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Lymphomas

Brentuximab Vedotin for the Treatment of Relapsed/Refractory HL and ALCL By Colleen Erb, MSN, CRNP, ACNP-BC, AOCNP, and Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC Fox Chase Cancer Center—Medical Oncology, Philadelphia, Pennsylvania

Case Study BS is a 63-year-old male who was well until the summer of 2008 when he developed right calf discomfort along with the sensation of his foot feeling cold. He had throbbing discomfort that led him to the emergency room. A Doppler ultrasound was completed of the right lower extremity that showed no evidence of a deep vein thrombosis. Due to evidence of a distinct mass on the right calf on MRI, an excisional biopsy was completed, and he was diagnosed with anaplastic large cell lymphoma (ALCL), stage IE. He was treated with 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Following CHOP, he received involved-field radiation therapy (XRT) and was noted to be in complete remission. In the fall of 2009 (approximately 6 months after the completion of his initial therapy), he developed right upper arm discomfort. A fluorodeoxyglucose-avid lesion was noted on PET/CT, and a biopsy was performed that demonstrated recurrent ALCL. He was treated with XRT to the right upper arm. While receiving XRT, he developed lymphadenopathy that was biopsied and found to be positive for ALCL. He was started on pralatrexate on a clinical trial but had progression of disease during the first cycle. He was then treated with mesna, ifosfamide, mitoxantrone, and etoposide (MINE) but experienced disease progression during the second cycle. He was started on brentuximab vedotin and achieved a complete response while on therapy. He reported numbness of his fingers and toes and experienced the sensation of his hands and feet feeling cold. He had a dose reduction after 10 cycles but completed 16 cycles. He remains in complete response 6 months after completion of therapy.

rentuximab vedotin was ap proved by the US Food and Drug Administration (FDA) on August 18, 2011, for the treatment of Hodgkin lymphoma (HL) that has relapsed after autologous stem cell transplant (ASCT) as well as for the management of relapsed anaplastic large cell lymphoma (ALCL).1 It is an anticancer antibody conjugated to a cytotoxic agent, monomethyl auristatin E (MMAE). The antibody component is a chimeric antibody that targets CD30, a member of the tumor necrosis factor receptor superfamily. Because of its limited expression on healthy tissue, CD30 is an attractive target for monoclonal antibody therapy.1 CD30 expression is restricted to activated B and T lymphocytes in healthy individuals; however, the function of CD30 is poorly understood. No diseases in humans have been linked to defects in CD30 genes.2 The CD30 antigen is expressed in both benign and malignant disorders. The nonmalignant disorders in which CD30 is expressed include lymphomatoid papulosis and disorders with virally transformed B cells, such as infectious mononucleosis, hepatitis C, and HIV, and in human T-lymphotropic virus 1– associated lymphoma cells. Malignant disorders in which CD30 is expressed include ALCL, thyroid carcinoma, embryonal carcinomas, and select subtypes of B-cell–derived non-Hodgkin lymphomas and mature T-cell lymphomas. Other lymphoid malignancies in which CD30 is expressed include primary mediastinal B-cell lymphoma, primary effusion lymphoma harboring the human herpesvirus 8, immunoblastic lymphoma and multiple myeloma, adult T-cell lymphoma/leukemia, and mycosis

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fungoides.2 HL and ALCL are the 2 most common tumors expressing CD30. Attempts to target the CD30 antigen with an unconjugated monoclonal antibody have demonstrated minimal activity. To enhance the antitumor effect of CD30-directed therapy, the monoclonal antibody SGN-30 was modified by the addition of a valine-citrulline dipeptide linker to enable attachment of the antitubulin agent MMAE, resulting in the CD30 antibody-drug conjugate (ADC) brentuximab vedotin (SGN35).1 ADCs combine the specificity of targeting found with monoclonal anti-

bodies with the ability to deliver a highly toxic chemotherapy agent that cannot be administered systemically.1 Brentuximab vedotin is designed to be stable in the bloodstream but to release MMAE once it is internalized into CD30-expressing tumor cells. MMAE binds to tubulin and disrupts the microtubule network within the cell and induces cell cycle arrest and apoptotic cell death (Figure).1,3 In vitro, the drug is potent and selective against CD30positive tumor cell lines. The recommended dose is 1.8 mg/kg administered over 30 minutes every 3 weeks. The

Figure. Mechanism of Action of Brentuximab Vedotin3

The antibody-drug conjugate (ADC) brentuximab vedotin binds to CD30 proteins on the cell surface. ADC then forms a complex with CD30 and enters the cell. Inside the cell, the ADC’s chemotherapy component is released and kills the cancer cell.

Colleen Erb, MSN, CRNP, ACNP-BC, AOCNP

Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC

maximum dose is 180 mg. It is administered as an intravenous (IV) infusion, not as a bolus or IV push. Treatment can be continued to a maximum of 16 cycles.4 Two phase 1 clinical trials have been completed using different schedules including either 1- or 3-week intervals. In the initial phase 1 dose-escalation study in CD30-positive hematologic malignancies, brentuximab vedotin was administered to 45 patients (42 with HL, 2 with ALCL, and 1 with CD30positive angioimmunoblastic T-cell lymphoma) every 3 weeks at dose levels from 0.1 to 3.6 mg/kg. The phase 2 dose was determined to be 1.8 mg/kg administered every 3 weeks. Objective responses, including 11 complete responses, were noted in 17 patients. Objective responses were noted in 6 patients (50%) who received the 1.8 mg/kg dose. Tumor regression was noted in 86% of evaluable patients. The median duration of response was at least 9.7 months. Most patients (88%) with objective responses demonstrated responses within 4 treatment cycles. Median progression-free survival (PFS) was at least 5.9 months, and a trend toward longer PFS was seen in patients who received doses of ≥1.2 mg/kg. The drug was well tolerated overall across dose levels. Dose-limiting toxicities included neutropenia and hyperglycemia. The most common treatment-related adverse events were fatigue (36%), pyrexia (33%), neutropenia (22%), peripheral neuropathy Continued on page 14

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Lymphomas Brentuximab Vedotin for the Treatment... (PN) (22%), nausea (22%), and diarrhea (22%). The adverse events were primarily grade 1 or 2. Fatigue, neutropenia, and PN were considered to be dose related.5 In the second phase 1 study, brentuximab vedotin was administered weekly for 3 weeks with 1 week off (4-week cycle). A total of 44 patients were treated, with 38 of the patients having HL, 5 ALCL, and 1 peripheral T-cell lymphoma. Doses ranged from 0.4 to 1.4 mg/kg, with the maximum tolerated dose determined to be 1.2 mg/kg. The most common side effects were peripheral sensory neuropathy (66%), fatigue (52%), nausea (50%), diarrhea (32%), arthralgia (27%), and pyrexia (25%). Grade 3 adverse events occurring in ≥2 patients were peripheral sensory neuropathy, anemia, neutropenia, peripheral motor neuropathy, hyperglycemia, diarrhea, and vomiting. Grade 4 adverse events occurred in 3 patients and included hyperglycemia, low potassium and magnesium, and neutropenia. The overall objective response rate (ORR) was 59%, with 34% of patients attaining a complete response. Tumor regression occurred in 85% of patients.6 Two phase 2 clinical trials have been completed in patients with relapsed HL and relapsed ALCL. In the first study, the efficacy of brentuximab vedotin was evaluated in patients with relapsed or refractory HL who experi-

enced disease progression after undergoing ASCT.7 Patients received brentuximab vedotin 1.8 mg/kg every 3 weeks as a 30-minute infusion. The maximum number of cycles was 16. The median age of the 102 patients treated was 31 years. Patients had received a median of 3.5 prior therapies and must have had failure with an ASCT. The ORR was 75%, with 34%

Continued from page 13

cycles. The median age of the patients was 52 years. Patients had received a median of 2 prior regimens. The majority of patients (62%) had primary refractory disease, and 50% were refractory to their most recent therapy. Seventy-two percent of the patients in the trial had ALK-negative disease. The ORR was 86%, with 53% of the patients achieving a complete response.

Management of side effects is of particular importance when caring for patients receiving brentuximab vedotin.

achieving a complete response. Treatment-related toxicities included peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Adverse events that were grade 3 or higher and occurred in ≥5% of patients included neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia.7 In the second phase 2 study,8 58 patients with relapsed systemic ALCL were treated with brentuximab vedotin 1.8 mg/kg every 3 weeks for up to 16

The median duration of response had not been reached. Of the 15 patients with malignant cutaneous lesions at baseline, 93% had resolution of all lesions. The median time to resolution was about 5 weeks.8 Since a significant number of patients who receive brentuximab vedotin achieve a complete response, an important question is whether patients can be successfully re-treated with brentuximab vedotin. Bartlett and colleagues reported on patients who were re-treated

Table 1 Common Toxicities of Brentuximab Vedotin Occurring in ≥20% of Patients4 Hodgkin Lymphoma Toxicity

Anaplastic Large Cell Lymphoma

Any Grade

Grade 3/4

Any Grade

Grade 3/4

54% 33%

21% 10%

55% 52%

21% 2%

28%

16%

10%

52%

53%

10%

Fatigue

49%

41%

Pyrexia

29%

38%

47%

12%

Nausea

42%

38%

Diarrhea

36%

29%

Abdominal pain

25%

Vomiting

22%

17%

27%

31%

25%

17%

Blood and lymphatic system disorders Neutropenia Anemia Thrombocytopenia Nervous system disorders Peripheral sensory neuropathy General disorders and administration site conditions

Infections and infestations Upper respiratory tract infection Gastrointestinal disorders

Skin and subcutaneous tissue disorders Rash Respiratory, thoracic, and mediastinal disorders Cough

May 2012 I VOL 5, NO 4

with brentuximab vedotin in 3 multicenter studies.9 Patients who had any level of tumor response with prior brentuximab vedotin treatment and subsequently experienced relapse were retreated with brentuximab vedotin. Patients were treated at a dose of either 1 mg/kg once a week or 1.8 mg/kg every 3 weeks, depending on their original treatment schedule. Seven patients re-treated had a total of 8 retreatment experiences, with 2 complete responses, 4 partial responses, and 2 stable disease. Therefore, it is believed that no significant resistance is developed to brentuximab vedotin after the initial treatment.9 The most common side effects of brentuximab vedotin (≥20%) are neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough, and vomiting (Table 1).4 The most common grade 3/4 side effects include neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. MMAE is a strong inhibitor of CYP3A4. Administration of brentuximab vedotin along with ketoconazole caused increased exposure to MMAE of approximately 34%. Therefore, patients taking strong CYP3A4 inhibitors along with brentuximab vedotin should be closely monitored for adverse reactions.4 In January 2012, the FDA notified healthcare professionals that 2 additional cases of progressive multifocal leukoencephalopathy (PML) had been reported associated with brentuximab vedotin, now totaling 3 cases of PML.10 PML is a rare but serious brain infection that can result in death. Symptoms can include changes in mood or usual behavior; confusion; thinking problems; loss of memory; changes in vision, speech, and walking; and decreased strength or weakness in one side of the body. Due to its seriousness, the FDA required a Boxed Warning to highlight this risk. Additionally, a new contraindication warning was added against using brentuximab vedotin with bleomycin due to inceased risk of pulmonary toxicity.4,10 This was noted in a clinical trial evaluating combination therapy in HL. Noninfectious pulmonary toxicity was more common with brentuximab vedotin plus ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), with an incidence of 40%, than with brentuximab plus AVD (doxorubicin, vinblastine, and dacarbazine) with an incidence of 0%. Other literature evaluating bleomycinbased regimens without brentuximab vedotin for HL have indicated the incidence of pulmonary toxicity to be between 10% and 25%.10,11

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Lymphomas

Management of Toxicities Management of side effects is of particular importance when caring for patients receiving brentuximab vedotin. Grade 3/4 side effects, including neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia, are among the most commonly occurring toxicities related to brentuximab vedotin,4 requiring close monitoring and early assessment to prevent complications. Anemia is caused by the reduction of circulating red blood cells due to damage to existing stem cells in the bone marrow. Normally, when there is increased demand for red blood cell production, the bone marrow responds to the demand by increasing production. This compensatory response is diminished in patients receiving cytotoxic therapy (eg, brentuximab vedotin) because of damage to the precursor cells in the bone marrow.12 Monitoring for side effects of anemia, including increased fatigue, lightheadedness, dizziness, palpitations, and shortness of breath, is important. One important intervention in the management of chemotherapy-induced anemia is transfusion of packed red blood cells. Transfusion criteria vary by institution, but generally, transfusion of packed red blood cells is ordered to maintain hemoglobin between 7 g/dL and 9 g/dL in asymptomatic patients with no significant comorbidities or between 8 g/dL and 10 g/dL in patients with acute coronary syndrome, cerebrovascular disease, chronic obstructive pulmonary disease or hypoxemia, tachycardia, fever, or angina.12 The most common risks related to red blood cell transfusions are transfusion reactions (including hemolytic, febrile, and nonhemolytic transfusion reactions as well as transfusion-related acute lung injury), congestive heart failure (especially if the patient has known cardiac disease), virus transmission (though this risk is extremely low), bacterial contamination, iron overload, and increased thrombotic events.13 Informed consent should be obtained prior to administering blood transfusions.13 In addition to transfusion of packed red blood cells, erythrocytestimulating agents can be used in the palliative setting at provider discretion.13 Thrombocytopenia, caused by a reduction in the rate of platelet production, can be due to marrow injury from myelosuppressive medications that lead to destruction of the precursor megakaryocytes.14 Patients receiving brentuximab vedotin are at risk for thrombocytopenia during their treatment. Thrombocytopenia commonly occurs 10 to 14 days following the administration of chemotherapy. In some patients, dose decreases or delays are necessary due to delayed platelet

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Table 2 NCI CTCAE Version 4.03 Grading of Peripheral Neuropathy21,22 Grade 1 Peripheral motor neuropathy

Grade 2

Asymptomatic; Moderate sympclinical or diagnostic toms; limiting observations only; instrumental ADL intervention not indicated

Grade 3

Grade 4

Grade 5

Severe symptoms; limiting self-care ADL; assistive device indicated

Life-threatening Death consequences; urgent intervention indicated

Peripheral sensory Asymptomatic; Moderate symp- Severe symptoms; neuropathy loss of deep tendon toms; limiting limiting self-care reflexes or instrumental ADL ADL paresthesia

Life-threatening Death consequences; urgent intervention indicated

Abbreviations: ADL, activities of daily living; CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute. recovery. Patients may not have any symptoms until platelets fall below 20,000/µL. Symptoms include petechiae, ecchymosis, hemorrhagic bullae on mucous membranes, gingival bleeding, epistaxis, menorrhagia, hematuria, GI bleeding, and bleeding from injection sites. In patients with prolonged thrombocytopenia, there is risk of cranial hemorrhage.15 Indications for prophylactic platelet transfusion are controversial. In general, evidence-based practice leads to a trigger for platelet transfusion at levels <10,000/µL unless there are other risk factors making this unreasonable, including fever, increased white blood cell (WBC) count, coagulopathy, bleeding, or invasive procedures.15 Neutropenia is also associated with brentuximab vedotin. Neutropenia is defined as an absolute neutrophil count (ANC) <500 neutrophils/µL or <1000 neutrophils/µL and a predicted decline to ≤500 neutrophils/µL over the next 48 hours.16 The severity and duration of neutropenia correlate with patient outcomes and influence the frequency and severity of infection as well as the response to chemotherapy.14 Patients with prolonged severe neutropenia are at significantly increased risk of developing severe bacterial, viral, and fungal infections.14 The management of neutropenia includes the use of growth factors to increase the WBC count, as well as preventing and treating infections related to neutropenia. Myeloid growth factors, including filgrastim and sargramostim, have been approved by the FDA for use in the prevention of neutropenia related to chemotherapy administration. Both effectively increase the ANC, but they have different side effect profiles. Filgrastim is a granulocyte colony-stimulating factor (G-CSF) and is more specific for activation of neutrophils.17 Filgrastim is available in a pegylated form (pegfilgrastim) that has a half-life of 46 to 62 hours, compared with the plasma half-life of 3 to 4 hours for filgrastim.18 Sargramostim is a granulo-

cyte-macrophage colony-stimulating factor (GM-CSF) that stimulates monocytes, eosinophils, and neutrophils, prolongs their half-lives, and enhances their function.18 In patients who have had neutropenic complications during a prior cycle of brentuximab vedotin without CSF support, CSFs can be instituted to decrease the need for dose reductions or treatment delays. Dosing of filgrastim is 5 µg/kg/day subcutaneously until an ANC level >5000/µL is reached or pegfilgrastim 6 mg subcutaneously once, with

Of all the side effects of brentuximab vedotin noted, peripheral sensory neuropathy can affect quality of life the most. both to be administered at least 24 hours after chemotherapy infusion. Administration of CSFs during chemotherapy or within 24 hours of chemotherapy may expose the rapidly dividing myeloid cells to the cytotoxic chemotherapy and result in more profound neutropenia. The most common side effect of CSFs is bone pain,18 which can be treated successfully with NSAIDs or acetaminophen if not contraindicated.19 Other, infrequent side effects include fever, petechiae, rash, splenomegaly, increased liver enzymes, epistaxis, hypertension or hypotension, cardiac arrhythmias, headache, nausea, vomiting, peritonitis, leukocytosis, and transfusion reactions.19 Of all the side effects of brentuximab vedotin noted, peripheral sensory neuropathy can affect quality of life the most. PN can require dose reductions or delays and can significantly impact daily life.20 PN related to brentuximab vedotin is similar to that experienced by patients receiving microtubule-targeting agents (MTAs),5 such as vinca alka-

loids, taxanes, and the recently introduced epothilone analog, ixabepilone.21 MTAs interfere with the normal function and structure of the microtubules in cells, leading to tumor cell death by arresting the cell cycle.21 This mechanism of action leads to interruption of the active transport of proteins and other components within the neurons, thereby affecting axonal transport in the neurons. Neurons depend on this transport of proteins for survival.21 Because the peripheral nerves have longer axon length and more permeability due to their structure, they are more frequently and quickly affected by this interruption, causing neuropathy.21 PN is manifested in most patients receiving brentuximab vedotin by sensory findings, including paresthesia, pain or burning, allodynia, hyperesthesia or numbness, decreased vibratory sensation, and reduced or absent deep tendon reflexes. There may also be motor findings consistent with neuropathy that include generalized muscle weakness, decreased fine motor skills, and vocal cord dysfunction. Lastly, autonomic findings, though less likely, can include abdominal cramping, constipation, severe ileus, and urinary retention. Grading usually takes into account the effect on quality of life and daily activities (Table 2).21,22 Preexisting PN from any other causes increases the risk and severity of PN related to treatment.22 Certain conditions that put patients at increased risk of developing PN from brentuximab vedotin include diabetes, alcoholism, nutritional deficiencies, and infectious diseases such as AIDS or Lyme disease.21 Assessment of patients in whom there is suspicion of neuropathy should include evaluation for signs of decreased strength or diminished reflexes; symptoms including pain, paresthesia, or hyperesthesia; and any interference with activities of daily living.20 In most cases of neuropathy, signs or symptoms will begin in the distal extremities and Continued on page 16

