TON_May_2013_Issue

May 2013

www.TheOncologyNurse.com

Vol 6, No 4

Fifth Annual Review Recent Advances in Anticancer Agents

Renal Cell Carcinoma

Colorectal Cancer

Second-Line Treatment for Metastatic Renal Cell Carcinoma

Managing Adverse Events Associated With Antiangiogenic Biologic Agents for Metastatic Colorectal Cancer

Susanne Bond, FNP-ANP Taussig Cancer Center

Julie A. Koch, RN, BSN, OCN, CCRP Vanguard Health Systems

Prostate Cancer

New Agent Improves Survival in Castration-Resistant Prostate Cancer

Expanded Indication for the Treatment of Metastatic Prostate Cancer

Gary Shelton, MSN, NP, ANP-BC, AOCNP

Shawn Bliss, MSN, ARNP, AOCN

NYU Clinical Cancer Center Prostate Cancer Image Source: Otis Brawley (Photographer)

Florida Cancer Specialists

Breast Cancer

New Option for the Treatment of HER2-Positive Breast Cancer

A New Treatment for Hormone Receptor–Positive Advanced Breast Cancer

Sharon Gentry, RN, MSN, AOCN, CBCN Novant Health Derrick L. Davis Cancer Center

Christine M. Rafferty, RN, BSN, OCN Mammogram with Obvious Cancer Source: Dr. Dwight Kaufman.

National Cancer Institute

Fox Chase Cancer Center

Hematologic Malignancies

The Treatment of Chronic Myeloid Leukemia: A Nursing Perspective

Clinical Advances in the Treatment of Relapsed and Refractory Multiple Myeloma Sandra Kurtin, RN, MS, AOCN, ANP-C Arizona Cancer Center

Also In This Issue, Complimentary CE

Ann Q. Shen, BSc, BScN

Emory University

Katharine F. Lord, PA-C, MMSc Texas Oncology

Considerations in Multiple Myeloma—Ask the Experts: Maintenance Settings Complete the pretest, posttest, and evaluation online at www.mlicme.org/P13008B.html See page 14

©2013 Green Hill Healthcare Communications, LLC

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eO seri Vie nc es w olo on the gy line Nu a rse t .co m

2ND ANNUAL

CONQUERING THE CANCER CARE CONTINUUM

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CONQUERING THE CANCER CARE CONTINUUM CONQUERING CANCER CARTHE C E CONT I

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The publishers of The Oncology Nurse-APN/PA, The Oncology Pharmacist, and Personalized Medicine in Oncology are proud to present our 2nd annual Conquering the Cancer Care Continuum series.

Upcoming topics include:

• Palliation IN THIS ISSUE

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Challenges Patients Face in Cancer Care: Implications for the Healthcare Team Lea Ann Hansen, PharmD, BCOP Associate Professor, Virginia Commonwealth University

ancer is an illness associated with substantial cancer.1 More than half are living well beyond 5 years physical, emotional, social, and financial ramafter diagnosis. Women comprise a majority of longifications for affected individuals and their term survivors due to the favorable outcomes with families. In a significant number of cases, the diagnosis breast, cervical, and uterine cancers.2 The number of of cancer is either preceded by a period people living with a history of cancer

of gradual, nonspecific symptoms or is projected to grow considerably over

discovered by routine screening, and the next 20 years for 2 major reasons. individuals are then thrust into a First, the number of Americans over whirlwind of diagnostic testing, inage 65 is predicted to double between vasive procedures, and complicated the years 2000 and 2030.3 Consetreatments with very little warning or Lea Ann Ha quently, as a disease primarily of older nsen, Associat e Profes PharmD, BCOP adults, cancer will also increase. Secopportunity to assimilate their circumsor, Virgin ia Commond, as the effectiveness of cancer stances. Frequently, a multidisciplinary onwealt iversity ™ h Unimproves, approach to treatment is necessary, retreatments the number of he past dec ade has see quiring patients to engage with numercured of the disease will inn a drapatients the utiliza ma

tic upsurge tio n of specia several ous medical teams comprising and an in even larger percentage lty phcrease, types of Medic arm acies for are Moder rapeutic Lea Annthe Hansen, all different specialties, often in different those for can will be living longer with disease nization Ac mo dalities, as “athe cer. The BCOP PharmD, t defined part D dru including cost of can a specialty locations. Many patients have beenabout $125 billio receiving multiple “lines� of g with plan-n cer carwhile ceed $4 drug e may rise egotiated n in 2010 00 per mo lio from etc) over time. n byand to 07 bil prices tha relatively healthy prior to the cancer event second-line, thethereend of the therapy$2(first-line, fine specia The nth.� 2 Other he t exalth plans dec ltyinade. demand drugs dif specialtyserfore are not sophisticated consumerstim ofe,medical overall By that for oncology services is expected to may defer en drugs are tly. In gen accon predic ounthealthcare era hig l, vices. Consequently, it is incumbent crease byted 48% by 2020, while the supply of oncologists h for 2 of eve the cos to y are t, admini ry 5 pharm stered by lars spent.

1 acy dol-by only 14% based on current patterns.4or infusion professionals to be able to facilitate patients’ transition injection The purpo will increase , require spe se of thi to explai y isdistress cial hand ersittheir , BCO into carePin order to minimize and need for a wide varietyor are used for article underscore the n maxiling, the evolut Theses statistics sen, PharmD Commonwealth Univ 80%, complex ion cialty ph inia their clinical outcomes.

Lea Ann Han essor, Virgmize e from 17% toand other support personnel torequire of diseases tha rang sthe of health professionals armacy men spe Prof e regi spe ion ciat ion t cial monit and the Asso medicat oral can mon assumpt functi term oring. In ser cology, ho Ascom ve in theand .2-4 Challenges existc beyond the initial diagnosis play a on part each and every patient to rent itin enabling nd 50% onwever, the arou agetre atm systemi treatme ts would be an aver andwith ent of can most com cer agen to the agents dis t scenario forperiod as well. dis According to National quality care that addresses all of their needs antican cus cer mon oralceive s the pensed by to ten he predominan treatment invo been ce po lved administra- andthat adh eren a specialty tia disease, has of the illness. Patients del ben macy pro allenges traditionally ofefithe (NCI), more throughout million individrity pharhighlythan 12ch ts the continuum seve vid by of the of cancer has Cancer Institute the py er the to cate (SP hera due system fro indi P) are the po high er, targeted nous chemot of vie mrue. fineunt quality of dies care based on are their ability to5: United States aw history ent.livingintwith theStu newer patiare of theofpatproven agents tha tion of intraveuals in the apy ient. monitored the t are admi tered ora s for cancer ther el who closely nislly. After adherence rate 5 erence has trained personn e in an The Evolu a system view 97%. Nonadh atic reedures took plac tion of Sp15% to Green Hill outc Healthcare omes Communications, LLC of the literature, When these proc se infu Dr wor ec ital ugs and one academ ialtyciated with group of e or in a hosp authors pro ic been asso the oncologist’s offic Pharmac Specialty states and with posed the critical de e education of ber of disease Lea Annhosnsiv mo y num exte a st scr in Ha ter, iptors of er nse high sion cen . More There is drug to be 3 armD, BC n, a specia sician visits,Ph ily was possible a lack of lty : increased phy ital stays,OP consen patient and fam com hosp spe er ngly cia sus long • easi s, lty Hi on therate drug. The gh cost (pr ever, an incr definition Food andpitalization escriptions recently, how not define of one or of aeased mor Drug wormi ng, and incr than $600 cost more seni d the term. involves the use nistration one-third •toDifficult diseaseAd per month Initially, mon situation synonym medicati self-admin) matelyhas the6 App ous with on delive ications and el roxi was virtuaication-related— Speci biotechn tality. lab ry, such as more oral med teins pro s in the al handlin ology pro rds of all med lly apie Le ther s du a eou An ced g du requiring n Hansen, by recom two-thi cts, either pro to medication contro onistered subcutan stri mo resp bin ct Ph l ct As no due an tem arm so dire are clo t ns ciate Pro DNA zatio perature na D,l an BCtib ment. The techniqu — OP fesbri odies pro hospitali sodo home environ r, Vir admincost of $100 bil- Restricted locati duced wi erence— atesa or magin iat Co s, bu on for me acquisition and thismm nonadhth cellular aris noonlon dication pre we sibility for drug alt ents and purp h Unive - ose of this or distribution site ger Thehy y.7 y paration the rsit ting to the pati casuall ann —ts e. Th lion sen, ileribe istration is shif 2007 Lea Ann Han P general concep Restricted locati he ork, if ava pre netw desc vio ort to on , BCO us insPha for medic to ticle is talrmD their social supp lmen ation adm e than 20 t in this can erence and the research related tration ent time, mor ries examine inis e Green ceradh car d the able. At the pres g patient dence, risk facroved for se- Hill wi inci rega alth ngrdin are FDA app therap1). In addition, growi importacan treatment. TheHe thcarabe e les Co ewe mm revi ser uni oral medications nccer e of orathis Md.cat adherence to PRion(8 cancer (Table ies for the ofpli s, LL problem will tre ntim l 2% tme C atm that of trea ors es e vs cat en enc ine de tum t, and 78%). 4 (M ionused riventl sequ of can y exam concer s of for ed fro the first-lin patient adAcequ ts are tors m subs agen PR an ele will d oral s is r ctr the serie a metric he onic prescr othe present referen on its article in this and clinical a number of timinitial treatment. -renceThe ce tte ill pa lastsuc iption record cess. for refractory to e, more tha rns over tim Net or are ica Atmax s based on theimizing adh have relapsed e, and 80% tions prehensive Cancern 20 oral me best practices point for ad thedthe National Comare appro is an arbitr vends herence use d byinthe pou cording to the ary cut Drug omes.

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is in addition comes in al outself-admini chronic my to stered sub eloid leuke cutaneous and childho pies for th mia theraod acute lym e home en vironment phoblastic leukemia. 5-8 are under that For each of FDA review these disor. ders, prolon When canc ge d er medicati oral thera been the py has ons are ad ministered standard Lea Ann orally in th of care for Hansen, decade or e home en ronment rat a PharmD, more. It is viher than in BCOP likely that ative conse the clinic of adheren negor hospital quences of ce range fro , the rates nonadhere m 15% to with other at the end nce will be docu 97%. 2 For ora of the first l ca ncer medic example, mented in year of tre hormonal ations the future atment wi apy matur treatment as their rol th adjuvan es. The pu (AHT) for e in thert cer, only 79 rpose of th early-stage the result % of patie is article is breast can s of avail nts remain to dis a gap exce ab cuss le ed on therap adherence research eding 60 da on maxim and suggest y without ys and 85% ceeding 18 izing best practi ical outco without a 0 days. By ces to impro mes. gap exyear 5, on ve mained wi cli nly 27% an thout 60d 29% reand 180-d In another ay gaps, res

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TON KING-SIZE CCC_051513

Editorial Board EDITOR-IN-CHIEF

Beth Faiman,

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

Elizabeth Bilotti, RN, MSN, APRN, BC, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Catherine Bishop, DNP, NP, AOCNP

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Rita Wickham,

PhD, RN, AOCN

Avid Education Partners, LLC Sharpsburg, MD

CS, FNP

Mayo Clinic Rochester, MN

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

Shannon Hazen,

Melinda Oberleitner, RN,

Karla Wilson, RN,

MSN, CRNP

RN, BSN, OCN Novant Health Presbyterian Cancer Center Charlotte, NC

Patricia Irouer Hughes, RN, MSN,

MSN, FNP-C, CPON

DNS, APRN, CNS

City of Hope National Medical Center Duarte, CA

Jayshree Shah, NP

Pharmacy John F. Aforismo,

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

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

BSN, OCN

Piedmont Healthcare Rex, GA

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Deena Damsky Dell, MSN, RN-BC,

Taline Khoukaz,

Gary Shelton,

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

NYU Clinical Cancer Center New York, NY

Somerset Medical Center Somerville, NJ

Sandra E. Kurtin,

Lori Stover, RN,

Patient Advocate Peg Ford

Arizona Cancer Center Tucson, AZ

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ovarian Cancer Advocacy Alliance San Diego, CA

Ann McNeill,

Joseph D. Tariman,

Social Work Carolyn Messner,

AOCN, LNC

Fox Chase Cancer Center Philadelphia, PA

Wendy DiSalvo,

DNP, APRN, AOCN Genentech New London, NH

Denice Economou,

RN, MN, CNS, AOCN City of Hope National Medical Center Duarte, CA

Constance Engelking, RN,

MS, CNS, OCN

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

Amy Ford, RN,

BSN, OCN Quintiles Dallas, TX

NP, MSN, ACNP-C

RN, MS, AOCN, ANP-C

MSN, RN, NP-C, OCN

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Kena C. Miller, RN, MSN, FNP

Roswell Park Cancer Institute Buffalo, NY

Patricia Molinelli, MS, RN, APN-C, AOCNS

Somerset Medical Center Somerville, NJ

MSN, NP, ANP-BC, AOCNP

BSN

PhD, APRN, BC

BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Nutrition Karen Connelly, RD, CSO

Northwestern University Myeloma Program Chicago, IL

DSW, MSW, LCSW-R, BCD

Jacqueline Marie Toia, RN, MS, DNP

Genetic Counseling Cristi Radford,

Northwestern University Myeloma Program Chicago, IL

Pamela Hallquist Viale, RN, MS,

CS, ANP, AOCN Saratoga, CA

CancerCare New York, NY

MS, CGC

Sarasota, FL

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS

OncoMed Onco360 Great Neck, NY

Sharon S. Gentry, RN, MSN, AOCN, CBCN

Novant Health Derrick L. Davis Cancer Center Winston-Salem, NC

www.TheOncologyNurse.com

Ellen A. Neylon, MSN, FNP-BC, CCRP, OCN

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

Connie Visovsky, RN, PhD, APRN

University of South Florida College of Nursing Tampa, FL

Isabell Castellano, RN

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

Jeanne Westphal, RN

Meeker County Memorial Hospital Litchfield, MN

May 2013 I VOL 6, NO 4

3

From The Editor

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PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Publisher Russell Hennessy russell@greenhillhc.com Editorial Director Kristin Siyahian kristin@greenhillhc.com Managing Editor Kristen Olafson kristen@greenhillhc.com Copy Editors Mollie Friedman Peggy Roeske Editorial Assistant Jennifer Brandt

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

his month’s Fifth Annual Review issue of The Oncology Nurse-APN/PA® (TON) highlights some of the recent advances in anticancer care.

We focus on some of the therapies that received approval from the US Food and Drug Administration (FDA) in 2012.

This month’s issue demonstrates how rapidly practices are changing and how important it is for oncology nurses to be aware of those

advances in care already affecting patients or likely to affect them in the near future. Informed nurses can help educate patients about the newer treatments—from having realistic expectations about the therapy and its side effects to providing information about financial assistance programs to help pay for the drug regimen.

We would like to thank all of the authors who contributed to this issue of TON. Some were directly involved with the clinical studies that were evaluated during the FDA approval process while others are experts in the therapeutic area discussed. All authors have a deep understanding of the subject area and share a passion for improving care for patients with cancer. l

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July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

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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, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2013 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®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology 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 mentioned 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.

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Offering patients a choice may help improve long-term adherence $10 CO-PAY * FOR MOST PRESCRIPTIONS PLEASE SEE THE COMPLETE BLACK BOX WARNING AND BRIEF SUMMARY ON THE FOLLOWING PAGES. IMPORTANT SAFETY INFORMATION Tamoxifen citrate is contraindicated in patients with known hypersensitivity and also in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus. As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued. There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy.

When tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients.

