JULY 2012, VOl 5, NO 6 by The Oncology Nurse

JULY 2012

www.TheOncologyNurse.com

VOL 5, NO 6

BLADDER CANCER

CANCER CENTER PROFILE

Screening for Bladder Cancer

Cancer Institute of New Jersey

By Gary Shelton, MSN, NP, ANP-BC, AOCNP NYU Clinical Cancer Institute

The Cutting Edge of Oncology Nursing

lthough the increased incidence of bladder cancer (BC) has softened in recent years, proposed to be due in part to smoking cessation strategies, BC remains a significant healthcare problem with high recurrence rates.1,2 Currently, there is inadequate evidence that screening for BC in the asymptomatic population promotes improved overall morbidity or mortality.3 Despite this current state of the science,

there is great interest in bettering the gold standard for early diagnosis—cystoscopy, cytology, and imaging—as these are expensive, uncomfortable, and not suggested for low-risk individuals or for those without hematuria.4 Background Bladder cancer is projected to be the fourth most common cancer diagnosed in Continued on page 14

BREAST CANCER Leah Scaramuzzo, MSN, RN-BC, AOCN; Pam Scott, RN; Vicki Hess, MS, RN, CSP (employee engagement expert); Yuk Wong, RN, BSN, MA, OCN; Janet Gordils-Perez, MA, APN-C, AOCNP; and Carla Schaefer, BSN, RN, OCN (left to right), during the 2012 Nurses Day celebration at CINJ.

he Cancer Institute of New Jersey (CINJ) was established in 1991 as a partnership between the Robert Wood Johnson Medical School and the New Brunswick Affiliated Hospitals. The groundbreaking ceremony in New Brunswick took place in 1994. In 1997, CINJ received its Clinical Cancer Center status from the National Cancer Institute (NCI) and was designated as a Comprehensive Cancer Center in 2002, confirmation of its position as a leader in treatment, research, and education. Janet Gordils-Perez, MA, APN-C, AOCNP, Director of Oncology Nursing Services at CINJ, answered our questions about the role oncology nurses play in patient care.

Continued on page 26

T-DM1 in Metastatic Breast Cancer It’s Just the Beginning for an Exciting New Class of Agents By Caroline Helwick

he biggest newsmaker at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) was a compound whose name and actions sound practically missile-like: T-DM1. Because of its highly targeted and potent effect that spares surrounding healthy tissue, T-DM1 not only has

potent antitumor effects but is also very well tolerated. Trastuzumab emtansine (T-DM1) is part of an emerging class of drugs called antibody-drug conjugates (ADCs) that link a monoclonal antibody (in this case, trastuzumab) to a cytotoxic agent (in this case, a potent antimicrotubule agent

CONFERENCE NEWS: ASCO 2012

Continued on page 17

By Alice Goodman

INSIDE

Duloxetine in Peripheral Neuropathy

he antidepressant duloxetine (Cymbalta) appears to reduce painful peripheral neuropathy associated with taxane- or platinumbased chemotherapy in some, but not all, patients, according to a randomized phase 3 study presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

About one-third of patients treated with duloxetine reported at least a 30% or greater reduction in pain scores versus 17% of placebo patients. “Unfortunately, no medication is completely effective. Duloxetine isn’t perfect and did not work for every patient in our study, but it was effective

Supportive Care

GenetiC CounSelinG

Many Febrile Neutropenia Patients Can Be Treated at Home . . . . . . . 15

Emerging Cancer Panels for Testing Patients for Inherited Cancer Predisposition

Use of Bone-Modifying Agents in Oncology Patients . . . . . . . . . . . . 28 Complimentary Ce

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Considerations in Multiple Myeloma—Ask the Experts: Maintenance Settings

.......

DruG ShortaGe

Exploring the Drug Shortage Crisis . . . . . . . . . . . . . . . . . 33 Quantifying the Drug Shortage: One Center’s Experience . . . . . . . 34

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

APPROVED FOR SUBCUTANEOUS ADMINISTRATION*

Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP† vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months‡; 60.1-month median follow-up§)

VELCADE (bortezomib) Indication and Important Safety Information INDICATION

▼

CONTRAINDICATIONS

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ADVERSE REACTIONS WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼

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▼ ▼ ▼

▼ ▼

Living Proof

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

V-12-0151

4/12

5:32 PM

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, MSN, APRN, BC, OCN

RN, BSN, OCN

Melinda Oberleitner, RN,

Karla Wilson, RN, MSN, FNP-C, CPON

DNS, APRN, CNS

City of Hope National Medical Center Duarte, CA

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, DNP, NP, AOCNP

Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN,

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

Jayshree Shah, NP

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

Sibley Memorial Hospital Johns Hopkins Medicine Washington, DC

Fox Chase Cancer Center Philadelphia, PA

BSN, OCN

PhD, RN, AOCN

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

Wendy DiSalvo,

Sandra E. Kurtin,

Lori Stover, RN,

DNP, APRN, AOCN

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

Genentech New London, NH

Denice Economou, RN, MN, CNS, AOCN

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

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

JULY 2012 I VOL 5, NO 6

From the Editor

elcome to the July issue of The Oncology NurseAPN/PA (TON). This month, we continue our coverage of the news from the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). Some of the most exciting news involves trastuzumab emtansine (T-DM1), part of an emerging class of targeted agents called antibodyBeth Faiman, PhD(c), MSN, APRN-BC, AOCN drug conjugates, which link a monEditor-in-Chief oclonal antibody to a cytotoxic agent. T-DM1 is being used to treat patients with HER2-positive metastatic breast cancer who are part of an international phase 3 study. The promising early results have excited many healthcare professionals, and we at TON will be following the results of the clinical trials involving T-DM1. The drug shortage situation was addressed at ASCO, and we provide you with an update on the status of the congressional legislation aiming to help remedy this problem. We also report on the experience of a New York cancer center, where “about 10% of the patients…treated had an actual change in treatment,” according to one of the researchers who presented the results of the study. Our

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Noteworthy Numbers

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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. BPA Worldwide membership applied for April 2011.

December 2011 reader survey about the drug shortage showed how frustrated oncology nurses are about the situation and how we all want a solution as soon as possible. Be sure to visit our Web site, www.TheOncology Nurse.com, to participate in this month’s Reader Poll to let us know how confident you are that the actions taken by the US Food and Drug Administration and recent congressional legislation will resolve the drug shortage issue. In addition to our ASCO coverage, we present an article by Gary Shelton, MSN, NP, ANP-BC, AOCNP, about screening for bladder cancer and the possibilities of early detection in asymptomatic adults (currently, there are no guidelines for screening this population). July is bladder cancer awareness month, so our Noteworthy Numbers column focuses on the statistics for this cancer. Cristi Radford, MS, CGC, and Tuya Pal, MD, FABMG, tell us about “cancer panels,” which allow for multiple genes to be analyzed simultaneously for mutations by using next-generation sequencing technology. Cristi and Tuya let us know when using a cancer panel may be an appropriate strategy. Please let us know what you think about TON—the good and the bad. Tell us what you want to see covered and consider contributing an article yourself. We are interested in all topics that relate to the practice of oncology nursing. Please contact us at editorial@greenhillhc.com. l

JULY 2012 I VOL 5, NO 6

Although the rates of bladder cancer incidence and bladder cancer deaths have been fairly stable over the past 20 years, the disease is still just as serious and deadly. In an effort to learn more about it, let’s take a closer look at bladder cancer, the fourth most common cancer diagnosed in men.

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

Whites are diagnosed with bladder cancer almost twice as often as blacks, and Hispanics have an even lower incidence rate than blacks.

And, if the cancer spreads to distant parts of the body (about 4% of cases), the 5-year survival rate is only 6%.

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

For the more than 500,000 people in the United States who are survivors of this cancer, the American Urological Association recommends patient assessment every 3 months in the first 2 years after initial diagnosis followed by every 6 months for the subsequent 2 to 3 years, and then annually thereafter.

Approximately 35% of bladder cancer patients have a tumor that is invasive but has not yet spread outside the bladder. The 5-year survival rate for these patients is 75%. If bladder cancer spreads to the lymph nodes or nearby organs, the 5-year survival rate decreases to 36%.

Sources www.cancer.org/Cancer/BladderCancer/ DetailedGuide/bladder-cancer-what-iscancer; www.cancer.net/patient/Cancer+ Types/Bladder+Cancer?sectionTitle=Statis tics; www.auanet.org/content/guidelinesand-quality-care/clinical-guidelines/ main-reports/bladcan07/chapter1.pdf.

www.TheOncologyNurse.com

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Conference News: ASCO 2012 Duloxetine in Peripheral Neuropathy Continued from cover for a majority of patients. This was the first randomized trial to show that any drug is effective for this terrible pain,” stated lead author Ellen M. Lavoie Smith, PhD, assistant professor in the School of Nursing at the University of Michigan in Ann Arbor. Painful peripheral neuropathy, which affects 20% to 30% of patients treated with taxane- or platinum-based chemotherapy, can be debilitating, interfering with the ability to perform activities of daily living. Thus far, there is no established effective treatment for this adverse event, which can persist for years after chemotherapy is completed. The study randomized 231 patients to duloxetine followed by placebo versus placebo followed by duloxetine; 220 patients received the initial treatment with 187 patients completing the initial treatment period. All patients reported high levels of pain from peripheral neuropathy prior to enrollment. Duloxetine was given as one 30-mg oral capsule per day for 1 week, followed by 2 capsules per day (60 mg) for 4 more weeks.

amount of pain that interfered with general activity, mood, walking, work, enjoyment of life, and social relationships,” Smith told listeners.

Severe (grade 3) nonhematologic toxicity was seen in 11% of those who received duloxetine, and 41% reported moderate (grade 2) toxicity. Grade 2 or

higher fatigue was the most common adverse event in the duloxetine-treated patients, reported in 11% versus 3% of placebo patients. Less than 10% experi-

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

This is his therapy.

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

“The gradual dosing was employed to reduce the side effects of duloxetine, which can include fatigue, dry mouth, sleepiness, and nausea,” Smith said. Patients completed the Brief Pain Inventory-Short Form survey at baseline and then every week. Decrease in pain scores was reported by 59% of the duloxetine-treated patients versus 38% for placebo. Thirty-three percent of the duloxetine group reported at least a 30% decrease in pain severity, and 21% reported at least a 50% decrease in pain severity. No change in pain score was seen in 30% of the duloxetine group and 34% of placebo patients. Pain was increased in 11% of those taking duloxetine versus 28% of placebo patients. No difference in duloxetine efficacy was observed based on the specific neurotoxic chemotherapy given. “Patients treated with duloxetine enjoyed a greater decrease in the

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Conference News: ASCO 2012 enced fatigue, insomnia, nausea, somnolence, or dizziness. The incidence of adverse events was lower than in previous trials of duloxetine for diabetic neuropathy, which Smith attributed to the lower

starting dose in this trial. Gabapentin has been used off-label for chemotherapy-related peripheral neuropathy, but it causes somnolence, explained Hope Rugo, MD, of the University of California San Francisco,

who commented on this paper during a press conference. “Duloxetine doesn’t have that side effect, so it could be advantageous for patients who need treatment for peripheral neuropathy,” Rugo commented. l

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

Single-agent TREANDA tripled median PFS* 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. 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

6 months median PFS

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

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

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301) • TREANDA is administered with a convenient dosing schedule – The recommended dose for TREANDA is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day treatment cycle, up to 6 cycles – In the phase 3 trial, patients received chlorambucil at a dose of 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles • In the pivotal phase 3 trial, the most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150) Important Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA

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

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Olanzapine Effective Antiemetic for Breakthrough CINV

atients with breakthrough chemotherapy-induced nausea and vomiting (CINV) can gain superior relief from olanzapine (Zyprexa), a drug approved by the US Food and Drug Administration as an antipsychotic,

compared with standard antiemetic therapy with metoclopramide. The results from this phase 3 study address an important unmet need for patients who experience these side effects despite being given standard antiemetic therapy.