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Lymphomas Brentuximab Vedotin for the Treatment... progress proximally in a stocking-glove distribution.20 The only proven treatment methods for PN are discontinuation, delay, or dose reduction of brentuximab vedotin.5 In one study, resolution of PN was noted in 10 of 16 patients (63%) at the last safety assessment, approximately 30 days from the last dose of brentuximab vedotin; the only grade 3 event, which was observed in a patient in the 2.7-mg cohort, returned to grade 1 after approximately 4 months.5 In most cases, neuropathy will resolve after discontinuation of therapy or by decreasing the dose of brentuximab vedotin, but in some cases it becomes severe and irreversible.21 Other interventions have been used in the treatment of chemotherapyinduced PN (CIPN), but none have been proven by prospective randomized clinical trial data, and none are FDA approved at this time. Some of these include tricyclic antidepressants, including amitriptyline, desipramine, and imipramine, that modulate sodium channels and inhibit reuptake of norepinephrine and serotonin, which leads to decreased pain.23 Anti convulsants, including gabapentin, are also often used, although there have been no data to show true reduction of pain.20 Opioid pain medication has been used to treat CIPN, with good relief reported by patients. Opioids can be titrated to achieve maximal reduction of pain. Once maximal relief is achieved, the preferred plan of care includes a longacting opioid analgesic with a short-acting medication used only for breakthrough pain.20 Other compounds under investigation specifically for neuropathy caused by MTAs include amifostine, glutamine, and glutathione.21 There are no large randomized trials demonstrating efficacy of these agents and, in general, all evidence and current clinical guidelines do not recommend using amifostine.21 Glutamine and glutathione have shown some promise in reducing the severity of PN, but again, there are no large trials to support their use.21 In general, continued assessment and early intervention are key to preventing severe, irreversible PN, and patients should be advised to report symptoms immediately.21

Nursing management of patients receiving brentuximab vedotin includes good assessment and patient education. Patients should be educated to report symptoms early and should be asked about symptoms of PN or myelosuppression at each visit, as early intervention will prevent serious complications. Patients should be educated about early detection of PN and how to avoid falling or other harmful situations should they lose sensation, proprioception, or reflexes.21 Patient education should also include defining myelosuppression for the patient, listing symptoms to report, and explaining the rou-

Nursing management of patients receiving brentuximab vedotin includes good assessment and patient education. tine of laboratory evaluations and chemotherapy treatments. Nurses should also take time before the start of treatment to teach patients about the potential for and consequences of neutropenia. They should tell patients to report signs and symptoms of infection or any fever immediately to their physician or nurses and let patients know about prevention of infection by way of hand washing and avoiding contact with anyone who appears ill.24 Nurses can also help define fatiguefighting strategies such as prioritizing tasks and taking breaks to rest if necessary.25 Many studies have been conducted to evaluate the use of exercise in combating fatigue. There is strong evidence supporting the benefits of exercise in managing fatigue.26 Exercise can effectively reduce fatigue in many settings, including fatigue resulting from chemotherapy. In this case, home-based moderate exercise, both aerobic and strength training, has been proven to be beneficial.26 The current recommendation from the National Comprehensive Cancer Network (NCCN) is to start

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with low-intensity exercise of short duration and then increase and modify the plan as conditions change.27 Currently, data are insufficient to recommend specific amounts of time for activity, but the US Surgeon General does recommend 30 minutes of activity on most days for all populations.27 With this in mind, caution should be taken in patients with comorbidities such as respiratory or cardiac disease and in those with bone metastasis, thrombocytopenia, anemia, and fever.27 In these patients, activity regimens should be closely monitored and individualized based on current physical activity level and ability.27 Brentuximab vedotin is a novel ADC that targets CD30. Responses have been shown in patients with Hodgkin lymphoma and anaplastic large cell lymphoma that is relapsed or refractory to prior therapy. Responses have also been shown in the retreatment setting. While overall the therapy is tolerable, significant side effects (grade 3 or greater) with brentuximab vedotin can include neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Nursing assessment to detect side effects early may be useful in attenuating their severity. In addition, interventions should be initiated to minimize the impact of therapy on the patient’s quality of life. ● References 1. Katz J, Janik JE, Younes A. Brentuximab vedotin (SGN-35). Clin Cancer Res. 2011;17:6428-6436. 2. Younes A. CD30-targeted antibody therapy. Curr Opin Oncol. 2011;23:587-593. 3. Phillips C. Special report: trial suggests new treatment option for Hodgkin lymphoma. NCI Cancer Bulletin. 2010;7(24):5. http://www.cancer.gov/ncicancerbulletin/ 121410/page5. Accessed February 12, 2012. 4. Adcetris [package insert]. Bothell, WA: Seattle Genetics, Inc; 2012. 5. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;363:1812-1821. 6. Fanale MA, Forero-Torres A, Rosenblatt JD, et al. A phase I weekly dosing study of brentuximab vedotin in patients with relapsed/refractory CD30-positive hematologic malignancies. Clin Cancer Res. 2012;18:248-255. 7. Chen RW, Gopal AK, Smith SE, et al. Results from a pivotal phase II study of brentuximab vedotin (SGN35) in patients with relapsed or refractory Hodgkin lymphoma (HL). J Clin Oncol (ASCO Meeting Abstracts). 2011;29(suppl):Abstract 8031. 8. Pro B, Advani R, Brice P, et al. Durable remission with brentuximab vedotin (SGN-35): updated results of a phase II study in patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). J Clin Oncol (ASCO Meeting Abstracts). 2011; 29(suppl):Abstract 8032. 9. Bartlett N, Grove LE, Kennedy DA, et al. Objective responses with brentuximab vedotin (SGN-35) retreat-

ment in CD30-positive hematologic malignancies: a case series. J Clin Oncol (ASCO Meeting Abstracts). 2010;28(suppl):Abstract 8062. 10. FDA (2012). FDA drug safety communication: new boxed warning and contraindication for Adcetris (brentuximab vedotin). http://www.fda.gov/Drugs/Drug Safety/ucm287668.htm. Accessed April 6, 2012. 11. Younes A, Connors JM, Park SI, et al. Frontline therapy with brentuximab vedotin combined with ABVD or AVD in patients with newly diagnosed advanced stage Hodgkin lymphoma. Blood (Proc ASH). 2011;118(suppl):Abstract 955. 12. Means RT Jr. Anemias secondary to chronic disease and systemic disorders. In: Greer JP, Foerster J, Rodgers GM, et al, eds. Wintrobe’s Clinical Hematology. Vol 1. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, a Wolters Kluwer business; 2009:1221-1238. 13. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Cancer- and Chemotherapy-Induced Anemia. V2.2012. http://www. nccn.org/professionals/physician_gls/pdf/anemia.pdf. Accessed August 20, 2011. 14. Alvandi F, Klein HG. Blood transfusion. In: Rodgers GP, Young NS, eds. Bethesda Handbook of Clinical Hematology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:341-354. 15. Lynch MP, Rogers BB. Thrombocytopenia. In: Camp-Sorrell D, Hawkins RA, eds. Clinical Manual for the Oncology Advanced Practice Nurse. Pittsburgh, PA: Oncology Nursing Society; 2006:859-864. 16. Galel SA, Nguyen DD, Fontaine MJ, et al. Transfusion medicine. In: Greer JP, Foerster J, Rodgers GM, et al, eds. Wintrobe’s Clinical Hematology. Vol 1. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, a Wolters Kluwer business; 2009:689. 17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Myeloid Growth Factors. V1.2011. http://www.nccn.org/profes sionals/physician_gls/pdf/myeloid_growth.pdf. Accessed August 21, 2011. 18. Green MD, Koelbl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003;14:29-35. 19. Mohebtash M, Arlen PM. Hematopoietic growth factors. In: Abraham J, Gulley JL, Allegra CJ, eds. The Bethesda Handbook of Clinical Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:433-440. 20. Quirion E. Filgrastim and pegfilgrastim use in patients with neutropenia. Clin J Oncol Nurs. 2009;13:324-328. 21. Carlson K, Ocean AJ. Peripheral neuropathy with microtubule-targeting agents: occurrence and management approach. Clin Breast Cancer. 2011;11:73-81. 22. US Department of Health and Human Services. National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE); V4.03. 2010. 23. Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice. Clin J Oncol Nurs. 2007;11:361-376. 24. O’Leary C. Neutropenia and infection. In: Brown CG, ed. Guide to Oncology Symptom Management. Pittsburgh, PA: Oncology Nursing Society; 2010:347362. 25. Miller S. Anemia. In: Brown CG, ed. Guide to Oncology Symptom Management. Pittsburgh, PA: Oncology Nursing Society; 2010:29-47. 26. Barsevick AM, Newhall T, Brown S. Management of cancer-related fatigue. Clin J Oncol Nurs. 2008;12(5 suppl):21-25. 27. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology™: Cancer-Related Fatigue. V1.2012. http://www.nccn.org/professionals/ physician_gls/pdf/fatigue.pdf. Accessed August 20, 2011.

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Oncology Nurse Excellence Award Finalists Vote Now for Your Choice

www.TheOncologyNurse.com/award It was a difficult process, but we have selected 4 finalists from among the peers you nominated for the second annual Oncology Nurse Excellence (ONE) award. All the nominees were outstanding, but these 4 individuals stood out for their display of leadership and compassion and for their commitment to evidence-based practices. Now it’s your turn. After you read about each finalist, please go to www.TheOncologyNurse.com/award and tell us your pick for the ONE award. We will announce the readers’ choice in the June issue of The Oncology Nurse-APN/PA.

Darcie Deaver, MSN, NP-C Moffitt Cancer Center Tampa, Florida

arcie Deaver has been an oncology nurse since 2003, when she began her career as a staff nurse in the inpatient bone marrow transplant unit. She completed a master of science degree in nursing at the University of South Florida (USF) in 2006 and is currently a nurse practitioner in the malignant hematology program at Moffitt Cancer Center in Tampa, Florida. According to her colleagues, she “has been a rock of support for our patients, our physicians, and our nurses. She consistently communicates with and includes the primary care team in the patient care plan.” The most important information she gives patients is the truth, explaining the disease in a way that makes sense to them, focusing on the facts, research, and reality. Her col-

Wendy Miano, RN, MSN, DNP, DN University Hospitals Case Medical Center Cleveland, Ohio

May 2012 I VOL 5, NO 4

inalist Wendy Miano became interested in nursing as an undergraduate student when she had the opportunity to volunteer at a hospice and was “struck by the notion of the patient and family as a unit of care, focusing on quality of life and empowerment.” This focus has continued through her career as an oncology nurse at University Hospitals, Case Medical Center (UH/CMC), beginning in 1984. Wendy has practiced in adult and pediatric acute care oncology and adult and pediatric hospice, in addition to contributing to the development of new nurses as an instructor of medical/surgical nursing. Her career path turned to nursing leadership in 1996 when she became Administrative Director of the Ireland Cancer Center Ambulatory Services and, in 2008, Chief Nursing Officer for Cancer Services at UH/CMC. Wendy believes the most important qualities in an oncology

leagues say Darcie’s delivery of this information is what makes her unique. She loves her job of caring for patients, and they experience her confidence and compassion. If she weren’t a nurse, Darcie would probably go to medical school.

Valuing a quest for knowledge and exhibiting a never quitting spirit, Darcie

is also a doctoral candidate at USF. She now spends most of her day seeing patients for her research. She has extensive knowledge about cutaneous T-cell lymphoma, peripheral T-cell lymphoma, mycosis fungoides, and Sézary syndrome and has given many presentations on these topics. Darcie has received a number of awards, including an Oncology Nursing Society commendation for outstanding achievement for her article “The Development of Pericarditis Following Peripheral Blood Stem Cell Transplantation: A Case Report” and Moffitt’s 2010 Advanced Practice Professional. In nominating her for the ONE award, Darcie’s colleagues emphasize she “is always professional in her demeanor, gets along well with her peers, and always gives her best to patient care.”

nurse are critical thinking skills and emotional maturity that accompany a focus on holistic communication with patients to help them successfully navigate the complex multimodality nature of cancer treatment. Wendy’s colleagues view her as a key member of the team that collaborated to design, construct, and open the Seidman Cancer Center in 2011. This freestanding cancer hospital contains 144 inpatient beds, ambulatory clinics, and support services. In writing their nomination, they emphasized that Wendy was “truly a leader and role model who effectively utilized clinical knowledge in cancer patient care to create a new physical and programmatic model of oncology patient care, a unique achievement accomplished rarely in this field.” Staying true to her early impressions as an undergraduate student, Wendy attributes the success of the new facility to the input of 15 to

20 patient and family volunteers who were involved in all facets of the design process, “sitting as partners with organizational leaders.” Based on this input, the new facility has comfortable rooms outside each patient room where family and friends can be close to the patient, while also being able to have personal time meeting their own needs and attending to other responsibilities. Even a small detail such as including a small safe in each room allows what Wendy characterizes as a “monumental shift in how patients and families move within the space.” When asked to reflect on what she would be if not a nurse, Wendy would see herself as an oceanographer, caring for the earth through the interaction of water and animals. It is unmistakable that Wendy Miano considers the big picture, while emphasizing the importance of the individual, no matter what the situation.

The most important information Darcie gives patients is the truth, explaining the disease in a way that makes sense to them.

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the

hen nominating Patti Palmer for the ONE award, her colleagues described her as an exceptional oncology nurse educator who, during the past 2 years, guided the inpatient oncology team at the University of California Davis Medical Center through Putting Evidence Into Practice initiatives that improved satisfaction scores for communication

cell transplant multidisciplinary teams, for whom she identifies patients who may need to be seen for education or emotional support. She participates in institutional committees for the online chemotherapy order project, the shared governance research committee, the scientific review committee for the Cancer Center, and the clinical nurse specialist group.

ONE Award

from 40% to 92%, teamwork from 57% to 81%, cohesiveness from 30% to 81%, and overall excellent quality of care from 40% to 92%. Patti is involved with many aspects of oncology care at the Medical Center, including daily huddles with the medical oncology, surgical oncology, and stem

Patti has been an oncology nurse for 38 years. When she was preparing to go to college, she thought nursing was a good fit for someone like herself who likes science and math. Over the years she has found that “empathy, compassion, caring, and a mind with a neversatisfied thirst for learning” are impor-

tant qualities for an oncology nurse to possess. She strives to get to know her patients as individuals so she can make a plan of care that is uniquely suited to them. In the future, Patti believes that the patient’s treatment experience can be changed for the better by improving teamwork from outpatient to inpatient and back again. Patti enjoys oncology as an ever-changing specialty and has noticed that in the beginning she spent “a lot of time helping people die (and not doing it very well), and now we really focus on living full lives until and if you die.” She sees 2012 as a very exciting time for oncology and a great time to be an oncology nurse. If she weren’t a nurse, Patti enthusiastically proclaimed that she would see herself as a small and large animal veterinarian. This would be in addition to keeping her current hobby as a fiber artist. Combining science and softness, calculations and caring are characteristics that make Patti Palmer a worthy nominee for the ONE award.

Deborah and her coworkers administer chemotherapy, immunotherapy, and blood products to 35 to 45 patients per day. In almost 3 decades of practice, she has seen many improvements in medications available to the oncology patient. She relates that when she first started practicing, patients became deathly ill with nausea and vomiting after chemotherapy, and that is rare now. She has seen a significant shift in chemotherapy administration from the

The importance of education is also manifest by Deborah’s other possible career choice if not a nurse, that of a health reporter. She feels that increased knowledge in the community about diseases, and the importance of regular check-ups and early reporting of problems, is very important. Deborah believes in the importance of providing patients with hope and encourages them to keep a positive attitude during their journey toward an

Patti believes that the patient’s treatment experience can be changed for the better by improving teamwork from outpatient to inpatient and back again.

hen Deborah Thompson describes the connections she hopes to form with her patients, she calls them “her family members.” She explains that her first priority is to help the patient develop trust in her and comfort within the environment, because when they first come to the infusion center where she works, they are afraid. To create this, Deborah talks about “taking part in the journey together” with the patients, their family, and their friends, and she has found that when she refers to her patients as family members, they view her differently. Other important qualities for an oncology nurse, according to Deborah, are compassion, honesty, integrity, dedication, and dependability. As evidence that Deborah practices what she preaches, one of her patients wrote a letter of appreciation to Eric Shinseki, Secretary of Veterans Affairs, commending the care she rendered to him. For the past 29 years, Deborah has been an oncology staff nurse at the Atlanta Veterans Administration Medical Center. In the infusion center,

www.TheOncologyNurse.com

Deborah believes in the importance of providing patients with hope and encourages them to keep a positive attitude during their journey toward an end goal. inpatient to the outpatient setting, and most importantly, patients are living much longer after treatment. Ac cording to her colleagues, Deborah is a dedicated nurse who is “enthusiastic about educating her peers, the veterans, and the community, as evidenced by her consistent educational offerings.”