WARNING In Women with Ductal Carcinoma in Situ (DCIS) and Women at High Risk for Breast Cancer Serious and life-threatening events were associated with tamoxifen in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. (see CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence In High Risk Women). Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer. The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer. www.Soltamox.com www.DaraBiosciences.com

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SOLTAMOX - tamoxifen citrate solution Brief Summary: Consult package insert for full prescribing information FOR WOMEN WITH DUCTAL CARCINOMA IN SITU (DCIS) AND WOMEN AT HIGH RISK FOR BREAST CANCER Serious and life-threatening events associated with tamoxifen in the risk reduction setting (women at high risk for cancer and women with DCIS) include uterine malignancies, stroke and pulmonary embolism. Incidence rates for these events were estimated from the NSABP P-1 trial (see CLINICAL PHARMACOLOGY, Clinical Studies, Reduction in Breast Cancer Incidence In High Risk Women in the full prescribing information). Uterine malignancies consist of both endometrial adenocarcinoma (incidence rate per 1,000 women-years of 2.20 for tamoxifen vs. 0.71 for placebo) and uterine sarcoma (incidence rate per 1,000 women years of 0.17 for tamoxifen vs. 0.0 for placebo)*. For stroke, the incidence rate per 1,000 women years was 1.43 for tamoxifen vs. 1.00 for placebo**. For pulmonary embolism, the incidence rate per 1,000 women years was 0.75 for tamoxifen versus 0.25 for placebo**. Some of the strokes, pulmonary emboli, and uterine malignancies were fatal. Health care providers should discuss the potential benefits versus the potential risks of these serious events with women at high risk of breast cancer and women with DCIS considering tamoxifen to reduce their risk of developing breast cancer. The benefits of tamoxifen outweigh its risks in women already diagnosed with breast cancer. * Updated long-term follow-up data (median length of follow-up is 6.9 years) from NSABP P-1 study. See WARNINGS, Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma. ** See Table 3 under (see CLINICAL PHARMACOLOGY, Clinical Studies in the full prescribing information) INDICATIONS AND USAGE Metastatic Breast Cancer Tamoxifen citrate is effective in the treatment of metastatic breast cancer in women and men. In premenopausal women with metastatic breast cancer, tamoxifen citrate is an alternative to oophorectomy or ovarian irradiation. Available evidence indicates that patients whose tumors are estrogen receptor positive are more likely to benefit from tamoxifen citrate therapy. Adjuvant Treatment of Breast Cancer Tamoxifen citrate is indicated for the treatment of node-positive breast cancer in postmenopausal women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. In some tamoxifen citrate adjuvant studies, most of the benefit to date has been in the subgroup with four or more positive axillary nodes. Tamoxifen citrate is indicated for the treatment of axillary node-negative breast cancer in women following total mastectomy or segmental mastectomy, axillary dissection, and breast irradiation. The estrogen and progesterone receptor values may help to predict whether adjuvant tamoxifen citrate therapy is likely to be beneficial. Tamoxifen citrate reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen citrate therapy for breast cancer. Ductal Carcinoma in Situ (DCIS) In women with DCIS, following breast surgery and radiation, tamoxifen citrate is indicated to reduce the risk of invasive breast cancer see (BOXED WARNING at the beginning of the label).

The decision regarding therapy with tamoxifen for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen therapy. Current data from clinical trials support five years of adjuvant tamoxifen citrate therapy for patients with breast cancer. Reduction in Breast Cancer Incidence in High Risk Women Tamoxifen citrate is indicated to reduce the incidence of breast cancer in women at high risk for breast cancer. This effect was shown in a study of 5 years planned duration with a median follow-up of 4.2 years.

Twenty-five percent of the participants received drug for 5 years. The longer term effects are not known. In this study, there was no impact of tamoxifen on overall or breast cancer-related mortality (see BOXED WARNING at the beginning of the label).

Tamoxifen citrate is indicated only for high-risk women. “High risk” is defined as women at least 35 years of age with a 5-year predicted risk of breast cancer3 1.67%, as calculated by the Gail Model. Examples of combinations of factors predicting a 5-year risk³ 1.67% are: Age 35 or older and any of the following ombination of factors: One first degree relative with a history of breast cancer, 2 or more benign biopsies, and a history of a breast biopsy showing atypical hyperplasia; or At least 2 first degree relatives with a history of breast cancer, and a personal history of at least one breast biopsy; or CIS Age 40 or older and any of the following combination of factors: One first degree relative with a history of breast cancer, 2 or more benign biopsies, age at first live birth 25 or older, and age at menarche 11 or younger; or At least 2 first degree relatives with a history of breast cancer, and age at first live birth 19 or younger; or One first degree relative with a history of breast cancer, and a personal history of a breast biopsy showing atypical hyperplasia. Age 45 or older and any of the following combination of factors: At least 2 first degree relatives with a history of breast cancer and age at first live birth 24 or younger; or One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, age at menarche 11 or less and age at first live birth 20 or more. Age 50 or older and any of the following combination of factors: At least 2 first degree relatives with a history of breast cancer; or History of one breast biopsy showing atypical hyperplasia, and age at first live birth 30 or older and age at menarche 11 or less; or History of at least two breast biopsies with a history of atypical hyperplasia, and age at first live birth 30 or more. Age 55 or older and any of the following combination of factors: One first degree relative with a history of breast cancer with a personal history of a benign breast biopsy, and age at menarche 11 or less; or History of at least 2 breast biopsies with a history of atypical hyperplasia, and age at first live birth 20 or older. Age 60 or older and: 5-year predicted risk of breast cancer³ 1.67%, as calculated by the Gail Model. For women whose risk factors are not described in the above examples, the Gail Model is necessary to estimate absolute breast cancer risk. Health Care Professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-833-3533. There are no data available regarding the effect of tamoxifen citrate on breast cancer incidence in women with inherited mutations (BRCAl, BRCA2). After an assessment of the risk of developing breast cancer, the decision regarding therapy with tamoxifen citrate for the reduction in breast cancer incidence should be based upon an individual assessment of the benefits and risks of tamoxifen citrate therapy. In the NSABP P-1 trial, tamoxifen citrate treatment lowered the risk of developing breast cancer during the follow-up period of the trial, but did not eliminate breast cancer risk. CONTRAINDICATIONS Tamoxifen citrate is contraindicated in patients with known hypersensitivity to the drug or any of its ingredients. Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS Tamoxifen is contraindicated in women who require concomitant coumarin-type anticoagulant therapy or in women with a history of deep vein thrombosis or pulmonary embolus. WARNINGS Effects in Metastatic Breast Cancer Patients. As with other additive hormonal therapy (estrogens and androgens), hypercalcemia has been reported in some breast cancer patients with bone metastases within a few weeks of starting treatment with tamoxifen. If hypercalcemia does occur, appropriate measures should be taken and, if severe, tamoxifen should be discontinued. Effects on the Uterus-Endometrial Cancer and Uterine Sarcoma.

An increased incidence of uterine malignancies has been reported in association with tamoxifen treatment. The underlying mechanism is unknown, but may be related to the estrogen-like effect of tamoxifen. Most uterine malignancies seen in association with tamoxifen are classified as adenocarcinoma of the endometrium. However, rare uterine sarcomas, including malignant mixed mullerian tumors, have also been reported. Uterine sarcoma is generally associated with a higher FIGO stage (III/IV) at diagnosis, poorer prognosis, and shorter survival. Uterine sarcoma has been reported to occur more frequently among long-term users (³ 2 years) of tamoxifen than nonusers. Some of the uterine malignancies (endometrial carcinoma or uterine sarcoma) have been fatal. In the NSABP P-1 trial, among participants randomized to tamoxifen there was a statistically significant increase in the incidence of endometrial cancer (33 cases of invasive endometrial cancer, compared to 14 cases among participants randomized to placebo (RR=2.48, 95% CI: 1.27-4.92). The 33 cases in participants receiving tamoxifen were FIGO Stage I, including 20 IA, 12 IB, and 1 IC endometrial adenocarcinomas. In participants randomized to placebo, 13 were FIGO Stage I (8 IA and 5 IB) and 1 was FIGO Stage IV. Five women on tamoxifen and 1 on placebo received postoperative radiation therapy in addition to surgery. This increase was primarily observed among women at least 50 years of age at the time of randomization (26 cases of invasive endometrial cancer, compared to 6 cases among participants randomized to placebo (RR=4.50, 95% CI: 1.78-13.16). Among women £ 49 years of age at the time of randomization there were 7 cases of invasive endometrial cancer,

compared to 8 cases among participants randomized to placebo (RR=0.94, 95% CI: 0.28-2.89). If age at the time of diagnosis is considered, there were 4 cases of endometrial cancer among participants £ 49 randomized to tamoxifen compared to 2 among participants randomized to placebo (RR=2.21, 95% CI: 0.4-12.0). For women³ 50 at the time of diagnosis, there were 29 cases among participants randomized to tamoxifen compared to 12 among women on placebo (RR=2.5, 95% CI: 1.3-4.9). The risk ratios were similar in the two groups, although fewer events occurred in younger women. Most (29 of 33 cases in the tamoxifen group) endometrial cancers were diagnosed in symptomatic women, although 5 of 33 cases in the tamoxifen group occurred in asymptomatic women. Among women receiving tamoxifen the events appeared between 1 and 61 months (average=32 months) from the start of treatment. In an updated review of long-term data (median length of total follow-up is 6.9 years, including blinded follow-up) on 8,306 women with an intact uterus at randomization in the NSABP P-1 risk reduction trial, the incidence of both adenocarcinomas and rare uterine sarcomas was increased in women taking tamoxifen. During blinded follow-up, there were 36 cases of FIGO Stage I endometrial adenocarcinoma (22 were FIGO Stage IA, 13 IB, and 1 IC) in women receiving tamoxifen and 15 cases in women receiving placebo [14 were FIGO Stage I (9 IA and 5 IB), and 1 case was FIGO Stage IV]. Of the patients receiving tamoxifen who developed endometrial cancer, one with Stage IA and 4 with Stage IB cancers received radiation therapy. In the placebo group, one patient with FIGO Stage IB cancer received radiation therapy and the patient with FIGO Stage IVB cancer received chemotherapy and hormonal therapy. During total follow-up, endometrial adenocarcinoma was reported in 53 women randomized to tamoxifen (30 cases of FIGO Stage IA, 20 were Stage IB, 1 was Stage IC, and 2 were Stage IIIC), and 17 women randomized to placebo (9 cases were FIGO Stage IA, 6 were Stage IB, 1 was Stage IIIC, and 1 was Stage IVB) (incidence per 1,000 women-years of 2.20 and 0.71, respectively). Some patients received post-operative radiation therapy in addition to surgery. Uterine sarcomas were reported in 4 women randomized to tamoxifen (1 was FIGO IA, 1 was FIGO IB, 1 was FIGO IIA, and 1 was FIGO IIIC) and one patient randomized to placebo FIGO IA); incidence per 1,000 women-years of 0.17 and 0.04, respectively. Of the patients randomized to tamoxifen, the FIGO IA and IB cases were a MMMT and sarcoma, respectively; the FIGO II was a MMMT; and the FIGO III was a sarcoma; and the one patient randomized to placebo had a MMMT. A similar increased incidence in endometrial adenocarcinoma and uterine sarcoma was observed among women receiving tamoxifen in five other NSABP clinical trials. Any patient receiving or who has previously received tamoxifen who reports abnormal vaginal bleeding should be promptly evaluated.

Patients receiving or who have previously received tamoxifen should have annual gynecological examinations and they should promptly inform their physicians if they experience any abnormal gynecological symptoms, e.g., menstrual irregularities, abnormal vaginal bleeding, changes in vaginal discharge, or pelvic pain or pressure.

In the P-1 trial, endometrial sampling did not alter the endometrial cancer detection rate compared to women who did not undergo endometrial sampling (0.6% with sampling, 0.5% without sampling) for women with an intact uterus. There are no data to suggest that routine endometrial sampling in asymptomatic women taking tamoxifen to reduce the incidence of breast cancer would be beneficial. NonMalignant Effects on the Uterus. An increased incidence of endometrial changes including hyperplasia and polyps has been reported in association with tamoxifen treatment. The incidence and pattern of this increase suggest that the underlying mechanism is related to the estrogenic properties of tamoxifen. There have been a few reports of endometriosis and uterine fibroids in women receiving tamoxifen.

The underlying mechanism may be due to the partial estrogenic effect of tamoxifen.

Ovarian cysts have also been observed in a small number of premenopausal patients with advanced breast cancer who have been treated with tamoxifen. Tamoxifen has been reported to cause menstrual irregularity or amenorrhea. Thromboembolic Effects of Tamoxifen. There is evidence of an increased incidence of thromboembolic events, including deep vein thrombosis and pulmonary embolism, during tamoxifen therapy. When tamoxifen is coadministered with chemotherapy, there may be a further increase in the incidence of thromboembolic effects. For treatment of breast cancer, the risks and benefits of tamoxifen should be carefully considered in women with a history of thromboembolic events. Data from the NSABP P-1 trial show that participants receiving tamoxifen without a history of pulmonary emboli (PE) had a statistically significant increase in pulmonary emboli (18-tamoxifen, 6-placebo, RR=3.01, 95% CI: 1.15-9.27). Three of the pulmonary emboli, all in the tamoxifen arm, were fatal. Eighty-seven percent of the cases of pulmonary embolism occurred in women at least 50 years of age at randomization. Among women receiving tamoxifen, the events appeared between 2 and 60 months (average = 27 months) from the start of treatment. In this same population, a non-statistically significant increase in deep vein thrombosis (DVT) was seen in the tamoxifen group (30tamoxifen, 19-placebo; RR=1.59, 95% CI: 0.86-2.98). The same increase in relative risk was seen in women £ 49 and in women³ 50, although fewer events occurred in younger women. Women with thromboembolic events were at risk for a second related event (7 out of 25 women on placebo, 5 out of 48 women on tamoxifen) and were at risk for complications of the event and its treatment (0/25 on placebo, 4/48 on tamoxifen).

Among women receiving tamoxifen, deep vein thrombosis events occurred between 2 and 57 months (average=19 months) from the start of treatment.

There was a non-statistically significant increase in stroke among patients randomized to tamoxifen (24-placebo; 34-tamoxifen; RR=1.42; 95% CI 0.82-2.51).

Six of the 24 strokes in the placebo group were considered hemorrhagic in origin and 10 of the 34 strokes in the tamoxifen group were categorized as hemorrhagic.

Seventeen of the 34 strokes in the tamoxifen group were considered occlusive and 7 were considered to be of unknown etiology. Fourteen of the 24 strokes on the placebo arm were reported to be occlusive and 4 of unknown etiology. Among these strokes 3 strokes in the placebo group and 4 strokes in the tamoxifen group were fatal.

Eighty-eight percent of the strokes occurred in women at least 50 years of age at the time of randomization. Among women receiving tamoxifen, the events occurred between 1 and 63 months (average = 30 months) from the start of treatment. Effects on the Liver: Liver Cancer. In the Swedish trial using adjuvant tamoxifen 40 mg/day for 2-5 years, 3 cases of liver cancer have been reported in the tamoxifen treated group vs. 1 case in the observation group (See PRECAUTIONS,-Carcinogenesis). In other clinical trials evaluating tamoxifen, no cases of liver cancer have been reported to date. One case of liver cancer was reported in NSABP P-1 in a participant randomized to tamoxifen. Effects on the Liver: Non-Malignant Effects. Tamoxifen has been associated with changes in liver enzyme levels, and on rare occasions, a spectrum of more severe liver abnormalities including fatty liver, cholestasis, hepatitis

and hepatic necrosis. A few of these serious cases included fatalities. In most reported cases the relationship to tamoxifen is uncertain. However, some positive rechallenges and dechallenges have been reported. In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on tamoxifen). Serum lipids were not systematically collected. Other Cancers: A number of second primary tumors, occurring at sites other than the endometrium, have been reported following the treatment of breast cancer with tamoxifen in clinical trials. Data from the NSABP B-14 and P-1 studies show no increase in other (non-uterine) cancers among patients receiving tamoxifen.

Whether an increased risk for other (non-uterine) cancers is associated with tamoxifen is still uncertain and continues to be evaluated. Effects on the Eye: Ocular disturbances, including corneal changes, decrement in color vision perception, retinal vein thrombosis, and retinopathy have been reported in patients receiving tamoxifen.

An increased incidence of cataracts and the need for cataract surgery have been reported in patients receiving tamoxifen. In the NSABP P-1 trial, an increased risk of borderline significance of developing cataracts among those women without cataracts at baseline (540-tamoxifen; 483-placebo; RR=1.13, 95% CI: 1.00-1.28) was observed. Among these same women, tamoxifen was associated with an increased risk of having cataract surgery (101-tamoxifen; 63-placebo; RR=1.62, 95% CI 1.18-2.22). Among all women on the trial (with or without cataracts at baseline), tamoxifen was associated with an increased risk of having cataract surgery (201-tamoxifen; 129-placebo; RR=1.58, 95% CI 1.26-1.97). Eye examinations were not required during the study. No other conclusions regarding non-cataract ophthalmic events can be made. Pregnancy Category D. Tamoxifen may cause fetal harm when administered to a pregnant woman. Women should be advised not to become pregnant while taking tamoxifen or within 2 months of discontinuing tamoxifen and should use barrier or nonhormonal contraceptive measures if sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. Effects on reproductive functions are expected from the antiestrogenic properties of the drug. In reproductive studies in rats at dose levels equal to or below the human dose, nonteratogenic developmental skeletal changes were seen and were found reversible. In addition, in fertility studies in rats and in teratology studies in rabbits using doses at or below those used in humans, a lower incidence of embryo implantation and a higher incidence of fetal death or retarded in utero growth were observed, with slower learning behavior in some rat pups when compared to historical controls. Several pregnant marmosets were dosed with 10 mg/kg/day (about 2-fold the daily maximum recommended human dose on a mg/m2 basis) during organogenesis or in the last half of pregnancy. No deformations were seen and, although the dose was high enough to terminate pregnancy in some animals, those that did maintain pregnancy showed no evidence of teratogenic malformations.