â&#x20AC;&#x153;Breakthrough CINV usually occurs on day 2 through 4 after chemotherapy, despite guideline-directed prophylaxis. This study found that olanzapine is significantly better than metoclopramide in controlling CINV in this group of

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. Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be â&#x2030;Ľ 1 x 109/L and the platelet count should be â&#x2030;Ľ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naĂŻve 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 â&#x2030;Ľ 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) 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

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Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study Chlorambucil TREANDA (N=141) (N=150) Grade 3/4 All Grades Grade 3/4 All Grades Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous 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. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. t Aseptically SFDPOTUJUVUF FBDI 53&"/%" WJBM BT GPMMPXT t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP t NH 53&"/%" WJBM "EE N- PG POMZ 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 VTFE t "TFQUJDBMMZ XJUIESBX UIF WPMVNF OFFEFE GPS UIF SFRVJSFE EPTF CBTFE PO NH N- DPODFOUSBUJPO BOE 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 0.2â&#x20AC;&#x201C;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 BENJYUVSF TIPVME CF B DMFBS BOE DPMPSMFTT UP TMJHIUMZ ZFMMPX TPMVUJPO t 6TF 4UFSJMF 8BUFS GPS *OKFDUJPO 641 GPS reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride *OKFDUJPO 641 GPS EJMVUJPO BT PVUMJOFE BCPWF /P PUIFS EJMVFOUT IBWF CFFO TIPXO UP CF DPNQBUJCMF t 1BSFOUFSBM drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8Â°C or 36-47Â°F) or for 3 hours when stored at room temperature (15-30Â°C or 59-86Â°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 singleuse 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 25Â°C (77Â°F) with excursions permitted up to 30Â°C (86Â°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

patients,â&#x20AC;? stated lead author Rudolph Navari, MD, PhD, of the University of Indiana in Indianapolis. Olanzapine achieved superior emesis control at 72 hours: 71% of those receiving olanzapine had no emesis versus 32% of those treated with metoclopramide (P <.01). Patients treated with olanzapine also had significantly improved control of nausea: 67% of the olanzapine group versus 24% of the metoclopramide group had complete control of nausea (P <.01). No patient experienced any grade 3 or 4 toxicity, and no central nervous system adverse events were seen in this shortterm study comparing the 2 drugs. Olanzapine is known to have several adverse effects when used as long-term antipsychotic therapy, but Navari emphasized that these effects were not seen with short-term administration of the drug.

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ÂŠ2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 (Label Code: 00016287.06) This brief summary is based on TRE-006 TREANDA full Prescribing Information.

April 2012

â&#x20AC;&#x153;This study was a reminder that in the era of precision medicine, we still need to improve the patient experience.â&#x20AC;? â&#x20AC;&#x201D;Sandra Swain, MD

â&#x20AC;&#x153;This is the first study to show a treatment is effective in breakthrough CINV,â&#x20AC;? Navari stated. The study included 205 chemotherapy-naive patients receiving highly emetogenic chemotherapy who were given standard drugs to control CINV. Of these, 80 experienced breakthrough CINV on standard therapy and were randomized 1:1 to olanzapine 10 mg orally daily for 3 days versus metoclopramide 10 mg TID for 3 days. Patients with breakthrough CINV were observed for 72 hours and were asked to fill out a daily diary. Incoming ASCO President Sandra Swain, MD, said, â&#x20AC;&#x153;This study was a reminder that in the era of precision medicine, we still need to improve the patient experience. CINV can be quite limiting. Patients donâ&#x20AC;&#x2122;t eat and they can be tired. Olanzapine is another tool we now have to treat this side effect.â&#x20AC;? l â&#x20AC;&#x201D;AG Reference Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 9064.

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Better Transition From Oncology to Primary Care Required to Address Long-term Side Effects of Chemotherapy

any primary care physicians (PCPs) are unaware of the long-term side effects of 4 commonly used chemotherapy drugs for breast and colorectal cancer, according to results of the large Survey of Physician Attitudes Regarding the Care of Cancer Survivors (SPARCCS). Oncologists were much more likely to be aware of the late effects of all 4 drugs, but the survey suggested that there is still room for improvement in educating oncologists about late effects of cyclophosphamide, 1 of the 4 drugs included in the study. With nearly 12 million cancer survivors in the United States who transition from the oncologist’s office to primary care settings, knowledge about late effects of treatment is a growing area of importance to optimize survivorship care, explained lead author Larissa Nekhlyudov, MD, assistant professor at Harvard Medical School and internist at Harvard Vanguard Medical Associates in Boston, Massachusetts. “While we strongly encourage patients to be aware of the chemotherapy drugs they receive and their side effects, it is vitally important that oncologists relay this information to patients’ primary care providers so their risks can be appropriately managed throughout their lives,” she stated. SPARCCS surveyed 1072 PCPs and 1130 oncologists by mail in 2009. Doctors were asked to identify which of 5 late effects of doxorubicin, paclitaxel, oxaliplatin, and cyclophosphamide were most common in their practices or mentioned in the literature. While 95% of oncologists correctly identified cardiac dysfunction as a late effect of doxorubicin, only 55% of PCPs were able to do so. Peripheral neuropathy was correctly identified as being a late effect of oxaliplatin and paclitaxel by approximately 97% of oncologists, whereas only 22% of PCPs correctly cited this late effect for both drugs. The findings were even more worrisome for 2 late effects of cyclophos-

Knowledge about late effects of treatment is a growing area of importance to optimize survivorship care. phamide, with premature menopause and second cancers being correctly identified by 72% and 62% of oncologists, respectively, versus only 15% and 17% of PCPs, respectively. Finally, only 6% of PCPs were able to correctly identify late side effects of all 4

drugs compared with 65% of oncologists. In an adjusted analysis, being board certified in oncology and spending more time on patient care were strongly associated with the likelihood of correctly identifying late effects of these drugs. “These findings should give us pause.

Patients need summaries of the care and guidelines for survivorship to bring with them to primary care. This study makes a good case for electronic medical records. We need to educate primary care physicians and make sure the ball does not get dropped [during the transition to primary care],” stated ASCO President Michael Link, MD. l —AG Reference Nekhlyudov L, Aziz N, Lerro CC, Virgo KS. Oncologists’ and primary care providers’ awareness of late effects of cancer treatment: implications for survivorship care. Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract 6008.

ASCO QOPI for Family History Taking

SCO’s Quality Oncology Practice Initiative (QOPI), an oncology-led, quality assessment and improvement program, measured family history taking and genetic counseling/testing practices among 750 community oncology practices. Results of this study revealed gaps that need to be addressed in making sure the taking of family history is accurate and patients whose cancers may have a heritable component get referred for genetic counseling and testing. In general, among community practices, higher rates of family history taking were observed than for appropriate genetic counseling and testing. The study was confined to patients with breast cancer and colorectal cancer. “An accurate family history and appropriate referral for genetic testing has important implications for the treatment and follow-up of patients, as well as for their family members,” said lead author Marie Wood, MD, professor of medicine and director of the Familial Cancer Program at the University of Vermont in Burlington. “We found that community oncologists were better at

“An accurate family history and appropriate referral for genetic testing has important implications for the treatment and follow-up of patients, as well as for their family members.” —Marie Wood, MD

documenting family history information than we assumed, but there is room for improvement.” The study included 212 community oncology practices and 10,466 patients’ charts. More than three-quarters (77%) of charts included first-degree family histories of cancer, and 62% documented second-degree cancer histories as well. However, less than half of charts documented the age at diagnosis for all relatives with cancer. Twenty-two percent of all patients were referred for genetic counseling or testing. Of patients with guidelinedefined hereditary risk, 52% of breast cancer and 26% of colorectal cancer patients were referred for genetic coun-

seling or testing. When genetic testing was performed by the practice, consent was documented in 78% and discussion of results was documented in 79%. The authors stated that significant developments are needed to improve identification and management of patients at high risk who should be counseled and tested. Education is an important component to address this problem. l —AG Reference Wood M, Kadlubek P, Lu KH, et al. Quality of cancer family history and referral for genetic counseling and testing among oncology practices: a pilot test of quality measures as part of the ASCO Quality Oncology Practice Initiative (QOPI). Presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 2012; Chicago, IL. Abstract CRA1505.

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Ginseng Improves Cancer-Related Fatigue

inseng has significant activity against fatigue in adults with cancer, according to a randomized trial.1 Eight weeks of treatment with ginseng significantly improved fatigue

scores by 20% versus 10% for patients treated with placebo (P = .003). Moreover, ginseng was as safe as placebo in this preliminary trial. Fatigue is almost universally com-

mon in patients treated for cancer, and many patients continue to experience fatigue for up to 10 years after their treatments are completed, explained lead author Debra Barton,

“Quality care is everyone’s business.” Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Nurse Practitioner, Multiple Myeloma Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH

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RN, PhD, of the Mayo Clinic Cancer Center in Rochester, Minnesota. Erythropoietin had been used to treat cancer-related fatigue, but it is no longer used because serious adverse events were found to outweigh the benefits. The trial enrolled 364 cancer patients being treated with curative intent at 40 sites; all patients reported at least moderate fatigue, reflected by a score of 4 or higher on a 10-point fatigue scale. Other causes of fatigue were ruled out, including anemia, pain, and insomnia. Patients received double-blind, randomized assignment to 2000 mg/day of ground Wisconsin ginseng root in the form of 2 capsules or to placebo taken before noon for 8 weeks. Mean age was 55 years, about 80% were female, and about 90% were white. About 60% had breast cancer, and about 10% had colon cancer. Pain scores improved over the course of treatment. At 4 weeks, a trend was seen favoring ginseng, according to change on the 100-point Multidimensional Fatigue Symptom Inventory score: an improvement of 14.4 points was reported with ginseng versus an 8.2 improvement in placebo patients (P = .07). By 8 weeks, scores improved by 20 points from baseline in the ginseng group versus 10.3 points with placebo (P = .003). Rates of nausea, diarrhea, and vomiting were quite low and were similar in the 2 groups. Insomnia and anxiety were reported less often in the ginseng group than in the placebo patients. Grade 3 or 4 adverse events were reported in 8% and 6% of patients, respectively. Formal discussant of this trial, Karen M. Mustian, PhD, MPH, of the University of Rochester, New York, commended the authors for using wellvalidated measures of cancer-related fatigue. “Ginseng has no discernible toxicity. This is only the second nutritional supplement to show effectiveness in reducing cancer-related fatigue,” she said. The NCCN guidelines for cancerrelated fatigue recommend psychological intervention, physical activity, psychostimulants, and steroids.2 Mustian said, “It may be time to recommend specific nutritional supplements, such as ginseng.” l —AG References

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

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Prostate Cancer

MDV3100 Extends Survival in Men With Advanced Prostate Cancer By Alice Goodman

he novel agent MDV3100 prolonged survival in men with castration-resistant prostate cancer (CRPC) who progressed on treatment with docetaxel, according to results of the large phase 3 AFFIRM trial reported at the 2012 American Society of Clinical Oncology Genitourinary Cancers Symposium held in San Francisco, California. The trial was halted early by an Independent Data Monitoring Committee in November 2011 due to the obvious survival benefit of MDV3100, and men in the placebo group were offered MDV3100 treatment. Results reported were based on interim results leading to the trial’s discontinuation. “MDV3100 significantly and meaningfully prolonged survival by nearly 5 months in men with late-stage prostate cancer. Secondary measures of time to progression and response were all consistent with the survival benefit. The drug was well tolerated. The favorable benefit:risk ratio will likely position

MDV3100 as the frontline agent in the post-docetaxel setting,” stated Howard Scher, MD, Memorial Sloan-Kettering Cancer Center, New York City. MDV3100 is a first-in-class, oral investigational agent designed to target and inhibit androgen receptor signaling, which is a major driver of prostate cancer growth. The randomized, double-blind, placebo-controlled, multinational AFFIRM trial enrolled 1199 men with late-stage CRPC in whom docetaxel chemotherapy failed. They were randomized 2:1 to treatment with MDV3100 160 mg/day versus matched placebo. MDV3100 achieved a median overall survival of 18.4 months versus 13.6 months for placebo, reflecting a highly significant 37% reduction in risk of death (P <.0001). The survival benefits were supported by secondary outcome measures. A significantly higher proportion of patients in the MDV3100 arm demonstrated evidence of tumor shrinkage on CT or

MRI imaging (soft tissue response on imaging 28.9% for MDV3100 vs 3.8% for placebo; P <.0001). Additionally, significantly more men treated with the androgen receptor signaling inhibitor had declines of 50% or greater in prostate-specific antigen (PSA) levels

MDV3100 is a first-inclass, oral investigational agent designed to target and inhibit androgen receptor signaling. from baseline versus placebo patients (54% vs 1.5%, respectively; P <.0001). Median time to confirmed PSA progression was 8.3 months for MDV3100 versus 3 months for placebo (P <.0001). MDV3100 had exceptionally good tolerability in this compromised group of patients. A similar percentage of

men experienced adverse events: 98.1% in the MDV3100 group and 97.7% in the placebo group. More serious adverse events were reported in the placebo group: 45.3% for MDV3100 and 53.1% for placebo. Further, more drug discontinuations due to adverse events were reported in the placebo group (7.6% and 9.8%, respectively), and more adverse events led to death in placebo patients (2.9% and 3.5%, respectively). Scher said that it is unusual for placebo patients to experience more serious adverse events than treated patients. MDV3100 joins the list of drugs known to extend survival in CRPC. These positive results were greeted with much enthusiasm. Press Cast moderator, Nicholas Vogelzang, MD, said: “I have just one word: Wow!” Vogelzang went on to say this drug will be studied earlier in the course of disease and in sequence or combination with other drugs known to improve survival in CRPC. l