Patricia (Patti) Palmer, RN, MS, AOCN University of California Davis Medical Center Sacramento, California

Deborah Thompson, BSN, ONC Veterans Administration Medical Center Atlanta Decatur, Georgia

end goal. In fact, each day she writes a positive affirmation on the wall. Two of our ONE award nominee’s favorites are “A word of encouragement can mean the difference between giving up and going on” and “When life knocks you down, try to land on your back, because if you can look up, you can get up.”

May 2012 I VOL 5, NO 4

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Thank you to all for Participating in the 2012

Oncology Nurse Excellence Award Joann Ackler, RN, OCN

Susan Epting, MSN, AOCN

Rita M. Levy, RN, OCN

Kimberly Rohan, MS, APN, AOCN, BSN, MSN, NP

Albert Einstein Cancer Center

Genentech

Doylestown Hospital

Edward Cancer Center

Khaled Alqawasmeh, MSN

Sylvia S. Estrada, RNC, WHCNP, CBCN, CCRP, MSN, MSHCM, BSN

Robin Lewis, RN, BSN, CBCN

Julie Ross, NP

Wake Forest Baptist Medical Center

Roswell Park Cancer Institute

Jennifer Lindeman, MS

Kim Ryan, APRN, OCN

Roswell Park Cancer Institute

Saul and Joyce Brandman Breast Center, Cedars-Sinai Medical Center

Roswell Park

CT Oncology Group

Toni Armstrong, BSN, ACLS

Sharon Etris, MSN, NP

Vera Luzietti, RN, ONS

Julie Sanner, RN, ONS, CBCN

UC Health

Coborn Cancer Center

Suzanne “Windy” Lyle, MS, FNP, AOCNP, MS, NP

Susan Schneider, PhD, RN, AOCN, ACNS-BC, FAAN

Portland VA Medical Center

Duke University School of Nursing

Denise Margiotta, Acute Nurse Practitioner

Marie Christine Seitz, RN, MSN, ANP-BC, AOCN

New York University Memorial Sloan-Kettering Cancer Center

Mount St. Mary’s College

David Lee Cancer Center, affiliated with Charleston Area Medical Center

Evangeline Masalta, BSN, APN

Moffitt Cancer Center and Research Institute

University of Texas MD Anderson Cancer Center

Kathy Shine, BSN, RN

Sara Flickner, RN, BSN, OCN

Toni McCoy, RN, BSN

Ironwood Cancer & Research Centers

Northwestern Memorial Hospital

Longview Regional Medical Center

Michelle Shriner, BSN, OCN

Jana Floershiem, RN, ADN, OCN

Susan McDonald, BSN, OCN

Adams County Cancer Center

Miners Colfax Medical Center

Brigham and Women’s Hospital

Anne Skwira-Brown, RN, CNP

Sandy Forrester, RN, OCN

Melissa McEwen, ADN, OCN

Essentia Duluth Clinic Cancer Center

Auerbach Hematology-Oncology

Texas Oncology

Elisabeth Smith, BSN

Diashea Foster

Myra Mcgrath, RN

Winship Cancer Institute, Emory University

Methodist Infusion Center

Halifax Health Center for Oncology

Maria Solaun, BSN

Lana Fournier, BS

Holly Meyerowich, RN, OCN

City Of Hope

Minnesota Oncology

Jupiter Medical Center

Karen Sommers, NP

Susan Foy, RN, OCN

Amy Miller, OCN

University of California Irvine

Reston Hospital Center

Paynesville Area Health Care System

Pauline Soucy, RN, AD, OCN

Jennifer Goldschmitt, NP

MaryKay Moore, BSN

Southern New Hampshire Medical Center

North Shore University Hospital/ Monter Cancer Center

Cleveland Clinic

Maria Stir, RN

Andrea Moran, APRN

Bayhealth Medical Center, Kent General Hospital

Cassie Gossett, RN, BSN, OCN

Cristina Suarez, CPN

University Medical Center Brackenridge

Neag Comprehensive Cancer Center University of Connecticut Health Center

Deborah Hancock, RN

Sabrina Mosseau, BS, RN, OCN

Maggie Syta, RN/NP

Grady Memorial Hospital

Samaritan Hospital Cancer Treatment Center

Shannon Hazen, RN, BSN, OCN

Mary P. Murphy, RN, OCN, CBCN

Bone Marrow Clinic at Roswell Park Cancer Institute

Presbyterian Hospital

Albert Einstein Cancer Center

Rosemary Taormina, BSN, OCN

Kimberly Hess, ANP, OCN

Massey Nematollahi, BScN, MScN, RN

Coastal Carolina Health Care, New Bern Cancer Care

Stronack Cancer Center at Southlake

Nancy N. & J. C. Lewis Cancer and Research Pavilion

Iris Nieves, BSN, OCN

Kimberly Elizabeth Thorn, RN, BSN, OCN

Sarah Holmes, RN, OCN

Nassau University Medical Center

Texas Oncology-Tyler

Auerbach Hematology-Oncology

Bridget E. O’Brien, DNP, APN, FNP-BC, AOCNP

Rose Tiabbi, RN, BS, OCN

Christine Hull, MSN, AOCNS

Northwestern Faculty Foundation, Robert H. Lurie Comprehensive Cancer Center of Northwestern University

North Shore Long Island Jewish Health System at Glen Cove Sara M. Tinsley, MS, ARNP, AOCN

Marsha Opalach, RN, OCN, MeD, CHPN

Moffitt Cancer Center

CentraState Medical Center

Jennifer Tripp, BSN, OCN

Lisa Pittman, RN

Parkland Medical Center

Adventist Hinsdale Hospital

Julie Vaday, MSN

Tina Pryor, RN

Kaiser Permanente Santa Clara Medical Center

Virginia Oncology Associates

Nancy Warner, RN

Meghan C. Punda, CRNP

Minnesota Oncology

Center for Cancer and Blood Disorders

Wendy Waters, RN, OCN

Anna Quincy, BSN, OCN

South Carolina Oncology Associates

Providence Sacred Heart Medical Center

Marigo Werner, RN, BSN, OCN

Annette Quinn, RN, MSN

Pikeville Medical Center Megan Wholey, NP/OCN

Tawam Hospital Rebecca Amirian, BSN

Terrebonne General Medical Center

Winship Cancer Institute of Emory University

Monica Averia, MSN, ACNP, NP

Trudie Eubanks, RN

USC Kenneth Norris Cancer Hospital

Forrest General Hospital

Gayle Balmaceda, RN, BSN, ANP-BC, GNP-BC

Helen Evers, BSN, RN

University of Texas MD Anderson Cancer Center Anne Beatie, BSN, ONC, OCN

UCDMC, Adult Infusion Center Patricia Bluml, MSN, ARNP, OCN

Via Christi Hospitals, Wichita-Blood and Marrow Transplant Center of Kansas Carolyn Bowers, RN, OCN

Ochsner Baptist Radiation Oncology Megan Brown

Methodist Infusion Center Michele Brown, NP

St. Luke’s Mountain State Tumor Institute Tess Buckles, RN, OCN

South Carolina Oncology Associates Dyane Bunnell, MSN, RN-BC, CPON, AOCNS

Nemours/Alfred I. duPont Hospital for Children Matthew Burke, MBA, RN, MSN, APRN-BC

Smilow Cancer Hospital at Yale Joan Burnham, RN

Methodist Willobrook Dorothy Cafran, RN, BSN, OCNS, CHPN

Northern Westchester Hospital Kim Calabro, BSN, RN, OCN

OSF Saint Anthony Medical Center-Center for Cancer Care Pamela Calarese, MS, RN, CS, OCN

Dana Farber Cancer Institute Mahnaz Capps, BSN

Walter Reed National Military Medical Center Sherry Cesati, RN

LRGHealthcare Oncology Carlin Cialino, BSN, OCN

Abramson Cancer Center, Hospital of the University of PA Freda Clark, RN, OCN

Grady Memorial Hospital Mark Clark, RN, OCN, AOCN, MSN, FNP-BC

Northeast Georgia Diagnostic Clinic Kathleen Clifford, RN, MSN, C-FNP, AOCN

Saint Luke’s Health System Linda Cothron, BSN, MSN, FNP, OCN

Chapters Healthcare Cyndi Cramer, BA, RN, OCN, PCRN

Tampa General Hospital

Methodist Hospital Division, Thomas Jefferson University Hospital Beverly Farmer, ADN, OCN

Inova Loudoun Hospital Arlene Jacobson, RN, BSN, OCN

Maimonides Cancer Center Stephany Jacques, RN, OCN

Rumford Hospital Robin Johnson, RN, OCN

Providence Holy Family Hospital Lisa Karem, RN, BSN, OCN

UPMC Cancer Center Sarah C. Kaveney, MSN, RN, OCN, NEA-BC

The Regional Cancer Center Cheri Kennedy, RN, OCN

Santa Clara Valley Medical Center

Andrea Shaffer, RN, BSN, ARNP, OCN

Miami Children’s Hospital

Florida Cancer Specialists

St Mary Medical Center

UPMC Shadyside Hospital, Dept. of Radiation Oncology, University of Pittsburgh Cancer Institute

Julie Dartez White, RN, BSN, OCN

Sandra Kurtin, RN, MS, AOCN, ANP-C

Denise Menonna Quinn, RN-BC, MSN, AOCNS

Ray County Memorial Hospital Alicia Wojchik, RN, MA, CNP, AOCNP Maryanne Yarrington, RN, OCN

Tracey Curtis, MSN, Board Certified, Family Practice Hematology/Oncology NP

Colleen Krumpe, BSN, RN, OCN

Cancer Care Associates

The University of Arizona Cancer Center

Beth Delaney, APRN, OCN, BC-PC

Zoe Lambrecht, RN, OCN, ELNEC

Hackensack University Medical Center and Bergen Regional Medical Center

Ohio State University, James Cancer Center

Tampa General Hospital

Dawn Reininger, BSN, OCN

Lourdes Dimafelix, RN, OCN

Cheryl Larschan, ADN

University of Wisconsin Hospital and Clinics

Robert and Carol Weissman Cancer Center at Martin Health System

Stella Rineer, RN

Carol Layug, BSN

Maria Rivera, RN

Medical City Dallas Janet Ditello, ADN, ACLS

Provena Saint Joseph Medical Center Iryna Durnyeva, RN, BSN, OCN

Maimonides Medical Center Eva Edrial, BSN

Provena Saint Joseph Medical Center

Provena Saint Joseph Medical Center Toni Maria Le Donne, BSN, RN

Methodist Infusion Center Colleen Lemoine, MSN/APRN-BC/CNS

Interim Louisiana State University Hospital

Auerbach Hematology-Oncology The Center for Cancer and Blood Disorders Susan Roche, CRNP, MSN, DNP, AOCNP, APRN-BC

The Regional Cancer Center Ronda Rogers, RN, CBPN-IC

Texas Health Physician Group

Virginia Hospital Center Beverly Williams, RN

MN Oncology Providence Hospital and Medical Centers Lyn Zehner, RN, MN, AOCNS

Inova Alexandria Hospital Jennifer Zimmerman, AD

Penn State Hershey Medical Center

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Supportive Care

Prevention and Treatment of Thromboembolism in Patients With Cancer By Aaron D. Dush, PharmD, CACP The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University

he link between cancer and thrombosis has been known for many years. Recently this connection has come to the forefront with increased recognition by healthcare providers and mandates by governing bodies. The results of a thromboembolic event can be catastrophic in a patient with cancer. Malignant neoplasms alone are associated with a 4-fold increased risk of a venous thromboembolic event (VTE), and cytotoxic or immunosuppressive chemotherapy increases the malignant neoplasm–associated risk to more than 6-fold.1,2 VTE leads to a significant reduction in survival3-5 and is the second-leading cause of death in patients with cancer.6 Patients with cancer who have a VTE are also at increased risk of recurrence, bleeding complications, and morbidity.7 Patients with cancer have multiple factors that increase their risk of VTE. First, the cancer itself produces a hypercoaguable state for these patients. Certain cancers appear to carry a higher risk than others (malignant brain tumors; adenocarcinoma of the lung, ovary, pancreas, colon, stomach, prostate, and kidney; and hematologic malignancies),8 but all cancers will increase the patient’s overall VTE risk. The patient’s therapy also plays a major role in the risk of VTE. Many newer chemotherapeutic agents, such as bevacizumab, carry an increased risk of thromboembolism.9 VTE risk increases 2- to 5-fold when women with breast cancer are treated with tamoxifen.10,11 Aromatase inhibitors also increase this risk, but at about half the rate of tamoxifen.12 Thalidomide or lenalidomide increases thromboembolic risk, especially when used in combination with chemotherapy or highdose dexamethasone.13 All of these are additive to the other general risk factors that these patients may already be exposed to, such as decreased mobility, surgeries or procedures, age, indwelling catheters, and other comorbidities. Due to the high risk faced by cancer patients, many guidelines have been developed to help assist in the prevention and treatment of thromboembolic events in these patients. The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), and the American College of Chest Physicians (CHEST)

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have issued guidelines to help practitioners prevent and treat thrombosis in patients with cancer. These guidelines have much overlap in their recommendations, and rightfully so. I will attempt to give a brief summary of some of these guidelines specific to patients with cancer (Table). For prevention of VTE, all 3 societies agree that pharmacologic prophylaxis should be initiated in hospitalized cancer patients in the absence of contraindications.14-16 Low-dose unfractionated heparin (LDUH), lowmolecular-weight heparin (LMWH), or fondaparinux should be utilized. Pharmacologic prophylaxis would be contraindicated in patients who are bleeding or have a high risk for major bleeding. In these patients, consider mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression. If the thrombotic risk persists once the bleeding risk has subsided, the use of pharmacologic prophylaxis should be reassessed and substituted for mechanical prophylaxis.

For prevention of VTE in the surgical patient with cancer, again all 3 societies agree. The guidelines recommend extended prophylaxis for surgical cancer patients for up to 4 weeks, particularly in high-risk abdominal or pelvic surgery.14,15,17 All 3 recommend LMWH. NCCN and ASCO also support unfractionated heparin as an alternative, and NCCN supports fondaparinux as well. Mechanical methods can be added to pharmacologic prophylaxis in patients at highest risk. For patients in the ambulatory setting, the societies previously agreed that routine prophylactic anticoagulation was not recommended except in patients with multiple myeloma who were receiving thalidomide- or lenalidomide-based combination regimens and in whom the risk of VTE warranted prophylaxis.14,15 The latest additions to the CHEST guidelines have extended this recommendation. These guidelines suggest that outpatients with solid tumors who have additional risk factors for VTE but who have a low risk for bleeding use

Aaron D. Dush, PharmD, CACP

prophylactic doses of LMWH or LDUH over no prophylaxis.16 The additional risk factors include previous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, and again thalidomide or lenalidomide therapy. This recommendation is based on moderate-quality evidence of reduction in mortality and high-quality evidence of reduction in VTE. These effects were larger than any plausible increase in bleeding risk. For patients with cancer who have indwelling central venous catheters (CVCs), routine prophylactic anticoagulation is not recommended.14-16 Over the next few years, more evidence may become available on the efficacy and cost-effectiveness, and specific groups of patients with CVCs that may benefit from prophylaxis, taking into consideration VTE risk versus bleeding risk. Continued on page 22

Table Recommendations for Prevention and Treatment of VTE in Patients With Cancer ASCO

CHEST

NCCN

Prevention of VTE in the Prophylactic anticoagulation hospitalized patient with considered for all in the cancer absence of contraindications

Prophylactic anticoagulation Prophylactic anticoagulation considered for all in the considered for all in the absence of contraindications absence of contraindications

Prevention of VTE in the Extended prophylaxis up to surgical patient with 4 weeks postprocedure cancer high-risk surgery

Extended prophylaxis up to 4 weeks postprocedure high-risk surgery

Prevention of VTE in the Not recommended except ambulatory patient with with thalidomide/ cancer lenalidomide-based regimens

Prophylactic anticoagulation Not recommended except with suggested in patients with thalidomide/lenalidomidesolid tumors who have addi- based regimens tional risk factors for VTE and who are at low risk of bleeding

Prevention of VTE in patients with CVC and cancer

Not recommended

Treatment of VTE in patients with cancer

LMWH preferred and treated indefinitely as long as cancer persists

LMWH preferred and treated LMWH preferred and treated indefinitely as long as cancer indefinitely as long as cancer persists persists

Treatment of catheterrelated thrombosis in patients with cancer

Extended prophylaxis up to 4 weeks postprocedure high-risk surgery

Not recommended

Anticoagulation as long as Anticoagulation as long as catheter is in place or at least catheter is in place or at least 3 months after removal 3 months after removal

Abbreviations: ASCO, American Society of Clinical Oncology; CHEST, American College of Chest Physicians; CVC, central venous catheter; LMWH, low-molecular-weight heparin; NCCN, National Comprehensive Cancer Network; VTE, venous thromboembolic event.