In rodent models of fetal reproductive tract development, tamoxifen (at doses 0.002 to 2.4-fold the daily maximum recommended human dose on a mg/m2 basis) caused changes in both sexes that are similar to those caused by estradiol, ethynylestradiol and diethylstilbestrol. Although the clinical relevance of these changes is unknown, some of these changes, especially vaginal adenosis, are similar to those seen in young women who were exposed to diethylstilbestrol in utero and who have a 1 in 1,000 risk of developing clear-cell adenocarcinoma of the vagina or cervix. To date, in utero exposure to tamoxifen has not been shown to cause vaginal adenosis, or clearcell adenocarcinoma of the vagina or cervix, in young women. However, only a small number of young women have been exposed to tamoxifen in utero, and a smaller number have been followed long enough (to age 15-20) to determine whether vaginal or cervical neoplasia could occur as a result of this exposure. There are no adequate and well-controlled trials of tamoxifen in pregnant women. There have been a small number of reports of vaginal bleeding, spontaneous abortions, birth defects, and fetal deaths in pregnant women. If this drug is used during pregnancy, or the patient becomes pregnant while taking this drug, or within approximately two months after discontinuing therapy, the patient should be apprised of the potential risks to the fetus including the potential long-term risk of a DES-like syndrome. Reduction in Breast Cancer Incidence in High Risk Women -Pregnancy Category D For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. In women with menstrual irregularity, a negative b-HCG immediately prior to the initiation of therapy is sufficient (See PRECAUTIONS Information for Patients -Reduction in Breast Cancer Incidence in High Risk Women). PRECAUTIONS General Decreases in platelet counts, usually to 50,000-100,000/mm3, infrequently lower, have been occasionally reported in patients taking tamoxifen for breast cancer.

In patients with significant thrombocytopenia, rare hemorrhagic episodes have occurred, but it is uncertain if these episodes are due to tamoxifen therapy.

Leukopenia has been observed, sometimes in association with anemia and/or thrombocytopenia. There have been rare reports of neutropenia and pancytopenia in patients receiving tamoxifen; this can sometimes be severe. In the NSABP P-1 trial, 6 women on tamoxifen and 2 on placebo experienced grade 3-4 drops in platelet count (£ 50,000/mm3). Information for Patients Patients should be instructed to read the Medication Guide supplied as required by law when tamoxifen citrate is dispensed.

The complete text of the Medication Guide is reprinted at the end of the Full Prescribing Information. Reduction in Invasive Breast Cancer and DCIS in Women with DCIS Women with DCIS treated with lumpectomy and radiation therapy who are considering tamoxsifen to reduce the incidence of a second breast cancer event should assess the risks and benefits of therapy, since treatment with tamoxifen decreased the incidence of invasive breast cancer, but has not been shown to affect survival. Reduction in Breast Cancer Incidence in High Risk Women Women who are at high risk for breast cancer can consider taking tamoxifen therapy to reduce the incidence of breast cancer. Whether the benefits of treatment are considered to outweigh the risks depends on a woman’s personal health history and on how she weighs the benefits and risks. Tamoxifen therapy to reduce the incidence of breast cancer may therefore not be appropriate for all women at high risk for breast cancer.

Women who are considering tamoxifen therapy should consult their health care professional for an assessment of the potential benefits and risks prior to starting therapy for reduction in breast cancer incidence. Women should understand that tamoxifen reduces the incidence of breast cancer, but may not eliminate risk.

Tamoxifen decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. In women with breast cancer who are at high risk of developing a second breast cancer, treatment with about 5 years of tamoxifen reduced the annual incidence rate of a second breast cancer by approximately 50%. Women who are pregnant or who plan to become pregnant should not take tamoxifen to reduce her risk of breast cancer.

Effective nonhormonal contraception must be used by all premenopausal

women taking tamoxifen and for approximately two months after discontinuing therapy if they are sexually active. Tamoxifen does not cause infertility, even in the presence of menstrual irregularity. For sexually active women of child-bearing potential, tamoxifen therapy should be initiated during menstruation. in women with menstrual irregularity, a negative b-HCG immediately prior to the initiation of therapy is sufficient (See WARNINGS-Pregnancy Category D). Two European trials of tamoxifen to reduce the risk of breast cancer were conducted and showed no difference in the number of breast cancer cases between the tamoxifen and placebo arms. These studies had trial designs that differed from that of NSABP P-1, were smaller than NSABP P-1, and enrolled women at a lower risk for breast cancer than those in P-1.

Monitoring During Tamoxifen Therapy Women taking or having previously taken tamoxifen should be instructed to seek prompt medical attention for new breast lumps, vaginal bleeding, gynecologic symptoms (menstrual irregularities, changes in vaginal discharge, or pelvic pain or pressure), symptoms of leg swelling or tenderness, unexplained shortness of breath, or changes in vision. Women should inform all care providers, regardless of the reason for evaluation, that they take tamoxifen. Women taking tamoxifen to reduce the incidence of breast cancer should have a breast examination, a mammogram, and a gynecologic examination prior to the initiation of therapy. These studies should be repeated at regular intervals while on therapy, in keeping with good medical practice. Women taking tamoxifen as adjuvant breast cancer therapy should follow the same monitoring procedures as for women taking tamoxifen for the reduction in the incidence of breast cancer. Women taking tamoxifen as treatment for metastatic breast cancer should review this monitoring plan with their care provider and select the appropriate modalities and schedule of evaluation.

Laboratory Tests Periodic complete blood counts, including platelet counts, and periodic liver function tests should be obtained. Drug Interactions When tamoxifen is used in combination with coumarin-type anticoagulants, a significant increase in anticoagulant effect may occur. Where such coadministration exists, careful monitoring of the patient’s prothrombin time is recommended. In the NSABP P-1 trial, women who required coumarin-type anticoagulants for any reason were ineligible for participation in the trial (See CONTRAINDICATIONS). There is an increased risk of thromboembolic events occurring when cytotoxic agents are used in combination with tamoxifen. Tamoxifen reduced letrozole plasma concentrations by 37%. The effect of tamoxifen on metabolism and excretion of other antineoplastic drugs, such as cyclophosphamide and other drugs that require mixed function oxidases for activation, is not known. Tamoxifen and N-desmethyl tamoxifen plasma concentrations have been shown to be reduced when coadministered with rifampin or aminoglutethimide.

Induction of CYP3A4-mediated metabolism is considered to be the mechanism by which these reductions occur; other CYP3A4 inducing agents have not been studied to confirm this effect. One patient receiving tamoxifen with concomitant phenobarbital exhibited a steady state serum level of tamoxifen lower than that observed for other patients (i.e., 26 ng/mL vs. mean value of 122 ng/mL). However, the clinical significance of this finding is not known. Rifampin induced the metabolism of tamoxifen and significantly reduced the plasma concentrations of tamoxifen in 10 patients. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. Concomitant bromocriptine therapy has been shown to elevate serum tamoxifen and N-desmethyl tamoxifen. Drug/Laboratory Testing Interactions During postmarketing surveillance, T4 elevations were reported for a few postmenopausal patients which may be explained by increases in thyroid-binding globulin. These elevations were not accompanied by clinical hyperthyroidism.

Variations in the karyopyknotic index on vaginal smears and various degrees of estrogen effect on Pap smears have been infrequently seen in postmenopausal patients given tamoxifen. In the postmarketing experience with tamoxifen, infrequent cases of hyperlipidemias have been reported. Periodic monitoring of plasma triglycerides and cholesterol may be indicated in patients with pre-existing hyperlipidemias (See ADVERSE REACTIONS Postmarketing Experience section).

Carcinogenesis A conventional carcinogenesis study in rats at doses of 5, 20, and 35 mg/kg/day (about one, three and seven-fold the daily maximum recommended human dose on a mg/m2 basis) administered by oral gavage for up to 2 years revealed a significant increase in hepatocellular carcinoma at all doses. The incidence of these tumors was significantly greater among rats administered 20 or 35 mg/ kg/day (69%) compared to those administered 5 mg/kg/day (14%). In a separate study, rats were administered tamoxifen at 45 mg/kg/ day (about nine-fold the daily maximum recommended human dose on a mg/m2 basis); hepatocellular neoplasia was exhibited at 3 to 6 months. Granulosa cell ovarian tumors and interstitial cell testicular tumors were observed in two separate mouse studies. The mice were administered the trans and racemic forms of tamoxifen for 13 to 15 months at doses of 5, 20 and 50 mg/kg/day (about one-half, two and five-fold the daily recommended human dose on a mg/m2 basis). Mutagenesis No genotoxic potential was found in a conventional battery of in vivo and in vitro tests with pro-and eukaryotic test systems with drug metabolizing systems. However, increased levels of DNA adducts were observed by 32P post-labeling in DNA from rat liver and cultured human lymphocytes. Tamoxifen also has been found to increase levels of micronucleus formation in vitro in human lymphoblastoid cell line (MCL-5). Based on these findings, tamoxifen is genotoxic in rodent and human MCL-5 cells. Impairment of Fertility Tamoxifen produced impairment of fertility and conception in female rats at doses of 0.04 mg/kg/day (about 0.01-fold the daily maximum recommended human dose on a mg/m2 basis) when dosed for two weeks prior to mating through day 7 of pregnancy. At this dose, fertility and reproductive indices were markedly reduced with total fetal mortality. Fetal mortality was also increased at doses of 0.16 mg/kg/day (about 0.03-fold the daily maximum recommended human dose on a mg/m2 basis) when female rats were dosed from days 7-17 of pregnancy. Tamoxifen produced abortion, premature delivery and fetal death in rabbits administered doses equal to or greater than 0.125 mg/kg/day (about 0.05-fold the daily maximum recommended human dose on a mg/ m2 basis). There were no teratogenic changes in either rats or rabbits. Pregnancy Category D Nursing Mothers Tamoxifen has been reported to inhibit lactation. Two placebo-controlled studies in over 150 women have shown that tamoxifen significantly inhibits early postpartum milk production. In both studies tamoxifen was administered within 24 hours of delivery for between 5 and 18 days. The effect of tamoxifen on established milk production is not known. There are no data that address whether tamoxifen is excreted into human milk. If excreted, there are no data regarding the effects of tamoxifen in breast milk on the breastfed infant or breastfed animals.

However, direct neonatal exposure of tamoxifen to mice and rats (not via breast milk) produced 1) reproductive tract lesions in female rodents (similar to those seen in humans after intrauterine exposure to diethylstilbestrol) and 2) functional defects of the reproductive tract in male rodents such as testicular atrophy and arrest of spermatogenesis. It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. Reduction in Breast Cancer Incidence in High Risk Women and Women with DCIS It is not known if tamoxifen is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from tamoxifen, women taking tamoxifen should not breast feed. Pediatric Use The use of SOLTAMOX™ in pediatric patients has not been evaluated. Geriatric Use In the NSABP P-1 trial, the percentage of women at least 65 years of age was 16%. Women at least 70 years of age accounted for 6% of the participants. A reduction in breast cancer incidence was seen among participants in each of the subsets: A total of 28 and 10 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. Across all other outcomes, the results in this subset reflect the results observed in the subset of women at least 50 years of age. No overall differences in tolerability were observed between older and younger

patients. In the NSABP B-24 trial, the percentage of women at least 65 years of age was 23%. Women at least 70 years of age accounted for 10% of participants. A total of 14 and 12 invasive breast cancers were seen among participants 65 and older in the placebo and tamoxifen groups, respectively. This subset is too small to reach any conclusions on efficacy. Across all other endpoints, the results in this subset were comparable to those of younger women enrolled in this trial. No overall differences in tolerability were observed between older and younger patients. ADVERSE REACTIONS Adverse reactions to tamoxifen are relatively mild and rarely severe enough to require discontinuation of treatment in breast cancer patients. Continued clinical studies have resulted in further information which better indicates the incidence of adverse reactions with tamoxifen as compared to placebo. In one single-dose pharmacokinetic study in healthy perimenopausal and postmenopausal female volunteers, throat irritation was reported by 3 of 60 evaluable subjects (5.0%) in the SOLTAMOX™ treatment groups while none of the subjects in the tamoxifen reference group reported this event. All events were mild and occurred within an hour after dosing. All events were resolved within 24 hours. Metastatic Breast Cancer Increased bone and tumor pain and, also, local disease flare have occurred, which are sometimes associated with a good tumor response. Patients with increased bone pain may require additional analgesics. Patients with soft tissue disease may have sudden increases in the size of preexisting lesions, sometimes associated with marked erythema within and surrounding the lesions and/or the development of new lesions. When they occur, the bone pain or disease flare are seen shortly after starting tamoxifen and generally subside rapidly. In patients treated with tamoxifen for metastatic breast cancer, the most frequent adverse reaction to tamoxifen is hot flashes. Other adverse reactions which are seen infrequently are hypercalcemia, peripheral edema, distaste for food, pruritus vulvae, depression, dizziness, light-headedness, headache, hair thinning and/ or partial hair loss, and vaginal dryness. Premenopausal Women The following table summarizes the incidence of adverse reactions reported at a frequency of 2% or greater from clinical trials (Ingle, Pritchard, Buchanan) which compared tamoxifen therapy to ovarian ablation in premenopausal patients with metastatic breast cancer.

Table 1.

Summary of Incidence of Adverse Reactions Reported at Frequency of ≥2% From Clinical Trials Tamoxiden Ovarian Ablation All Effects All Effects % of Women % of Women Adverse Reactionsa n = 104 n = 100 Flush 33 46 Amenorrhea 16 69 Altered Menses 13 5 Oligomenorrhea 9 1 Bone Pain 6 6 Menstrual Disorder 6 4 Nausea 5 4 Cough/Coughing 4 1 Edema 4 1 Fatigue 4 1 Musculoskeletal Pain 3 0 Pain 3 4 Ovarian Cyst(s) 3 2 Depression 2 2 Abdominal Cramps 1 2 Anorexia 1 2 a = Some women had more than 1 adverse reaction.

Male Breast Cancer Tamoxifen is well tolerated in males with breast cancer. Reports from the literature and case reports suggest that the safety profile of tamoxifen in males is similar to that seen in women. Loss of libido and impotence have resulted in discontinuation of tamoxifen therapy in male patients. Also, in oligospermic males treated with tamoxifen, LH, FSH, testosterone and estrogen levels were elevated. No significant clinical changes were reported. Adjuvant Breast Cancer In the NSABP B-14 study, women with axillary node-negative breast cancer were randomized to 5 years of tamoxifen 20 mg/day or placebo following primary surgery. The reported adverse effects are tabulated below (mean follow-up of approximately 6.8 years) showing adverse events more common on tamoxifen than on placebo. The incidence of hot flashes (64% vs. 48%), vaginal discharge (30% vs. 15%), and irregular menses (25% vs. 19%) were higher with tamoxifen compared with placebo. All other adverse effects occurred with similar frequency in the 2 treatment groups, with the exception of thrombotic events; a higher incidence was seen in tamoxifen-treated patients (through 5 years, 1.7% vs. 0.4%). Two of the patients treated with tamoxifen who had thrombotic events died. In the Eastern Cooperative Oncology Group (ECOG) adjuvant breast cancer trial, tamoxifen or placebo was administered for 2 years to women following mastectomy. When compared to placebo, tamoxifen showed a significantly higher incidence of hot flashes (19% vs. 8% for placebo). The incidence of all other adverse reactions was similar in the 2 treatment groups with the exception of thrombocytopenia where the incidence for tamoxifen was 10% vs. 3% for placebo, an observation of borderline statistical significance.

NSABP B-14 Study Table 2.

Comparison of Tamoxifen to Placebo Administered for 2 Years to Women Following Mastectomy % of Women Adverse Reactions Tamoxifen (n = 1422) Placebo (n = 1437) Hot Flashes 64 48 Fluid Retention 32 30 Vaginal Discharge 30 15 Nausea 26 24 Irregular Menses 25 19 Weight Loss (>5%) 23 18 Skin Changes 19 15 Increased SGOT 5 3 Increased Bilirubin 2 1 Increased Creatinine 2 1 2 1 Thrombocytopeniaa Thrombotic Events Deep Vein Thrombosis 0.8 0.2 Pulmonary Embolism 0.5 0.2 Superficial Phlebitis 0.4 0.0 a = Defined as a platelet count of <100,000/mm3.

SGOT = Serum glultamic oxalo-acetic transaminase.

In other adjuvant studies, Toronto and tamoxifen Adjuvant Trial Organization (NATO), women received either tamoxifen or no therapy. In the Toronto study, hot flashes were observed in 29% of patients for tamoxifen vs. 1% in the untreated group. In the NATO trial, hot flashes and vaginal bleeding were reported in 2.8% and 2.0% of women, respectively, for tamoxifen vs. 0.2% for each in the untreated group. Ductal Carcinoma in Situ (DCIS) The type and frequency of adverse events in the NSABP

B-24 trial were consistent with those observed in the other adjuvant trials conducted with tamoxifen. Reduction in Breast Cancer Incidence in High Risk Women In the NSABP P-1 Trial, there was an increase in five serious adverse effects in the tamoxifen group: endometrial cancer (33 cases in the tamoxifen group vs. 14 in the placebo group); pulmonary embolism (18 cases in the tamoxifen group vs. 6 in the placebo group); deep vein thrombosis (30 cases in the tamoxifen group vs. 19 in the placebo group); stroke (34 cases in the tamoxifen group vs. 24 in the placebo group); cataract formation (540 cases in the tamoxifen group vs. 483 in the placebo group) and cataract surgery (101 cases in the tamoxifen group vs. 63 in the placebo group). The following table presents the adverse events observed in NSABP P-1 by treatment arm.