Neoadjuvant Sipuleucel-T Generates Immune Response in Early Prostate Cancer

se of neoadjuvant sipuleucelT (Provenge) engendered an immune response in men with early-stage prostate cancer slated for radical prostatectomy (RP), according to a study presented at a poster session at the 2012 American Society of Clinical Oncology Genitourinary Cancers Symposium held in San Francisco, California. The vaccine is approved by the US Food and Drug Administration in the setting of rising prostate-specific antigen (PSA) level in metastatic castration-resistant prostate cancer, and this study suggests that it may be beneficial when used up front. Large randomized trials of sipuleucel-T at earlier stages of disease are ongoing. “This is an off-label use of sipuleucel-T. We wanted to see if we could induce an immune response similar to what we induce in castration-resistant prostate cancer when given earlier in the course of disease. We also wanted to assess its safety in this setting. The data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site,” said lead author Lawrence Fong, MD, UCSF

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Comprehensive Cancer Center, San Francisco, California. The tissue-based study included 40 patients with early prostate cancer slated to undergo RP. Median age was 61 years, and 98% were Caucasian. Patients were treated with 3 planned infusions of sipuleucel-T at approxi-

Thirty-eight of 42 patients (90%) received all 3 preoperative infusions of the vaccine; 3 received 2 infusions, and 1 received 0 infusions. IHC analysis was completed on 25 patients for CD3 and CD8 expression and on 23 for CD4 and FOXP3 expression. A greater than 3-fold increase was

“The data suggest that sipuleucel-T may modulate the presence of lymphocytes at the prostate tumor site.” —Lawrence Fong, MD

mately 2-week intervals, beginning 6 to 7 weeks prior to planned RP. Immunohistochemistry (IHC) to measure immune cell response was performed on tissue from pre-RP biopsies and on the prostatectomy specimen following sipuleucel-T treatment. Patients were followed for 72 weeks post-RP for safety and immune responses.

observed in mean CD3+ and CD3+/CD4+ cells per area as well as 2- to 3-fold increase in CD3+/CD8+ cells/area at the RP interface compared with pretreatment biopsy, RP tumor, and benign tissue. Regulatory T cells (CD3+/CD4+/FOXP3+ cells) were also increased at the tumor interface but represent a small population of the observed T cells.

On day 1 following pre-RP sipuleucel-T infusion, the following adverse events were reported in >5% of patients: fatigue (36%), headache (17%), myalgia (12%), arthralgia (10%), and chills (7%). One serious adverse event (infusion-related reaction) was reported. There did not appear to be any impact of sipuleucelT on surgery, Fong said. Nicholas Vogelzang, MD, Chair and Medical Director of the Developmental Therapeutics Committee of US Oncology, said this abstract was important. “The myth has been that sipuleucel-T is not a good immunotherapy and that we are not able to measure its effect on tumor. Yet we use other therapies in cancer that extend progression-free survival without being able to show an effect on the tumor. This abstract showed at a cellular level that immune cells are penetrating into cancer, providing proof of principle for studying it earlier in the disease.” A study is now under way in patients with rising PSA after RP or radiotherapy, comparing sipuleucel-T given before or after hormone therapy. l —AG

JULY 2012 I VOL 5, NO 6

Bladder Cancer Screening for Bladder Cancer Continued from cover American men in 2012, with an expected incidence of over 55,000 cases; for women, the incidence is estimated to be just under 18,000 new cases. More than 10,000 men are expected to die of the disease in 2012, with an estimated 4000 women succumbing as well. BC occurs 4 times more commonly in men than in women, and in twice as many white men as African American men.5 Efforts should be made to promote smoking cessation, as smoking is the most wellestablished risk factor for BC. Other risk factors include work-related exposures to dyes, rubber, and leather, as well as exposure to paints, solvents, and arsenic; certain previous infections of the bladder; older age; and a positive personal or family history of BC.1,3,5,6 It has been hypothesized that BC risk is related to the concentration of carcinogens in urine and the amount of time urothelial tissues are exposed to such causative agents. Therefore, increasing hydration as well as nocturia may be protective.1 Screening/Early Detection There are currently no guidelines for BC screening of asymptomatic adults. The American Cancer Society reviews its data annually and continues to recommend against screening for BC in patients at average risk.1,3,5 The US Preventive Services Task Force, upon review of the evidence of benefits versus harms of screening for BC in low-risk, asymptomatic individuals, and further based on their statement from 2004, states that the evidence is insufficient to recommend screening.3 Healthcare professionals, nonetheless, need to individualize their approach to care. Healthcare professionals need to consider the potential harms of screening for BC, including the possibility of false-positive results, which may lead to unnecessary diagnostic procedures. This can be the source of great stress and anxiety for patients. On the other hand, early detection of disease and, if possible, the identification of more aggressive cancers that require immediate interventions may have an important effect on morbidity and mortality. Therefore, screening some individuals may prove beneficial. However, current data do not provide certainty that earlier, less toxic

therapies improve outcomes versus waiting to use more toxic treatment in those with symptomatic or advanced tumors.3 For the asymptomatic individual, incidental microhematuria is often found on routine urinalysis and workup for other planned interventions, such as elective surgeries and annual physical exams. Occult blood found in the urine often prompts the patient to visit a urologist for further workup, generally urine cytology, cystoscopy, and imaging—the gold standard. For those at risk, this gold standard is employed for screening/early detection, minimally every 3 months, depending on interventions. Not only are these tests uncomfortable and

negatives) and high specificity (true negatives and no false-positives), as optimum sensitivity is crucial for screening and high specificity is imperative for disease confirmation. Lastly, the tool must also be acceptable to the population who will be assessed.1,9,10 Approved Markers Clinical application of markers includes screening, confirmation of diagnosis, classification and staging, prognosis, monitoring response, surveillance, and early detection of disease recurrence.9 However, the definition of markers useful for these applications is broad. Tumor markers are generally substances secret-

Current data do not provide certainty that earlier, less toxic therapies improve outcomes versus waiting to use more toxic treatment in those with symptomatic or advanced tumors.

embarrassing, but they are not always sensitive enough to detect cancer. Because superficial BC can be missed or may not be of metastatic potential, the standard is not enough to effect positive outcomes. For example, cystoscopy can miss flat tumors or carcinoma in situ, leading to 10% to 30% false-negative results.7 Consequently, the limitations of cytology and the invasiveness of cystoscopy have generated interest and investigation into various noninvasive diagnostic tools.8 In order for a diagnostic tool—ie, a screening method, biomarker, or tumor marker—to be effective, several elements must be in place. First, the disease prevalence must be an obvious healthcare issue, and diagnosing early would seem of benefit. Second, there should be acceptable treatments available. Third, the tool should be minimally invasive or noninvasive and cost-effective, or at least not prohibitively expensive. Fourth, the tool must be useful in the asymptomatic population, with high sensitivity (true positives and no false-

ed by the tumor, overexpressed by malignant cells, or secreted by the host in response to malignancies. These can be hormones, proteins, enzymes, receptors, and genomic alterations.9-11 It is hypothesized that the levels of these markers reflect tumor burden, thus increasing with malignancy and progression of disease and decreasing in response to treatment and with remission. For BC, there are a few US Food and Drug Administration (FDA)-approved markers available for use in the clinical setting, although currently they are utilized by discerning clinicians for complementary use alongside more standard interventions. Nevertheless, the use of these markers is not currently included in algorithms of recommended screening guidelines. Listed below are several FDAapproved markers for screening of BC: Nuclear matrix protein (NMP22) is a nuclear mitotic apparatus protein, released into urine as BC cells die. It is responsible for chromatid regulation and cell separation during replication. Approximately 70% of BC carcinomas

are positive for NMP22. The NMP22 BladderChek (NMP22BC) test kit detects antibodies in voided urine and thus is noninvasive. The overall sensitivity and specificity reported for this test are 50% to 90% and 60% to 90%, respectively. The FDA has approved this test for screening and monitoring of BC; note, however, that it is not currently included in screening guidelines.10-12 In their nonrandomized study (N = 203) comparing the sensitivity and specificity of urine cytology, NMP22BC, and UroVysion fluorescence in situ hybridization (FISH) (see below) in the detection of BC, Kehinde and colleagues concluded that NMP22BC appeared to be more cost-effective, more rapid, and relatively higher in sensitivity and specificity over urine cytology.13 They suggested that NMP22BC should replace urine cytology as the gold standard, although it should be coupled with cystoscopy. According to Sagnak and colleagues, in their small study (N = 164) looking at patients with asymptomatic hematuria, an ultrasound of the upper urinary tract coupled with the NMP22BC test for lower urinary tract investigation was found to be a better first-line screening tool than urine cytology, as it was more sensitive and less expensive. This combination of noninvasive testing also helped guide next steps, instead of going directly to cystoscopy.4 Two other recent studies evaluated the performance of NMP22BC over urine cytology, due in part to its rapid response and lesser expense. Both Weber and colleagues14 and Smrkolj and colleagues15 concluded that NMP22BC was more sensitive than urine cytology and suggested its use as a replacement for cytology; neither research group was able to suggest its use as a replacement for cystoscopy, however. Bladder tumor–associated analytes (BTA) are composed of collagen, fibronectin, laminin, and proteoglycan, which are components of basement membrane, released when bladder tumor cells attach to the bladder wall. BTA is elevated in approximately 30% of low-grade and 60% of high-grade tumors. The BTA assay detects H-relatContinued on page 16

Get involved: have you ever wanted to write an article for TON? We’re interested in articles about the everyday issues that affect nurses—everything from chemotherapy safe handling to supportive care for patients to challenging cases.

Contact editorial@greenhillhc.com for information. 14

JULY 2012 I VOL 5, NO 6

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Supportive Care

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

utpatient management of febrile neutropenia is appropriate for carefully selected lowrisk patients, according to Ashley Morris Engemann, PharmD, Duke University Medical Center, Durham, North Carolina, who spoke at the 2012 Pharmacy Program held in Hollywood, Florida, during the 17th Annual Conference of the National Comprehensive Cancer Network (NCCN). Engemann noted that treating patients at home is clearly the patient’s preference and is cost saving. Risk assessment is the first step, as outpatient management is not appropriate for high-risk patients but can be considered in low-risk patients. Highrisk patients are those with a score <21 on the MASCC (Multinational Association of Supportive Care in Cancer) index, which generally includes patients expected to have prolonged neutropenia (>7 days) or profound neutropenia (absolute neutrophil count ≤100 cells/mm3) following chemotherapy, and those with significant medical comorbidities or hepatic or renal insufficiency. “In general, we recommend hospitalization for IV antibiotics in these cases,” Engemann said. Low-risk patients (MASCC score ≥21) are anticipated to have a brief (≤7 days) neutropenic period or no or few comorbidities. “These patients may be treated with oral and/or outpatient empirical antibiotic therapy,”1 Engemann said. The 2012 NCCN Guidelines allow selected low-risk patients who are not already on fluoroquinolone prophylaxis to be considered for initial therapy with oral broad-spectrum antibiotics, most commonly with the following: • Ciprofloxacin 500 mg PO q8h plus amoxicillin/clavulanate 50 mg PO q8h • Ciprofloxacin plus clindamycin if allergic to penicillin While not part of the NCCN guidelines, there is supporting literature for levofloxacin 750 mg PO daily in selected patients.2 Recent Study Supportive but Underpowered Two key studies have evaluated the outpatient treatment of febrile neutropenia.3,4 A study from 2006 identified 178 outpatients who presented to the hospital with a first febrile neutropenia episode and who were deemed to be at low risk for complications.3 They were

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treated with oral ciprofloxacin and amoxicillin/clavulanate and observed over 24 hours while hospitalized. Of

these, 79 subjects (44%) were discharged early (median hospitalization time of 26 hours), while the other 56%

remained hospitalized. No difference in complication rates was observed. Three Continued on page 17

Pushing Your Limits Current activities at www.COEXM.com include:

Scan Here to Register.