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Supportive Care Prevention and Treatment of Thromboembolism... For treatment of VTE in cancer patients, therapy is driven by the findings of the CLOT trial.18 This trial was conducted over a 6-month period. It compared the efficacy of LMWH (dalteparin) to oral anticoagulation in the prevention of recurrent thrombosis in patients with cancer. The trial showed

no significant difference in bleeding risk or 6-month mortality but did show a statistically significant difference in recurrent thromboembolism at 6 months favoring the LMWH group. When treating cancer patients who have a pulmonary embolism (PE) or deep vein thrombosis (DVT), LMWH

Continued from page 21

is the preferred agent. These patients should be treated indefinitely as long as they have active cancer or risk factors persist.14,15,19 Well-managed vitamin K antagonists, such as warfarin, may be an acceptable alternative when LMWH is not advisable. This may be true in patients who cannot afford

â&#x20AC;&#x153;Quality care is everyoneâ&#x20AC;&#x2122;s business.â&#x20AC;? Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Nurse Practitioner, Multiple Myeloma Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH

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May 2012 I VOL 5, NO 4

LMWH, patients who are opposed to daily injections, or those who have renal insufficiency. As for the dose of LMWH, in the CLOT trial dalteparin was given at 200 IU/kg once daily for the first month then 150 IU/kg once daily for the remaining 5 months.18 Enoxaparin carries an indication for inpatient treatment of DVT with or without PE at a dose of 1 mg/kg every 12 hours or 1.5 mg/kg every 24 hours. For outpatient DVT without PE, the indicated dose is 1 mg/kg every 12 hours.20 Both indications are in conjuction with the initiation/administration of warfarin. The quality of evidence comparing once-daily versus twice-daily LMWH is low because of impression and inconsistency in studies comparing the 2 types of administration. A metaanalysis of studies showed similar rates of mortality, recurrent DVT, and major bleeding.21 Keep in mind, these studies were not for long-term treatment with LMWH. LMWH was administered for a period of 5 to 10 days in conjunction with a vitamin K antagonist. The study by Merli and colleagues, published in Annals of Internal Medicine in 2001, suggested that outcomes may be inferior with once-daily versus twice-daily regimens.22 In the subset of patients with malignancy, the study showed a 12.2% rate of recurrence with the once-daily dose and only a 6.4% rate of recurrence with the twice-daily group; however, statistical significance was not achieved. This study also did not include long-term use of LMWH. These studies did lead to the latest CHEST recommendation for patients with acute DVT of the leg treated with LMWH. They suggest once-daily over twice-daily administration, but this recommendation applies only if the approved once-daily regimen uses the same total daily dose as the twice-daily regimen.19 This would be true for dalteparin using 200 IU/kg once daily but not for enoxaparin that uses 1.5 mg/kg once daily (twice-daily dose is 1 mg/ kg every 12 hours). This recommendation could then be interpreted as indicating that the preferred treatments are dalteparin 200 IU/kg every 24 hours or enoxaparin 1 mg/kg every 12 hours. The recommendation carries a 2C grade from CHEST, which is a weak recommendation with low- or very low-quality evidence. In patients with cancer, again based on the CLOT trial that did study long-term LMWH therapy, clinicians should utilize LMWH dosing where the full total daily dose is utilized. Dalteparin is the only LMWH to carry a treatment indication for patients with cancer at 200 IU/kg daily for the first month, then 150 IU/kg

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Supportive Care daily. If we carry this to a class indication, enoxaparin should be dosed at 1 mg/kg every 12 hours initially for treatment of VTE in patients with cancer. Also, one must remember that LMWH is eliminated renally, so dose adjustments may be necessary based on the patient’s renal function. For the treatment of catheter-related thrombosis, it is suggested that the catheter not be removed if it is still functioning. The treatment for this thrombosis is based on whether the catheter is or is not removed. If the catheter is removed, the patient should be treated for 3 months after the catheter is removed. If the catheter is not removed, the patient should be treated with anticoagulation therapy as long as the catheter remains in place.15,19 Two new oral anticoagulants have recently joined the market, and more are in the pipeline. These will most likely be approved in the next few years, as will additional indications for the oral anticoagulants already available. Two agents that have recently been approved are dabigatran (Pradaxa) and rivaroxaban (Xarelto). Dabigatran is a direct thrombin inhibitor, and rivaroxaban is a selective inhibitor of factor Xa. Currently both are approved for nonvalvular atrial fibrillation, and rivaroxaban is also approved for DVT prophylaxis post knee and hip replacement.23,24 Neither is currently approved for the treatment of VTE. The goal for any of the new anticoagulants is to develop an agent that is oral, requires minimal monitoring, has a predictable and rapid effect, has a large therapeutic index, and has minimal drug interactions. Dabigatran is a twice-daily medication, whereas rivaroxaban is given once daily. Both are eliminated by the kidneys, so are contraindicated in patients with renal impairment. They do have a rapid onset and a larger therapeutic index. There are no regular monitoring recommendations with these agents. Although these medications seem to make anticoagulation therapy simpler, there are a few things to consider in patients with cancer. There is currently no reversal agent available to completely reverse the anticoagulation effect of these agents. This plays a major role in anticoagulation therapy in patients with cancer who are already at a higher risk of bleeding. With the rapid onset and rapid clearance of these agents, a short half-life syndrome can result. If compliance is an issue, patients on these medications can return to baseline after missing only 1 or 2 doses, which can rapidly increase their risk of a thromboembolic event. An interesting phase 2 trial by Levine and colleagues that was recently published in the Journal of Thrombosis

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and Haemostasis initiated patients receiving chemotherapy on apixaban for 12 weeks.25 Apixaban is a factor Xa inhibitor that is not yet approved by the FDA. These were patients without a prior history of VTE. The outcomes were to determine major or clinically relevant nonmajor bleeding, VTE, and adverse events related to the drug. The trial did show a low bleeding risk for these patients and a decrease in VTE. The study protocol did potentially select for patients with a lower bleeding risk by not including patients with a prolonged bleeding time or patients receiving moderate to high doses of aspirin or other antiplatelet agents, and caution should be used when extrapolating these results to a less selective population. This does introduce what may be on the horizon for anticoagulation and cancer and the use of the newer agents. Further studies will need to be completed to support these findings. In cancer patients in whom bleeding risk is already elevated, a clear picture of the real-life bleeding risk associated with these agents is still not available. Lack of monitoring may actually be a negative in these patients. With the other agents, we have a standard laboratory value that can measure the extent of the patient’s anticoagulation. There is no standard laboratory value to measure the newer agents. Certain anticoagulation markers may be elevated with therapy, but there is no direct correlation to the actual level of anticoagulation. With cancer patients receiving chemotherapy and

having frequent procedures or surgeries, we cannot assess their true bleeding risk. In patients with cancer, these medications should be used with extreme caution until more postmarketing data are available and analyzed. ● References 1. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000;160:809-815. 2. Blom JW, Doggen CJ, Osanto S, et al. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005;293:715-722. 3. Alcalay A, Wun T, Khatri V, et al. Venous thromboembolism in patients with colorectal cancer: incidence and effect on survival. J Clin Oncol. 2006;24:1112-1118. 4. Chew HK, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458-464. 5. Sørensen HT, Mellemkjaer L, Olsen JH, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med. 2000;343:1846-1850. 6. Khorana AA, Francis CW, Culakova E, et al. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost. 2007;5:632-634. 7. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood. 2002;100:3484-3488. 8. Falanga A, Donati MB. Pathogenesis of thrombosis in patients with malignancy. Int J Hematol. 2001;73:137144. 9. Nalluri SR, Chu D, Keresztes R, et al. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA. 2008;300:2277-2285. 10. Lee AY, Levine MN. Venous thromboembolism and cancer: risks and outcomes. Circulation. 2003;107(23 suppl 1):I17-I21. 11. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst. 2005; 97:1652-1662. 12. Thürlimann B, Keshaviah A, Coates AS, et al. Breast International Group (BIG)1-98. Collaborative Group. A comparison of letrozole and tamoxifen in

postmenopausal women with early breast cancer. N Engl J Med. 2005;353:2747-2757. 13. El Accaoui RN, Shamseddeen WA, Taher AT. Thalidomide and thrombosis. A meta-analysis. Thromb Haemost. 2007;97:1031-1036. 14. Lyman GH, Khorana AA, Falanga A, et al. American Society of Clinical Oncology Guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol. 2007;25:5490-5505. 15. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Venous Thromboembolic Disease. Version 1.2009. http://www. oncologycast.net/guidelinecasts/NCCN_Guidelines.pdf. Accessed April 26, 2012. 16. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e195Se226S. 17. Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e227S-e277S. 18. Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349:146-153. 19. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians EvidenceBased Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e419S-e494S. 20. Lovenox [package insert]. Bridgewater, NJ: sanofiaventis US LLC; 2011. 21. Couturaud F, Julian JA, Kearon C. Low molecular weight heparin administered once versus twice daily in patients with venous thromboembolism: a meta-analysis. Thromb Haemost. 2001;86:980-984. 22. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med. 2001;134:191202. 23. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim; 2012. 24. Xarelto [package insert]. Leverkusen, Germany: Bayer HealthCare; 2011. 25. Levine MN, Gu C, Liebman HA, et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10:807-814.

O Outstanding utstanding O Opportunity pportunity for for

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IIMMEDIATE MMEDIATE O OPPORTUNITY PPORTUNITY for an experienced Oncology NP at Marshall Hematology and Oncology, an independent, nonprofit community healthcare provider located in the heart of the Sierra Foothills between Sacramento and South Lake Tahoe. R RESPONSIBILITIES ESPONSIBILITIES F FOR OR O ONCOLOGY NCOLOGY N NP P IINCLUDE: NCLUDE: Work collaboratively with oncologist to provide direct patient care to outpatient population and oversee chemotherapy administration. Management experience required to facilitate staff ff,, physician, infusion center, clinic operations and oversight. Requires current CA RN license, BLS certification, Masters of Science degree in nursing with 12-24 xperimental learning as a nurse months of specialized classroom and ex practitioner, minimum 2 years related clinical experience. Oncology certification strongly preferred. Certification by the American Nurse Credentialing Center to be obtained within 12 months of employment and must apply for, be aw waarded, and maintain privileges as an Allied Health Professional in accordance with the bylaws, rules & regulations of the medical staff of Marshall Medical Center.

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Myelofibrosis

Myelofibrosis—A Myeloproliferative Neoplasm By Catherine Bishop, DNP, NP, AOCNP, Hematology/Oncology Nurse Practitioner Lansdowne, Virginia

Prognostic Factors

Cytopenias

Weight loss

Constitutional symptoms

Low or high white cell count

Transformation to acute leukemia •Blast percent

Increasing bone marrow fibrosis

Catherine Bishop, DNP, NP, AOCNP

yeloproliferative neoplasms (MPNs) are somewhat rare chronic hematologic malignancies. There are no known cures, but the disease itself is treatable. According to the World Health Organization’s revised WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues, MPNs include essential thrombocythemia (ET), polycythemia vera (PV), and idiopathic myelofibrosis (IMF), also referred to as primary myelofibrosis (Table 1).1 IMF, ET, and PV are considered Philadelphia chromosome (Ph) negative. Chronic myelogenous leukemia (CML) is considered Ph positive. This review article will focus on IMF, and the new treatment approved by the US Food and Drug Administration (FDA). In 1951, William Dameshek, a preeminent American hematologist, described the concept of myeloproliferTable 1 WHO 2008 Revised Classification of MPNs1 CML (BCR-ABL1–positive) Polycythemia Vera (PV) 1. Chronic-phase PV 2. Post-PV myelofibrosis 3. Blast-phase PV Essential Thrombocythemia (ET) 1. Chronic-phase ET 2. Post-ET myelofibrosis 3. Blast-phase ET Primary Myelofibrosis 1. Chronic-phase primary myelofibrosis 2. Blast-phase primary myelofibrosis Abbreviations: CML, chronic myelogenous leukemia; MPNs, myeloproliferative neoplasms. Adapted from Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951.

May 2012 I VOL 5, NO 4

Low total cholesterol

Progressive splenomegaly/hepatomegaly

Figure. Clinical Manifestations of Idiopathic Myelofibrosis Indicated in Worsening Prognosis9 Adapted from “Development of New Therapies for Myelofibrosis” presentation by Srdan Verstovsek, MD, PhD, Associate Professor, Department of Leukemia, University of Texas, MD Anderson Cancer Center.

ative disorders by grouping together CML, ET, PV, IMF, and erythroleukemia. He articulated that a self-perpetuating trilineage myeloproliferation underlined their pathogenesis.2 Etiology IMF is a disorder of the blood cells wherein the bone marrow reveals fibrous tissue, and lab values demonstrate varying degrees and combinations of leukopenia, anemia, and thrombocytopenia. The disease is thought to originate from the neoplastic transformation of a single hematopoietic stem cell. The disease presents either de novo or in the setting of PV or ET.3 Bone marrow morphology is critical to the diagnosis and will generally show a dramatic increase in reticulin fibers and collagen together with a loss of normal hematopoietic cells. Additionally, normocytic anemia with nucleated red blood cells and an increase in megakaryocytes is seen on histologic examination.4 The disease affects both men and women equally and is usually diagnosed in the fifth to seventh decade of life. There are no known risk factors, but there have been reports that myelofibrosis may be linked to immunologic-mediated hyperplasia of marrow suggestive of lupus erythematosus, and other connective tissue diseases.4 Additionally, exposure to benzenes or high-dose ionizing radiation has preceded the diagnosis of primary myelofibrosis.5 Prognosis varies accord-

ing to a set of clinical factors, including hemoglobin level, constitutional symptoms, circulating blasts, leukocyte count, and cytogenetics.6 Morbidity and mortality are commonly associated with leukemic transformation, infection, portal hypertension, and thrombohemorrhagic events.7

Approximately one-quarter of patients

normochromic anemia is present in almost all patients. In 1 study the hemoglobin concentration in patients at diagnosis was 9.5 to 11.6 g/dL, with a range of 4 to 20 g/dL among a total of 539 patients in 4 studies.8 Anisocytosis (variation in size) and poikilocytosis (variation in shape) are constant findings, as are teardrop-shaped red cells.7 Prognosis worsens with increased presence of the clinical manifestations listed above and shown in the Figure.9 In 2008, WHO recommended 2 sets of specific criteria (major and minor) to help clinicians make an accurate diagnosis (Table 2).10

with idiopathic myelofibrosis are asymptomatic at the time of diagnosis.

Clinical Presentation and Diagnosis Approximately one-quarter of patients with IMF are asymptomatic at the time of diagnosis.8 Patients who are symptomatic may present to the primary care provider with complaints of fatigue, weakness, shortness of breath, and weight loss. Some patients may also complain of left upper quadrant pain or discomfort due to splenomegaly.8 Lab values can be very broad. Normocytic-

Role of the Janus-Associated Kinase (JAK) Pathway Advances in the understanding of the pathogenesis of Ph-negative MPNs such as IMF have led to the discovery of the JAK2V617F mutation as a prospective therapeutic target.11 The JAK pathway plays a major role in blood cell production and immune and inflammatory responses.12 Overactivity or imperfections in this pathway are thought to be responsible, in part, for many disease states, including IMF. The JAK pathway sends out signals from blood cell growth factors, cytokines, or hormones outside the bone marrow stem cell to its nucleus. Under normal functioning of the bone marrow, suitable blood cell development and utility are ensured.12 There is a strong association between abnor-

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Myelofibrosis mal cell signaling in the JAK pathway and the development of MPNs.12,13

Table 2 Diagnostic Criteria for Primary Myelofibrosis (WHO 2008)10 3 major criteria + 2 minor criteria must be met to confirm diagnosis.

Treatment Allogeneic stem cell transplantation (SCT) offers the possibility of cure for some patients with IMF.14 However, the risk of graft-vs-host disease, transplantrelated death, and relapse of the myelofibrosis requires careful selection of appropriate candidates. Until recently there were few, if any, treatments that provided hope for patients ineligible for transplant. Most of the treatment options were palliative in nature, intended to minimize anemia, neutropenia, or thrombocytopenia, as well as the many constitutional symptoms experienced by the majority of IMF patients. Given the essential role of the JAK pathway in blood cell production and immune function, scientists began researching the potential of JAK inhibition for treating patients with IMF.

Major diagnostic criteria 1. Megakaryocyte proliferation and atypia* 2. Not meeting WHO criteria for PV, BCR-ABL1−positive CML, MDS, or other myeloid neoplasm 3. Presence of JAK2V617F or other clonal marker or no evidence of secondary bone marrow fibrosis in absence of clonal marker

Approval of a New Drug On November 16, 2011, the FDA approved ruxolitinib (Jakafi) for the treatment of intermediate- and highrisk myelofibrosis.15,16 The oral drug is the first in a new class of drugs known as JAK inhibitors. The drug inhibits JAK1 and JAK2 pathways. The approval was based on results from 2 randomized phase 3 trials—COMFORT-I and COMFORT-II—which tested the drug in patients with postPV myelofibrosis and post-ET myelofibrosis. Patients in both trials were resistant or refractory to available therapy. Additionally, they were ineligible for SCT. The COMFORT trials established that patients treated with ruxolitinib experienced significant reductions in splenomegaly. COMFORT-I also demonstrated improvements in symptoms as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) and the MFSAF Total Symptom Score to include abdominal discomfort, pain under left ribs, satiety, night sweats, bone and muscle pain, and itching. Most patients on placebo had worsening of these symptoms.15 At the time of approval, 75% of the patients on study 1 and 67% on study 2 who achieved at least a 35% reduction in spleen volume maintained this

Science has been focusing on personalized

Minor diagnostic criteria 1. Leukoerythroblastosis 2. Increase in serum lactate dehydrogenase 3. Anemia 4. Splenomegaly *Accompanied by either reticulin and/or collagen fibrosis, or in the absence of significant reticulin fibrosis, a prefibrotic cellular-phase disease. Abbreviations: CML, chronic myelogenous leukemia; MDS, myelodysplastic syndrome; PV, polycythemia vera; WHO, World Health Organization.

medicine, and for the few diagnosed with IMF, the JAK inhibitors represent a new option for IMF management.

reduction. The most common adverse events in both studies were thrombocytopenia and anemia. These were manageable and rarely led to discontinuation of the drug.16 The recom-

The oral drug is the first in a new class of drugs known as JAK inhibitors.

mended starting dose of ruxolitinib is 20 mg orally twice daily for patients with a platelet count above 200 x 109/L, and 15 mg twice daily for those with a platelet count between 100 and 200 x 109/L.16

Conclusion Patients diagnosed with IMF do not comprise a great proportion of patients in the oncology setting. However, their uncommon, mostly incurable disease makes them at least as vulnerable as those with the most commonly diagnosed cancers. Science has been focusing on personalized medicine, and for the few diagnosed with IMF, the JAK inhibitors represent a new option for IMF management. Based on the data from the COMFORT studies, ruxolitinib has been approved for use in patients with intermediate/high-risk myelofibrosis, offering patients some hope now, and for the future development of other targeted therapies. ● References 1. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951. 2. Tefferi A. The history of myeloproliferative disorders:

before and after Dameshek. Leukemia. 2008;22:3-13. 3. Passamonti F, Malabarba L, Orlandi E, et al. Polycythemia vera in young patients: a study on the long-term risk of thrombosis, myelofibrosis and leukemia. Haematologica. 2003;88:13-18. 4. el Mouzan MI, Ahmad MA, al Fadel Saleh M, al Sohaibani MO, al Gindan YM. Myelofibrosis and pancytopenia in systemic lupus erythematosus. Acta Haematol. 1988;80:219-221. 5. Tondel M, Persson B, Carstensen J. Myelofibrosis and benzene exposure. Occup Med (Lond). 1995;45:51-52. 6. Arana-Yi C, Quintás-Cardama A, Giles F, et al. Advances in the therapy of chronic idiopathic myelofibrosis. Oncologist. 2006;11:929-943. 7. Thiele J, Kvasnicka HM, Steinberg T, et al. Survival in primary (idiopathic) osteomyelofibrosis, so called agnogenic myeloid metaplasia. Leuk Lymphoma. 1992;6:389. 8. Lichtman MA. Idiopathic myelofibrosis (agnogenic myeloid metaplasia). In: Beutler E, Lichtman MA, Coller BS, et al, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:chap 95. http://med textfree.wordpress.com/2012/01/23/chapter-95. Accessed April 18, 2012. 9. Verstovsek S. Development of new therapies for myelofibrosis. Presented at Mayo Clinic, Scottsdale, Arizona, February 2009. 10. Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haemopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008. 11. Quintás-Cardama A, Kantarjian H, Cortes J, Verstovsek S. Janus kinase inhibitors for the treatment of myeloproliferative neoplasias and beyond. Nat Rev Drug Discov. 2011;10:127-140. 12. The JAK/STAT pathway: fact sheet. Novartis Oncology Web site. http://www.novartisoncology.com/ files/media/research/JAK-STAT%20Pathway%20 Fact%20Sheet_FINAL.pdf. Accessed April 1, 2012. 13. Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol. 2008;83:491-497. 14. Bacigalupo A, Soraru M, Dominietto A, et al. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant. 2010;45:458-463. 15. FDA approves Incyte’s Jakafi(TM) (ruxolitinib) for patients with myelofibrosis [press release]. Wilmington, DE: Incyte Corporation; November 16, 2011. http://investor.incyte.com/phoenix.zhtml?c=69764&p= irol-newsArticle&ID=1631201&highlight=. Accessed April 18, 2012. 16. Pazdur R. FDA approval for ruxolitinib phosphate. National Cancer Institute Web site. http://www.can cer.gov/cancertopics/druginfo/fda-ruxolitinibphosphate. Accessed April 4, 2012.