Only adverse events more common on tamoxifen than placebo are shown. NSABP P-1 Trial: All Adverse Events Table 3.

Adverse Events Observed in NSABP P-1 by Treatment Arm: Adverse Events More Common on Tamoxifen Than Placebo % of Women Treatment Arm/ Tamoxifen Placebo Adverse Event (n = 1422) (n = 1437) N = 6469a Self-Reported N = 6441a Symptoms Hot Flashes 80 68 Vaginal Discharges 55 35 Vaginal Bleeding 23 22 N = 6535b Laboratory N = 6520b Abnormalities Platelets Decreased 0.7 0.3 Adverse Effects N = 6492c N = 6484a Other Toxicities Mood 11.6 10.8 Infection/Sepsis 6.0 5.1 Constipation 4.4 3.2 Alopecia 5.2 4.4 Skin 5.6 4.7 Allergy 2.5 2.1 a = Number with quality of life questionnaires. b = Number with treatment follow-up forms. c = Number with adverse drug reaction forms.

In the NSABP P-1 trial, 15.0% and 9.7% of participants receiving tamoxifen and placebo therapy, respectively, withdrew from the trial for medical reasons. The following are the medical reasons for withdrawing from tamoxifen and placebo therapy, respectively: Hot flashes (3.1% vs. 1.5%) and Vaginal Discharge (0.5% vs.

0.1%). In the NSABP P-1 trial, 8.7% and 9.6% of participants receiving tamoxifen and placebo therapy, respectively, withdrew for non-medical reasons. On the NSABP

P-1 trial, hot flashes of any severity occurred in 68% of women on placebo and in 80% of women on tamoxifen. Severe hot flashes occurred in 28% of women on placebo and 45% of women on tamoxifen. Vaginal discharge occurred in 35% and 55% of women on placebo and tamoxifen respectively; and was severe in 4.5% and 12.3% respectively. There was no difference in the incidence of vaginal bleeding between treatment arms. Postmarketing Experience Less frequently reported adverse reactions are vaginal bleeding, vaginal discharge, menstrual irregularities, skin rash and headaches. Usually these have not been of sufficient severity to require dosage reduction or discontinuation of treatment. Very rare reports of erythema multiforme, Stevens-Johnson syndrome, bullous pemphigoid, interstitial pneumonitis, and rare reports of hypersensitivity reactions including angioedema have been reported with tamoxifen therapy. In some of these cases, the time to onset was more than one year. Rarely, elevation of serum triglyceride levels, in some cases with pancreatitis, may be associated with the use of tamoxifen (see PRECAUTIONS, Drug/Laboratory Testing Interactions section). OVERDOSAGE Signs observed at the highest doses following studies to determine LD50 in animals were respiratory difficulties and convulsions. Acute overdosage in humans has not been reported. In a study of advanced metastatic cancer patients which specifically determined the maximum tolerated dose of tamoxifen in evaluating the use of very high doses to reverse multidrug resistance, acute neurotoxicity manifested by tremor, hyperreflexia, unsteady gait and dizziness were noted. These symptoms occurred within 3-5 days of beginning tamoxifen and cleared within 2-5 days after stopping therapy.

No permanent neurologic toxicity was noted. One patient experienced a seizure several days after tamoxifen was discontinued and neurotoxic symptoms had resolved. The causal relationship of the seizure to tamoxifen therapy is unknown. Doses given in these patients were all greater than 400 mg/m2 loading dose, followed by maintenance doses of 150 mg/m2 of tamoxifen given twice a day. In the same study, prolongation of the QT interval on the electrocardiogram was noted when patients were given doses higher than 250 mg/m2 loading dose, followed by maintenance doses of 80 mg/m2 of tamoxifen given twice a day. For a woman with a body surface area of 1.5 m2 the minimal loading dose and maintenance doses given at which neurological symptoms and QT changes occurred were at least 6 fold higher in respect to the maximum recommended dose. No specific treatment for overdosage is known; treatment must be symptomatic. DOSAGE AND ADMINISTRATION For patients with breast cancer, the recommended daily dose is 20-40 mg. Dosages greater than 20 mg per day should be given in divided doses (morning and evening). A 20 mg dose of SOLTAMOX™ is administered as 10 mL (equivalent to 2 teaspoons) of the oral solution. In three single agent adjuvant studies in women, one 10 mg tamoxifen citrate tablet was administered two (ECOG and NATO) or three (Toronto) times a day for two years. In the NSABP B-14 adjuvant study in women with node-negative breast cancer, one 10 mg tamoxifen citrate tablet was given twice a day for at least 5 years. Results of the B-14 study suggest that continuation of therapy beyond five years does not provide additional benefit. In the EBCTCG 1995 overview, the reduction in recurrence and mortality was greater in those studies that used tamoxifen for about 5 years than in those that used tamoxifen for a shorter period of therapy. There was no indication that doses greater than 20 mg per day were more effective. Current data from clinical trials support 5 years of adjuvant tamoxifen citrate therapy for patients with breast cancer. Ductal Carcinoma in Situ (DCIS) The recommended dose is tamoxifen citrate 20 mg daily for 5 years. Reduction in Breast Cancer Incidence in High Risk Women The recommended dose is tamoxifen citrate 20 mg daily for 5 years. There are no data to support the use of tamoxifen citrate other than for 5 years.

RX only Dated: 9/14/2006 Manufactured by: Rosemont Pharmaceuticals Ltd, Yorkdale Industrial Park, Braithwaite Street Leeds, LS11 9XE, UK. Distributed by: Cytogen Corporation Princeton, NJ 08540, USA.

Address medical enquiries to: Cytogen Corporation • 650 College Road East Suite 3100, Princeton, NJ 08540 1-800-833-3533. © 2004-6, Rosemont Pharmaceuticals Ltd. Printed in the U.K.

RENAL CELL CARCINOMA The US Food and Drug Administration (FDA) approved axitinib (Inlyta; Pfizer, Inc.) for the treatment of patients with advanced renal cell carcinoma after failure of 1 prior systemic therapy. This approval was granted on January 27, 2012. For more information about the FDA approval, see http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289439.htm.

Axitinib as Second-Line Treatment for Metastatic Renal Cell Carcinoma Susanne Bond, FNP-ANP Taussig Cancer Center Cleveland, Ohio

A

xitinib is a more selective inhibitor of vascular endothelial growth factor (VEGF) receptor and thereby is the most potent tyrosine kinase inhibitor. It specifically targets VEGF 1, 2, and 3 but does not affect the platelet-derived growth factor (PDGF) receptor as do sunitinib and other less-selective VEGFs.1 Because of this, the side effect profile of axitinib is narrower and the treatment is better tolerated.

Peak plasma concentration of axitinib is noted at 3 hours after a high-fat, high-calorie meal and 2 hours after overnight fasting.1 It can be taken with or without meals and is always dosed twice daily.2 Its plasma half-life is 2.5 to 6.1 hours, and steadystate is achieved in 2 to 3 days.1,2

Pretreatment Evaluation As axitinib can affect blood pressure, it is important to control any hypertension prior to initiating therapy.

Other important issues to review are thyroid or liver problems and a history of blood clots or bleeding disorders.2

Mrs G, an ICU nurse, was in her usual state of health until late 2011, when she developed nonspecific rib cage pain and right hip pain. A chest x-ray showed a suspicious mass in the pleural region.

A subsequent whole body bone scan and CT scan of the chest, abdomen, and pelvis revealed bone metastases, mediastinal lymphadenopathy, pulmonary nodules, and a large right kidney mass with invasion into the liver. Pathology results from a biopsy of the right kidney mass showed renal cell carcinoma, clear cell type, Fuhrman nuclear grade 4.

She was started on frontline therapy with sunitinib and completed 2 cycles.

Restaging scans showed a mixed response, with decreased size of the right kidney mass but increased size of the right iliac bone metastasis and 2 new hepatic metastases, as well as progression of erosion of a rib on her left side, with pathologic fracture. Her sunitinib was stopped, and she was enrolled in a phase 2 study and randomized to everolimus. She experienced severe treatment-related hyperglycemia and was started on insulin. She also developed treatment-related hypothyroidism and hypertension. Although she showed stable disease, there was no noted decrease in her tumor burden. Because of her side effects and no real improvement in disease, she was moved to axitinib in May 2012.

Stress the importance of early reporting of any symptoms, as prompt treatment of side effects and follow-up to assess the effectiveness of interventions may reduce the need for treatment interruption and/or dose reduction.

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A review of Mrs Gâ&#x20AC;&#x2122;s history indicates 2 areas of concern: (1) her blood pressure, for which she had been prescribed lisinopril 10 mg by her primary care physician, resulting in average at-home blood pressures of 118/68 mm Hg; and (2) her thyroid, for which she had already been started on 88 mcg of levothyroxine, as she had become somewhat hypothyroid from previous treatments.

Availability of Medication Axitinib is provided by a specialty pharmacy and often needs prior authorization or patient assistance related to the cost. Because it can take 1 to 3 weeks before the medication arrives, a great deal of anxiety can be avoided if this is made clear prior to the patient leaving the office.

Possibly because Mrs G had previously been on sunitinib and much of the paperwork was already done, she received the drug within 4 days.

Dosing The recommended starting dose of axitinib is 5 mg twice daily.2 From this point, the dose can be titrated up or down as tolerated and indicated.

The patient is usually kept on the starting dose for 2 cycles of 30 days, at which time restaging scans are done. Certainly if there are intoler-

able adverse effects greater than grade 2, or the patient is not tolerating the medication, then there is a need to reduce the dose. The first dose reduction is to 3 mg twice daily.2 If there are no adverse effects, specifically no increase in blood pressure, then dose escalation is indicated. On occasion, patients have been dose escalated after the first cycle.

Because an increase in blood pressure is anticipated, using diastolic hypertension as a marker of efficacy is one method to determine the correct dose (this will be discussed later in this article).1 Monitoring Stress the importance of early reporting of any symptoms, as prompt treat-

ment of side effects and follow-up to assess the effectiveness of interventions may reduce the need for treatment interruption and/or dose reduction.3 Patients should be instructed to monitor their blood pressure daily after starting axitinib. Two weeks after axitinib initiation, liver function should be checked. At 4 and 8 weeks, blood work should include a complete metabolic panel, complete blood cell count, and a thyroid-stimulating hormone test. At 8 weeks, restaging scans are done, preferably CT of the chest, abdomen, and pelvis, both with and without contrast.

All lab work remained essentially normal. Mrs G had scans after 2 cycles of 30 days each. Her response was good, with decreases in renal mass, pulmonary nodules, and liver metastasis.

Adverse Events and Treatments The most frequently reported side effects of axitinib treatment in clinical trials were diarrhea (55%), hypertension (40%), and fatigue (39%); the most common grade 3 and 4 adverse events were noted in these 3 side effects.1,2

Diarrhea Diarrhea is the number one complication frequently presenting with axitinib.1 Patients should be instructed in medical management, such as being sure to take medication 30 minutes before eating. Patients can also take a combination of commonly prescribed medications, such as loperamide, diphenoxylate hydrochloride/ atropine sulfate (Lomotil), and tincture of opium 10%. Psyllium fiber (Benefiber), 1 tablet with each meal, can also help.1,3,4 A nutrition consultation is always appropriate, but if unavailable or inconvenient, then be sure to discuss that eating simple foods or foods that are known to constipate, such as the BRAT (bananas, rice, applesauce, and toast) diet, can be helpful.4 Consumption of high-potassium foods, such as potatoes, nectarines, and bananas, should also be encouraged. Ensure the patient maintains an oral intake of 2 to 3 quarts of fluids daily.4 Equally important is teaching the patient about foods they should avoid, such as spicy food.1 Mrs G struggles the most with her diarrhea. She had been taking paregoric, Lomotil, and ocreotide acetate (Sandostatin). Most recently we started her on tincture of opium. Initially she had some positive results with probiotics, but she stopped taking them when they were no longer helping. She has also tried Benefiber (wheat dextrin), which did not help. Over the course of her illness she has lost more than 70 pounds; her recent BMI was 17.71 kg/m2. At this point we have exhausted diarrhea medication support options and have actually recommended short drug holidays. She took an extended (10-day) break over

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Hypertension As discussed above, if the patient already has hypertension it should be well managed before the patient starts therapy.2 Hypertension is noted as early as 3 to 4 hours after initiating axitinib therapy, and although hypertension is never a desired side effect, there is an indication that it may be associated with improved clinical outcomes.1,3,5,6 Hypertension as a biomarker. Hypertension can be a reflection of the axitinib dose being “on target.”1 For example, in one 8-week analysis, median progression-free survival (PFS) in the 2 metastatic renal cell carcinoma studies was significantly higher in patients with diastolic hypertension (defined as diastolic pressure ≥90 mm Hg) than in those without diastolic hypertension (16.5 months vs 6.4 months, respectively).5 It is important to note that treating the hypertension did not diminish the outcome. A subset analysis of hypertension at day 15 of cycle 1 versus baseline showed that patients with a mean increase in diastolic blood pressure of ≥15 mm Hg had a higher overall response rate than those with an increase <15 mm Hg (61% vs 53%, respectively).1,6 Treatment of hypertension. If the patient’s hypertension is already being treated with blood pressure medication, then it is best to have the prescribing doctor continue to manage it. If, however, this is a new symptom with axitinib, antihypertensive treatment should be initiated, either by the practitioner or by referral to a cardiologist.

Mrs G was advised to check her blood pressure daily, and she called within 3 days because she had noticed an increase. Her averages had gone to 135/high 80s mm Hg. As her blood pressure went up but did not exceed 140/90 mm Hg, her blood pressure medication was left as it was.

Fatigue Unfortunately, fatigue frequently accompanies this type of targeted therapy. It is important to look for

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secondary causes, such as hypothyroidism, insomnia, depression, hypogonadism, anemia, and uncontrolled pain.7 Additionally, it is important to monitor the daily caloric intake. If no secondary cause of fatigue is found, then educating the patient in ways to combat fatigue would include advising the patient to take more frequent short breaks rather than a long nap; go for short walks and perform light exercise; and stay as active as possible. It is important to emphasize to patients the importance of setting realistic expectations: operating at about 70% of what they think they can normally do is an appropriate goal.7

to eat a higher daily calorie count. She was asked to track her food intake for 1 week, and it was noted that her average daily calorie intake was between 1200 and 1600 calories, which is somewhat low, although from her perspective she was eating “a lot.”

Dysphonia Encourage the patient to drink plenty of water, write things down instead of speaking, and avoid shouting and whispering; the use of lozenges is also helpful. Inform the patient that, while this is a common side effect, it does not usually last long.3

Axitinib, with its more targeted therapy, may provide a less symptomatic and longer survival for patients with metastatic renal cell carcinoma.

Other Possible Side Effects Nausea Instruct the patient to eat frequent small meals and to avoid fatty, fried, spicy, and very sweet foods. Make sure that the patient has antinausea medications available and knows how to use them before starting treatment with axitinib. It is recommended to prescribe 8 mg of ondansetron (Zofran) to be taken every 8 hours, plus 10 mg of prochlorperazine (Compazine) every 4 hours. It is also helpful to prescribe an antacid. It is important to tell the patient that these medications can be taken concurrently.

Lack of Appetite, Weight Loss, and Taste Alteration Giving olanzapine (Zyprexa) 10 mg at bedtime and megestrol acetate (Megace) 400 mg in the morning has shown to increase appetite. Also, again encourage frequent small meals.

Be sure the patient is tracking his/her daily calorie intake.

Mrs G is struggling with weight loss.

She has diarrhea, which could account for some of the weight loss, but she needs

Hypothyroidism Hypothyroidism is a possible side effect of this medication and should be closely monitored, especially when the patient complains of increasing fatigue. Thyroid-hormone replacement therapy should be used as needed to maintain a euthyroid state.

Hand-Foot Syndrome Hand-foot syndrome (HFS) can be an issue with axitinib as well as other VEGF inhibitors. The “3C” approach can be used to treat the symptoms of HFS8: Controlling calluses. If a patient already has many calluses, then a referral to a podiatrist may be in order. If calluses are not extensive, then using a pumice stone or similar will be beneficial. Soaking feet in Epsom salts can also help.

Comforting with cushions. The patient should wear thick cotton socks and well-fitting and padded soft shoes with a large toe box. Insole cushions and inserts can also help.

Covering with creams: Frequent use of emollient creams and keratolytic

agents (eg, urea, alpha hydroxy acids, and salicylic acid) can soften callused areas of palms and soles. Hemorrhoid creams for foot calluses can also help.

Summary A phase 2 trial of axitinib by Sonpavde and colleagues demonstrated a median response duration of 23 months, as well as a median time to progression of 15.7 months and overall survival of 29.9 months.9 Official studies from Pfizer state only that results of a headto-head study showed a median PFS of 6.3 months versus 4.6 months for those on axitinib versus sorafenib, respectively.2 The goal of treatment must always be kept in mind. As Brian Rini, MD, states: “The goal for every metastatic RCC patient is to delay for as long as possible a lethal burden of disease while maximizing quality of life and patient convenience.”10 Axitinib, with its more targeted therapy, may provide a less symptomatic and longer survival for patients with metastatic renal cell carcinoma. l References

1. Mittal K, Wood LS, Rini BI. Axitinib in metastatic renal cell carcinoma. Biol Ther. 2012;2(1):1-13. http://link.springer.com/article/10.1007%2Fs13554012-0005-2#page-1.