To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s web browser, and select “Download” • Visit the app store for your smartphone

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JULY 2012 I VOL 5, NO 6

Bladder Cancer Screening for Bladder Cancer Continued from page 14 ed protein in voided urine. The overall sensitivity and specificity for this test are reported to be 57% to 83% and 60% to 92%, respectively. The FDA has approved the BTA assay for monitoring of disease, along with cystoscopy.10-12 UroVysion is a multitarget FISH assay that detects aneuploidy in chromosomes 3, 7, and 17 as well as loss of the 9p21 locus of the p16 tumor suppressor gene (P16). The FDA has approved this test for both screening and monitoring of BC, as it outperforms urine cytology in sensitivity. The high cost and need for large volumes of urine to detect tumor exfoliation, however, have prevented wider use of this test.10,12 ImmunoCyt combines cytology with immunofluorescence assay. It detects cellular biomarkers for BC in exfoliated urothelial cells for a high molecular weight form of carcinoembryonic antigen and 2 bladder tumor–associated mucins. The test is expensive and requires training to perform. It may perform better than cytology but should be coupled with cystoscopy. It is FDA approved for monitoring BC.10,12 Investigational Urine Markers Several promising, noninvasive urine tests are currently being investigated for use in various stages of the BC continuum (eg, screening, surveillance, monitoring). The high rate of disease recurrence in BC requires lifelong surveillance, gen-

erally with cystoscopy (painful, embarrassing, expensive), along with urine cytology (not very sensitive). Thus, the use of noninvasive markers will significantly improve disease management. Whether these markers can and will move into the cancer screening arena, ongoing investigation will reveal. Listed below are a few of the urine markers being investigated2,7,12,16,17:

Many tumor markers and biomarkers are being investigated for diagnosing and following bladder cancer in a noninvasive way. • The Aurora kinase A gene (AURKA) encodes a serine/threonine kinase associated with aneuploidy and chromosome instability • BLCA-1 and BLCA-4 are nuclear transcription factors present in BC • Human carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a cell adhesion molecule with proangiogenic activity • Epigenetic urinary markers analyze gene methylation

• Fibroblast growth factor receptor 3 (FGFR3) is mutated in 50% to 70% of primary bladder tumors and might be associated with good prognosis • Urinary hyaluronic acid (HA), a nonsulfated glycosaminoglycan, has been shown to yield 92% sensitivity and 93% specificity for BC detection • Microsatellite analysis allows for the evaluation of heterogeneity in chromosomes 9, 4p, 8p, 11p, and 17p • MicroRNAs (miRNAs) are noncoding RNAs that posttranscriptionally regulate gene expression • Survivin, a novel member of the inhibitor of apoptosis gene family, is overexpressed in human cancers and can be detected in urine • Telomerase is a ribonucleoprotein enzyme that acts in chromosomal instability by synthesizing telomere Conclusions Bladder cancer is a major healthcare concern, both in the United States as well as worldwide. More than 70,000 individuals are expected to be diagnosed in the United States this year. To date, there are no agreed-upon guidelines, based on evidence, for screening of the asymptomatic population. Problematic as well is the invasiveness of diagnostics, once workup is begun. Even microhematuria, often an incidental finding, requires further investi-

Reader Survey

Do patients talk to you about pain?

n the June issue, we published an article, “Let the Truth Be Told About Pain!” A patient currently receiving treatment for cancer told us how a nurse’s straightforward response helped her deal with her anxiety about pain. We asked our online reading community if their patients talked about pain. Clearly, this is an important issue for nurses, as we received more responses for this question than we have for any other question. • 83% said their patients talked to them about pain • 17% indicated that their patients did not talk to them about pain Here’s a sample of the comments: • Some patients require prodding to describe the pain or admit to pain because they equate pain with disease progression. • We ask. Every visit. • Pain assessment is the fifth vital sign. • I usually tell my patients that in the oncology setting there are many issues related to their disease that we don’t have control over, but pain is an issue that can be addressed and managed, and oftentimes relieved….No one should be suffering in pain.

Our sincere thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 33 for details.

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JULY 2012 I VOL 5, NO 6

gation. The current gold standard for diagnosis of BC is urine cytology, cystoscopy, and imaging. Many tumor markers and biomarkers are being investigated for diagnosing and following BC in a noninvasive way. The FDA has approved a number of these markers, which utilize voided urine, but currently, none has been incorporated into screening guidelines. Large randomized clinical trials are required to provide greater evidence on sensitivity and specificity for new markers and combinations of interventions for asymptomatic populations at variable risks. Better data for stratifying risk will enable improved algorithms for directing interventions. Until reliable markers or combinations of interventions are validated, cystoscopy remains the gold standard. l References 1. Shelton G. Bladder cancer. In: Yarbro CH, Wujcik D, Gobel BH, eds. Cancer Nursing Principles and Practice. 7th ed. Sudbury, MA: Jones and Bartlett; 2010:1080-1090. 2. Datta A, Adelson M, Mogilevkin Y, et al. Oncoprotein DEK as a tissue and urinary biomarker for bladder cancer. BMC Cancer. 2011;11:1-7. 3. Moyer VA; U.S. Preventive Services Task Force. Screening for bladder cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2011;155:246-251. 4. Sagnak L, Ersoy H, Gucuk O, et al. Diagnostic value of a urine-based tumor marker for screening lower urinary tract in low-risk patients with asymptomatic microscopic hematuria. Urol Int. 2011;87:35-41. 5. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. http://www.cancer.org. Accessed January 20, 2012. 6. Roobol MJ, Bangma MD, el Bouazzaoui S, et al. Feasibility study of screening for bladder cancer with urinary molecular markers (the BLU-P project). Urol Onc. 2010;28:686-690. 7. Murali A, Kasman L, Voelkel-Johnson C. Adenoviral infectivity of exfoliated viable cells in urine: implications for the detection of bladder cancer. BMC Cancer. 2011;11:168. 8. Tanaka MF, Sonpavde G. Diagnosis and management of urothelial carcinomas of the bladder. Postgrad Med. 2011;123:43-55. 9. Handy B. The clinical utility of tumor markers. Labmedicine. 2009;40:99-103. 10. Viale PH. Cancer diagnosis and staging. In: Gobel BH, Triest-Robertson S, Vogel WH, eds. Advanced Oncology Nursing Certification Review and Resource Manual. Pittsburgh, PA: Oncology Nursing Society; 2009:77-147. 11. DeMoranville VE, Best ME. Tumor marker tests. Encyclopedia of Surgery Web site. http://www.surgeryen cyclopedia.com/St-Wr/Tumor-Marker-Tests.html. Accessed April 17, 2012. 12. Tilki D, Burger M, Dalbagni G, et al. Urine markers for detection and surveillance of non-muscle-invasive bladder cancer. Eur Urol. 2011;60:484-492. 13. Kehinde EO, Al-Mulla F, Kapila K, Anim JT. Comparison of the sensitivity and specificity of urine cytology, urinary nuclear matrix protein-22 and multitarget fluorescence in situ hybridization assay in the detection of bladder cancer. Scand J Urol Nephrol. 2011;45:113-121. 14. Weber CM, Cauchi M, Patel M, et al. Evaluation of a gas sensor array and pattern recognition for the identification of bladder cancer from urine headspace. Analyst. 2011;136:359-364. ˆ 15. Smrkolj T, Mihelic M, Sedlar A, et al. Performance of nuclear matrix protein 22 urine marker and voided urine cytology in the detection of urinary bladder tumors. Clin Chem Lab Med. 2011;49:311-316. 16. Van Tilborg AAG, Bangma CH, Zwarthoff EC. Bladder cancer biomarkers and their role in surveillance and screening. Int J Urol. 2009;16:23-30. 17. Zuiverloon TCM, Tjin SS, Busstra M, et al. Optimization of nonmuscle invasive bladder cancer recurrence detection using a urine based FGFR3 mutation assay. J Urol. 2011;186:707-712.

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Breast Cancer

DM1 [a derivative of maytansine]). “First and foremost, the design of an ADC centers on the selection of an antigen that is tumor specific and accessible to antibody binding at the tumor cell,” explained Howard A. Burris III, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee. T-DM1, with its ability to bind HER2 with the same affinity as trastuzumab, maintains the activity of trastuzumab in addition to providing intracellular delivery of the antimicrotubule agent DM1. Presumably, the binding of T-DM1 to HER2 receptors leads to receptor internalization, followed by lysosomal degradation. Activated DM1 is then released from the lysosome into the cellular cytoplasm, which inhibits microtubule assembly and causes cell death, Burris explained at an educational session on ADCs. Potent cytotoxic agents are necessary for maximizing the role of the drug conjugates, a requirement that maytansine fills; however, its toxicity was prohibitive. Researchers recently improved the therapeutic index through conjugation with trastuzumab, leading to the development of its derivative, DM1. The in vitro cytotoxicity of DM1 is 10 to 200 times greater than that of taxanes. The compound also requires a highly stable linker: heterobifunctional reagent, N-succinimidyl

Photo © ASCO/Todd Buchanan 2012.

T-DM1 in Metastatic Breast Cancer Continued from cover

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

4-(N-maleimidomethyl)cyclohexane1-carboxylate (SMCC). EMILIA Shows the Drug’s Potential At the ASCO plenary session, investigators reported early results of the international phase 3 EMILIA study of TDM1 in metastatic breast cancer patients (Abstract LBA1). In a population of 991 advanced or metastatic patients who had already received trastuzumab and taxanes, treatment with T-DM1 was associated with an approximately 30% increase in progression-free survival (PFS) compared with a standard treatment regimen.

“For patients facing metastatic breast cancer, this is a breakthrough,” said lead author Kimberly L. Blackwell, MD, of Duke Cancer Institute at Duke University, Winston-Salem, North Carolina. Louis Weiner, MD, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, DC, the invited discussant of the study, commented, “Stated simply, T-DM1 really works in this patient population. It is an important new weapon in the therapeutic armamentarium for breast cancer.” Patients received intravenous TDM1 or capecitabine plus lapatinib every 3 weeks until disease progression. Those getting T-DM1 had a median PFS of 9.6 months, compared with 6.4 months for those on capecitabine/lapatinib. This represented a 35% reduction in the risk of progression (P <.0001), Blackwell reported. Median overall survival was not reached with TDM-1, and was 23.3 months with standard treatment, for a 38% reduction in mortality risk (P = .0005). This did not, however, meet the prespecified threshold for statistical significance for this end point at the first analysis. Nevertheless, after 2 years, 65.4% of the T-DM1 patients were alive, compared with 47.5% of the conventionally treated group. “There is an apparent survival benefit with T-DM1,” Blackwell said. It is expected that further analyses

will show a survival difference. Tolerability was far better with T-DM1 as well. Dose reductions were required for 16.3% of this arm, compared with 53.4% for capecitabine and 27.3% for lapatinib. With T-DM1, the diarrhea, vomiting, hand-foot syndrome, and alopecia typically observed with the chemotherapy regimen were not seen. The Future of T-DM1 Additional trials are now being conducted to evaluate T-DM1 as first-line treatment, including 2 randomized multicenter phase 3 trials of the drug in earlier lines of therapy. The MARIANNE trial is comparing the efficacy and safety of T-DM1 alone and in combination with pertuzumab—another drug with striking activity in breast cancer when combined with trastuzumab. The experimental combination will be compared with the standard trastuzumab/taxane regimen, Burris noted. Burris concluded, “T-DM1 meets the criteria for a successful ADC by combining the targeted effect of trastuzumab with the cytotoxic potency of DM1 using a stable linker and minimizing systemic toxicity. In addition, other tumor histologies, such as gastrointestinal cancers that are HER2-positive, may be sensitive to this agent.…An aggressive portfolio of phase 2 and 3 clinical trials will help determine the role of T-DM1 in earlier lines of therapy or with combination of other targeted agents.” l

Supportive Care Many Febrile Neutropenia Patients Can Be Treated at Home Continued from page 15 patients in the early discharge group were readmitted for various reasons. The success rate for outpatient treatment was 96%. In 2011, Talcott and colleagues also reported success with early discharge in a study of 121 patients who developed postchemotherapy fever and neutropenia and were deemed at low risk.4 Patients were either discharged for home treatment (n = 50) or continued on hospital treatment (n = 71) with the same IV antibiotic regimen (penicillin/aminoglycoside combination or ceftazidime alone; imipenemor aztreonam-based regimen if allergic; vancomycin added at discretion of physician). Oral antibiotic therapy was not standard at the time. “Unfortunately, this study was closed early due to poor accrual so we cannot draw significant conclusions,” Engemann said, “but it showed the feasibility of outpatient treatment.” The median duration of fever was

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3 days; of neutropenia, 4 days; and of febrile neutropenia, 4 days. Sub sequent antibiotic changes were more common in hospitalized patients (24% vs 9%; P = .04). Four outpatient episodes (9%) resulted in hospital readmission. Major medical complications occurred in 8% of hospitalized patients and 9% of outpatients. Quality-of-life measures slightly favored the outpatient treatment, but most measures were equivalent. Home Treatment Is Less Expensive “It’s no surprise the cost of home management is much less,” she added. This was confirmed by a study published in 2011 in which investigators collected direct medical and self-reported indirect costs for 57 inpatient and 35 outpatient episodes (2008 dollars).5 In the hospitalized group versus the home treatment group, mean total charges were 49% higher ($16,341 vs $10,977; P <.01), mean estimated total costs were 30%

higher ($10,143 vs $7830; P <.01), and patient/caregiver out-of-pocket costs were higher (mean, $201 vs $74;

Risk assessment is the first step, as outpatient management is not appropriate for high-risk patients but can be considered in low-risk patients.