Did You Know? Prospective data from a recent study links the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) with the increased risk for renal cell carcinoma. The use of acetaminophen and aspirin was not associated with the risk for renal cell carcinoma. —Arch Intern Med. 2011;171:1487-1493.

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Prostate Cancer

Metastatic Castrate-Resistant Prostate Cancer— Treatment Overview By Shari L. Black, MAN, CNP Cleveland Clinic Foundation Taussig Cancer Center, Cleveland, Ohio

orldwide, there are approximately 500,000 men diagnosed with prostate cancer each year, and in those men prostate cancer is the third most common type of malignancy, surpassed only by cancer of the lung and stomach.1 Other than nonmelanoma skin cancer, prostate cancer is the most commonly diagnosed male cancer in the United States.2 There is disparity in risk of prostate cancer diagnosis between races. Prostate cancer is more common in African American males than it is in white American males.3 Higher mortality is associated with late detection.4 The prevalence of prostate-specific antigen (PSA) screening has caused a drastic reduction in the number of patients who have distant metastatic disease at the time of diagnosis.5 For those patients who present with metastatic disease, local definitive therapy is no longer an appropriate option. The standard of care is systemic therapy. Androgen deprivation therapy (ADT) remains the standard frontline treatment for metastatic prostate cancer. Patients can be treated with singleagent therapy gonadotropin-releasing hormone (GnRH) agonists, of which there are several options, or with combined androgen blockade, pairing GnRH with an antiandrogen such as bicalutamide. This therapy is widely effective; however, complications or side effects can include hot flushes, fractures, anemia, fatigue, loss of muscle mass and strength, and loss of libido, as well as changes in cognitive function. All of these side effects can potentially alter a patient’s quality of life (QOL), sometimes significantly. It is important for the practitioner to obtain a complete assessment of the side effects each patient is experiencing, as well as the consequences those effects have upon the patient’s QOL, and then to make clinical recommendations for palliative measures that can improve the patient’s QOL. The majority of hormone-dependent cancers become castrate-resistant in about 1 to 3 years, resuming growth despite ADT.6 In 1996, the US Food and Drug Administration (FDA) approved mitoxantrone, at 12 mg/m2, in combination with corticosteroids, typically prednisone 5 mg twice daily, for the treatment of patients with pain related to advanced hormone-refractory prostate cancer, now known as castrate-

May 2012 I VOL 5, NO 4

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Prostate Cancer resistant prostate cancer (CRPC). Prior to 2004, treatments for metastatic CRPC were palliative, without any proven survival benefit. Since that time, several therapies have emerged that have demonstrated a survival advantage. Docetaxel in combination with prednisone was approved by the FDA in

2004 for the treatment of metastatic castrate-resistant disease. The 3-arm TAX 327 study, which led to FDA approval, compared docetaxel at 75 mg/m2 administered every 3 weeks, docetaxel at 30 mg/m2 weekly for every 5 of 6 weeks, and mitoxantrone at 12 mg/m2 every 3 weeks, each with prednisone 5 mg twice daily. The original analysis,

done in August 2003, showed significantly better survival and response rates for pain, PSA, and QOL in the every-3week docetaxel with prednisone group when compared with the mitoxantrone with prednisone group. Median survival time was 18.9 months (95% confidence interval [CI], 17.0-21.2) in the every-3week docetaxel with prednisone arm,

17.4 months (95% CI, 15.7-19.0) in the weekly docetaxel and prednisone arm, and 16.5 months (95% CI, 14.4-18.6) in the mitoxantrone and prednisone arm.7 By March 2007, data on 310 additional deaths were obtained and updated. These data demonstrated a continued survival benefit for the Continued on page 28

After multiple failures,

single-agent response Indicated for the treatment of: • Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

sALCL: 86% ORR (95% CI: 77%-95%)

32%

40%

57%

29%

complete remission (95% CI: 23%-42%)1

partial remission (95% CI: 32%-49%)1

complete remission (95% CI: 44%-70%)1

partial remission (95% CI: 18%-41%)1

N = 102, 15-77 years (median: 31 years)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS™ (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

Important Safety Information BOXED WARNING Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

Warnings and Precautions: • Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly. • Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted. • Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

• Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS™ (brentuximab vedotin)–treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed. • Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy. • Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions: ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions: Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

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Prostate Cancer Metastatic Castrate-Resistant Prostate Cancer... every-3-week docetaxel with prednisone group. Median survival time was 19.2 months in the every-3-week docetaxel with prednisone arm, 17.8 months in the weekly docetaxel and prednisone arm, and 16.3 months in the mitoxantrone and prednisone arm (P = .004).8 The every-3-week docetaxel

with twice-daily prednisone chemotherapy regimen has remained a standard of care for first-line therapy for metastatic CRPC since its FDA approval. Cabazitaxel was approved by the FDA on June 17, 2010, in combination with prednisone for the treatment of patients with castrate-resistant metastat-

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage

ic prostate cancer previously treated with a docetaxel-containing regimen. This was the first therapy found to provide significant survival benefit in second-line metastatic castrate-resistant prostate cancer. A multinational phase 3 trial, known as TROPIC, included patients who were progressing either during or

ADCETRIS™ (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions

These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS™ (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Contraindications

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions. Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression. Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

Effect of other drugs on ADCETRIS CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Use in specific populations Pregnancy Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers It is not known whether brentuximab vedotin 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 ADCETRIS 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 ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased. ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

Continued from page 27

May 2012 I VOL 5, NO 4

General dosing information

Dose modification Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued. Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA

US/BVP/2011/0150b

after docetaxel (cumulative dose ≥225 mg/m2). The patients were randomized to receive 10 mg per day of prednisone with an every-3-week infusion of either mitoxantrone at 12 mg/m2 or cabazitaxel at 25 mg/m2. Analysis revealed that the patients receiving cabazitaxel and prednisone demonstrated a statistically significantly longer overall survival compared with those receiving mitoxantrone and prednisone (P <.0001). The median survival in the cabazitaxel and prednisone group was 15.1 months compared with 12.7 months in the mitoxantrone and prednisone group. Progression-free survival was also found to be statistically significantly in favor of the cabazitaxel and prednisone arm. The most frequent grade 3/4 toxicity was neutropenia observed in 81.7% of patients treated with cabazitaxel and prednisone and 58.0% of those treated with mitoxantrone and prednisone. Rates of febrile neutropenia were 7.5% and 1.3%, respectively.9 In clinical practice, one may want to consider either growth-factor support or a dose reduction of the cabazitaxel, or sometimes both, in efforts to minimize the degree of neutropenia and its sequelae. Sipuleucel-T, an autologous cellular immunotherapy, was approved by the FDA on April 29, 2010, to treat asymptomatic or minimally symptomatic metastatic CRPC. In a phase 3 study, patients were randomly assigned in a 2:1 ratio to receive either sipuleucel-T or placebo every 2 weeks, for a total of 3 infusions. Analysis showed that in the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (P = .03). This reduction represented a 4.1-month improvement in median survival. However, no significant effect on the time to objective disease progression was observed.10 The rationale for treating patients with sipuleucel-T can be a difficult concept for patients to understand, as it is typical for patients to have neither a drop in PSA nor any improvement in their imaging studies. Carefully detailed patient education is warranted to ensure that patients have an adequate understanding of the potential benefit they may receive from this therapy. Abiraterone acetate, in combination with prednisone, is the most recently approved therapy for metastatic CRPC patients who have received prior docetaxel therapy, obtaining FDA approval on April 28, 2011. In the clinical trial that led to FDA approval, patients were randomized in a 2:1 ratio to receive abiraterone acetate, 1000 mg once daily in combination with prednisone 5 mg twice daily or placebo in combination with prednisone 5 mg

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Prostate Cancer twice daily. At the preplanned interim analysis, there was a 35% reduction in the risk of death. Overall survival was 14.8 months for the abiraterone acetate plus prednisone arm in comparison to 10.9 months in the placebo plus prednisone arm (P <.001).11 Abiraterone acetate has particular appeal to patients since it is administered orally. It should be taken on an empty stomach, and is generally well tolerated. Side effects that can be associated with elevated mineralocorticoid levels, due to CYP17 inhibition, include fluid retention/ edema, hypokalemia, and hypertension. Liver function tests should be monitored routinely. In addition to the aforementioned antitumor therapies, there are therapies available to decrease the risk of skeletal events, which are prevalent in this patient population. Zoledronic acid, an intravenous bisphosphonate, is used to reduce and delay bone complications due to bone metastases from solid tumors, including metastatic CRPC. As it is renally excreted, zoledronic acid requires dose adjustment in accordance with renal function. Patients with a normal creatinine clearance receive 4 mg intravenously over at least 15 minutes. Side effects can include flu-like symptoms, including arthralgias, myalgias, and fever.

Recent advancements in therapy have not only broadened the options for patients in this setting but have, more importantly,

important that patients who receive this therapy take a daily calcium supplement. Osteonecrosis of the jaw (ONJ), a rare complication, can occur with either zoledronic acid or denosumab. About 94% of published cases of ONJ are patients with multiple myeloma or metastatic carcinoma to the skeleton who are receiving IV nitrogen-containing bisphosphonates. The most important predisposing factors for the

development of bisphosphonate-associated ONJ are the type and total dose of bisphosphonate and history of trauma, dental surgery, or dental infection.13 It is reasonable to require patients on these therapies to contact their treating practitionerâ&#x20AC;&#x2122;s office prior to dental appointments. Caring for the patient with metastatic CRPC can be challenging; however, recent advancements in therapy have not only broadened the options for patients

in this setting but have, more importantly, improved survival. Ongoing studies are investigating new treatments and include research in the areas of androgen manipulation, chemotherapy, and immunotherapy, to mention a few. Early results appear promising and potentially will not only expand the existing treatment arsenal but may also show survival benefit for patients who live with the devastating diagnosis of metastatic CRPC. â&#x2014;? Continued on page 39

Pushing Your Limits

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improved survival.

Denosumab, a monoclonal antibody, was FDA approved on November 18, 2010, for the prevention of skeletalrelated events in patients with bone metastases from solid tumors. A phase 3 trial was conducted, in which patients with metastatic CRPC were randomized 1:1 to receive either 120 mg subcutaneous denosumab plus intravenous placebo or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks. Median time to first on-study skeletal-related event was 20.7 months with denosu mab compared with 17.1 months with zoledronic acid (P = .008).12 The most common adverse reactions for patients are fatigue/asthenia, hypophosphatemia, and nausea. In addition, severe hypocalcemia can occur. It is

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Third Annual Navigation and Survivorship Conference PRELIMINARY AGENDA* Friday, September 14 12:45 – 1:00pm

1:00 – 2:00pm & 2:15 – 3:15pm

3:15 – 3:30pm 3:30 – 5:00pm

5:00 – 6:00pm 6:00 – 8:00pm

Welcome Conference Co-Chairs: Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS Pre-Conference Workshops Beginners Track • Core Principles of Navigation Nicole Messier, BSN, RN Pamela J. Vlahakis, RN, MSN, CBCN Members • Grant Writing, Research, and Getting Published Linda Fleisher, PhD, MPH Elaine Sein, RN, BSN, OCN, CBCN • Panel Discussion: Providing Optimal Community Outreach – Lay and Community Jean B. Sellers, RN, MSN, OCN (Moderator) Leah Leilani Beck, BS Jessica Denton, MSW • Implementing a Survivorship Program/Clinic Cindy Waddington, RN, MSN, AOCN Break Administrators Track • Administering a Navigation Program Elizabeth Whitley, PhD, RN Bonnie J. Miller, RN, BSN, OCN, FAAMA Navigators Track • How Do Case Managers and Navigators Interface? Nancy Skinner, RN-BC, CCM FREE TIME Welcome Reception/Posters in the Exhibit Hall

Saturday, September 15 7:30 – 8:30am 8:30 – 8:45am

Breakfast Symposium/Product Theater Welcome & Introductions Conference Co-Chairs 8:45 – 9:45am General Session 1: Navigation Update: 2012 Current Regulations – Navigation & Survivorship Care Plan Linda Ferris, PhD 9:45 – 10:00am Break 10:00 – 11:30amDisease-Site–Specific Breakouts Stand-Alone Sessions • Breast Cancer Navigation Mary Rooney, RN, BSN, OCN • Lung Cancer Navigation & Smoking Cessation Pamela Matten, RN, BSN, OCN • GI Cancer Navigation Coralyn Martinez, MSN, RN, OCN

•

Colorectal Cancer Navigation Maura Kadan, RN, MSN, OCN • GYN Cancer Navigation Robin Atkinson, RN, BSN, OCN • Prostate Cancer Navigation Juli Aistars, RN, APN Rapid Fire Sessions with Panel • Head, Neck, & Neuro Navigation Heather Stern, RN, BSN, CNOR, OCN And • Hematology/Oncology Tina Scherer, RN, MSN, OCN Administrators Session • The Role of the Administrator Lisa Shalkowski, RN, BSN, MSM 11:45 – 1:00pm Lunch in the Exhibit Hall 1:15 – 2:15pm Advocacy Keynote Speaker TBD 2:15 – 3:15pm General Session 2: Best Practices in Survivorship Care Rehabilitation (Importance of implementing cancer rehab on day of diagnosis)

3:15 – 4:15pm

4:15 – 6:15pm 6:15pm

Julie Silver, MD General Session 3: Plenary Session Financial and Legal Issues for Our Cancer Patients David S. Landay, Esq. Poster Award Reception in the Exhibit Hall Pamela Matten, RN, BSN, OCN Conclusion of Day – Networking FREE TIME

Sunday, September 16 7:30 – 8:30am 8:30 – 9:30am

Breakfast Symposium/Product Theater General Session 4: Navigation in the Age of Personalized Cancer Care Sharon Gentry, RN, MSN, AOCN, CBCN Lillie D. Shockney, RN, BS, MAS 9:30 – 10:30am General Session 5: Best Practices in Addressing Health Inequities Lauren Kelley, MSW, MPA Adrienne Lofton, RN 10:30 – 10:45am Break 10:45 – 12:15pm Practice Setting – Panel Discussion with Moderator • Academic Bonnie J. Miller, RN, BSN, OCN, FAAMA • Community Hospital–Based Karyl Blaseg, RN, MSN, OCN • Office-Based Roxanne Parker, MSN 12:15 – 1:15pm Lunch in the Exhibit Hall 1:30 – 2:30pm Clinical Survivorship Guidance Mandi Pratt-Chapman, MA 2:30 – 2:45pm Conclusion/Final Remarks Conference Co-Chairs *Preliminary agenda, subject to change.

www.regonline.com/aonn2012

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September 14-16, 2012 Phoenix, Arizona Arizona Grand

CONFERENCE REGISTRATION Register online: www.regonline.com/aonn2012 Current Members New Members Nonmembers

$295 $345 $425*

*Register by July 15 and save $100 off full registration of $525.

TARGET AUDIENCE

CONFERENCE CO-CHAIRS Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Depts of Surgery and Oncology Administrative Director, Johns Hopkins Breast Clinical Programs Administrative Director, Johns Hopkins Cancer Survivorship Programs Associate Professor, JHU School of Medicine, Depts of Surgery & Gynecology and Obstetrics Associate Professor, JHU School of Nursing Baltimore, MD

FACULTY* Juli Aistars, RN, APN Robin Atkinson, RN, BSN, OCN

Roxanne Parker, MSN

Leah Leilani Beck, BS

Mary Rooney, RN, BSN, OCN

Karyl Blaseg, RN, MSN, OCN

Tina Scherer, RN, MSN, OCN

Jessica Denton, MSW

Elaine Sein, RN, BSN, OCN, CBCN

Linda Ferris, PhD

Jean B. Sellers, RN, MSN, OCN

Linda Fleisher, PhD, MPH

Lisa Shalkowski, RN, BSN, MSM

Maura Kadan, RN, MSN, OCN

Julie Silver, MD

Lauren Kelley, MSW, MPA

Nancy Skinner, RN-BC, CCM

David S. Landay, Esq.