2. Inlyta [package insert]. New York, NY; Pfizer, Inc; January 2012.

3. Wood LS, Gornell S, Rini BI. Maximizing clinical outcomes with axitinib therapy in advanced renal cell carcinoma through proactive side-effect management. Community Oncol. 2012;9(2):46-55.

4. National Cancer Institute. Gastrointestinal complications (PDQ®): diarrhea. http://www.cancer.gov/ cancertopics/pdq/supportivecare/gastrointestinalcom plications/HealthProfessional/page5. Updated July 18, 2012. Accessed March 2, 2013.

5. Rini BI, Schiller JH, Fruehauf JP, et al. Diastolic blood pressure as a biomarker of axitinib efficacy in solid tumors. Clin Cancer Res. 2011;17(11):38413849.

6. Rini BI, Grunwald V, Fishman MN, et al. Axitinib for first-line metastatic RCC: overall efficacy and pharmacokinetic analyses from a randomized phase II study. Symposium presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. 7. Lindsey H. Fatigue: the forgotten symptom? Oncol Times. 2013;35(4):26-28.

8. Wood LS, Lemont H, Jatoi A, et al. Practical considerations in the management of hand-foot skin reactions associated with the multikinase inhibitors.

Community Oncol. 2010;7(1):23-29.

9. Sonpavde G, Hutson TE, Rini BI. Axitinib for renal cell carcinoma. Expert Opin Investig Drugs.

2008;17(5):741-748.

10. Rini BI. Metastatic renal call carcinoma: many treatment options, one patient. J Clin Oncol.

2009;27(19):3225-3234.

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.

May 2013 I VOL 6, NO 4

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RENAL CELL CARCINOMA

the Christmas holidays and was able to gain 15 pounds. However, when she went back on drug, the diarrhea started almost instantly, and she quickly lost the weight she had gained. She is now on a regimen of 5 days on axitinib and 2 days off, and she has started regaining weight.

At the last office visit, her BMI was 19.8 kg/m2, with a great increase in her energy level and well-being. Although there is no evidence in the literature that supports this regimen, she is doing well and will be rescanned shortly.

COLORECTAL CANCER The US Food and Drug Administration (FDA) approved ziv-aflibercept injection (Zaltrap, Sanofi US, Inc.) for use in combination with 5-fluorouracil/leucovorin/ irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed following an oxaliplatin-containing regimen. This approval was granted on August 3, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm314438.htm.

Managing Adverse Events Associated With Antiangiogenic Biologic Agents for Metastatic Colorectal Cancer: A Nursing Perspective of Ziv-Aflibercept Julie A. Koch, RN, BSN, OCN, CCRP Vanguard Health Systems Berwyn, Illinois

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Figure Kaplan-Meier Curve for Overall Survival in the VELOUR Trial10 Aflibercept/FOLFIRI Placebo/FOLFIRI OS Kaplan-Meier estimates, months [95.34% CI] 7.62 (6.57 to 8.48) 6.83 (6.14 to 7.59) 25% quartile 13.50 (12.52 to 14.95) Median 12.06 (11.07 to 13.11) 25.59 (22.01 to 31.70) 21.03 (18.92 to 22.80) 75% quartile HR (95.34% CI) = 0.817 (0.713 to 09.37); log rank: P = .0032

1.0 Overall Survival (Probability)

Overview Survival outcomes for colorectal cancer (CRC) are poor, particularly for patients whose metastatic disease has progressed despite previous treatment.1,2 The vascular endothelial growth factor (VEGF) family of growth factor ligands is thought to play several roles in tumor angiogenesis, including metastatic colorectal cancer (mCRC). Ziv-aflibercept (formerly known as aflibercept in the United States), an agent that inhibits the VEGF pathway, was approved by the US Food and Drug Administration (FDA) in August 2012 in combination with 5-fluorouracil (5-FU), leucovorin (LV), and irinotecan (FOLFIRI) for patients with mCRC that is resistant to or has progressed following an oxaliplatin-containing regimen.3 For the past several years, bevacizumab (Avastin; Genentech, Inc.)—a monoclonal antibody that binds with VEGF-A to inhibit the VEGF pathway—has been approved by the FDA to treat mCRC in combination with cytotoxic therapy, including fluoropyrimidine-containing chemotherapy such as IFL (irinotecan/ bolus 5-FU/LV) or FOLFOX4 (5-FU/ LV/oxaliplatin).4-7 Unlike bevacizumab, ziv-aflibercept is a multiple angiogenic factor trap that binds to and prevents not only VEGF-A but also VEGF-B and placental growth factor from activating their native receptors; it targets multiple pathways to inhibit tumor angiogenesis, tumor growth, endothelial cell proliferation, and recruitment of bone marrow– derived myeloid progenitors.8,9 This review summarizes clinical trial data on the efficacy of ziv-aflibercept plus chemotherapy along with the incidence of treatment-related toxicities and strategies for their management based on clinical practice guidelines. Because bevacizumab’s adverse events (AEs) profile is well characterized and similar to that of ziv-aflibercept, this will also be discussed. It should be noted that experience with bevaciz-

0.8 0.6 0.4 0.2

Aflibercept/FOLFIRI Placebo/FOLFIRI

0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (Months) Number at Risk Placebo 614 485 286 131 51 14 Aflibercept 612 498 311 148 75 33 Survival Probability (%) Placebo 79.1 50.3 30.9 18.7 12.1 Aflibercept 81.9 56.1 38.5 28.0 22.3 Overall survival in 1226 patients comprising the primary analysis. The hazard ratio (HR) for the placebo/irinotecan, leucovorin and fluorouracil (FOLFIRI) group relative to the aflibercept/FOLFIRI group was 0.817 (95.34% CI, 0.713 to 0.937; P = .0032, stratified log-rank test), with median overall survival of 12.06 months (95.34% CI, 11.07 to 13.11) and 13.5 months (95.34% CI, 12.52 to 14.95), respectively.

Van Cutsem E et al. J Clin Oncol. 2012;30(28):3499-3506. Reprinted with permission. ©2013 American Society of Clinical Oncology. All rights reserved.

Table 1 Efficacy Results From the VELOUR Trial10 Placebo + FOLFIRI (n = 614)

Ziv-Aflibercept + FOLFIRI (n = 612)

P Value

OS, median, mo

12.06

13.50

.0032

PFS, median, mo

4.67

6.90

<.0001

ORR (CR + PR), %

11.1

19.8

<.001

Abbreviations: CR, complete response; FOLFIRI, 5-fluorouracil/leucovorin/ irinotecan; mo, month; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response: VELOUR, Aflibercept Versus Placebo in Combination With 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxiplatin-Based Regimen.

umab in combination with FOLFIRI in mCRC is limited to phase 2 trials. Oncology nurses need to understand and manage the AEs associated with antiangiogenic therapies; this review will present the nurse’s role in managing toxicities.

The VELOUR Trial The efficacy and safety of ziv-aflibercept in patients with mCRC previously treated with oxaliplatin were demonstrated in the VELOUR (Aflibercept Versus Placebo in Combination With 5-FU in the Treatment of Patients

With Metastatic Colorectal Cancer After Failure of an Oxiplatin-Based Regimen) trial. Patients who progressed during or after completing a single oxaliplatin-containing regimen, including those who relapsed within 6 months of completing adjuvant oxaliplatin-based therapy, were enrolled. Patients were randomized to receive ziv-aflibercept 4 mg/kg + FOLFIRI or placebo + FOLFIRI, administered every 2 weeks until disease progression or unacceptable toxicity. Ziv-aflibercept was administered as a 1-hour infusion prior to any component of the FOLFIRI regimen on the day of treatment. Median overall survival improved significantly with ziv-aflibercept + FOLFIRI versus placebo + FOLFIRI (13.50 vs 12.06 months, respectively; P = .0032) (Figure). Median progression-free survival with ziv-aflibercept versus placebo (6.90 vs 4.67 months, respectively; P <.0001) and response rate (complete + partial response; 19.8% vs 11.1%, respectively; P = .0001) also significantly improved (Table 1).10 Combination ziv-aflibercept + FOLFIRI demonstrated generally the same safety profile as placebo + FOLFIRI. Chemotherapy-associated AEs included nausea, vomiting, diarrhea, constipation, fatigue, and myelosuppression.10 Some AEs (all grades), however, occurred more frequently in patients receiving ziv-aflibercept compared with placebo (Table 2).3 The differences in incidence of AEs between the ziv-aflibercept + FOLFIRI versus placebo + FOLFIRI groups are similar to those observed with bevacizumab + IFL versus placebo + IFL.4 AEs (grade ≥3) that occurred more frequently with the ziv-aflibercept + FOLFIRI versus placebo + FOLFIRI (≥5% incidence and ≥2% higher in the ziv-aflibercept arm), in order of decreasing frequency, were neutropenia, diarrhea, hypertension, leukopenia, stomatitis, fatigue, proteinuria, and asthenia.3 AEs leading to treatment discontinuation occurred in 26.6% of patients treated with ziv-aflibercept and 12.1% of those who received placebo10; these

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Management of Anti-VEGF Adverse Events Management of AEs in patients treated with ziv-aflibercept must address those that are anti-VEGF as well as those from chemotherapy (ie, FOLFIRI). As observed in the VELOUR trial, chemotherapy-related AEs included nausea, vomiting, diarrhea, constipation, fatigue, and myelosuppression. These and less frequently observed AEs are often managed by using institutional protocols. Alternatively, guidelines are available from the National Cancer Institute,17 the American Society of Clinical Oncology,18 and the National Comprehensive Cancer Network.19 Several strategies can help to manage anti-VEGF AEs, such as identifying patients at increased risk or providing supportive care before or during treatment.

Strategies to Minimize Anti-VEGF Adverse Events Screening patients to determine if they have a history of or are at increased risk for vascular-related AEs (ie, hypertension, proteinuria, hemorrhage, thrombosis) is important because of the possibility of end-organ damage and death. If blood pressure is elevated, secondary causes such as uncontrolled pain should be investigated.20 A morning urine spot for urinary protein:creatinine ratio (UPCR) should be used to detect proteinuria; ziv-aflibercept should not be initiated in a patient with severe hemorrhage.3 Once bevacizumab or ziv-aflibercept therapy is initiated, regular monitoring is necessary. Blood pressure should be monitored every 2 to 3 weeks, or more frequently if clinically indicated. A 24-hour urine collection is recommended for a urine dipstick

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Table 2 Adverse Events (All Grades) Occurring With an Incidence ≥20% and More Frequently in Patients Treated With Ziv-Aflibercept (≥2% Higher in Ziv-Aflibercept Arm) in the VELOUR Trial3 Adverse Event

Placebo + FOLFIRI, % (n = 605)

Ziv-Aflibercept + FOLFIRI, % (n = 611)

Diarrhea

57

69

AST increased

54

62

ALT increased

39

50

Stomatitis

33

50

Fatigue

39

48

Decreased appetite

24

32

Weight decreased

14

32

Abdominal pain

24

27

3

25

19

23

9

22

Leukopenia

72

78

Neutropenia

57

67

Proteinuria

41

62

Thrombocytopenia

35

48

Hypertension

11

41

7

28

Dysphonia Serum creatinine increased Headache Anti-VEGF associated

Epistaxis

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FOLFIRI, 5-fluorouracil/leucovorin/ irinotecan; VEGF, vascular endothelial growth factor; VELOUR, Aflibercept Versus Placebo in Combination With 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxiplatin-Based Regimen.

reading ≥2 prior to the bevacizumab dose or a UPCR >1 for ziv-aflibercept, if proteinuria is suspected.3,4 However, this approach has been questioned because of its high cost and low impact on treatment decisions.21 Monitor the complete blood count and differential at baseline and before initiation of each cycle of ziv-aflibercept.3

or ziv-aflibercept combined with cytotoxic chemotherapy.3,4 Consequently, prophylactic use of colony-stimulating factors (CSFs; ie, filgrastim or pegfilgrastim) is recommended for patients at high risk (>20%) for febrile neutropenia. For patients at intermediate risk (10%–20%) of febrile neutropenia, prophylactic CSF therapy can be considered. Should febrile neutrope-

Management of adverse events in patients treated with ziv-aflibercept must address those that are anti-VEGF as well as those from chemotherapy.

Supportive Care Supportive care includes premedication, palliative therapy, or dose modification, interruption, or discontinuation. Premedication for emesis may not be necessary because the emetic risk with ziv-aflibercept is low3,10; however, antiemetic prophylaxis is common with FOLFIRI.22 Grade ≥3 neutropenia occurs in about one-third of patients treated with bevacizumab

nia occur, filgrastim can also be used for treatment.23 Hypertension Antihypertensive therapy should be optimized or initiated, based on patient characteristics, to achieve blood pressure <140/90 mm Hg (<130/80 mm Hg for those with chronic kidney disease or diabetes).20,24 For most patients, a thia-

zide, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, beta-blocker, or calcium channel blocker is appropriate, based on comorbidities.25 A thiazide is not recommended if diarrhea is present (author’s opinion). For older persons, a calcium channel blocker (preferably with vasodilatory properties, such as nifedipine or amlodipine) may be preferred.20,25 Diarrhea Management of diarrhea is based on severity and its classification as uncomplicated (grade 1/2 with no other signs or symptoms) or complicated. There is no clearly superior approach for uncomplicated diarrhea.

Therefore, management is often empiric and nonspecific. Bulk laxatives and promotility agents such as metoclopramide should be discontinued, and clear fluid intake increased to ≥3 liters per day. Various dietary approaches have been investigated, but few have been shown to be effective. Broths, soups, sports drinks, canned fruits, and bananas may help to replenish electrolytes. Opioids (notably loperamide because it is the least likely to impair cognition) may be used, as they reduce transit time within the gastrointestinal tract. The initial dose of loperamide Continued on page 12

May 2013 I VOL 6, NO 4

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COLORECTAL CANCER

AEs most frequently included asthenia/ fatigue, infections, diarrhea, dehydration, hypertension, stomatitis, venous thromboembolic events, neutropenia, and proteinuria.3 As with bevacizumab, some AEs observed with ziv-aflibercept treatment—hypertension, proteinuria, neutropenia, leukopenia, wound healing complications, bleeding/hemorrhage, thromboembolic events, and gastrointestinal perforation—arise from its anti-VEGF properties. In other trials of anti-VEGF therapy (ie, bevacizumab + chemotherapy), the most common grade 3/4 toxicities were neutropenia (16%–64%), leukopenia (4%–37%), diarrhea (2%– 32.4%), arterial/venous thromboembolic events (0%–22%), hypertension (2%–19%), venous thromboembolic events (5%–19%), fatigue (3%–14%), and anorexia (1%–8%).7,11-16

COLORECTAL CANCER

Managing Adverse Events... Continued from page 11 is typically 4 mg followed by 2 mg after each unformed stool, to a maximum of 12 mg daily. Probiotics— nutritional supplements containing a specified amount of viable microorganisms such as Lactobacillus or Bifidobacterium—have also been investigated for the management of

diarrhea.17 While some benefit with probiotic therapy has been reported, further investigation is needed.26 Dose Reduction, Interruption, or Discontinuation Several situations exist where the dose of bevacizumab or ziv-aflibercept

VBCC0112_VBMAsize_Layout 1 2/15/12 3:28 PM Page 2

should be modified. Although there are no recommended dose reductions for bevacizumab, the ziv-aflibercept dose should be reduced to 2 mg/kg on resuming treatment after recurrent or severe hypertension or proteinuria ≥2 g/24 hours.3,4 At least 4 weeks before elective surgery, interrupt bevacizumab

VISIT THE NEW ONLINE RESOURCE FOR NURSES AND THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“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

Value-BasedCare IN Myeloma

™

RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2012 All rights reserved.

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May 2013 I VOL 6, NO 4

if a patient has uncontrolled severe hypertension, moderate to severe proteinuria, or a severe infusion reaction.4 Ziv-aflibercept therapy should be interrupted 4 weeks before and after major surgery (longer if the wound has not healed) if a patient has moderate proteinuria, recurrent or severe hypertension, or a neutrophil count <1.5 x 109/L.3 Discontinuation is appropriate in cases of severe hemorrhage, gastrointestinal perforation, compromised wound healing, fistula formation, hypertensive crisis or hypertensive encephalopathy, arterial thromboembolic events, nephrotic syndrome or thrombotic microangiopathy, or reversible posterior leukoencephalopathy syndrome.3,4 Implications for Oncology Nurses Since its approval in 2004, bevacizumab has been associated with improved response rates and survival in mCRC, yet in 2013, the 5-year survival rate for patients with mCRC is only 20%.2 As demonstrated in the VELOUR trial, combining ziv-aflibercept with FOLFIRI provides opportunities for improved outcomes in these patients.