P <.01). Informal caregivers in both groups reported similar time caring for patients and time lost from work. “The study concluded that home IV antibiotic treatment was less costly than

continued inpatient care for carefully selected patients,” Engemann said. “At this point, it’s not known whether oral and IV therapy are equally effective, but we do know that early discharge following evaluation is a strategy we can use and it has cost savings.” l References 1. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2011;52:e56-e93. 2. Freifeld A, Sankaranarayanan J, Ullrich F, et al. Clinical practice patterns of managing low-risk adult febrile neutropenia during cancer chemotherapy in the USA. Support Care Cancer. 2008;16:181-191. 3. Klastersky J, Paesmans M, Georgala A, et al. Outpatient oral antibiotics for febrile neutropenic cancer patients using a score predictive for complications. J Clin Oncol. 2006;24:4129-4134. 4. Talcott JA, Yeap BY, Clark JA, et al. Safety of early discharge for low-risk patients with febrile neutropenia: a multicenter randomized controlled trial. J Clin Oncol. 2011;29:3977-3983. 5. Hendricks AM, Loggers ET, Talcott JA. Costs of home versus inpatient treatment for fever and neutropenia: analysis of a multicenter randomized trial. J Clin Oncol. 2011;29:3984-3989.

JULY 2012 I VOL 5, NO 6

CONTINUING EDUCATION JULY 2012 • VOLUME 5 • NUMBER 2

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

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

Chief Operating Officer Pam Rattananont Ferris

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

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

Director, Production and Manufacturing Alaina Pede

FROM THE

EDITOR-IN-CHIEF

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

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

Director, Creative and Design Robyn Jacobs

FACULTY

Quality Control Director Barbara Marino

Web Coordinator Jose Valentin

Business Manager Blanche Marchitto

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

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

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

Executive Administrator Jackie Luma

Circulation Department circulation@greenhillhc.com

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

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

JULY 2012 I VOL 5, NO 6

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

through the joint sponsorship of the Medical Learning Institute, Inc. and the Center of Excellence Media, LLC. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute, Inc. (MLI). Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours. Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.25 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-12-024-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by MLI for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose. Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosed that her spouse is investigator on a study for Agenix and Lilly; on the data monitoring committee for Infinity; and on the data monitoring committee and principal investigator on a study for Pfizer.

*Amrita Y. Krishnan, MD, FACP, is a consultant for Celgene Corporation, and is on the speakers’ bureau for Celgene Corporation, Genentech, and Millennium: The Takeda Oncology Company. Christina Boeckman, RN, ANP-C, AOCNP, has nothing to disclose. *Sepideh Shayani, PharmD, BCOP, is on the advisory board for Genzyme. *Content will include non–FDA-approved uses. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Agenda: 1.25 hours Articles/Commentaries: 60 minutes Evaluation/Posttest: 15 minutes Date of original release: July 12, 2012 Valid for CME/CE credit through: July 12, 2013

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

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

Introduction Despite the development of more effective induction regimens and the increased use of autologous stem cell transplant (ASCT), most patients with multiple myeloma (MM) eventually relapse and suc-

response, as this has been correlated with improved overall survival (OS).1,2 Maintenance therapy with novel agents can contribute to these treatment goals, especially in patients who do not achieve a CR with transplant alone. I am less likely to use maintenance in standard-risk patients who achieve CR, because of concern that the risk of continued drug treatment may outweigh benefit in this population. Of course, there are always exceptions, and the approach to therapy must be individualized to the patient. Many questions remain on the optimal use of maintenance therapy, because we do not yet have unequivocal evidence that it prolongs OS in specific MM subgroups.3,4

cumb to progressive disease. Novel agents that have demonstrated good clinical activity in the frontline and relapsed settings continue to be evaluated as maintenance therapy, with the goal of delaying

What evidence has influenced your approach to maintenance therapy?

relapse and extending survival. However, important questions related to the use of these therapies remain unresolved. In this article, Amrita Y. Krishnan, MD, FACP, shares her insight on recent clinical data and ongoing issues in the maintenance setting for myeloma.

When do you consider maintenance therapy for your patients with MM?

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

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

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CONTINUING EDUCATION

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

80 70

Patients (%)

60 50 40 30 20 10 0

All pts

t(4;14)

del(17p)

PFS

All pts

t(4;14)

del(17p)

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

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

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

Placebo

P Value

46 months

27 months

<.001

3-Year PFS rate

66% (95% CI, 59-73)

39% (95% CI, 33-48)

—

3-Year OS rate

88% (95 CI, 84-93)

80% (95 CI, 74-86)

—

Median TTP

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

65/GMMG-HD4 suggested a benefit with bortezomib-based induction plus maintenance,5 as did data from the Total Therapy 3 trial.7 In addition, a recent study by Neben and colleagues reported that patients with del(17p) who received bortezomib before and after ASCT had a median PFS of 26.2 months compared with 12.0 months for patients who did not receive bortezomib (P=.024), with 3-year OS rates of 69% and 17%, respectively (P=.028).8 The results of this trial are changing the landscape of treatment for patients with del(17p). For patients with a partial response after ASCT, I generally use lenalidomide maintenance, based on results from the CALGB 100104 and IFM 2005-02 trials.9,10 CALGB 100104 compared single-agent lenalidomide maintenance with placebo in patients with stable disease or better (including patients who achieved CR) following ASCT. This study demonstrated significantly longer time to progression and improved survival in the lenalidomide arm versus the placebo arm (Table).9 IFM 2005-02 also compared singleagent lenalidomide maintenance with placebo post-ASCT (after 2 courses of lenalidomide consolidation in both arms).10 In this study, lenalidomide maintenance improved median PFS to 41 months versus 23 months with placebo (P<.001), with benefit across cytogenetic subgroups. Three-year and 4-year OS rates were comparable in the lenalidomide versus placebo groups: 80% versus 84% (3-year) and 73% versus 75% (4-year), respectively. Recent data from the RV-MM-PI-209 trial add further support to the use of lenalidomide maintenance after consolidation.11 Patients received induction with lenalidomide and low-dose dexamethasone, followed by either

JULY 2012 I VOL 5, NO 6

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

Currently, there is no consensus regarding the optimal duration of maintenance therapy for myeloma. In HOVON-65/GMMG-HD4, patients received bortezomib maintenance for 2 years.5 In CALGB 100104, lenalidomide maintenance was given until progression.9 The investigators in the IFM 2005-02 trial planned to use lenalidomide until progression but stopped therapy once secondary malignancies arose.10 In the ongoing phase 3 multicenter BMT CTN 0702 trial, we plan to give lenalidomide maintenance therapy for 3 years.17 However, many questions remain unresolved. What is the optimal duration of lenalidomide therapy to improve PFS and possibly OS? Since bortezomib-related neuropathy may shorten maintenance time, can we reduce the incidence and severity of this toxicity and extend the duration of time that patients can stay on maintenance by using subcutaneous bortezomib18 or an alternate proteasome inhibitor such as carfilzomib or MLN9708?19-22 Hopefully, emerging clinical data and ongoing research will better define the role of novel agents in the maintenance setting and provide answers to these questions. ◆ References 1. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009;27:5720-5726.

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CONSIDERATIONS IN MULTIPLE MYELOMA

2. Harousseau J-L, Attal M, Avet-Loiseau H. The role of complete response in multiple myeloma. Blood. 2009;114:3139-3146. 3. Ludwig H, Duries BGM, McCarthy P, et al. IMWG consensus on maintenance therapy in multiple myeloma. Blood. 2012;119:3003-3015. 4. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011;118:3205-3211. 5. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 40. 6. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634. 7. Shaughnessey JD, Zhou Y, Haessler J, et al. TP53 deletion is not an adverse feature in multiple myeloma treated with total therapy 3. Br J Haematol. 2009;147:347-351. 8. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948. 9. McCarthy PL, Owzar K, Hofmeister CG, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 10. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 11. Cavallo F, Hardan I, Gay F, et al. Lenalidomide maintenance significantly reduces the risk of progression in newly diagnosed young multiple myeloma patients enrolled in RV-MM-PI-209 trial. Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands. 12. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-ineligible newly diagnosed multiple myeloma: update on patients aged 65-75 years enrolled in MM-015. Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands. 13. Hicks LK, Haynes AE, Reece DE, et al. A meta-analysis and systematic review of thalidomide

for patients with previously untreated multiple myeloma. Cancer Treat Rev. 2008;34:442-452. 14. Morgan GJ, Jackson GH, Davies FE, et al. Maintenance thalidomide may improve progression free but not overall survival: results from the Myeloma IX maintenance randomisation. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 656. 15. Stewart AK, Trudel S, Bahlis NJ, et al. A randomized phase III trial of thalidomide and prednisone as maintenance therapy following autologous stem cell transplantation (ASCT) in patients with multiple (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 39. 16. Delforge M, Dimopoulos M, Adam Z, et al. Safety profile and management in MM-015 comparing lenalidomide-melphalan-prednisone followed by lenalidomide maintenance (MPR-R) with MP and MPR in newly diagnosed multiple myeloma (NDMM). Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands. 17. Stem cell transplant with lenalidomide maintenance in patients with multiple myeloma (BMT CTN 0702). ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01109004. Updated March 28, 2012. Accessed June 30, 2012. 18. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 19. Jakubowiak AJ, Griffith KA, Dytfeld D, et al. Stringent complete response (sCR) in patients (pts) with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012; 30(suppl):Abstract 8011. 20. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8017. 21. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8033. 22. Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): a phase I study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8034.

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

Introduction Along with the clinical benefits seen with maintenance regimens for multiple myeloma (MM), new challenges have arisen, due to the increased risk of adverse events associated with prolonged use of therapy. As a member of the cancer care team, it is the nurseâ&#x20AC;&#x2122;s responsibility to anticipate which toxicities and complications are likely to occur, to employ the necessary interventions, and to counsel patients

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

accordingly. In this article, Christina Boeckman, RN, ANP-C, AOCNP, discusses effective nursing strategies in the maintenance setting, and shares her perspectives on preventing and managing common

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

adverse events related to the use of novel agents.

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

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

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

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

Modification of Dose and Regimen

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

No action

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

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

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

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

Grade 4 (permanent sensory loss that interferes with function)

Discontinue bortezomib

Grading based on NCI Common Toxicity Criteria CTCAE V 3.0.

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

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

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

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

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1. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology Am Soc Hematol Educ Program. 2009:566-577. 2. Tariman JD, Love G, McCullagh E, Sandifer S; IMF Nurse Leadership Board. Peripheral neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):29-36. 3. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 4. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030. 5. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica. 2010;95:311-319. 6. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals; January 2012. 7. Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; October 2010.

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CONSIDERATIONS IN MULTIPLE MYELOMA

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

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

age or comorbidities, the schedule of bortezomib (1.3 mg/m2) used for induction was reduced from twice weekly to once weekly. In addition, both the VMPT and VMP schedules were changed to nine 5-week cycles. Results showed a benefit with VMPT/VT compared with VMP alone, in terms of complete response rates (38% vs 24%; P<.001), PFS (56% vs 41%, P=.008), and time to next treatment. Importantly, the once-weekly schedule of bortezomib lowered discontinuation rates and prolonged time on therapy. This finding has important clinical implications, especially for the treatment of older patients who may have difficulty tolerating a standard regimen. The schedule adjustment used in this study also significantly reduced the incidence of severe sensory PN from 16% to 3% (P<.001).

ed agents, such as bortezomib and lenalidomide, have the potential to extend duration of response following frontline therapy, and are generally better tolerated and more effective than older, conventional therapies used for this indication. In this article, Sepideh Shayani, PharmD, BCOP, discusses recent advances in the maintenance setting, and answers questions related to the administration of

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

novel agents.