Heather Stern, RN, BSN, CNOR, OCN

Adrienne Lofton, RN Coralyn Martinez, MSN, RN, OCN Pamela Matten, RN, BSN, OCN Nicole Messier, BSN, RN

Bonnie J. Miller, RN, BSN, OCN, FAAMA

AONN’s Third Annual Conference is the only meeting that gives you access to decision-makers and key practitioners involved in oncology navigation and survivorship. If your company provides any of the following services/products for the oncology healthcare community, this is the meeting for you. This educational initiative is directed toward oncology nurse navigators, patient navigators, and social workers. • • • • •

Pharmaceutical/Biotech Genetic Laboratory Services Navigation Software Patient Advocacy Training

• • • • •

Patient Access Reimbursement Publishers Education Certification

CONTINUING EDUCATION INFORMATION Goal AONN’s Third Annual Navigation and Survivorship Conference will advance the role of navigation and survivorship in cancer care to ultimately improve the quality of patient care. Objectives • Discuss the evolution of the role of navigation in healthcare • Assess strategies for navigating diverse patient populations by cancer type and environmental factors • Define methods for providing patient support and guidance in the age of personalized cancer care • Evaluate best practices regarding survivorship and psychosocial care

CALL FOR ABSTRACTS This is an opportunity to share research, programs, and results with your colleagues. Submit your abstract via e-mail to Liz@aonnonline.org. Abstract Deadline: August 1, 2012

Pamela J. Vlahakis, RN, MSN, CBCN Cindy Waddington, RN, MSN, AOCN Elizabeth Whitley, PhD, RN *For full information visit www.aonnonline.org

CONFERENCE OVERVIEW AONN’s Third Annual Conference will continue to advance the navigation profession by expanding the scope of educational sessions, networking opportunities, and poster presentations. In addition, this year’s conference will address the evolving challenges of program improvement, the role of personalized medicine, and implementing best practices in navigation, survivorship, and psychosocial care.

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

REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.25 contact hours.

SOCIAL WORK DESIGNATION This activity is pending approval from the National Association of Social Workers. Contact hours for this continuing social worker education activity have been submitted to the National Association of Social Workers.

www.regonline.com/aonn2012

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Multiple Myeloma

Managing Bortezomib Therapy in Patients With Multiple Myeloma By Linda Caldwell, RN, MS, AEP New York, LLC, Millbrook, New York; Cass Hammond, RN, MSN, CRNP, ATD Partners, LLC, Millbrook, New York; Kathleen Colson, RN, BSN, BS, Dana-Farber Cancer Institute, Boston, Massachusetts

ultiple myeloma (MM) is a B-cell neoplasm originating from the plasma cell. The American Cancer Society estimates that in 2012 there will be 21,700 new cases and 10,710 deaths in the United States due to MM, making it the third most common hematologic malignancy.1 The median age at diagnosis is 69, and it is more prevalent in men versus women and in blacks versus whites.2 Using data generated between 2002 and 2008, the 5-year overall survival rate in myeloma is approximately 41%, a number that is steadily increasing, due primarily to the newer treatment regimens currently being used.2 Although highly treatable, there is still no cure for MM and almost all patients become chemotherapy resistant at some point during treatment. The former gold standard treatment for MM, melphalan and prednisone, was introduced more than 30 years ago. Since then, newer immunomodulatory agents (IMiDs) and a proteasome inhibitor have been studied in numerous clinical trials and approved by the US Food and Drug Administration (FDA) in an attempt to offer patients newer, more effective treatment options and to overcome the multidrug resistance that is common among MM patients.3 Other agents for treating MM, including new proteasome inhibitors and IMiDs, are currently in clinical trials. The treatment landscape in MM is changing rapidly. Helping patients manage the side effects of these therapies and supporting their adherence to therapy can potentially increase survival rates and promote a better quality of life. Bortezomib Velcade (bortezomib) for injection (Millennium, The Takeda Oncology Company) is a proteasome inhibitor indicated for the treatment of patients with MM and for patients with mantle cell lymphoma who have received at least 1 prior therapy.4 The recommended starting dose of bortezomib is 1.3 mg/m2, administered intravenously (IV) over 3 to 5 seconds at a concentration of 1 mg/mL, or subcutaneously (SC) at a concentration of 2.5 mg/mL.4 Additional details about the new SC indication will be discussed in a later section of this article. Consult the full prescribing information at www. velcade.com for detailed dosage and administration guidelines.

May 2012 I VOL 5, NO 4

The most commonly reported side effects (incidence ≥30%) in clinical trials include asthenic conditions (fatigue, malaise, weakness), diarrhea, nausea, constipation, peripheral neuropathy (PN), vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia.4 We discuss selected side effects in this article, as well as some of the newer data regarding administration and the implications for nursing practice. Peripheral Neuropathy PN can be either disease or treatment related, and bortezomib-induced peripheral neuropathy (BIPN) is a frequent cause of either dose reduction or changes in the treatment plan.5 In the pivotal trial of previously untreated MM patients using bortezomib in combination with melphalan and prednisone, 47% developed some degree of sensory PN (13% grade 3, 1% grade 4).4 However, severe sensory and motor PNs have also been reported. Sensory nerves affected by neuropathy include small fibers, which manifest as altered pain, temperature, and sensation, and large fibers that can result in loss of position sense (proprioception), and ability to feel vibrations, touch, or pressure.6 The underlying mechanism for development of BIPN is not known, but accumulation of bortezomib in the dorsal root ganglia cells, mitochondrial-mediated dysregulation of Ca2+ homeostasis, and

dysregulation of neurotrophins have been implicated.5 A recent article in the Journal of the Peripheral Nervous System, the official journal of the Peripheral Nerve Society, notes that preexisting neuropathy is not an uncommon finding in oncology patients.7 For patients with newly diagnosed MM, the incidence of preexisting PN at diagnosis has been estimated from less than 1% to a high of 13%.8 Bruna and colleagues evaluated the role of preexisting neuropathy induced by vincristine or bortezomib as a risk factor for development of more severe bortezomib-induced neuropathy in a mouse model. They reported that the presence of a severe neuropathy prior to treatment with bortezomib resulted in a more marked involvement of peripheral nerves.7 Richardson and colleagues assessed PN in two phase 2 studies (256 patients total) with relapsed and/or refractory MM treated with IV bortezomib 1.0 or 1.3 mg/m2.9 Patients were evaluated for PN at baseline, during, and after the study using both the Functional Assessment of Cancer Therapy Scale/Gynecologic Oncology GroupNeurotoxicity (FACT/GOG-Ntx) questionnaire and neurologic examination. They found that at baseline, 81% of 239 patients had PN by questionnaire and 203 of 244 patients (83%) had PN by neurologic exam. Not surprisingly, the incidence of grade ≥3 PN during the study was higher among patients with

baseline neuropathy compared with those patients without (14% vs 4%, respectively). The BIPN seen in this trial appeared to be a cumulative, dose-related effect with increased incidence during the first 5 treatment cycles. For 71% of the patients with clinically significant neuropathy, there was resolution or improvement of symptoms after dose modification or completion of therapy.9

Managing PN Because of the increased incidence of PN in MM patients treated with bortezomib, they should be carefully assessed for preexisting neuropathies prior to beginning therapy and periodically during treatment. Patients who are diagnosed with PN prior to starting bortezomib therapy should receive a careful risk-benefit evaluation. In addition, starting bortezomib SC may be an option for patients with preexisting or at high risk for developing PN.4 When assessing patients, pay particular attention to those patients with conditions such as diabetes or autoimmune disorders (rheumatoid arthritis or lupus), chronic kidney disease, infections, low levels of vitamin B12, poor circulation, heavy alcohol use, exposure to environmental workplace toxins, or hypothyroidism, which can place patients at higher risk for developing neuropathies.10 Patients receiving bortezomib may complain of feeling cold, a burning sensation, and/or tingling/numbness in their extremities, the classic stocking

Table 1 Recommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy4 Severity of Peripheral Neuropathy Signs and Symptoms*

Modification of Dose and Regimen

Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function

No action

Grade 1 with pain or grade 2 (moderate symptoms; limiting Reduce bortezomib dose to 1 mg/m2 instrumental ADL)† Grade 2 with pain or grade 3 (severe symptoms; limiting self-care ADL)‡

Withhold bortezomib therapy until toxicity resolves; when toxicity resolves, reinitiate with a reduced dose of bortezomib at 0.7 mg/m2 once per week

Grade 4 (life-threatening consequences; urgent intervention Discontinue bortezomib indicated) *Grading based on National Cancer Institute Common Terminology Criteria for Adverse Events; v 4.0. † Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc. ‡ Self-care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Abbreviation: ADL, activities of daily living.

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Multiple Myeloma and glove distribution.11 Dose modification guidelines found in the prescribing information should be followed when patients report or are found to have grade 2 neuropathy or grade 1 associated with pain, as listed in Table 1. Many different grading scales are available to diagnose PN, but no standard method for administration or interpretation of the scales has been developed.12 One example of testing uses Semmes-Weinstein monofilaments. With the patient’s eyes closed, a fine filament is applied to each hand and foot, and the patient is instructed to note when the filament is felt. In the Romberg test, the patient stands still with his/her heels together and eyes closed. If the patient loses his/her balance, the test is positive for loss of proprioception. Another simple test can also be performed using a sharp safety pin or similar object, alternating between the sharp and dull ends, asking the patient to report the sensation. There is no standard treatment for BIPN, and patients should be assessed individually for appropriate potential therapy. In addition to bortezomib dose reduction or schedule modification, BIPN can be treated with antidepressants, anticonvulsants, amino acids, lidocaine patches, and narcotics, albeit with limited response and potential side effects such as sedation, dry mouth, and constipation.12 Nonpharmacologic approaches include massage, physical and occupational therapy, and more recently, acupuncture. A recent case report in the literature describes a 48-year-old African American man with MM who was successfully treated with bortezomib and stem cell transplantation but developed debilitating PN during his third cycle of bortezomib and was resistant to both gabapentin and morphine sulfate treatment. He was successfully treated with 14 acupuncture sessions, was able to return to work, and remained pain free and asymptomatic 1 year later.13 Nurses have a unique opportunity to assess, educate, and follow up with patients regarding PN. Patient education safety checklists should include reviewing items such as ensuring the water heater temperature is adjusted according to their ability to feel hot and cold; use of rubber gloves for dishwashing and heavyduty pot holders for handling pans; wear-

Table 2 Dose Modifications During Cycles of Combination Bortezomib, Melphalan, and Prednisone Therapy4 Toxicity

Dose Modification or Delay

Hematologic toxicity during a cycle: If prolonged grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle

Consider reduction of the melphalan dose by 25% in the next cycle

If platelet count is not above 30 × 109/L or ANC is not above 0.75 × 109/L on a bortezomib dosing day (other than day 1)

Bortezomib dose should be withheld

If several bortezomib doses in consecutive cycles are withheld due to toxicity

Bortezomib dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)

Grade 3 or higher nonhematologic toxicities

Bortezomib therapy should be withheld until symptoms of the toxicity have resolved to grade 1 or baseline; then bortezomib may be reinitiated with 1 dose-level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)

Abbreviation: ANC, absolute neutrophil count. For information concerning melphalan and prednisone, see manufacturers’ prescribing information.

ing cotton socks and gloves in cold temperatures; and avoiding clutter in their homes, including slippery area rugs and bath mats.14-16 Ongoing assessment for PN should be done on a regular basis and include such items as asking patients about stocking and glove numbness, tingling, burning, sensitivity to touch, pain, and interference with their activities of daily living. Nurses should observe the patient’s gait to note any difficulty related to altered proprioception or numbness in the feet and check his or her ability to button, zipper, or tie. If PN is confirmed, nurses should counsel the patient about his or her ability to drive or operate machinery safely and take action with family members as appropriate. Thrombocytopenia Thrombocytopenia (platelet count <100 × 109/L) associated with bortezomib therapy is thought to be due to a reversible effect on megakaryocytic function rather than a direct cytotoxic effect on megakaryocytes or their progenitors.17 Platelet budding from megakaryocytes is regulated in part by the activity of nuclear factor κB (NF-κB), and the proteasome inhibition seen with bortezomib prevents activation of NF-κB. Further, the cyclic, transient thrombocytopenia seen with bortezomib administration is predictable when compared with cyto-

toxic chemotherapies such as alkylating agents. Lonial and colleagues assessed patients from 2 studies using bortezomib: the Study of Uncontrolled Multiple Myeloma Managed With Proteasome Inhibition Therapy (SUMMIT) and Clinical Response and Efficacy Study of Bortezomib in the Treatment of Relapsing Multiple Myeloma (CREST). They found that significant predictors of grade 3/4 thrombocytopenia included low baseline platelet count, high baseline M-protein concentration, and the number of previous treatments. Further analysis revealed that the thrombocytopenia seen with bortezomib is transient; lower platelet counts are seen during the first 10 days of treatment, with recovery during the 10day rest period. Most importantly, overall response rates to bortezomib did not appear to be impacted by the baseline platelet count.17

Managing Thrombocytopenia The pretreatment nursing assessment of MM patients should include a thorough patient history for any previous bleeding from mucosal or other sites (eg, gastrointestinal [GI]), history of bruising, or prolonged bleeding following injury or surgery. A neurologic assessment should also be performed to monitor for symptoms of intracranial bleeding.18 Nurses should discuss with their

patients that the thrombocytopenia associated with bortezomib therapy is an expected, cyclical, transient, and manageable side effect of therapy. Reviewing thrombocytopenic precautions is essential, and if your institution or practice does not have a specific teaching sheet on this topic, an excellent version is available free from the National Institutes of Health: Patient Education: Understanding Your Complete Blood Count.19 Some important points to stress when teaching thrombocytopenic precautions include using a soft toothbrush and electric shavers; avoid enemas, rectal thermometers, suppositories, and tampons; blow the nose gently; avoid eating irritating foods such as popcorn or apple peels; avoid using knives or other sharp instruments; and a review of aspirin-containing medications such as pain relievers and certain prescription medications. (The patient guide referenced above contains a list of common aspirin-containing products.) The manufacturer’s recommended dose-modification guidelines for bortezomib-associated hematologic toxicities are listed in Table 2. GI Events and Management The incidence of grade 3/4 selected GI side effects among previously untreated MM patients receiving bortezomib-melContinued on page 34

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Multiple Myeloma Managing Bortezomib Therapy in Patients... phalan-dexamethasone in a prospective randomized trial was 33% to 48%.4 Nausea (48%), diarrhea (46%), constipation (37%), and vomiting (33%) were the most common side effects observed in this group of patients.4 Since the median age of newly diagnosed MM patients is 62 years, they may have preexisting GI conditions that could be exacerbated by the combination of bortezomib-melphalan-prednisone.20 Patients should be educated about the potential GI side effects prior to beginning bortezomib therapy and appropriate interventions reviewed with them (eg, use of antiemetics, laxatives, antidiarrheals, fluid intake, and dietary restrictions). Herpes Virus Infection (Shingles) and Management Because patients with MM are more susceptible to infections, it is important to note that in the randomized trials of patients with previously untreated and relapsed MM, the reactivation of herpes simplex virus was more common in patients treated with

Figure. SC Injections Site Rotation.