It is critically important to manage AEs caused by pharmacologic agents used to treat malignancies. Patients receiving bevacizumab or ziv-aflibercept should be educated about the occurrence and management of chemotherapy- and anti-VEGF–related AEs, as treatment decisions are made and again at each visit. Good communication and a collaborative relationship will enable individualized patient education. Providing information to patients and family members—preferably in writing—as to how to report distressing symptoms and other concerns they may have between office visits is key. Educational resources for patients who wish to manage treatment-related AEs are available from the National Cancer Institute,27 the American Society of Clinical Oncology,28 and the National Comprehensive Cancer Network29; another excellent resource is the Oncology Nursing Society’s Putting Evidence Into Practice.30 l Acknowledgments Medical editorial assistance was provided

by Susan DePetris, PhD, of Phase Five Communications Inc, and supported by Sanofi-Aventis US LLC, in collaboration with Regeneron Pharmaceuticals.

References

1. Ferlay J, Shin HR, Bray F, et al. International Agency for Research on Cancer. GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide:

www.TheOncologyNurse.com

75C, 63M, 63Y

5

4

3

29. National Comprehensive Cancer Network Web site. NCCN Guidelines for Patients: Managing Side Effects. Version 1.2012. http://www.nccn.org/ patients/patient_guidelines/colon/index.html#/1/.

Accessed March 28, 2013.

30. Mitchell SA, Friese CR. ONS PEP (Putting Evidence into Practice). Weight of Evidence Classification Schema: Decision Rules for Summative Evaluation of a Body of Evidence. http://www.ons.org/Research/PEP/ Topics/media/ons/docs/research/outcomes/weight-ofevidence-table.pdf. Accessed March 28, 2013.

Oncology Nurse

1 in 5 of your patients with advanced non-small cell lung cancer (NSCLC) may have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation.1-4

IDENTIFY BIOMARKER STATUS TO INFORM NSCLC TREATMENT DECISIONS Help improve patient outcomes through a multidisciplinary approach to biomarker testing • Raise awareness of the incidence of EGFR M+ and ALK+ NSCLC • Educate patients about biomarker testing and why it’s important • Streamline the biomarker testing process to help drive timely initial clinical decisions

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Find current information on biomarker testing and treatment decisions in advanced NSCLC

5

95

75

Review innovative techniques on streamlining biomarker testing and implementing a multidisciplinary approach

50C, 39M, 39Y

25

25

50K

25

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M+Y

25

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Watch expert videos and thought leader commentary

80K, 80C, 70M, 70Y

Access interactive tools and patient education resources

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+ – X =

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WORKING TOGETHER FOR PATIENTS WITH LUNG CANCER

75

25 25

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M+Y

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25K

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25C, 16M, 16Y

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75K

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1

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4

96

26. Reid G, Gaudier E, Guarner F, et al. Responders and non-responders to probiotic interventions: how can we improve the odds? Gut Microbes. 2010; 1(3):200-204.

27. National Cancer Institute Web site. Managing physical effects. http://www.cancer.gov/cancertopics/ coping/physicaleffects. Accessed March 28, 2013.

28. American Society of Clinical Oncology Web site.

Managing Side Effects. http://www.cancer.net/allabout-cancer/treating-cancer/managing-side-effects.

Accessed March 28, 2013.

95

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professionals/physician_gls/pdf/myeloid_growth.pdf.

Accessed March 28, 2013.

24. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289(19):2560-2572.

25. Copur MS, Obermiller A. An algorithm for the management of hypertension in the setting of vascular endothelial growth factor signaling inhibition.

Clin Colorectal Cancer. 2011;10(3):151-156.

Copyright © 2013. Boehringer Ingelheim Pharmaceuticals, Inc.

All rights reserved.

(4/13)

OC551268PROF-D

References: 1. Riely GJ. Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer. J Thorac Oncol. 2008;3(suppl 2):S146-S149.

2. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380. 3. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967. 4. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

N Engl J Med. 2010;363(18):1693-1703.

31714_Oncology_Nurse.indd 1

www.TheOncologyNurse.com

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COLORECTAL CANCER

IARC CancerBase No. 10. 2010. http://www.globo can.iarc.fr. Accessed March 28, 2013.

2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30.

3. Zaltrap [package insert]. Bridgewater, NJ: SanofiAventis US, LLC, Regeneron Pharmaceuticals, Inc; 2012.

4. Avastin [package insert]. South San Francisco, CA: Genentech, Inc; 2013.

5. Guan ZZ, Xu JM, Luo RC, et al. Efficacy and safety of bevacizumab plus chemotherapy in Chinese patients with metastatic colorectal cancer: a randomized phase III ARTIST trial. Chin J Cancer. 2011;30(10):682-689.

6. Giantonio BJ, Catalano PJ, Meropol NJ, et al.

Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.

J Clin Oncol. 2007;25(12):1539-1544.

7. Hurwitz H, Fehrenbacher L, Novotny W, et al.

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335-2342.

8. Holash J, Davis S, Papadopoulos N, et al. VEGFTrap: a VEGF blocker with potent antitumor effects.

Proc Natl Acad Sci U S A. 2002;99(17):11393-11398.

9. Papadopoulos N, Martin J, Ruan Q, et al.

Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis.

2012;15(2):171-185.

10. Van Cutsem E, Tabernero J, Lakomy R, et al.

Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.

J Clin Oncol. 2012;30(28):3499-3506.

11. Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29-37.

12. Horita Y, Yamada Y, Kato K, et al. Phase II clinical trial of second-line FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: AVASIRI trial. Int J Clin Oncol. 2012;17(6):604-609.

13. Kopetz S, Hoff PM, Morris JS, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453-459.

14. Sobrero A, Ackland S, Clarke S, et al. Phase IV study of bevacizumab in combination with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) in first-line metastatic colorectal cancer. Oncology.

2009;77(2):113-119.

15. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779-4786.

16. Souglakos J, Ziras N, Kakolyris S, et al. Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC). Br J Cancer. 2012;106(3):453-459.

17. National Cancer Institute Web site. Gastrointestinal complications (PDQ). Diarrhea. 2012. http://www.cancer.gov/cancertopics/pdq/supportive care/gastrointestinalcomplications/HealthProfessional/ AllPages#5. Accessed March 28, 2013.

18. American Society of Clinical Oncology Web site.

Supportive Care and Quality of Life Guidelines. 2013. http://www.asco.org/guidelines/supportive-care-andquality-of-life. Accessed March 28, 2013.

19. National Comprehensive Cancer Network Web site. NCCN Guidelines for Supportive Care. http:// www.nccn.org/professionals/physician_gls/f_guide lines.asp#supportive. Accessed March 28, 2013.

20. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102(9):596-604.

21. Yeh J, Frieze D, Martins R, Carr L. Clinical utility of routine proteinuria evaluation in treatment decisions of patients receiving bevacizumab for metastatic solid tumors. Ann Pharmacother.

2010;44(6):1010-1015.

22. Ettinger DS, Amstrong DK, Barbour S, et al.

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Antiemesis.

Version 1.2013. http://www.nccn.org/professionals/ physician_gls/pdf/antiemesis.pdf. Accessed March 28, 2013.

23. Crawford J, Armitage J, Balducci L, et al.

National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Myeloid growth factors. Version 1.2013. http://www.nccn.org/

CONTINUING EDUCATION 6th Annual

MAY 2013 • VOLUME 6 • NUMBER 2

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Maintenance Settings PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen Grants/Project Associate Susan Yeager The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattanonont Ferris Vice President of Finance Andrea Kelly Director of Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore

LETTER

FROM THE

EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances.

In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related 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, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean

FACULTY Kenneth C. Anderson, MD Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Tina Flaherty, ANP-BC, AOCN Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute Boston, MA

Houry Leblebjian, PharmD, BCOP Clinical Pharmacy Specialist in Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma

Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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

Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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May 2013 I VOL 6, NO 4

www.TheOncologyNurse.com

CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 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 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 Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-012-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients

• Describe the pharmacokinetics and pharmacodynamics of novel agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens 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 Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

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/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose.

Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Sagar Lonial, MD, is on the Advisory Board for and is a Consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: the Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

Kenneth C. Anderson, MD, is on the Advisory Boards for Celgene Corporation, Gilead, Onyx Pharmaceuticals, and sanofi-aventis, and is a Scientific Founder for Acetylon Pharmaceuticals, Inc., and OncoPep, Inc. He does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

Tina Flaherty, ANP-BC, AOCN, has nothing to disclose. She does not intend to discuss any non-FDA-approved or investigational use for any products/devices.

Houry Leblebjian, PharmD, BCOP, is on the Advisory Board for Teva Pharmaceuticals Industries, Ltd. She does not intend to

discuss any non-FDA-approved or investigational use for any products/devices.

Disclaimer The information provided in this CME/CPE/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.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/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/P13008B. 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 Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net.

Estimated time to complete activity: 1.0 hour Date of initial release: May 14, 2013 Valid for CME/CPE/CE credit through: May 14, 2014

SCAN HERE to Download the PDF or Apply for Credit.

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

The Role of Consolidation and Maintenance Therapies for Improving Myeloma Care Kenneth C. Anderson, MD

Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics Kraft Family Professor of Medicine, Harvard Medical School Dana-Farber Cancer Institute, Boston, MA

Introduction With the advent of novel, targeted agents, consolidation and maintenance therapies have become a key component of care in multiple myeloma (MM). Lenalidomide, thalidomide, and bortezomib can consolidate response after stem cell transplantation and provide ongoing maintenance to prolong response duration. Improved outcomes result, but the efficacy of these agents must be weighed against the potential risks of additional treatment. In this article, Kenneth C. Anderson, MD, shares insights and best practices in the use of consolidation and maintenance in the age of molecularly targeted antimyeloma therapies.

How is maintenance therapy different from consolidation?

Consolidation therapy is given to increase the depth of response following treatment. As the term consolidation implies, this therapy is commonly used

www.TheOncologyNurse.com

after high-dose melphalan therapy and autologous stem cell transplantation (HDT/ASCT).1 Novel therapies—thalidomide, lenalidomide, or bortezomib—are currently used for consolidation, alone or in combination, for 1 or 2 cycles.2 Evidence shows that such consolidation does increase the depth of response,3 with a significant proportion of patients achieving a molecular complete response (CR).4 Maintenance therapy, in contrast, aims to prolong the duration of response. In the patient who has received HDT/ASCT, maintenance helps extend the response that has been previously achieved through induction, transplantation, and consolidation. Maintenance therapy can also be utilized to prolong response to initial therapy in the elderly population and others ineligible for transplant.

Early explorations of maintenance therapy in MM began with interferon alfa-2 and then corticosteroids.5 More recently, thalidomide, lenalidomide, and bortezomib have all been explored and accepted as maintenance therapies.6-10 For example, lenalidomide maintenance has been shown to increase progression-free survival (PFS) in transplant candidates9,10 and in elderly patients with newly diagnosed MM.7 In a US trial of patients receiving HDT/ASCT, the use of lenalidomide as posttransplant maintenance therapy prolonged both PFS and overall survival (OS; Figure).10 In the HOVON-65/GMMG-HD4 trial, bortezomib-based induction (bortezomib/doxorubicin/dexamethasone) plus posttransplant maintenance with bortezomib improved CR, PFS, and OS compared with vincristine-based induction (vincristine/doxorubicin/dexamethasone) followed by thalidomide maintenance.8

May 2013 I VOL 6, NO 4

15

CONTINUING EDUCATION

Figure. Three-year survival rates in the US randomized trial of lenalidomide maintenance post-HDT/ASCT (N=460).10

Placebo, n (%)

Attal 2012 (N=608)9

n=306

n=302

➢Hematologic malignancies

13 (4)

5 (2)

80%

80

Lenalidomide maintenance (n=231) Placebo (n=229)

66%

60

Patients (%)

Lenalidomide Maintenance, n (%)

88%

90

70

Table 1. Second Primary Cancers in Patients Receiving Lenalidomide Maintenance in Randomized, PlaceboControlled Trials9,10

50

39%

40 30 20

➢Solid tumors

10 (3)

4 (1)

McCarthy 2012 (N=460)10

n=231

n=229

➢Hematologic malignancies

8 (3.5)

1 (0.4)

➢Solid tumors

10 (4.3)

5 (2.2)

10 0

PFS*

OS

*Defined as freedom from progression or death.

ASCT indicates autologous stem cell transplantation; HDT, high-dose therapy; OS, overall survival; PFS, progression-free survival.

Which factors must be considered when recommending maintenance and choosing a specific agent?

Multiple clinical factors affect the decision to use maintenance therapy and the choice of agent. The first thing to consider is the patient’s response history. Trials have generally shown that patients with stable disease (SD), partial response, very good partial response (VGPR), or even CR all have benefited from maintenance therapy.6-10 This evidence suggests that patients who have at least SD as a result of initial treatment enjoy an advantage from maintenance treatment. So, the question that must be asked is: How likely is the patient to benefit, given his or her response to date?

A second factor to consider is risk stratification, as determined by cytogenetic abnormalities. To date, the best-studied agent in the maintenance setting is lenalidomide, which has been compared with placebo in 2 randomized trials posttransplant (IFM 2005-02 and CALGB 100104)9,10; in both of these trials, lenalidomide maintenance extended PFS, and in the CALGB trial, OS was prolonged as well.10 This advantage, however, was not evident among the subgroup of patients with high-risk cytogenetics, especially in those with del(17p). For this reason, high-risk patients require more than lenalidomide for maintenance. At our center, these patients receive bortezomib maintenance, often in combination with lenalidomide or thalidomide. This decision is based on recent data suggesting that bortezomib may improve the adverse outcomes usually associated with cytogenetic abnormalities.8,11,12 A third factor in decision-making is the patient’s prior therapy. For instance, if an individual has already received thalidomide in the induction regimen, one might consider using an alternative such as lenalidomide for maintenance. This approach anticipates the potential for development of resistance to the prior therapy. It is also a strategy to use when there is concern about exacerbating an adverse event (AE) seen with prior therapy, such as peripheral neuropathy with thalidomide.

Patients may now receive 2 or more novel agents during initial therapy before transplantation. The standard of care is becoming a 3-drug initial regimen, often combinations of targeted therapies. For example, high extent and frequency of response have been documented with lenalidomide/bortezomib/ dexamethasone (RVD)13 or cyclophosphamide/bortezomib/dexamethasone14 for induction in the transplant-eligible population. Regimens like this achieve very high overall response (OR) rates. After these patients receive a transplant, they may get consolidation therapy, often with the same combination of targeted therapies as they received during induction, then go on to receive maintenance therapy with lenalidomide or bortezomib. Similarly, in elderly patients and others who are ineligible for transplant, melphalan plus prednisone may be combined with novel agents (thalidomide, lenalidomide, or bortezomib), followed by maintenance with the same agents—an approach that appears to be effective.7,15,16

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In this context, it may be worth mentioning that, in the United States, the selection of thalidomide for initial therapy or maintenance is less common than in Europe. The United Kingdom’s Medical Research Council conducted a large trial (MRC IX) in patients who received initial therapy with thalidomide-containing regimens, with or without subsequent transplant, followed by thalidomide maintenance or no maintenance. In this trial, thalidomide maintenance enhanced survival outcomes compared with no maintenance—although this benefit did not fully extend to patients with adverse cytogenetics.17 The difference between the United States and Europe in the use of novel agents probably boils down to our ability, in the United States, to use drugs off-label. Lenalidomide, for example, is approved for treatment of relapsed and relapsed/refractory myeloma in the United States.18 Yet, we use lenalidomide commonly in the newly diagnosed patient, in consolidation, and in maintenance. In Europe, however, clinicians are required to use drugs on-label only. This helps explain the greater use in Europe of the older immunomodulatory drug thalidomide.

How often do you recommend maintenance for your patients?

I routinely recommend maintenance therapy to my patients. My main reason is the knowledge that, in the absence of this therapy, the disease is destined to relapse. My second reason for using maintenance is that randomized trials have demonstrated its value. As described above, lenalidomide maintenance posttransplant, as well as in elderly, nontransplant candidates, has been shown to prolong PFS and, in one major study, OS.7,9,10 Bortezomibbased maintenance has also been associated with longer PFS and OS in these settings,8,15,16 although maintenance with this agent is not as well studied as lenalidomide maintenance.

I feel there is an overwhelming benefit to maintenance that outweighs the risks. Lenalidomide is well tolerated; its common AEs in the maintenance setting include neutropenia, diarrhea, upper respiratory infections, and fatigue.9,10 One noteworthy effect is a 2- to 3-fold increased risk of second primary cancers among patients who receive HDT/ASCT plus lenalidomide maintenance treatment (Table 1).9,10 It is important to point out, however, that there are additional risk factors for developing second primary cancer posttransplant when using lenalidomide, including male gender, advanced stage III International Staging System myeloma, and, most importantly, the use of a regimen of dexamethasone/cyclophosphamide/etoposide/cisplatin (DCEP) before transplant.9 The DCEP regimen contains multiple alkylating or DNAdamaging chemotherapeutic agents, so it stands to reason that the avoidance of this combination as induction would markedly reduce the risk of second primary cancers. In our patients, however, I believe that the risk of developing progressive myeloma and dying rapidly from the disease is far greater than any potential risk of a second primary cancer after lenalidomide maintenance.