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

To date, a standard dose and schedule has yet to be established for bortezomib maintenance; however, data from recent clinical trials can be helpful in guiding therapeutic decisions. As in the frontline and relapsed/refractory settings, it is essential to strike a balance between efficacy and safety when using novel agents as maintenance, especially since patients will be on therapy for an extended period of time. In the phase 3 HOVON-65/GMMG-HD4 trial, transplant-eligible patients with MM were randomly assigned to induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD).1 This was followed by high-dose melphalan and autologous stem cell transplant (ASCT). Patients started on VAD received thalidomide maintenance at a dose of 50 mg/day for 2 years (arm A) and those randomized to PAD received bortezomib maintenance at a dose of 1.3 mg/m2 biweekly for 2 years (arm B). In this trial, progression-free survival (PFS) was lower with VAD/ ASCT/thalidomide compared with PAD/ASCT/bortezomib (42% vs 46% at 36 months, P=.047). Overall survival was significantly higher in arm B (P=.048). A total of 67% of patients in arm A and 57% in arm B started maintenance therapy, and 64% and 47% of those patients, respectively, went off protocol due to various factors (Table 1). Grade 3/4 peripheral neuropathy (PN) was observed in 7% of patients in arm A and 16% of patients in arm B. In the phase 3 GIMEMA trial, patients with MM were randomized to nine 6-week cycles of induction with bortezomib, melphalan, prednisone, and thalidomide (VMPT) followed by 2 years of maintenance with bortezomib (1.3 mg/m2 every 14 days) plus thalidomide (50 mg/day) (VT) or to nine 6-week cycles of VMP induction without maintenance.2 Early in this trial, which enrolled patients who were not eligible for transplant due to advanced

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

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

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

Progression

Other

Overall

Thalidomide

31%

64%

Bortezomib

29%

47%

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CONTINUING EDUCATION

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

MPR (Gr 3/4)

MPR-R (Gr 3/4)

Neutropenia (%)

29/8

64/32

67/35

Thrombocytopenia (%)

12/4

38/12

35/11

Anemia (%)

14/1

26/3

24/3

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

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

We are seeing RVD used more frequently as induction therapy in MM, so data from this study should be relevant to clinical practice. The phase 3 MM-015 trial randomized elderly, transplant-ineligible MM patients to 9 cycles of melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R), or to 9 cycles of MPR or MP without maintenance.7,8 In this study, the scheduled dose of lenalidomide (during induction and maintenance) was 10 mg/day, given on days 1 to 21. Patients could receive maintenance until disease progression or development of intolerance. After a median follow-up of 27 months, PFS was significantly longer with lenalidomide maintenance (31 vs 14 vs 13 months for MPR-R, MPR, and MP, respectively; MPR-R vs MP, P<.001). The most common adverse events were hematologic; these occurred more frequently in patients who received lenalidomide. Grades 3 and 4 hematologic toxicities in this study are shown in Table 2. However, during the maintenance phase of MPR-R, the incidence of new or worsening toxicities was low. Discontinuation due to adverse events in the MPR-R, MPR, and MP arms was observed in 16%, 14%, and 5%, respectively. These rates were higher in patients >75 years of age than in those 65 to 75 years of age, as was the need for dose reductions. Incidence of second primary malignancies was low, corresponding to 3.04, 2.57, and 0.98 per 100 patient-years for MPR-R, MPR, and MP, respectively.8 BMT CTN-0702, a new phase 3 multicenter trial, will evaluate the safety

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

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

References 1. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 40. 2. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalanprednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109. 3. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple myeloma: background and practical recommendations. Haematologica. 2010;95:311-319. 4. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals; January 2012. 5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440. 6. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791. 7. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 8. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-ineligible newly diagnosed multiple myeloma: update on patients aged 65-75 years enrolled in MM-015. Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands. 9. ClinicalTrials.gov Web site. Stem cell transplant with lenalidomide maintenance in patients with multiple myeloma (BMT CTN 0702). http://clinicaltrials.gov/ct2/show/NCT01109004. Updated March 28, 2012. Accessed July 3, 2012. 10. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8017. 11. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8033.

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Cancer Center Profile Cancer Institute of New Jersey Continued from cover What are you excited about right now in the cancer field? Janet Gordils-Perez (JGP): We are excited about “precision medicine.” This is a personalized approach to prescribing cancer treatment. CINJ has always been on the cutting edge of providing the latest treatments, and now efforts are directed at how molecular and genetic information is being used to diagnose and treat cancer. Lorna Oncology nurses at CINJ celebrate Nurses Day earlier this year. Rodriguez, MD, PhD, is leading CINJ’s initiative for precision understand and address all of the the field is to keep learning and asking questions. What you have learned in medicine. patient’s distinct needs. What has changed in nursing is that your educational preparation is just the What approach does your the care we now provide is not based on foundation. You need to build on this institution take to treating tradition or rituals but on evidence-based through continuous learning—by people with cancer? practice. We now use the latest research attending conferences; furthering your JGP: As 1 of only 41 NCI-designated findings and translate these into our education to receive a BSN, master’s comprehensive cancer centers and the nursing practice to improve patient care degree, DNP, or PhD; reading journals only one in New Jersey, CINJ is dedicat- and outcomes. Nurses are able to incor- to keep updated on the latest therapies; ed to improving the prevention, detec- porate best practices with clinical com- becoming certified in your specialty; tion, treatment, and care of patients with petence and patient preferences, values, etc. This will help you to maintain comcancer through the transformation of and beliefs. We personalize the evidence petency in nursing practice and provide laboratory discoveries into clinical prac- to fit the patient’s particular situation. your patients with the best nursing care tice. We are committed to providing We provide patient-centered care that possible. Nursing is such a rewarding treatment options that are as unique as is evidence based. Evidence Source field, and there are so many varied roles the patients we are treating. Equation = clinician experience + in nursing that one can hold. patient preferences + scientific findings. How does that translate to better If you weren’t working in this field, What inspired you to enter the field outcomes for your patients? what would you be doing? JGP: Breakthroughs in diagnosis and of oncology nursing? The following are responses from some of drug treatment as well as technology JGP: As a high school senior applying to the nurses at CINJ: and biomedical informatics will allow colleges, I knew I wanted to go into nursclinicians to tailor cancer treatments ing. However, I wanted to work on a sur- Treatment Area Nurse Manager to individual patients and will expec- gical unit. When I completed my BSN, Carla Schaefer, BSN, RN, OCN: A tantly lead to better patient outcomes. the college counselor suggested that my photographer. That is my biggest hobby. This can have a profound effect in the first interview be at an institution I real- I like to shoot nature shots—flowers, prevention, prognosis, and treatment ly wasn’t interested in to practice my bugs, and landscapes. interviewing skills. So I scheduled my of many cancers. first interview at an NCI-designated Staff Nurses in the Treatment Area How has the role of the oncology Comprehensive Cancer Center in New Andrew Kass, BSN, RN, OCN: nurse changed over the past York City. After touring 2 of the units, I I would be in the restaurant business. I 5 years? knew where I needed to work: at a can- would manage a restaurant. I like to JGP: I think nursing has always used cer center where cutting-edge research make people happy. This is what I do. the idea of personalized medicine— was taking place. Fortunately, I was treating the individual patient and hired, and my career in oncology began. Kira Lynn Voitle, BSN, RN, OCN: I not just the disease. Not on the genet- And what a wonderful journey it has would have a high-end wedding bouic or molecular level, of course, but by been and continues to be! tique with designer dresses. taking into consideration what makes up the individual patient (culture, Any advice for nurses just entering Alissa Coslit, BSN, RN, OCN: I would be a dolphin trainer. I like to have fun in beliefs, past experiences, family the field? dynamics, etc) to be able to better JGP: My advice to nurses just entering what I do—this seems like fun!

Cho Chan, BSN, RN, OCN: I would be a teacher. I love teaching my patients, and just seeing how they learn is very rewarding. Associate Director of Nursing and Patient Education Leah Scaramuzzo, MSN, RNBC, AOCN: I wouldn’t be anything else but a nurse—perhaps a nurse forest ranger. I love the outdoors, and I love nursing, so I would be doing both. Advance Practice Nurses Janice Germain, MSN, APN-C: I would still need to be in medicine. I would be a doctor. There has never been any doubt, I want to help people. When I was 13 years old, I was hospitalized and saw what doctors and nurses did for me; I was influenced by what they did. I love medicine. Carmela Hoefling, MSN, ANP-C, AOCNP: I would probably be teaching. It was between nursing and teaching to begin with. Never wanted to be sitting at a desk all day. Research Nurse Clinicians Marjorie LaRosiliere, RN: I would be a teacher. I enjoy working with kids. Sherri Damare, RN, MSN, OCN: I would love to teach. My MSN is in education. I enjoy teaching patients and nurses. Pediatric Staff Nurse, Treatment Area Dawn Yuhas, RN, CPON: I would be working somewhere in education (kindergarten to high school). Pediatric Nurse Manager Deena Centofanti, RN, MSN, AOCN: As a kid I was going to play the piano at Carnegie Hall. I didn’t really like to practice; hence, I wasn’t good enough. Once I decided to be a nurse, it was only oncology. Now, if I had to pick something, it would be in education. I guess that’s why I ran for school board. l

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Supportive Care

Use of Bone-Modifying Agents in Oncology Patients By Raj Duggal, PharmD Indiana University Simon Cancer Center, Indianapolis

Raj Duggal, PharmD

ith advances in the diagnosis and treatment of cancer, the estimated 5-year survival rate for cancer patients has significantly improved to approximately 67%.1 The most common malignancies in men and women in the United States—breast and prostate cancers— have 2 of the highest 5-year survival rates reported, at 90% and 99%, respectively.1 As oncology patients are living longer, bone health has become a pertinent issue in the treatment of both metastatic and nonmetastatic oncology patients.2 Bone metastases have been identified in approximately 68% of patients with metastatic prostate cancer and 73% of patients with metastatic breast cancer.2 Even though bone metastases are not typically life threatening, their complications, including severe pain, bone fractures, and spinal cord compression, can cause significant morbidity.3 Pharmacologic therapies utilized in the treatment of metastatic and nonmetastatic cancer, including hormone deprivation and corticosteroids, can stimulate osteoclast activity and result in bone demineralization. Prolonged therapy may result in significant bone loss leading to osteoporosis and bone fractures in both the metastatic and nonmetastatic populations.2

Bone Health in Metastatic Cancer In 2011, the American Society of Clinical Oncology (ASCO) published updated guidelines on the role of bonemodifying therapies in the management of metastatic breast cancer. While prior guidelines did include management of treatment-associated bone loss, ASCO limited this publication update to metastatic disease.4 Key changes in recommendations from this ASCO guideline update include4: • Bone-modifying agents are recommended for patients with metastatic disease and evidence of bone destruction; the following agents are recommended (none is recommended over another):

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– Denosumab 120 mg subcutaneously (SC) every 4 weeks – Zoledronic acid 4 mg intravenously (IV) over at least 15 minutes every 3 to 4 weeks – Pamidronate 90 mg IV over at least 2 hours every 3 to 4 weeks • Bone-modifying agents should be utilized as an adjunctive therapy, not as first-line treatment, for cancer-related bone pain, in addition to standard-of-care pain-management strategies (eg, nonsteroidal anti-inflammatory agents, opioid and nonopioid analgesics) This published guideline limits discussion to metastatic breast cancer with bone metastases.4 Since other solid tumors, including prostate cancer, frequently metastasize to the bone, clinicians should similarly support the implementation of bone-modifying therapies to promote bone health and decrease skeletal-related events in patients with bone metastases due to solid tumors.3

months to include the following7: • Treatment to increase bone mass in men at high risk for fracture receiving androgen-deprivation therapy for nonmetastatic prostate cancer • Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer • Treatment of postmenopausal women with osteoporosis at high risk for fracture Also in 2011, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) submitted a position paper on preventing bone loss and fractures in postmenopausal women receiving aromatase inhibitors for breast cancer.8 At a minimum, the final publication recommends measuring serum concentrations of parathyroid hormone, calcium, and 25-OH vitamin D prior to initiation of an aromatase inhibitor to establish the risk for osteoporosis. Pharmacologic interventions, including vitamin D and calcium supplementation, should be considered for all

Bone health has become a pertinent issue in the treatment of both metastatic and nonmetastatic oncology patients.