May 2012 I VOL 5, NO 4

Continued from page 33

bortezomib (13%) than in the control groups (4%-5%).4 Patients who received prophylactic antiviral therapy were less likely to experience reactivation of the herpes virus (3%) than those who did not receive the antiviral treatment (17%).4 It is therefore recommended that MM patients receiving bortezomib should also receive prophylactic antiviral therapy to avoid virus reactivation and/or other more serious complications.4,21

(38% vs 53%; P = .044). Injection site reactions consisted mainly of reversible redness and rarely resulted in reporting of an adverse event. In addition, in the SC group there were fewer dose reductions and discontinuations due to adverse events. The investigators suggested that in addition to reducing bortezomib-related PN, the increased patient convenience and similar efficacy of SC dosing may be a consideration for future studies of bortezomib maintenance therapy.23

SC Route of Administration Now Approved On January 23, 2012, the FDA approved bortezomib for SC administration in patients with MM and relapsed mantle cell lymphoma.22 This approval was based on a pivotal study by Moreau and colleagues,23 who conducted a randomized, phase 3, noninferiority study of 222 (221 evaluable) patients in 53 sites across 10 countries in Europe, Asia, and South America. Patients with relapsed MM who had received 1 to 3 previous therapies were randomly assigned to receive up to eight 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 by either SC injection (n = 147) or IV infusion (n = 74). The primary objective was to show noninferiority of SC versus IV bortezomib in terms of overall response rate (complete response + partial response; ORR) after 4 cycles in all patients with measurable disease who received 1 or more doses of drug. Noninferiority was defined as retaining 60% of the IV treatment effect. SC injections of 2.5 mg/mL (3.5 mg bortezomib reconstituted with 1.4 mL normal [0.9%] saline to limit the injection volume) were given on a rotating basis in the thighs or abdomen. Alternating sites between right and left abdomen, upper and lower quadrant, or right and left thigh (proximal and distal) was the protocol recommendation (Figure). IV injections were given at a concentration of 1 mg/mL (3.5 mg in 3.5 mL normal saline) as a 3-5 second IV push. Patients received a median of 8 cycles, and the ORR after 4 cycles was 42% in both treatment arms (P = .002), thus demonstrating the noninferiority hypothesis in ORR. There were no significant differences in the time to progression (10.4 vs 9.4 months) and 1-year overall survival (72.6 % vs 76.7%) with SC versus IV bortezomib, respectively. Grade 3 or worse adverse events were noted in 84 patients (57%) in the SC group versus 52 (70%) in the IV group, with the most common being thrombocytopenia (13% vs 19%), neutropenia (18% vs 18%), and anemia (12% vs 8%), respectively. Most significantly, the incidence of PN of any grade was less common with SC versus IV administration

Reconstitution of Bortezomib for SC and IV Use It is important to remember that the reconstitution of bortezomib for SC use is different from that for IV use, and caution should be used when calculating the volume to be administered. • The reconstituted concentration of bortezomib for SC administration (2.5 mg/mL) is greater than that for IV administration (1 mg/mL) • For SC dosing, add 1.4 mL 0.9% sodium chloride to make a final concentration of 2.5 mg/mL • For IV dosing, add 3.5 mL 0.9% sodium chloride to make a final concentration of 1 mg/mL • The recommended starting dose is 1.3 mg/m2 for both routes of administration4,24 • To calculate the total volume of reconstituted bortezomib to use, determine the patient’s body surface area (BSA) in square meters (m2) and use the following equations: IV Administration (1 mg/mL concentration) Bortezomib dose (mg/m2) × BSA 1 mg/mL SC Administration (2.5 mg/mL concentration) Bortezomib dose (mg/m2) × BSA 2.5 mg/mL Conclusion Through numerous trials and thousands of patient experiences, bortezomib has been shown to be a safe, effective treatment for patients with MM. Since patient adherence to treatment can significantly impact response rates, oncology nurses can have a positive effect on this important aspect of treatment by effectively and appropriately educating patients about managing the expected side effects of bortezomib therapy. As was effectively demonstrated by Moreau and colleagues,23 the use of SC bortezomib is a potential alternative to IV administration, especially for patients at risk of

developing side effects and/or those with poor venous access. ● References 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. http://www.cancer.org/Research/CancerFactsFigures/Can cerFactsFigures/cancer-facts-figures-2012. Accessed May 16, 2012. 2. Surveillance, Epidemiology, and End Results (SEER). SEER stat fact sheets: myeloma. http://seer.cancer.gov/ statfacts/html/mulmy.html#incidence-mortality. Accessed May 16, 2012. 3. Rajkumar SV. Multiple myeloma. Curr Probl Cancer. 2009;33:7-64. 4. Velcade (bortezomib) for Injection [package insert]. Cambridge, MA: Millennium: The Takeda Oncology Company; 2012. 5. Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood. 2008;112:1593-1599. 6. Wolfe GI, Trivedi JR. Painful peripheral neuropathy and its nonsurgical treatment. Muscle Nerve. 2004;30:3-19. 7. Bruna J, Alé A, Velasco R, et al. Evaluation of preexisting neuropathy and bortezomib retreatment as risk factors to develop severe neuropathy in a mouse model. J Peripher Nerv Syst. 2011;16:199-212. 8. Tariman JD, Love G, McCullagh E, et al; IMF Nurse Leadership Board. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):29-36. 9. Richardson PG, Briemberg H, Jagannath S, et al. Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol. 2006;24:3113-3120. 10. National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet. www. ninds.nih.gov/disorders/peripheralneuropathy. Updated August 10, 2011. Accessed November 14, 2011. 11. Richards T. Managing the side effects of lenalidomide and bortezomib. Community Oncol. 2009:56-57. www. communityoncology.net/co/journal/0602.html. Accessed October 28, 2011. 12. Wickham R. Chemotherapy-induced peripheral neuropathy: a review and implications for oncology nursing practice. Clin J Oncol Nurs. 2007;11:361-376. 13. Bao T, Zhang R, Badros A, et al. Acupuncture treatment for bortezomib-induced peripheral neuropathy: a case report. Pain Res Treat. 2011. www.ncbi.nlm.nih. gov/pmc/articles/PMC3199913/ ?tool=pubmed. Accessed November 28, 2011. 14. Almadrones LA, Arcot R. Patient guide to peripheral neuropathy. Oncol Nurs Forum. 1999;26:1359-1360. 15. Sorich J, Taubes B, Wagner A, et al. Oxaliplatin: practical guidelines for administration. Clin J Oncol Nurs. 2004;8:251-256. 16. Sweeney CW. Understanding peripheral neuropathy in patients with cancer: background and patient assessment. Clin J Oncol Nurs. 2002;6:163-166. 17. Lonial S, Waller EK, Richardson PG, et al; SUMMIT/CREST Investigators. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood. 2005;106: 3777-3784. 18. Miceli T, Colson K, Gavino M, et al. Myelosuppression associated with novel therapies in patients with multiple myeloma: a consensus statement of the IMF Nurse Leadership Board. Clin J Onc Nurs. 2008;12(3 suppl):13-20. 19. National Institutes of Health Clinical Center. Patient Education: Understanding Your Complete Blood Count. www.cc.nih.gov/ccc/patient_education/pepubs/cbc 97.pdf. Published November 2008. Accessed November 21, 2011. 20. Multiple Myeloma Research Foundation. Newly diagnosed patients: what is multiple myeloma. www.themmrf.org/living-with-multiple-myeloma/newlydiagnosed-patients/what-is-multiple-myeloma/. Accessed November 21, 2011. 21. Taniguchi D, Takahara O, Takasaki Y, et al. Fatal cytomegalovirus pneumonia and associated herpes virus infection in a relapsed/refractory multiple myeloma patient treated with bortezomib plus dexamethasone. Case Rep Oncol. 2009;2:140-143. 22. FDA Approves Subcutaneous Administration of VELCADE® In All Approved Indications. Businesswire; January 23, 2012. www.bioportfolio.com/ news/article/926407/Fda-Approves-SubcutaneousAdministration-Of-Velcade-In-All-ApprovedIndications.html. Accessed January 25, 2012. 23. 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. 24. Dear Healthcare Professional letter. Velcade Web site. http://www.velcade.com/Files/PDFs/V-12-0047_ SC_Patient_Announcement_Letter_FINAL.pdf. Accessed January 30, 2012.

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Multiple Myeloma

Five-Year Follow-up of VISTA Trial Confirms Long-term Survival Benefit for BortezomibContaining Regimen Up Front By Alice Goodman

t 5 years of follow-up of the VISTA trial, the combination of bortezomib plus melphalan and prednisone (VMP) demonstrated a survival advantage over MP alone as up-front treatment of patients with multiple myeloma who were not transplant candidates. At a median followup of 60.1 months, the absolute difference in overall survival (OS) between the treatment arms was 13 months, according to final results presented at the 53rd Annual Meeting of the American Society of Hematology. Patients assigned to the MP arm who took bortezomib at disease progression failed to achieve the survival advantage of those who received bortezomib as part of up-front treatment. “The 5-year results of VISTA confirm the significant survival benefit of

VMP versus MP…. These data demonstrate that it is important to provide the best induction therapy—VMP— up front,” stated Jesús San Miguel, MD, Universitario de Salamanca, Salamanca, Spain.

The benefit of up-front VMP was maintained across all prespecified subgroups. The study population included 682 patients, with a median age of 71 years; 30% were aged 75 and older, and one-third had advanced disease. Less than 5% of patients in each arm were lost to follow-up.

Median OS was 56 months with VMP versus 43 months with MP (P = .0004). The benefit of up-front VMP was maintained across all prespecified subgroups, including patients with high-risk cytogenetics. Time to next treatment was significantly longer in VMP-treated versus MP-treated patients (median of 27 months vs 19.2 months, respectively; P <.0001), and treatment-free interval was also longer (16.6 months vs 8.3 months, respectively; P <.0001). A similar percentage of patients in each group received subsequent therapies at relapse, with the exception of bortezomib: 22% in the VMP group versus 43% of patients in the MP group were treated with bortezomib at relapse. Among patients who required subsequent anticancer therapies, OS was significantly longer in patients treated

with VMP up front: median 55.7 months versus 46.4 months, respectively (P = .0162). Regarding the safety of VMP, San Miguel said, “We saw no emerging safety signal for an increase in secondary primary malignancies [SPMs]. I think these data on SPMs are solid, with the rate as expected in the general population or even lower. VMP is completely safe.” Hematologic SPMs were reported in 3 patients (1%) in each group over the 5-year follow-up; nonhematologic SPMs were found in 16 patients in the VMP group and 10 in the MP group. The expected rate of SPMs in the general population is 1.9 per 100 patientyears; the rate in the VMP arm was lower than expected at 1.6 per 100 patient-years, and the rate in the MP arm was 1.3. ●

Lymphomas

Retreatment With Rituximab as Effective as Maintenance Rituximab but Less Costly in Indolent Follicular Lymphoma

he best strategy for management of low-tumor-burden follicular lymphoma (FL) following response to induction therapy is controversial. The phase 3 RESORT study compared maintenance rituximab therapy versus rituximab retreatment at disease progression, and results suggest that retreatment is the preferred approach. The study was presented at the 53rd Annual Meeting of the American Society of Hematology. The strategies achieved a similar time to treatment failure (TTTF) in this FL patient population, with no difference in quality of life or anxiety at 12 months. Both strategies appear to delay time to chemotherapy compared with historical controls. Although maintenance therapy prolonged the time until cytotoxic therapy was needed, almost 4 times more rituximab was used, making maintenance therapy by far the more costly approach. “Given the excellent outcome with retreatment, the toxicity profile, the lack of quality of life difference [between the

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“The retreatment strategy is less costly, and we believe it is the preferred option to help patients with low-tumor-burden FL manage their disease.” —Brad Kahl, MD 2 approaches], and the required doses of rituximab, retreatment is our recommended strategy if electing to use rituximab,” stated lead investigator Brad Kahl, MD, University of Wisconsin, Madison. “The retreatment strategy is less costly, and we believe it is the preferred option to help patients with lowtumor-burden FL manage their disease.” Kahl said that the study did not determine which strategy is best for improving overall survival. Such a study would have to compare watch and wait versus retreatment versus maintenance therapy. RESORT enrolled 384 patients with FL histology; of these, 274 (71%) responded to induction therapy with rituximab and were randomized to

retreatment (n = 134) or maintenance rituximab (n = 140). Median TTTF (primary end point) was 3.6 years with retreatment versus 3.9 years with maintenance rituximab. At 3 years of follow-up, only 5% of patients in the maintenance arm required cytotoxic chemotherapy versus 14% of patients in the retreatment arm. However, patients assigned to retreatment used a mean of 4.5 doses of rituximab over that time, while those assigned to maintenance rituximab used a mean of about 16 doses. Fewer than 5% of patients in the trial experienced severe hematologic or nonhematologic toxicities. No difference between the arms was observed

in deaths and second cancers. There was 1 adverse event leading to discontinuation in the retreatment arm and 7 in the maintenance arm. At 12 months’ follow-up after randomization, no difference was found in health-related quality of life or burden of stress. Kahl said that the investigators were concerned that patients assigned to retreatment might experience more anxiety than those in the maintenance arm because they knew they had cancer and weren’t being treated, but this concern was not borne out. Commenting on this study, Jane Winter, MD, moderator of the press conference where RESORT was discussed, and Professor at Northwestern University Feinberg School of Medicine, Chicago, said: “If we can limit the frequency of treatment, or reduce the need for chemotherapy and still maintain good outcomes, we can reduce some of the burdens on both the patients and the healthcare community.” ● —AG

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Conference News:

Payer Trends in Oncology: Challenges and Solutions Putting Patients First Remains a Key Component By Caroline Helwick

he need to optimize the treatment of patients with cancer while using healthcare resources wisely—in other words, providing “value-based cancer care”—is not a topic of debate, but how to achieve this pressing goal is far from clear. In a panel discussion during the Association for Value-Based Cancer Care’s Second Annual Conference, held in Houston, Texas, strategists from the payer side of the issue discussed the current trends and the challenges they are facing. Burt Zweigenhaft, BS, President and Chief Executive Officer of OncoMed, Great Neck, New York, who led the discussion, noted that the rising cost of cancer care is clearly the trigger point for change. “The cost curve is unsustainable. Who will win and who will lose? Clearly, there are realignments.” Ira M. Klein, MD, MBA, Chief of Staff to the Chief Medical Officer at Aetna Oncology Strategy, New York, added, “We get feedback from our different customers as to what they want, from the self-insured employers to the small businesses down to the individual in the market. And the unifying theme is that they cannot sustain any more cost.”

Employers Are Confused Employers may be steadily downsizing their benefits, but this does not mean they do so without pain, participants noted. “Employers are more paternalistic than one would think. They are concerned about the care their employees are getting,” said Klein. “They want benefit designs that do not deny patients access to essential services, but they want these to be acquired at the most favorable unit price. Cost is a very big factor to them.” Maria Lopes, MD, MS, Chief Med ical Officer for AMC Health, Cresskill, New Jersey, agreed. “Employers are concerned about cost and about what is happening in the marketplace, and they are looking to payers for solutions.” Employers clearly do not understand why costs are so high, added Winston Wong, PharmD, Associate Vice President of Pharmacy Management with CareFirst BlueCross BlueShield in Maryland. “The employers ask their consultants. The consultants come to us because they think pharmacy is the silver bullet. When you look at it from the employer and consultant standpoints, you see there is not much

May 2012 I VOL 5, NO 4

understanding about what is driving the numbers,” he said. Drug Costs: The Big Bugaboo The exorbitant cost of new treatments clearly contributes to the crisis in paying for cancer care, and payers’ hands are relatively tied to do much about this, the panelists said. “We know drugs are the biggest part of the escalation,” observed Zweigenhaft, and John Fox, MD, MHA, Associate Vice President of Medical Affairs for Priority Health, Grand Rapids, Michigan, proposed 2 main reasons for this.

“Employers are concerned about cost and about what is happening in the marketplace, and they are looking to payers for solutions.” —Maria Lopes, MD, MS

“Number one, we do not have the wherewithal or interest in the public domain to say that society will not pay for a cancer drug because it is too expensive,” Fox offered. “Number two, there are state mandates to cover expensive drugs, and the drug companies have the power to set the price of the drug. We cannot control these prices, yet that is where the greatest cost is.” Fox contrasted the system in the United States with that of the United Kingdom, which does consider the cost of a drug when deciding its fate. “In the United Kingdom, they take the 2 independent variables, which are outcomes established through clinical trials and willingness to pay, and that defines the dependent variable, which is the cost of the drug,” he said. “In this country, the manufacturer sets the cost of the drug…. The conundrum is that the pharmaceutical industry has a responsibility to its investors and the innovators have to recoup their investments, yet the people who pay for that are increasingly unable to do so.” Although discussions about reducing emergency department visits and hospi-

talizations as a cost-savings approach have merit, they stem merely from the fact that these are “things we can control,” Fox said. “The reality is that until we find a way to provide more rationality around our drug reimbursements, I do not know that there is a solution.” Keeping Oncology CommunityBased Payers indicated and studies have shown that cancer care is more affordable when delivered in the community rather than the hospital setting; however, economic factors are steadily threatening the viability of this site of care, because community practices are being sold or absorbed by hospitals, or are merely closing. This trend worries Jeffrey A. Scott, MD, Senior Vice President and General Manager for P4 Healthcare Cardinal Health Specialty Solutions. “What will it take for this to stop?” he questioned. “When will health plans incentivize doctors to stay out of the hospital? We know the lowest cost comes from treating patients in the community, but how do we drive this?” Zweigenhaft noted that the “shift to a hospital base” is a universal concern in the payer community, because this essentially doubles the cost of delivering cancer care, with little or no improvement in outcomes. Panelists agreed that site of service is an important issue. Part of the lure of hospital-based care, as Zweigenhaft put it, is the 340B Drug Pricing Program, which limits the cost of covered outpatient drugs to certain federal grantees, federally qualified health center look-alikes, and qualified hospitals. Participation in the program results in savings estimated to be 20% to 50% of the cost of pharmaceuticals, which naturally appeals to providers. According to Zweigenhaft, the pitch made by hospital representatives to physician groups is the opportunity to share in the substantial additional revenue afforded through 340B drug pricing. Scott agreed that 340B pricing is “clearly a driver for getting new doctors into the hospital,” and part of the reason why struggling community practices view the hospital system as “the savior.” What it will take to strengthen community oncology practices is not completely clear, but Mona M. Chitre, PharmD, CGP, Director of Clinical Services, Strategy and Policy for Excellus BlueCross Blue Shield, FLRx

Pharmacy Management, Rochester, New York, said helping them maintain “cost neutrality” is important. Her company’s goals are to create innovative programs to pay for patient management, help patients avoid emergency department visits, and aid clinicians in reducing other unnecessary services. Guiding Physicians to Best Practices Value in cancer care, however, is not only about cost but also about quality, and the 2 components are necessary for optimizing value while maintaining good outcomes, the panel agreed. Lopes suggested that the concept of value must be aligned with an appropriate outcome, and this can be difficult to determine. Scott added that better measures are needed to define quality outcomes, and that there is increasing recognition that it is “total cost of care” that matters most—which includes reductions in downstream costs and returning patients to work. Klein agreed that benefits programs cannot be designed simply on the basis of cost. “We want quality first, then we deliver on cost,” he said. Scott added, “There is no question that good, quality care is already being provided, but it comes down to how to maintain that quality at a lower cost. That is the big discussion we have with providers.” Standardization is an important part of this strategy, typically via guidelines and clinical pathways. “We found that by more or less standardizing treatments in the program we have with community oncologists, we take out variability and have a gross savings of about 13%,” Wong reported. “These savings will be shared with the community oncologists as an effort to maintain their margins and to be an incentive to sustain their community practices.” Moving from branded to generic products has also been a big cost-saver, and reducing emergency department visits and hospitalization rates by 4% has produced additional savings. “We know the savings are there,” he said. According to Klein, this works best when providers are in the driver’s seat. “We delegate decision-making to physician groups and allow them to choose their pathways. You get higher quality and lower costs because you give control and power to the providers to use what they are comfortable with,” he said.

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Conference News: Scott suggested that pathways work best when they are “narrow,” which is what P4 attempts to do with providers. “We try to neutralize the name of the drugs so physicians are free to choose a regimen based on what is best for the patient and separate from the economics of it. We have demonstrated in 10 different markets that you can use consensus to drive a narrow set of pathways, and it works, although it may not be the long-term answer.” Lopes added that there is a need to do more to aid physicians in decision-making. “We want to align incentives,” she said, emphasizing that healthy collaboration is critical to success. “We will not win without good partnerships with our treating providers.”