The use of bortezomib as maintenance also has a favorable benefit-to-risk ratio, especially in patients with high-risk cytogenetics. Bortezomib significantly improved PFS and OS in patients with del(13) and del(17p) in the HOVON-65/GMMG-HD4 trial (Table 2),8 identifying a potentially effective treatment option in these types of patients. Therefore, when cytogenetic risk is high, I think adding bortezomib to lenalidomide is a useful approach.

The efficacy with less toxicity of subcutaneous bortezomib19 makes this drug more readily applied in the maintenance setting.

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table 2. Efficacy Results: HOVON-65/GMMG-HD48 VAD (n=414)

PAD (n=413)

P value

All patients

28

35

.002

Subgroup with del(17p)

12

22

.01

Not reached at 66 mo

Not reached at 66 mo

N/A

24

Not reached at 54 mo

.003

Median PFS,* mo

Median OS,* mo All patients Subgroup with del(17p)

*Median follow-up of 41 months.

N/A indicates not available; OS, overall survival; PAD, bortezomib/doxorubicin/dexamethasone; PFS, progression-free survival; VAD, vincristine/doxorubicin/dexamethasone.

How will maintenance therapy for MM continue to evolve?

An exciting development that may affect maintenance therapy is the advent of newer targeted agents, most notably, newer proteasome inhibitors such as carfilzomib and MLN9708 (ixazomib). These drugs represent alternative options to combine with lenalidomide in high-risk patients.

Carfilzomib is now approved by the US Food and Drug Administration for use in the relapsed/refractory setting,20 and it is being used and evaluated as frontline treatment as well.21,22 Carfilzomib/lenalidomide/dexamethasone (CRd) is a promising combination,21 as well as a potential successor to the very effective induction regimen, RVD.13 For example, in a seminal trial, RVD induction in newly diagnosed MM attained 100% OR, with 67% to 74% of patients achieving VGPR or better.13 A comparable universal response was seen with CRd induction in newly diagnosed patients, with 78% enjoying CR or near CR.21 A clinical trial is currently evaluating CRd both as induction and as posttransplant consolidation therapy and maintenance.23 Another novel proteasome inhibitor, the oral agent MLN9708, can also be combined with lenalidomide and dexamethasone upfront to achieve high response rates.24 This is an all-oral regimen, which is appealing to patients and clinicians alike. An oral proteasome inhibitor would also be a useful option in the maintenance setting.

In the near future, maintenance therapy may enable us to delay transplantation. A clinical trial is looking at RVD induction, collection of stem cells after 3 to 4 cycles, and then randomizing patients to receive either HDT/ ASCT plus lenalidomide maintenance or lenalidomide maintenance with no transplant.25 Our favorable experience with novel agents in initial therapy, consolidation, and maintenance has begun to shift the timing of ASCT away from the current standard of early transplant toward delayed transplant. We are gathering clinical evidence on the relative efficacy and safety of novelagent induction followed by early ASCT versus novel-agent induction with ASCT reserved until progression.

Maintenance therapy is also becoming more crucial in our efforts to sustain the profound responses we now achieve with these newer drugs. The increasing depth, duration, and frequency of responses have made us more stringent in the way we assess response. We can now regularly attain molecular CR with novel targeted agents, as measured by polymerase chain reaction for the immunoglobulin gene rearrangement or multicolor flow cytometry. A further degree of stringency is evolving from the use of positron emission tomography/computed tomography (PET/CT) in MM. It is now incumbent on us to utilize maintenance therapy in an attempt to prolong the response stringently defined by molecular CR and PET/CT. In summary, novel agents will continue to help us achieve good rates of high-quality response that were never before possible in MM. Consolidation with combination targeted treatments will continue to increase the depth of response, producing molecular CR in a significant fraction of patients.

Finally, maintenance therapies with novel agents will continue to prolong PFS and even OS. We will see more gains from ongoing trends. First, building upon 3-drug

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combinations such as RVD, we will see new combinations of immunomodulators, proteasome inhibitors, and steroids, with the addition of monoclonal antibodies, histone deacetylase inhibitors, and other targeted agents. As in other malignancies, a combination of 4 or 5 agents is likely to achieve CR in the majority of patients, if not all. Second, we will advance our ability to measure minimal residual disease and molecular CR, and we can use these metrics to determine the optimal duration of maintenance therapy in MM. Although we have already seen tremendous progress over the past few decades, I believe the best is yet to come in the care of the disease. ♦ References

1. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793.

2. San-Miguel JF. Consolidation therapy in myeloma: a consolidated approach? Blood. 2012; 120:2-3.

3. Cavo M, Pantani L, Petrucci MT, et al; for the GIMEMA Italian Myeloma Network.

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012;120:9-19.

4. Ladetto M, Pagliano G, Ferrero S, et al. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010;28:2077-2084.

5. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology®: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed March 8, 2013.

6. Attal M, Harousseau J-L, Leyvraz S, et al; for the Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294.

7. Palumbo A, Hajek R, Delforge M, et al; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769.

8. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955.

9. 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.

10. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781.

11. Jagannath S, Richardson PG, Sonneveld P, et al. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007; 21:151-157.

12. 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.

13. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010; 116:679-686.

14. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417.

15. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial.

J Clin Oncol. 2010;28:5101-5109.

16. Niesvizky R, Flinn IW, Rifkin RM, et al. Phase 3b UPFRONT study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib-based induction regimens in elderly, newly diagnosed multiple myeloma patients. Blood (ASH Annual Meeting Abstracts).

2010;116:Abstract 619.

17. Morgan GJ, Gregory WM, Davies FE, et al; on behalf of the National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood.

2012;119:7-15.

18. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012.

19. 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.

20. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.

21. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809.

22. Palumbo A, Bringhen S, Villani O, et al. Carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma (MM) patients. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 730.

23. Carfilzomib, lenalidomide, and dexamethasone before and after stem cell transplant in treating patients with newly diagnosed multiple myeloma, NCT01816971. http://www. clinicaltrials.gov. Accessed April 24, 2013.

24. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 332.

25. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DFCI2009), NCT01191060. http://www. clinicaltrials.gov. Accessed April 24, 2013.

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Nursing Considerations in the Maintenance Setting for Multiple Myeloma Tina Flaherty, ANP-BC, AOCN

Nurse Practitioner Division of Hematologic Malignancies Dana-Farber Cancer Institute, Boston, MA

Introduction Maintenance therapy is becoming a well-accepted recommendation for patients with multiple myeloma (MM), in both the transplant and nontransplant settings. However, there are several factors that must be considered when deciding which specific drugs, doses, and schedules should be used for this line of treatment, including age, performance status, prior response to therapy, patient preferences, and comorbidities. Elderly patients tend to be at greater risk for age-related diabetes or organ dysfunction (eg, cardiovascular disease, renal impairment) than younger patients, which may make disease management especially challenging.1,2 In this article, Tina Flaherty, ANP-BC, AOCN, answers questions related to the use of novel agents as maintenance and discusses the monitoring and management of treatment-related adverse events (AEs), including myelosuppression, neurotoxicity, and thromboembolic events.

How do you monitor for and treat myelosuppression in the maintenance setting?

We tend to see less hematologic toxicity in the maintenance setting than we do in the frontline and relapsed/refractory settings. This is because the novel agents being used are usually given at reduced doses and schedules. In addition, most patients have already achieved a complete or very good partial response when maintenance therapy begins; therefore, their disease is less likely to be causing myelosuppression. That being said, some patients will still be predisposed to hematologic toxicities due to age, preexisting conditions, or cumulative toxicities from previous treatments, and they will require appropriate management strategies to maintain safety and preserve quality of life.

To effectively manage such hematologic AEs as neutropenia, thrombocytopenia, and anemia, it is important to monitor patient blood counts on a regular basis, especially in the first and second cycles of therapy. When lenalidomide is used as maintenance, we typically check blood counts every 2 weeks during cycles 1 and 2. When bortezomib is used, counts are checked every 2 weeks prior to each administration of the drug. The interventions to use will depend on the grade or severity of the specific hematologic AEs (Table 1).3,4 The most common hematologic toxicity associated with lenalidomide is neutropenia.3 Grade 1 neutropenia usually does not require an adjustment in dose or schedule, but we do continue to monitor blood counts carefully.

Conversely, grade 4 neutropenia would prompt us to hold lenalidomide therapy until either the neutropenia returns to grade 1 or the absolute neutrophil count is in the normal range.2 If neutropenia continues at grade 2 or higher for 2 or more cycles, we typically reduce the dose of lenalidomide to 5 mg and may consider adjusting the schedule in certain patient populations. For example, we may administer lenalidomide 5 mg every Monday, Wednesday, and Friday. In patients with standard- to high-risk disease, it is important to try to at least maintain the customary dose of lenalidomide maintenance (10 mg every 21 days of a 28-day cycle) to ensure optimal benefit. In these individuals, granulocyte colony-stimulating factors such as filgrastim can be utilized in a once-weekly or once-monthly schedule, depending on the grade of neutropenia.

In the maintenance setting, hematologic toxicity rates tend to be low with bortezomib because this agent is administered every other week. However,

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May 2013 I VOL 6, NO 4

some patients may still develop thrombocytopenia. With grade 1 thrombocytopenia, there is typically no need to adjust the dose or schedule of bortezomib; however, careful monitoring of blood counts is recommended.3 Grade 4 thrombocytopenia usually necessitates holding treatment until the toxicity resolves. We may also consider a transfusion of platelets if there is an increased risk of bleeding. With grade 2 or 3 thrombocytopenia, we may consider holding the bortezomib dose, and if there is a continued trend of toxicity, we many change the dose from 1.3 mg/m2 to 1.0 mg/m2. If the patient has been receiving this drug intravenously, we will also consider switching to the subcutaneous (SC) mode of administration if possible.

Anemia may also occur with the use of novel agents in the maintenance setting. Some individuals are predisposed to this toxicity, especially if they have renal impairment from the myeloma itself, earlier therapy, or a preexisting condition.5 Management of anemia should take into account that some patients can tolerate a greater degree of this condition than others can.3 In addition to testing the numeric values of hemoglobin and hematocrit, quality of life should also be routinely assessed. A provider should ask questions concerning performance status, shortness of breath, and fatigue, which will assist in determining the need for transfusion versus erythropoietin-stimulating agents, such as darbepoetin alfa. With grade 1 or 2 anemia, depending on clinical circumstances, a patient may benefit from these agents, especially if he or she has concomitant renal dysfunction.5 With grade 4 anemia (and in certain scenarios, grade 2 or 3), the decision to transfuse must be balanced with the associated risks.3 In patients receiving lenalidomide maintenance, if grade 2 or 3 anemia is present for 2 or more cycles of therapy, we typically reduce the dose to 5 mg, especially in patients with renal impairment.

What other toxicities are commonly associated with newer agents used as maintenance?

Peripheral neuropathy (PN) is a well-known AE associated with the use of certain novel drugs, including bortezomib.6 This fact must be considered when choosing a maintenance therapy that individuals might be treated with for up to 2 years. In patients who already have grade 4 PN, we typically do not consider bortezomib for maintenance. If bortezomib is the drug of choice for a particular patient, then we frequently recommend the SC route of administration to decrease the incidence of neuropathy; fortunately, the

Grade 1 neutropenia usually does not require an adjustment in dose or schedule, but we do continue to monitor blood counts carefully. majority of our patients do not experience an increase in PN if they receive biweekly dosing of SC bortezomib. However, monitoring for signs and symptoms of this toxicity at the beginning of maintenance therapy and throughout the course of treatment remains essential.3 When bortezomib-related PN develops, the goal is to alleviate symptoms and prevent progression. We may consider holding the dose if grade 2 or 3 PN develops, and if painful symptoms continue, we may also reduce the dose from 1.3 mg/m2 to 1.0 mg/ m2 (given every other week).

Thromboembolic events, including deep-vein thrombosis (DVT) and pulmonary embolism (PE) are also seen in patients with MM in the maintenance setting.7 Patients can be at risk for these life-threatening events due to their disease, individual risk factors (eg, obesity, diabetes, blood-clotting disorders), and specific medications.7 The development of DVT and/or PE can permanently affect the lives of patients and their families, as well as interfere with

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table 1. NCI CTCAE: Hematologic Toxicity Grades3,4 Toxicity Neutropenia Thrombocytopenia Anemia

Unit of Measure ANC, ×10 /L 9

Grade 1

Grade 2

Grade 3

Grade 4

<LLN to 1.5

<1.5-1.0

<1.0-0.5

<0.5

Platelet count, × 10 /L

<LLN to 75

<75-50

<50-25

<25

Hb, g/dL

<LLN to 10.0

<10.0-8.0

<8.0-6.5

<6.5

9

ANC indicates absolute neutrophil count; Hb, hemoglobin; LLN, lower limit of normal; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.

Table 2. Symptoms of Venous Thromboembolic Event7 Pulmonary Embolism Anxiety Discomfort in the chest area Electrocardiogram right axis deviation or new right bundle branch block Low-grade fever

minimizing chronic diarrhea that patients may experience during treatment.

For this reason, we offer probiotics to our patients, being sure to recommend products that contain strains of bacteria that are considered very safe for the general population.13 What additional factors are important to consider in the maintenance setting?

Positive Homan’s sign (pain in the calf and popliteal area on passive dorsiflexion of the foot)a

To provide optimal care and adherence during maintenance, providers must consider prior response to therapy, cumulative toxicities, patient preferences, and psychosocial factors. Some patients may prefer oral lenalidomide, so that they do not have to travel back and forth to the clinic every other week for treatment. If we determine that a patient can be compliant with an oral regimen and that there are no contraindications, we will most likely use lenalidomide. For other individuals, bortezomib may be a better option, based on individual patient- and disease-related factors, such as a poor response to previous lenalidomide therapy or specific cytogenetic abnormalities. Regardless of which agent is used, nurses play an important role in improving patient compliance and outcomes. This requires good communication with patients and caregivers, careful monitoring for signs and symptoms of toxicities, and the prompt initiation of supportive or corrective strategies when necessary. ♦

Tachycardia

References

Sudden onset dyspnea Tachypnea or tachycardia Deep-Vein Thrombosis Cyanosis and cool skin in the presence of venous obstruction Distention of superficial venous collateral vessels Dull pain or tight feeling over area and with palpation Low-grade fever Obvious swelling (may not be present early)

Unilateral swollen, erythematous, warm extremity a

Present in approximately 35% of patients; high false-positive rate.

future treatment.7 Therefore, it is critical that patients are assessed for specific signs and symptoms that may indicate these events (Table 2).

Venous thromboembolism (VTE) has been reported in patients receiving treatment with bortezomib, but at a much lower rate than in patients receiving treatment with lenalidomide (with or without dexamethasone).7 Recommendations for prevention and prophylaxis of thromboembolic events in MM depend on institutional practices, drug combinations being used, and factors specific to each patient. Typically, if patients have no prior history of VTE and do not have individual factors that predispose them to clot, either baby aspirin or standard-dose aspirin can be considered when they are receiving lenalidomide maintenance.7-9 However, if patients do have an increased risk of clot or have had past thromboembolic events, low-molecular-weight heparin or warfarin should be utilized. It is important to remember that some antithrombotic agents may be contraindicated in the presence of thrombocytopenia, renal impairment, or other comorbidities, due to the MM itself or to specific antimyeloma therapy.7 A common but less-addressed AE that occurs during maintenance—especially with lenalidomide—is chronic diarrhea.10 This toxicity can directly affect adherence to therapy and can have a negative impact on a patient’s quality of life. Although the direct mechanism of action is not clearly understood, it may be a direct or indirect cumulative effect of lenalidomide on the intestinal microflora (population of microscopic organisms) of the gut. Over the past several years, we have seen emerging data on the importance of gastrointestinal (GI) and immune health.11,12 Recently, probiotics have been promoted as an aid to enhance GI health by regulating the digestive system and

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1. Mehta J, Cavo M, Singhal S. How I treat elderly patients with myeloma. Blood. 2010; 116:2215-2223.

2. 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.

3. 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.

4. National Cancer Institute. Common Terminology Criteria for Adverse Events v.3.0 (CTCAE). http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.

Published August 9, 2006. Accessed May 3, 2013.

5. Birgegård G. Managing anemia in lymphoma and multiple myeloma. Ther Clin Risk Manag. 2008;4:527-539.

6. 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.

7. Rome S, Doss D, Miller K, Westphal J; IMF Nurse Leadership Board. Thromboembolic events 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):21-28.

8. Palumbo A, Rajkumar SV, Dimopoulos MA, et al; International Myeloma Working Group. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.

Leukemia. 2008;22:414-423.

9. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88:67-71.

10. Smith LC, Bertolotti P, Curran K, Jenkins B; IMF Nurse Leadership Board. Gastrointestinal side effects 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):37-52.

11. Cummings JH, Antoine JM, Azpiroz F, et al. PASSCLAIM—gut health and immunity.

Eur J Nutr. 2004;43(suppl 2):ii118-ii173.