Bone Health in Nonmetastatic Cancer Some anticancer treatments commonly seen in breast and prostate cancer, including hormone deprivation and corticosteroids, increase osteoclast activity and result in loss of bone mass.2 Bone-modifying therapy should be considered for cancer patients with 1 of the following2: • T-score below -2.0 or • 10-year Fracture Risk Assessment Tool (FRAX) score: – ≥3% for hip fractures – >20% for all major fractures In 2011, the US Food and Drug Administration (FDA) completed the evaluation of the two phase 3 clinical trials of denosumab 60 mg SC every 6 months to prevent bone loss. These trials included patients with prostate cancer receiving androgen-deprivation therapy and breast cancer receiving aromatase inhibitors.5,6 As a result of these studies, the FDA expanded the approved indications for denosumab 60 mg SC every 6

patients receiving aromatase inhibitors to promote bone health.8 Bone-modifying therapy with either zoledronic acid 4 mg IV over at least 15 minutes every 6 months or denosumab 60 mg SC every 6 months should be considered in patients with osteoporosis or osteopenia with risk factors for fractures and continue as long as aromatase inhibitor therapy is maintained.8 There is no clear recommendation for bisphosphonate therapy in nonmetastatic prostate cancer for patients receiving androgen-deprivation therapy. Recent evaluations have studied zoledronic acid 4 mg IV every 3 months for 1 year and found that therapy improved bone mineral density. The FDA has approved the use of alendronate, risedronate, and zoledronic acid in men to decrease fractures and increase bone density.9 Oral bisphosphonate therapy can be considered as an alternative to IV therapy, but these agents may be associated with additional adverse effects and vari-

able compliance. In an evaluation on medication adherence, preference, and satisfaction in 250 postmenopausal women with low bone-mineral density, investigators determined that patients were significantly more compliant with denosumab 60 mg SC every 6 months compared with alendronate 70 mg by mouth once weekly.10 Additionally, at 12 months’ follow-up, those receiving denosumab were more likely to report being very satisfied or quite satisfied with the dosing frequency, route of administration, convenience, and overall satisfaction with treatment.10 Nonpharmacologic interventions should also be considered to further promote bone health. Additional supportive care measures include smoking cessation, minimizing alcohol consumption, and dietary supplementation with calcium (1000-1200 mg by mouth daily) and vitamin D (approximately 10,000 IU by mouth daily).8,9 Drug Safety Monitoring Safety concerns with bone-modifying therapies include, but are not limited to, renal toxicity, hypocalcemia, osteonecrosis of the jaw, and atypical femur fractures.4,11,12 Appropriate monitoring should occur at initiation of treatment and with each dose to minimize severe toxicities.4 The ASCO guidelines recommend the following for patients receiving bone-modifying therapies4: • Serum creatinine should be monitored prior to each dose of bisphosphonates • Serum calcium, electrolytes, phosphate, magnesium, and hemoglobin/hematocrit should be monitored regularly [no specific recommendation provided on the interval] • Calcium should be followed closely during denosumab therapy if the calculated creatinine clearance is less than 30 mL/min [no specific recommendation provided on the interval] • Prior to initiation of bone-modifying therapies, all patients should undergo a dental examination and preventive dentistry to minimize osteonecrosis of the jaw Although bisphosphonates are known to strengthen bone and prevent fractures, there have been reports that long-term therapy can lead to fragile bones and atypical fractures of the subtrochanteric or diaphyseal femur after minimal or no trauma; these atypical fractures account for less than 1% of hip

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Supportive Care and femur fractures overall.11-13 A safety announcement published by the FDA as an update to the bisphosphonate drug safety review in 2010 indicated that it is yet unclear whether these atypical fractures are related to bisphosphonate therapy; this safety evaluation is ongoing.13 Since this FDA update, 2 studies evaluating the rates of atypical fractures in nononcology patients with osteoporosis have been published. As described below, the studies do not rule out a correlation between bisphosphonate therapy and atypical fractures, but they do confirm that the rates of atypical femur fractures are very low with concurrent bisphosphonate therapy.11,12 In the first study, an evaluation of 12,777 Swedish women with femur fractures identified atypical fractures in 59 patients.11 The investigators concluded that, because 46 of the 59 patients with atypical fractures were on bisphosphonate therapy, there was a 47-fold increased risk compared to nonusers. Based on these results, they estimated that it would take 2000 bisphosphonate users per year to have 1 case of atypical fracture to occur.11 In the second study, investigators compared the incidence of atypical fractures between patients receiving either bisphosphonate therapy or nonbisphosphonate therapy (raloxifene or calcitonin) in 33,815 patients.12 Over the median follow-up of 2.13 years, 104 subtrochanteric or diaphyseal femur fractures occurred. There was no significant difference in the incidence of atypical femur fractures between bisphosphonate users and nonusers, however.12 Nevertheless, the authors could not eliminate the possibility that bisphosphonate therapy could increase the risk of atypical fractures with prolonged use.12 Ongoing Clinical Evaluations Many studies investigating novel therapies in the management of bone health are currently ongoing. New promising approaches to the management of bone health include tyrosine kinase inhibitors (dasatinib, cabozantinib, and saracatinib), endothelin-A receptor antagonists (atrasentan and zibotentan), and bisphosphonates tagged with radiopharmaceuticals.4,14,15 It is to be hoped that these novel therapies will provide more options for clinicians to manage the bone health of oncology patients. l References 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29. 2. Gralow JR, Biermann JS, Farooki A, et al. NCCN task force report: bone health in cancer care. J Natl Compr Netw. 2009;7(suppl 3):S1-S32. 3. Coleman RE, Guise TA, Lipton A, et al. Advancing treatment for metastatic bone cancer: consensus recommendations from the Second Cambridge Conference. Clin Cancer Res. 2008;14:6387-6395. 4. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-

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modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29:1221-1227. 5. Smith MR, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med. 2009;361:745-755. 6. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26:4875-4882. 7. Prolia [package insert]. Thousand Oaks, CA: Amgen Inc; September 2011. 8. Rizzoli R, Body JJ, De Censi A, et al; on behalf of the European Society for Clinical and Economical Aspects of Osteoporosis and Osteoarthritis (ESCEO). Guidance for the prevention of bone loss and fractures in post-

menopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper [published online ahead of print January 24, 2012]. Osteoporos Int. doi:10.1007/s00198-011-1870-0, http://www.springer link.com/content/0754828832806p24/fulltext.pdf. Accessed April 16, 2012. 9. Adler RA. Management of osteoporosis in men on androgen deprivation therapy. Maturitas. 2011;68:143147. 10. Kendler DL, McClung MR, Freemantle N, et al. Adherence, preference, and satisfaction of postmenopausal women taking denosumab or alendronate. Osteoporosis Int. 2011;22:1725-1735. 11. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364:1728-1737.

12. Kim SY, Schneeweiss S, Katz JN, et al. Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. J Bone Miner Res. 2011;26:993-1001. 13. US Food and Drug Administration. FDA drug safety communication: safety update for osteoporosis drugs, bisphosphonates, and atypical fractures. http://www. fda.gov/drugs/drugsafety/ucm229009.htm. Published October 13, 2010. Accessed April 18, 2012. 14. Hannon RA, Finkelman RD, Clack G, et al. Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a phase I study. Bone. 2012;50:885-892. 15. Saylor PJ, Lee RJ, Smith MR. Emerging therapies to prevent skeletal morbidity in men with prostate cancer. J Clin Oncol. 2011;29:3705-3714.

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

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

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

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

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

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

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

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

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

JULY 2012 I VOL 5, NO 6

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, RN, BSN Pamela J. Vlahakis, RN, MSN, CBCN Members • Getting Excited about Research – Case Examples Linda Fleisher, PhD, MPH Elaine Sein, RN, BSN, OCN, CBCN • Panel Discussion: Building Optimal Community Outreach – Lay and Community Jean B. Sellers, RN, MSN (Moderator) Leah Leilani Beck, BS Jessica Denton, MSW • Implementing a Survivorship Program/Clinic Cynthia Waddington, RN, MSN, AOCN Break Administrators Track • Administering a Navigation Program Bonnie J. Miller, RN, BSN, OCN, FAAMA Elizabeth Whitley, PhD, RN 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

Breakfast/Product Theater: New Route of Administration for Velcade® supported by Millennium Pharmaceuticals, Inc. 8:30 – 8:45am 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 – 11:30am Disease-Site–Specific Breakouts Stand-Alone Sessions • Breast Cancer Navigation Mary Rooney, RN, BSN, OCN • Thoracic Oncology Navigation 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 A. Atkinson, RN, BSN, OCN

•

Prostate Cancer Navigation Juli Aistars, RN, MS, APN, AOCN 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 TBD 2:15 – 3:15pm General Session 2: Best Practices in Survivorship Care Rehabilitation Julie Silver, MD 3:15 – 4:15pm General Session 3: Plenary Session Financial and Legal Issues for Our Cancer Patients David S. Landay, JD 4:15 – 5:00pm The Art of Exceptional Professional Performance – Making a Difference in Your Patients’ Lives Selinza Mitchell, RN 5:00 – 7:00pm Poster Award Reception in the Exhibit Hall Pamela Matten, RN, BSN, OCN 7:00pm 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, MSN 10:30 – 10:45am Break 10:45 – 12:15pm Practice Setting – Panel Discussion with Moderator • Office-Based Roxanne Parker, RN, MSN, CPN (Moderator) • Academic Bonnie J. Miller, RN, BSN, OCN, FAAMA • Community Hospital–Based Karyl Blaseg, RN, MSN, OCN 12:15 – 1:15pm Lunch in the Exhibit Hall 1:30 – 2:30pm Clinical Survivorship Guidance Mandi Pratt-Chapman, MA Katherine Sharpe, MTS 2:30 – 2:45pm Conclusion/Final Remarks Conference Co-Chairs *Preliminary agenda, subject to change.

September 14-16, 2012 Phoenix, Arizona Arizona Grand

CONFERENCE REGISTRATION Register online: www.regonline.com/aonn2012 *Early Bird Rate: $295 Includes Membership through September 30, 2013.

Conference Registration: $345 Includes Membership through September 30, 2013. *Early bird expires August 1, 2012.

TARGET AUDIENCE CONFERENCE CO-CHAIRS Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

This educational initiative is directed toward oncology nurse navigators, patient navigators, and social workers.

Lillie D. Shockney, RN, BS, MAS University Distinguished Associate Professor of Breast Cancer Adm Director, Johns Hopkins Clinical Breast Programs Adm Director, Johns Hopkins Cancer Survivorship Programs Depts of Surgery and Oncology Associate Professor, JHU School of Medicine, Depts of Surgery, Oncology and Gynecology Associate Professor, JHU School of Nursing Johns Hopkins Avon Foundation Breast Center Baltimore, MD

FACULTY* Juli Aistars, RN, MS, APN, AOCN

Roxanne Parker, RN, MSN, CPN

Robin A. Atkinson, RN, BSN, OCN

Mandi Pratt-Chapman, MA

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

Linda Fleisher, PhD, MPH

Lisa Shalkowski, RN, BSN, MSM

Maura Kadan, RN, MSN, OCN

Katherine Sharpe, MTS

Lauren Kelley, MSW, MPA

Julie Silver, MD

David S. Landay, JD

Nancy Skinner, RN-BC, CCM

Adrienne Lofton, RN, MSN

Heather Stern, RN, BSN, CNOR, OCN

Coralyn Martinez, MSN, RN, OCN

Pamela J. Vlahakis, RN, MSN, CBCN

Pamela Matten, RN, BSN, OCN

Cynthia Waddington, RN, MSN, AOCN

Nicole Messier, RN, BSN

Elizabeth Whitley, PhD, 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.

*For full information visit www.aonnonline.org

• • • • •

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 conference@aonnonline.org. Abstract Deadline: August 1, 2012

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

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.

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

Genetic Counseling

Emerging Cancer Panels for Testing Patients for Inherited Cancer Predisposition By Cristi Radford, MS, CGC Sarasota Memorial Health Care System, Sarasota, Florida Tuya Pal, MD, FABMG Moffitt Cancer Center, Tampa, Florida Cristi Radford, MS, CGC

Tuya Pal, MD, FABMG

enetic testing for inherited cancer predisposition is typically performed by testing for 1 condition at a time. For example, as discussed in the June issue of The Oncology Nurse-APN/PA, an individual with lobular breast cancer and a family history of breast and abdominal cancers may undergo testing for the BRCA genes and, if negative, then have the CDH1 gene analyzed. However, with the tremendous advances in genetic testing technologies over the past few years, the cost of testing has plummeted. To put this into perspective, the first human genome cost $2 billion to $3 billion to sequence and took over 10 years to complete. Today, the cost of sequencing a human genome would be less than $10,000 and would take 4 to 6 weeks to complete. Some predict that the cost may be less than $1000 by the end of 2012.1 As such, it has become realistic to test for multiple inherited cancer conditions at the same time using cancer panels.

What Are Cancer Panels? Cancer panels utilize a technology referred to as next-generation (nextgen) sequencing, which allows multiple genes to be analyzed simultaneously for mutations at a cost comparable to testing for a single inherited condition. The particular genes on a panel vary depending on the laboratory performing the test. So far, laboratories appear to be designing their panels specifically for cancer genes associated with a single or a few cancer types. For example, a breast panel includes genes known to predispose to breast cancer, and a colon panel includes genes known to predispose to colon cancer. Because some genes convey an increased risk for both breast and colon cancer, these genes would be included on each panel. To date, insurance reimbursement for testing has been encouraging. When Should Cancer Panels Be Utilized? Many factors go into determining a genetic testing strategy. Therefore, no single strategy would be appropriate for all patients. A general guideline is that if a family history does not appear consistent with a particular cancer syndrome, a cancer panel including all or the majority of genes in the differential diagnosis may be useful. Are There Limitations/Challenges Associated With Cancer Panels? Multiple studies have demonstrated that the majority of healthcare providers do not have adequate knowledge of genetics and are deficient in taking family histories, ordering the correct genetic testing, and/or interpreting genetic test results.