Need to Involve the Patient Central to any conversation about cancer care should be the patient. They should also become more active participants in the quest for value, and there is room for improvement in this area, the panel pointed out. “The ‘value proposition’ has to be considered at the patient level,” said Chitre. New York State now has chemotherapy parity. “Patients will not pay any differential for generic versus branded drugs, so the ‘value discussion’ with the patient is actually absent,” she noted. “If a drug is indicated or listed as 2A or 2B in the Compendia, it is covered and at a high level. There is very little patient out-of-pocket expense, and therefore very little driving our

members to ask ‘value questions’ of their providers.” She observed, however, that the trend toward high-deductible premiums is beginning to alter how patients talk about value to their providers. Wong reported that CareFirst programs are beginning to integrate oncology with primary care through the patient-centered medical home model, and this is helping to steer care in the direction of value. “These 2 specialties are collaborating. Primary care is directing patients to oncology practices they perceive will provide the best quality and value,” he said (see an interview with Wong below). Ultimately, what emerges as the picture of value-based cancer care must be

patient-centered, the panel agreed. A “fully engaged” patient is one who understands the treatment scenario and determines what is most important to him or her, said Fox. This is only done when physicians have time for it, added Klein. “If we could get physicians to spend more time talking to patients, all our costs would go down, because the patient would feel more empowered to do the right thing,” he maintained. “Comparatively speaking, physician labor time is cheap. The cost-over-quality balance must hierarchically satisfy all stakeholders as equitably as possible. We have to manage expectations. We cannot move cancer care forward until we change society’s perceptions.” ●

Site of Care Influences Value in Cancer Care Interview With Winston Wong, PharmD Associate Vice President, Pharmacy Management, CareFirst BlueCross BlueShield of Maryland

t the Association for ValueBased Cancer Care (AVBCC) second annual meeting, Winston Wong, PharmD, expressed concerns that the site of delivery of cancer care affects efforts to rein in costs and provide value in cancer care. Wong expanded on this issue in the following interview.

Why do you believe that the site of delivery of cancer care can impact the attempt to rein in costs of cancer care and provide value? Wong: Here is why. When chemotherapy is delivered to a patient in the physician’s office, there are the cost of the drug, administrative costs, and the cost of ancillary services. Let’s say the total office visit, including the cost of chemotherapy, is $4000. You can take that exact same service and drug and deliver it at a large center, such as, in our area, Johns Hopkins, and the cost could be $6000 or even up to $8000. Essentially, it may double or even triple in cost, depending on the procedure, the service, and the drug that is prescribed. Why is there such a large differential in cost? Wong: It is basically because the healthcare system cannot function without the large hospitals. They have market power and can negotiate better deals. At the end of the day, hospital billing will be at least twice that of a community practice, across the board. Do large hospitals and cancer centers acknowledge this? Wong: Their comment to payers would be that they are tertiary care hospitals,

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and that their patient population is sicker, and to some degree that is true. Large hospitals may get more difficult cases, administer more expensive third-line therapies, and so forth. But comparing apples to apples, their costs are much higher than in community practices.

What can be done to bring more equity? Wong: On the oncology side, we have not been able to achieve more equity yet. The strategy that we at CareFirst are trying to employ initially with our Pathways Program is to reimburse at a higher rate to community practices. We may not necessarily be directing patients away from hospitals, but we are doing something to help maintain community oncology practices so that they are available to treat these patients. If there are fewer community practices, patients with cancer have less choices. The site-of-care issue will be driven by the viability of community practices. If we cannot help community oncologists stay in business, the site of care will not be an issue. You have talked about the need to integrate primary care and to bring more value to oncology. Could you elaborate on this? Wong: Here is an example of the current state of things. My mother passed away in 2007. When she was diagnosed with cancer and was being treated with chemotherapy, she became neutropenic and ended up in the emergency department. The hospital contacted the primary care physician (PCP) on record, but he had no clue about her condition. Once an oncologist was taking care of

her, there had been no communication with the PCP. And let’s look at survivorship. She may have to go back to the oncologist for some routine tests, but she may have an annual check-up the following week with her PCP, and he may order the same laboratory tests. This kind of overlap and duplication should be eliminated from the system. Winston Wong, PharmD

How is CareFirst BlueCross BlueShield advancing this concept of more integrated care? Wong: With the primary care patientcentered medical home, we are trying to involve the PCP as the “quarterback of care,” as we say. Currently, when an individual is diagnosed with cancer and referred by his or her PCP to a specialist, the PCP usually severs ties with the patient. We are asking our PCPs to be more accountable and to follow these patients while they are under the care of specialists—oncologists or others—and maintain primary care as the patient’s home, but within an integrated process. Maybe 5 of 10 patients with cancer will ask their PCP to refer them to an oncologist, but the other 50% will choose an oncologist on the basis of favorable word of mouth. Or, they may want to go, for example, to MD Anderson, because of its reputation and not because they have seen scientific evidence that their care will be better or that community care is worse. We all pay more for that patient, with very little difference in quality of care or in outcomes compared with care in the community setting. We believe that the PCP can direct the patient more toward value-based cancer care. PCPs can help guide these referrals, and they can take

care of the non–cancer-related conditions that patients with cancer will have. We want this care to be under the PCP, not the oncologist.

How are PCPs and oncologists accepting this model? Wong: We do not know yet—our program just started—but this is something we are interested in learning. We believe that it is in everyone’s best interest for patients to have a coordinator of care, and we think that the most important provider in this regard is the PCP. We think that PCPs and oncologists working together will become inevitable with the changing time. As the PCP becomes more involved, there will have to be more communication between them. What progress is being made to bring this concept to fruition? Wong: There are many groups with their own small projects like ours, and none is known to be the best way to do this. I think that these will eventually merge into something that we will all use; however, we are still trying to get some accountability around these programs, and we are still very early in that game. ●

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Conference News:

Global Biomarkers Consortiumâ&#x20AC;&#x201D;Implementing the Promise of Personalized Cancer Care

he inaugural annual conference of the Global Biomarkers Consortium brought together an international panel of oncology experts to explore the rapidly evolving field of biomarker research. Cochairs of the event were Hope S. Rugo, MD, director of Breast Oncology and Clinical Trials Education at the University of California San Francisco, and RĂźdiger Hehlmann, MD, PhD, professor of medicine at the University of Heidelberg. Michael Kattan, PhD, Vincent Miller, MD, Edith Perez, MD, and Charles Bennett, MD, PhD, served as session chairs. At the conference, held March 9-11, 2012, in Orlando, Florida, a diverse field of experts addressed oncologists, hematologists, oncology nurses, pharmacists, and other healthcare professionals on a wide range of topics related to the clinical application of biomarkers in the treatment of solid tumors and hematologic malignancies. Conference attendees had numerous opportunities to ask questions. In addition, an audience response system provided opportunities for interactive learning experiences.

Personalized medicine based on an understanding of predictive molecular biomarkers holds great promise.

Hehlmann opened the conference with a valuable historical overview of genetic profiling and oncologic biomarkers. In discussing development of new technologies, Miller reported, â&#x20AC;&#x153;There are an unprecedented number of targeted therapies in clinical trialsâ&#x20AC;&#x201D;about 500 targeted therapies looking at about 140 genomic alterations.â&#x20AC;? In looking forward to next-generation sequencing, Miller concluded, â&#x20AC;&#x153;So Iâ&#x20AC;&#x2122;m really excited about these broader technologies that may allow us to help more patients and more rationally approach treating patients in the near future.â&#x20AC;? Case studies of several types of cancer were presented by panel members. Perez presented â&#x20AC;&#x153;Evidence-Based Medicine to Translational Medicine to Personalized Medicine: A Natural Evolution,â&#x20AC;? and Beth Faiman, PhD(c), MSN, APRN-

May 2012 I VOL 5, NO 4

BC, AOCN, discussed â&#x20AC;&#x153;Roles and Responsibilities of the Interprofessional Team.â&#x20AC;? Perez and Faiman led a group composed of several doctors who had presented case studies in a panel ques-

tion-and-answer session on â&#x20AC;&#x153;Incorporating Personalized Medicine Into Practice.â&#x20AC;? Personalized medicine based on an understanding of predictive molecular

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INDICATIONS AND USAGE: PROVENGEÂŽ (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. DOSAGE AND ADMINISTRATION Ĺ&#x2DC; For Autologous Use Only. Ĺ&#x2DC; 7KH UHFRPPHQGHG FRXUVH RI WKHUDS\ IRU 3529(1*( LV FRPSOHWH GRVHV JLYHQ DW DSSUR[LPDWHO\ ZHHN LQWHUYDOV Ĺ&#x2DC; 3UHPHGLFDWH SDWLHQWV ZLWK RUDO DFHWDPLQRSKHQ DQG DQ DQWLKLVWDPLQH VXFK DV diphenhydramine. Ĺ&#x2DC; %HIRUH LQIXVLRQ FRQĹľUP WKDW WKH SDWLHQWĹ&#x2018;V LGHQWLW\ PDWFKHV WKH SDWLHQW LGHQWLĹľHUV RQ the infusion bag. Ĺ&#x2DC; Do Not Initiate Infusion of Expired Product. Ĺ&#x2DC; ,QIXVH 3529(1*( LQWUDYHQRXVO\ RYHU D SHULRG RI DSSUR[LPDWHO\ PLQXWHV Do Not Use a Cell Filter. Ĺ&#x2DC; ,QWHUUXSW RU VORZ LQIXVLRQ DV QHFHVVDU\ IRU DFXWH LQIXVLRQ UHDFWLRQV GHSHQGLQJ RQ WKH VHYHULW\ RI WKH UHDFWLRQ (See Dosage and Administration [2] of full Prescribing Information.) CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS Ĺ&#x2DC; PROVENGE is intended solely for autologous use. Ĺ&#x2DC; Acute infusion reactions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ĹľUVW LQIXVLRQ DQG GHFUHDVHG WR following the third infusion. Some (1.2%) patients in the PROVENGE group were KRVSLWDOL]HG ZLWKLQ GD\ RI LQIXVLRQ IRU PDQDJHPHQW RI DFXWH LQIXVLRQ UHDFWLRQV 1R *UDGH RU DFXWH LQIXVLRQ UHDFWLRQV ZHUH UHSRUWHG LQ SDWLHQWV LQ WKH PROVENGE group. &ORVHO\ PRQLWRU SDWLHQWV ZLWK FDUGLDF RU SXOPRQDU\ FRQGLWLRQV ,Q WKH HYHQW RI DQ DFXWH LQIXVLRQ UHDFWLRQ WKH LQIXVLRQ UDWH PD\ EH GHFUHDVHG RU WKH LQIXVLRQ VWRSSHG GHSHQGLQJ RQ WKH VHYHULW\ RI WKH UHDFWLRQ $SSURSULDWH PHGLFDO WKHUDS\ VKRXOG EH administered as needed. Ĺ&#x2DC; Handling Precautions for Control of Infectious Disease. PROVENGE is not URXWLQHO\ WHVWHG IRU WUDQVPLVVLEOH LQIHFWLRXV GLVHDVHV 7KHUHIRUH SDWLHQW leukapheresis material and PROVENGE may carry the risk of transmitting infectious GLVHDVHV WR KHDOWK FDUH SURIHVVLRQDOV KDQGOLQJ WKH SURGXFW 8QLYHUVDO SUHFDXWLRQV should be followed. Ĺ&#x2DC; Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either FKHPRWKHUDS\ RU LPPXQRVXSSUHVVLYH DJHQWV VXFK DV V\VWHPLF FRUWLFRVWHURLGV JLYHQ FRQFXUUHQWO\ ZLWK WKH OHXNDSKHUHVLV SURFHGXUH RU 3529(1*( KDV QRW EHHQ VWXGLHG 3529(1*( LV GHVLJQHG WR VWLPXODWH WKH LPPXQH V\VWHP DQG FRQFXUUHQW XVH RI LPPXQRVXSSUHVVLYH DJHQWV PD\ DOWHU WKH HIĹľFDF\ DQG RU VDIHW\ RI 3529(1*( 7KHUHIRUH SDWLHQWV VKRXOG EH FDUHIXOO\ HYDOXDWHG WR GHWHUPLQH ZKHWKHU LW LV PHGLFDOO\ DSSURSULDWH WR UHGXFH RU GLVFRQWLQXH LPPXQRVXSSUHVVLYH DJHQWV SULRU WR WUHDWPHQW with PROVENGE. Ĺ&#x2DC; Product Safety Testing. PROVENGE is released for infusion based on the microbial DQG VWHULOLW\ UHVXOWV IURP VHYHUDO WHVWV PLFURELDO FRQWDPLQDWLRQ GHWHUPLQDWLRQ E\ *UDP VWDLQ HQGRWR[LQ FRQWHQW DQG LQ SURFHVV VWHULOLW\ ZLWK D GD\ LQFXEDWLRQ WR GHWHUPLQH DEVHQFH RI PLFURELDO JURZWK 7KH ĹľQDO GD\ LQFXEDWLRQ VWHULOLW\ WHVW UHVXOWV DUH QRW DYDLODEOH DW WKH WLPH RI LQIXVLRQ ,I WKH VWHULOLW\ UHVXOWV EHFRPH SRVLWLYH IRU PLFURELDO FRQWDPLQDWLRQ DIWHU 3529(1*( KDV EHHQ DSSURYHG IRU LQIXVLRQ Dendreon will notify the treating physician. Dendreon will attempt to identify the PLFURRUJDQLVP SHUIRUP DQWLELRWLF VHQVLWLYLW\ WHVWLQJ RQ UHFRYHUHG PLFURRUJDQLVPV and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination. (See Warnings and Precautions [5] of full Prescribing Information.) ADVERSE REACTIONS %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQ UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHĹśHFW WKH UDWHV REVHUYHG LQ SUDFWLFH

biomarkers holds great promise. Conferences such as this one help clinicians and other healthcare professionals keep up to date on developments in this challenging field. â&#x2014;?

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Any Adverse Event Chills Fatigue )HYHU %DFN SDLQ Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting $QHPLD Constipation Pain Paresthesia oral Pain in extremity 'L]]LQHVV Muscle ache $VWKHQLD Diarrhea ,QĹśXHQ]D OLNH LOOQHVV Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3)

247 (41.1)

186 (30.9)

7 (1.2)

291 (96.0)

Grade 3-5 n (%) 97 (32.0)

(Table 1 continued on next page.)

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Prostate Cancer Metastatic Castrate-Resistant Prostate Cancer... References

Prostate Cancer Outcomes Study. J Natl Cancer Inst. 2001;93:388-395. 4. Woods VD, Montgomery SB, Belliard JC, et al. Culture, black men, and prostate cancer: what is reality? Cancer Control. 2004;11:388-396. 5. Pashayan N, Pharoah P, Neal DE, et al. Stage shift in PSA-detected prostate cancers - effect modification by Gleason score. J Med Screen. 2009;16:98-101. 6. Seruga B, Ocana A, Tannock IF. Drug resistance in metastatic castration-resistant prostate cancer. Nat Rev Clin Oncol. 2011;8:12-23. 7. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus

1. Ferlay J, Bray F, Pisani P, et al. GLOBOCAN 2000: cancer incidence, mortality and prevalence worldwide. Version 1.0. IARC Cancer Base No. 5. Lyon, France: IARC Press; 2001. 2. US Cancer Statistics Working Group. United States Cancer Statistics: 1999-2007 Incidence and Mortality Webbased Report. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2010. 3. Hoffman RM, Gilliland FD, Eley JW, et al. Racial and ethnic differences in advanced-stage prostate cancer: the

Continued from page 29

prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 8. Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26(2):242-245. 9. de Bono JS, Oudard S, Ozguroglu M. Prednisone plus cabazitaxel or mitoxantrone for metastatic castrationresistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154. 10. Kantoff PW, Higano CS, Shore ND, et al.

Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 11. de Bono JS, Logethetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005. 12. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-822. 13. Woo SB, Hellstein JW, Kalmar JR. Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med. 2006;144:753-761.

Table 1 Incidence of Adverse Events Occurring in â&#x2030;Ľ5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension $QRUH[LD %RQH SDLQ Upper respiratory tract infection ,QVRPQLD Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

&RQWURO ZDV QRQ DFWLYDWHG DXWRORJRXV SHULSKHUDO EORRG PRQRQXFOHDU FHOOV

Cerebrovascular Events. ,Q FRQWUROOHG FOLQLFDO WULDOV FHUHEURYDVFXODU HYHQWV LQFOXGLQJ KHPRUUKDJLF DQG LVFKHPLF VWURNHV ZHUH UHSRUWHG LQ RI SDWLHQWV LQ WKH 3529(1*( JURXS FRPSDUHG ZLWK RI SDWLHQWV LQ WKH FRQWURO JURXS (See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

References: 1. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 2. PROVENGE [package insert]. Dendreon Corporation; June 2011. 3. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. V.4.2011. National Comprehensive Cancer Network Web site. www.nccn.org. Accessed October 24, 2011.

k 'HQGUHRQ &RUSRUDWLRQ $OO ULJKWV UHVHUYHG )HEUXDU\ 3ULQWHG LQ WKH 8 6 $ 'HQGUHRQ WKH 'HQGUHRQ ORJR DQG PROVENGE are registered trademarks of Dendreon Corporation. P-A-11.10-073.02(b)

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May 2012 I VOL 5, NO 4

TON_May2012_v7_TON 5/18/12 3:35 PM Page 40

IN ADVANCED PROSTATE CANCER...

PROVENGE ACTIVATE THE POWER OF THE IMMUNE SYSTEM. EXTEND SURVIVAL.

Resting T cell

PROVENGE

PROVENGE-activated T cell

Activated T cell attacks prostate cancer

Prostate cancer cell

s PROVENGE extends median survival beyond 2 years1 s Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events2 — The most common adverse events in PROVENGE trials were chills, fatigue, fever, back pain, nausea, joint ache, and headache2 s PROVENGE is the first and only FDA-approved immunotherapy for advanced prostate cancer s The NCCN recommends PROVENGE as a first-line treatment for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (NCCN Category 1 recommendation)3 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group. The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache. For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent page.