However, despite these deficiencies, professional guidelines, technologic advances, and consumer demand continue to increase the use of genetic testing. Therefore, at first glance, a colon panel that includes genetic testing for all the high-risk syndromes listed in the National Comprehensive Cancer Network guidelines for which clinical testing is available (such as Lynch syndrome, familial adenomatous polyposis, MYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, hereditary diffuse gastric cancer, and Li-Fraumeni syndrome) may seem like the perfect solution. However, other issues to consider are the higher likelihood of receiving â&#x20AC;&#x153;variant of uncertain significanceâ&#x20AC;? (VUS) results and the need for these patients to be managed by providers versed in medical management of these syndromes. Additionally, some of the panels include genes associated with a moderate increase in cancer risk (at times based on inconsistent data), which further compounds the complexity in delivering results. Because testing for mutations in these genes was rare prior to the availability of next-gen sequencing technologies, approach and data surrounding their cancer risks and corresponding medical management options are limited. Another potential issue influencing use of these tests is gene patents. For example, the BRCA1 and BRCA2 genes are patented, and laboratories offering breast panels cannot include the genes on their panel. Therefore, although a breast panel might be the most cost-effective approach for a patient with a diagnosis of breast cancer and a family history of abdominal

cancer, a provider cannot currently perform both tests at one time. He or she would need to perform a breast panel first and then send to Myriad Genetics for BRCA testing, or start with BRCA testing and, if negative, then send a sample to a laboratory offering a breast panel. Although current research, insurance coverage, and clinical uptake of cancer panels appear promising, these tests are in their infancy, and research studies are needed to determine how best to utilize them in clinical practice and to educate healthcare providers. Where Can I Obtain More Information About Cancer Panels? As with any genetic test, providers should contact a number of laboratories to determine which laboratory best meets the needs of their patients. Keep in mind that the genes analyzed on a particular panel (such as a breast panel or colon panel) may vary by laboratory, as does turnaround time, experience interpreting VUS results, and billing procedures. Your local genetics provider should be able to provide you with additional information. Laboratories offering cancer panels include:

Ambry Genetics: www.ambrygen.com City of Hope Laboratories: www.cityofhope.org University of Washington Medical Center: http://depts.washington.edu/labweb/Divi sions/MolDiag/MolDiagGen/index.htm Reference 1. Hill C. Beyond the $1,000 Genome. Forbes Web site. http://www.forbes.com/sites/colinhill/2012/02/09/beyon d-the-1000-genome/. Published February 9, 2012. Accessed June 21, 2012.

Visit our user-friendly Web site www.TheOncologyNurse.com In addition to Web-only exclusives, news coverage, journal articles, contests, and polling questions, youâ&#x20AC;&#x2122;ll have the opportunity to earn Continuing Education credits at NO CHARGE by participating in a number of activities offered!

JULY 2012 I VOL 5, NO 6

www.TheOncologyNurse.com

Drug Shortage

Exploring the Drug Shortage Crisis By Caroline Helwick

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

FDA Hypervigilant Kweder said that prevention of shortages is the FDA’s “absolute priority,” and a priority of Congress and the administration. In the past 6 months, more than 150 drug shortages have been averted through early notification by manufacturers. “These drugs have not appeared on the list of shortages,” she noted. “But things can change quickly. Early notification is the key….Our staff is vigilant, and we work under extraordinary conditions to pull out the stops every day to prevent shortages and address those that are occurring.” However, the early notification system is voluntary, and the FDA cannot mandate that companies up their production, she acknowledged. “One thing the FDA cannot do is tell a company they must make a drug.” But it can work with companies to “ferret out problems” and resolve manufacturing and drug quality issues, which account for most shortages. “These issues are not minor,” she noted. The FDA helps companies ramp up production for new or “relaunched” products and uses “regulatory discretion” to help companies import drugs, she said.

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

(S 3187), and the companion bill passed the United States House of Representatives as the FDA Reform Act (HR 5651). The next step was to reconcile the differences between the 2 versions, both of which contained a proposed user fee program for generic drugs

“Industry is very willing to pay these fees because they believe it will enable a more timely review of their applications, and a faster time getting their drugs to market.” —Richard Schilsky, MD

User Fee Legislation, Economic Incentives “ASCO believes a permanent solution will require congressional legislation,” Schilsky said. Progress has been made. On May 30, the Prescription Drug User Fee Act (PDUFA) reauthorization legislation passed the United States Senate as the FDA Safety and Innovation Act

and biosimilars and language on drug shortages. The program will allow the FDA to collect user fees from industry to help fund the agency’s timely review of applications. On June 18, the United States Congress released a reconciled version of the reauthorization bill, which was presented again to the House of Representatives and Senate. The House passed the final version on June

20 and the Senate passed it on June 26. The bill will now go to President Barack Obama for his signature. The PDUFA legislation will bring in an additional $1.5 billion to the FDA, which is expected to reduce the review time for a new drug application from the current 30 months to 10 months or less. “This is a huge step forward in getting manufacturers into the game,” said Schilsky. “Industry is very willing to pay these fees because they believe it will enable a more timely review of their applications, and a faster time getting their drugs to market.” The FDA “user fee” legislation that was passed by Congress, however, does not contain an enforcement mechanism that carries penalties for not reporting. “ASCO has concerns that if there is no teeth in that legislation, companies may decide not to report,” Schilsky said. “On the Hill, there is not much receptivity to putting that in the legislation.” “We also feel that Congress should consider making economic incentives for companies to stay in the market for these lower-cost drugs,” he added. “And that the provisions addressing drug shortages also apply to biologics, which Continued on page 34

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

Go to www.TheOncologyNurse.com to cast your vote and add your comments. Please tell us what you think about the efforts to resolve the drug shortage issue. JULY 2012 I VOL 5, NO 6

Drug Shortage Exploring the Drug Shortage Crisis Continued from page 33 at the moment are branded but will eventually be generic.” Would economic incentives encourage production of generics? The fact that virtually all shortages so far have been generics “speaks to the economic and business model,” Schilsky acknowledged. “These drugs have the smallest profit margins, but it’s hard to connect the dots on this.…The generic drug industry is thriving. Yes, they have manufacturing problems and yes, periodically plants go down, but it’s not like the economics of the situation is driving them out of business. Economic issues may be contributing to the shortage, but not at such a funda-

While the shortages to date have been almost restricted to generics, it appears possible that even supplies of the newest drugs may fall short of the demand. mental level that companies are folding their tents and going away.” Could New Drugs Be Affected? While the shortages to date have been almost restricted to generics, it appears possible that even supplies of the newest drugs may fall short of the demand. News of the FDA’s approval of per-

tuzumab (Perjeta) for HER2-positive metastatic breast cancer was welcomed, but in its announcement Genentech, the manufacturer, disclosed that production issues could affect the drug’s long-term supply. “We expect to meet demand for Perjeta following today’s FDA approval,” said spokesperson Patrick Y.

Yang, PhD, head of technical operations. “We recently identified a cell growth issue that might affect our future supply of the medicine. We take this very seriously and are working with the FDA to ensure a consistent manufacturing process that maintains drug supply for the people who need it.” In her FDA announcement of the drug’s approval, Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research, said, “Given the need for additional treatments for metastatic breast cancer, we made the decision to approve this drug today and not to delay its availability to patients pending resolution of the production issues relating to future supply.” l

Quantifying the Drug Shortage: One Center’s Experience

t one New York medical center, half of the cancer patients required drugs that were considered in short supply in 2010 and 2011, and 10% were forced to receive an alternative, according to a study presented at the 2012 ASCO Annual Meeting (Abstract 6114). While the investigators hope that this did not compromise efficacy, about one-third of the time the physicians felt the substitute was inferior, said Daniel J. Becker, MD, of St. Luke’s-Roosevelt and Beth Israel Medical Center, New York, who led the study presented at ASCO. Becker reported that drugs considered in shortage were used for 51% of patients in 2010, and this increased significantly to 64% in 2011. “When the shortage reached critical levels, about 10% of the patients we treated had an actual change in treatment mandated by the shortage,” he told The Oncology Nurse-APN/PA. The researchers reviewed pharmacy records for drug shortages, defined as supply issues that affect how the pharmacy prepares or dispenses a drug prod-

uct or influences patient care when prescribers must use an alternative agent, and examined records of outpatients who received chemotherapy from April 2010 to September 2010 (n = 335) and from April 2011 to September 2011

2011, and the percentage of patients treated with a shortage drug increased from 51% to 65%. Most of the shortages occurred in breast cancer patients (48%), followed by gynecologic cancer patients (26%).

“When the shortage reached critical levels, about 10% of the patients we treated had an actual change in treatment mandated by the shortage.” —Daniel J. Becker, MD

(n = 379). They also surveyed physicians about the efficacy and toxicity of the alternative regimen used during the shortage. The percentage of drugs in shortage increased from 30% in 2010 to 50% in

Of the 235 patients in the subgroup examined in August/September 2011 (when shortages peaked), 23 (9.8%) experienced a change in therapy, he reported. No substitutions occurred in 2010.

Three medications were unavailable at St. Luke’s-Roosevelt: paclitaxel (74%), liposomal doxorubicin (22%), and 5-fluorouracil (4%). Leucovorin was also in short supply, but the consequences were difficult to track for this project, since most patients continued to receive the drug in reduced dosages, Becker said. As a substitute for paclitaxel, the use of docetaxel increased by 80%, while paclitaxel decreased by 69% during the most critical period. The estimated cost of a single treatment with paclitaxel for the average patient was $47, versus $858 for docetaxel, a 1704% increase, Becker pointed out. “When we surveyed treating physicians about the change in therapy, we found that they considered the alternative regimen inferior to the standard regimen in 30% of patients and thought the alternative regimen was more toxic in around 35%,” Becker said. Today, he added, “Many drugs are still in shortage, but few affect care on a daily basis. There is definitely progress, though there is still vulnerability.” l

Contact editorial@greenhillhc.com for information. 34

JULY 2012 I VOL 5, NO 6

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Gastroesophageal Cancer

Late Effects of Treatment Common in Gastroesophageal Cancer Survivors By Alice Goodman

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

“Survivors…unanimously and voluntarily report significant health problems after treatment for

Caucasian. Average time from diagnosis was 3.8 years. Of the sample, 91% of those with esophageal cancer and 77% of those with gastric cancer underwent surgery; 79% and 85%, respectively, received chemo-

therapy; and 53% and 31%, respectively, were treated with radiation. Late effects, in descending order from most common to least frequent, were difficulty swallowing (100%), dry mouth/ taste changes (60%), cognitive changes

(42%), dental changes (40%), tinnitus (36%), cardiovascular disease (35%; hypertension, 21%; hyperlipidemia, 13%; angina, 2%), sexual changes (28%), peripheral neuropathy (24%), and chronic lung disease (14%). l

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Stephanie A. Gregory, MD

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

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

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

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

gastroesophageal cancers.” —James M. Metz, MD

The authors of this study utilized an Internet-based tool for creation of survivorship plans (available at www.live strongcareplan.org and through the OncoLink Web site). The tool enables survivors to enter data regarding diagnosis and treatments and provides customized guidelines for future care. Patients who use this tool are asked about late effects associated with specific treatment and answer “yes,” “no,” or “I don’t know.” They are also asked to score toxicity using World Health Organization criteria. Questions about late effects of treatment were answered by 66 survivors: 80% with esophageal cancer and 20% with gastric cancer. Median age was 55 years. Slightly less than two-thirds were female, and 93% were

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

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

ALL NEW CONTENT FOR 2012 Accreditation These activities will be accredited for physicians, nurses, and pharmacists. For complete accreditation information, please refer to each activity. This activity is jointly sponsored by Medical Learning Institute, Inc. and Center of Excellence Media, LLC.

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JULY 2012 I VOL 5, NO 6

Throughout the course of castration-resistant prostate cancer (CRPC)

THE R O OT OF TU M O R GR O W T H A N D R O G E N R E C E P TO R S I G N A L I N G

Despite low or undetectable levels of testosterone, androgen receptor signaling persists. 1,2

Androgen receptor signaling promotes tumor growth and drives prostate cancer progression. 1,3,4

Visit www.TargetAR.com to learn more. REFERENCES: 1. Harris WP, Mostaghel EA, Nelson PS, Montgomery B. Nat Clin Pract Urol. 2009;6:76-85. 2. Chen Y, Clegg NJ, Scher HI. Lancet Oncol. 2009;10:981-991. 3. Knudsen KE, Scher HI. Clin Cancer Res. 2009;15:4792-4798. 4. Sawyers CJ, Tran C, Wongvipat J, et al. Poster presented at: ASCO 2007 Prostate Cancer Symposium; February 22-24, 2007; Miami, FL. ÂŠ 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012D-075-5384 5/12