12. Fooks LJ, Gibson GR. Probiotics as modulators of the gut flora. Br J Nutr. 2002;88(suppl 1): S39-S49.

13. Piascik M, Sanders ME. Probiotic supplementation: what nurse practitioners need to know to recommend safe and effective formulations. Postgraduate Healthcare Education Web site. http://www.powerpak.com/course/preamble/108730. Accessed May 4, 2013.

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Pharmacologic Perspectives on Maintenance Therapy in the Era of Novel Agents Houry Leblebjian, PharmD, BCOP

Clinical Pharmacy Specialist in Hematology/Oncology Dana-Farber Cancer Institute Boston, MA

Introduction Recently, maintenance therapy with novel antimyeloma agents has been shown to be effective for prolonging duration of response following initial therapy, consolidation, or autologous stem cell transplantation (ASCT). This approach to myeloma treatment not only has the potential to improve quality of life, but may also extend survival.

In this article, Houry Leblebjian, PharmD, BCOP, responds to frequently asked questions regarding the safety and efficacy of novel drugs as maintenance, and discusses administration issues that must be considered when using these therapies in the clinical setting.

How is the dose and schedule of lenalidomide adjusted in the maintenance setting?

In multiple myeloma (MM), the dose of lenalidomide used in the maintenance setting differs from that used in other lines of treatment. As initial therapy or consolidation, this drug is typically used at a dose of 25 mg, given daily on days 1 to 14 of therapy repeated every 21 days or at a dose of 25 mg given daily on days 1 to 21 of therapy repeated every 28 days. Of course, these doses sometimes need to be reduced in patients with specific comorbidities, such as renal dysfunction.1,2 In the maintenance setting, lenalidomide is usually given at a dose of 15 mg at the same schedule used for induction, or sometimes daily without any break from therapy, if tolerated. Again, in patients who may be having difficulty tolerating this therapy, we have the option of lowering the dose to 10 mg or 5 mg.

Three phase 3 randomized trials have evaluated lenalidomide in the maintenance setting (2 in the posttransplant setting and 1 as consolidation in transplant-ineligible patients).3-5 In the IFM 2005-02 trial (N=614), following ASCT, patients were randomly assigned to receive either consolidation treatment with lenalidomide (25 mg per day, on days 1-21 of

each 28-day cycle, for 2 cycles), followed by maintenance therapy with lenalidomide (10 mg per day for the first 3 months, increased to 15 mg if tolerated), or the same consolidation treatment with lenalidomide, followed by maintenance therapy with placebo. At a median follow-up of 45 months, median progression-free survival (PFS) was 41 months in the lenalidomide maintenance group versus 23 months in the placebo group (P<.001). No improvement was seen in overall survival (OS).3 In the CALGB 100104 study (N=460), investigators also studied lenalidomide maintenance in the posttransplant setting. Patients were randomly assigned in a blinded manner to lenalidomide (10 mg per day, increased to 15 mg if tolerated) or placebo between day 100 and day 110 after ASCT. At a median follow-up of 34 months, median time to progression (TTP) was 46 months in the lenalidomide maintenance group versus 27 months in the observation group (P<.001). In this trial, an OS benefit was observed.4 In the MM-015 trial (N=459), transplant-ineligible patients were randomized to receive melphalan plus prednisone (MP), melphalan/prednisone/lenalidomide (MPR), or MPR followed by lenalidomide maintenance (MPR-R).

At a median follow-up of 30 months, PFS was 13 months, 14 months, and 31 months with MP, MPR, and MPR-R, respectively (P<.001 for MPR-R vs MPR and MPR-R vs MP). No difference in OS was observed between the groups.5 As evidenced by these studies, maintenance lenalidomide improves PFS, although a consistent OS benefit has yet to be reported.

Another factor to consider when analyzing results from these studies is the other drugs that were used during treatment, as they can contribute to additional toxicity.

Adverse events (AEs) must be carefully considered when treating MM patients with long-term lenalidomide. The most common AEs seen with this agent are myelosuppression, venous thromboembolism, and gastrointestinal toxicities. Lenalidomide may cause both thrombocytopenia and neutropenia, which may require dose modifications or temporarily withholding treatment until symptoms subside. However, the incidence of these and other AEs tends to be lower when lenalidomide is used as maintenance, compared with when it is used as frontline therapy (Table 1).3-5 It should be noted that the rates of hematologic toxicities in the IFM and the CALGB trials seem high because the Table 1. Incidence of Select Adverse Events in Phase 3 Trials of Lenalidomide percentages reported included the AEs observed throughout Maintenance3-5 the whole study窶馬ot just during maintenance therapy. On Grade 3/4 Grade 3/4 Grade 3/4 the other hand, investigators in the MM-015 study reported Neutropenia Thrombocytopenia Venous Secondary the rates of neutropenia and thrombocytopenia for the mainClinical Trial (%) (%) Thromboembolism (%) Cancers (%) tenance portion of the study separately, and these percentages 3 IFM 2005-002 were much lower than what was reported during frontline 51 14 6 7.5 Lenalidomide therapy. Another factor to consider when analyzing results 18 7 2 2.9 Placebo from these studies is the other drugs that were used during CALGB 1001044 treatment, as they can contribute to additional toxicity.3-5 45 14 1 7.8 Lenalidomide Investigators have reported a higher incidence of secondary 15 4 0 2.6 Placebo cancers in the lenalidomide arms of maintenance studies.3-5 MM-0155 This does not appear to be related to the dose of lenalidomide, 1 2 0 3 MP but rather to the duration of treatment, as well as the use of 0 2 1 7 MPR other alkylating agents during induction or conditioning prior 7 6 2 7 MPR-R to transplant. Additional follow-up is needed to continue assessing potential risk factors for secondary malignancies and MP indicates melphalan plus prednisone; MPR, melphalan/prednisone/lenalidomide; MPR-R, MPR followed by lenalidomide maintenance. to determine the optimal duration of treatment with lenalid-

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CONSIDERATIONS IN MULTIPLE MYELOMA

Table 2. Incidence of Peripheral Neuropathy in the Phase 3 MMY-3021 Trial8 SC Bortezomib (N=147) n (%)

IV Bortezomib (N=74) n (%)

P Value

Any peripheral neuropathy

56 (38)

39 (53)

.044

Grade ≥2

35 (24)

30 (41)

0.12

Grade ≥3

9 (6)

12 (16)

0.26

IV indicates intravenous; SC, subcutaneous.

omide. Fortunately, many studies are under way to evaluate the safety and efficacy of long-term lenalidomide in the maintenance setting for myeloma.

How is the recent approval of subcutaneous (SC) bortezomib impacting the use of this agent in the maintenance setting?

Bortezomib has shown efficacy when used in the maintenance setting. The phase 3 HOVON-65/GMMG-HD4 trial compared bortezomib/doxorubicin/ dexamethasone plus posttransplant maintenance followed by bortezomib versus vincristine/doxorubicin/dexamethasone followed by thalidomide maintenance.6 The phase 3 GIMEMA trial compared bortezomib/melphalan/prednisone/thalidomide followed by bortezomib and thalidomide maintenance for 2 years versus bortezomib/melphalan/prednisone without maintenance.7 Both of these trials showed a PFS benefit with maintenance therapy.

Peripheral neuropathy (PN), a common toxicity associated with bortezomib, occurs more frequently when patients receive this agent at a dose of 1.3 mg/m2 given intravenously on days 1, 4, 8, 11 every 21 days. Bortezomibinduced PN is often reversible with dose or schedule reductions or upon discontinuation of therapy. To reduce the incidence and severity of PN, we now have another option—SC bortezomib. A large phase 3 trial (N=222) randomized patients in a 2:1 ratio to receive intravenous (IV) or SC bortezomib at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks for 12 weeks.8 Results from this study confirmed the noninferiority of SC bortezomib in terms of overall response rate after 4 cycles. In addition, after a median follow-up of 12 months, no significant differences in TTP or OS were observed between the 2 arms. Grade ≥3 PN was significantly lower in the SC arm compared with the IV arm (6% vs 16%; P=.026). Neuropathy of any grade was also lower in the SC arm (38% vs 53%; P=.044) (Table 2). Other AEs, including myelosuppression, fatigue, and GI toxicities, were comparable among treatment arms.8 Given these results, I think SC bortezomib will continue to be used more frequently in the maintenance setting.

The use of SC bortezomib can cause local injection site reactions. Of the 159 patients in 2 trials of SC bortezomib, 60% reported at least 1 local SC injection site reaction during the study, with 56% having a reaction in the first cycle.

Two patients (1%) experienced local reactions that were considered severe (1 case of pruritis and 1 case of redness). These reactions resolved in a median of 6 days. Local reaction led to study discontinuation in only 1 patient and reduction in dose concentration in another.8,9 The recommended concentration of bortezomib when administered intravenously is 1.0 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL. Because each route of administration has a different reconstituted concentration, caution must be used when calculating the volume to be administered. When the SC route is used, the site for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.

Preparation times and administration for SC and IV bortezomib do not differ since both are prepared by reconstituting the vial of bortezomib with normal saline and administered to patients as a quick injection.10 How often is thalidomide being used in the maintenance setting for MM in 2013?

For years, thalidomide appeared to be a good choice for maintenance therapy due to its efficacy and the convenience of being an oral agent. Eight phase 3 studies assessed thalidomide in the maintenance setting, and the use of this agent led to improvement in event-free survival (EFS) and/or PFS.1118 However, only 2 studies showed improvement in OS. The first was the IFM 99-02 study (N=597) in which patients were randomized to receive 1 of the 3 treatment arms following double ASCT: (1) no maintenance, (2) pamidronate, or (3) thalidomide 400 mg daily plus pamidronate. Patients were to receive these treatments until progression. Increased EFS and OS was seen in patients in the thalidomide arm, but this benefit was observed only in patients who achieved less than a very good partial response after transplant and those without del(13) or high beta-2 microglobulin levels.11 A second trial, by Spencer and colleagues (N=269) randomized patients to receive thalidomide plus prednisone or prednisone alone following single ASCT. Patients were to receive thalidomide for 12 months. There was improvement in 3-year PFS and OS in the thalidomide arm (P<.001 and P =.004, respectively).12 Thalidomide maintenance has fallen out of favor in most clinics in the United States because of the high rates of treatment-related toxicity (especially PN) and the inconsistent data regarding OS benefit. Lenalidomide and bortezomib are now being used as maintenance therapy for almost all of the patients at our institution, either as monotherapy or in combination.

Newly approved drugs such as pomalidomide and carfilzomib are also undergoing investigation as maintenance in clinical trials and may provide additional options in the near future. ♦ References

1. Niesvizky R, Jayabalan DS, Christos PJ, et al. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008;111:1101-1109.

2. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123-2132.

3. 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.

4. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1770-1781.

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

6. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol. 2012;30:2946-2955.

7. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial.

J Clin Oncol. 2010;28:5101-5109.

8. 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.

9. Moreau P, Coiteux V, Hulin C, et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica. 2008; 93:1908-1911.

10. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals Inc; May 2013.

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

12. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27:1788-1793.

13. Morgan G, Jackson G, Davies F. Maintenance thalidomide may improve progression free but not overall survival: results from the Myeloma IX Maintenance Randomisation. Blood (ASH Annual Meeting Abstracts). 2008;Abstract 656.

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

15. Lokhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113-1120.

16. 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 myeloma (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 39.

17. Ludwig H, Adam Z, Tothova E, et al. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010; 95:1548-1554.

18. Maiolino A, Hungria VT, Garnica M, et al. Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012;87:948-952.

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Prostate Cancer The US Food and Drug Administration (FDA) approved enzalutamide (Xtandi; Medivation, Inc., Astellas Pharma US, Inc.) for the treatment of patients with metastatic castration-resistant prostate cancer who had previously received docetaxel. This approval was granted on August 31, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm317997.htm.

Enzalutamide Improves Survival in Castration-Resistant Prostate Cancer Gary Shelton, MSN, NP, ANP-BC, AOCNP NYU Clinical Cancer Center New York

Background Prostate cancer is diagnosed second only to skin cancer in men. The American Cancer Society has estimated that more than 238,000 men will be told they have prostate cancer during 2013.

Of the men already known to have prostate cancer, almost 30,000 men are projected to die of the disease this year.1,2 Although men are living longer with prostate cancer, our challenge in clinical practice is more often managing men with metastatic disease who are seeking their next treatment options.

Until recently, this talk was limited.

Before 2010, our only systemic therapy demonstrating a survival benefit in castration-resistant prostate cancer (CRPC) had been the chemotherapeutic agent docetaxel.3,4 However, in the past few years, 4 new agents have been approved by the US Food and Drug Administration (FDA) for use in the CRPC population, widening the discussion to include not only treatment options, but also sequential treatments.3,5 Enzalutamide was researched clinically against placebo at the same time that the other 3

agents also were in clinical trials. These recently approved therapies differ in their mechanisms of action, reflecting the advances in scientific understanding of CRPC: cabazitaxel is a novel taxane chemotherapeutic agent, abiraterone is an androgen biosynthesis inhibitor, sipuleucel-T is an autologous immunotherapeutic agent, and enzalutamide is an androgen receptor (AR) inhibitor.3,5,6

the AR, reactivation of prostate cancer has signified a more lethal phenotype of CRPC. Traditional therapies have targeted the disruption of ligand binding to the AR. Enzalutamide competes for the inhibition of ligand binding for the AR and appears to have a 5-fold affinity for such binding. Therefore, enzalutamide prevents the cascade of activation of tar-

Enzalutamide competes for the inhibition of ligand binding for the androgen receptor and appears to have a 5-fold affinity for such binding.

Androgen Deprivation Androgen deprivation has long been the focus of control of prostate cancer, and responses have been significant. However, despite the reduction of circulating testosterone, and with castrate levels of androgens and medications to limit androgen binding to

get genes necessary for tumor growth and appears to also cause apoptosis, or cell death.3,5-8 Enzalutamide (Xtandi) received FDA approval in August 2012 for the treatment of men with metastatic CRPC who had previously received chemotherapy with docetaxel. As

Case Study

M

r G, a 74-year-old psychotherapist, had had annual healthcare visits, including prostate-specific antigen (PSA) screening. His first diagnosis of prostate cancer was 11 years previous (age 63 years), at which time his PSA was 12, with a slightly palpable prostate on digital rectal examination. His Gleason score was 3 + 4 = 7, in 2 core biopsies. Bone scan was negative.

He opted for curative intent therapy with brachytherapy and external beam radiation. His PSA nadir was 0.7. At the age of 67, his PSA began to rise, and at a PSA of 5, he started bicalutamide and then a luteinizing hormone-releasing hormone agonist, every 3 months. A second bone scan was still negative. While in a foreign country 2 years later, he was treated for a painful urinary tract infection, thought to be nephritis with back pain. Although he improved on antibiotics, the pain returned a month later and he sought medical treatment in a small town away from home. An astute nurse practitioner in the emergency department worked him up for metastatic prostate

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cancer: his bone scan showed pelvic disease and computed tomography revealed positive lymph nodes. Once home, he started docetaxel 70 mg/m2 every 3 weeks. His pain resolved and his PSA, which had risen to 47, began to decrease. After his 6th cycle of chemotherapy, his repeat scans showed stable disease, but he was having difficulty in picking up his credit card and had noticed foot numbness. He feared that his neuropathy might worsen, and his healthcare team outlined treatment options. He then started enzalutamide 160 mg daily, once he secured the medication from a specialty pharmacy. He was told that although lab work would be performed in 2 weeks and then monthly for safety reasons, his PSA would not always be drawn. This was concerning to him until the pharmacokinetics of enzalutamide was explained. At 3 months, although he was more fatigued, his PSA went from 67 to 42. Bone pain was not an issue, although he says he has aches. Scans are stable and he will continue receiving enzalutamide.

noted in the AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) clinical trial, men derived both an overall survival benefit as well as secondary end point benefits of reduced prostate-specific antigen (PSA) levels, soft tissue response rates, improved quality of life, radiographic progression-free survival, and a prolonged time to the first skeletal-related event, compared with placebo.3,7,8 By targeting the AR signaling pathway, enzalutamide provides a novel therapeutic option for this population of men.

The Clinical Picture Enzalutamideâ&#x20AC;&#x2122;s current FDA approval is in the setting of CRPC, postdocetaxel chemotherapy. Treatment with docetaxel may have failed and thus patients present with progressive disease, or they may have been intolerant to docetaxel and are unable to continue treatment. As noted, there are several therapeutic options for second-line therapy in this metastatic prostate cancer setting. Although clinical trials are ongoing to determine the benefit of enzalutamide in the prechemotherapy setting (phase 3, PREVAIL [A Safety and Efficacy Study of Oral MDV3100 in ChemotherapyNaive Patients With Progressive Metastatic Prostate Cancer] trial), in current practice patients may receive enzalutamide as second-line therapy, and this agent can be considered for men with metastatic CRPC who may not be candidates for treatment with docetaxel.9 The approved dose of enzalutamide, as administered in the phase 3, global, placebo-controlled, randomized AFFIRM study, is 160 mg daily.

Enzalutamide is supplied as a 40-mg capsule; thus the patient swallows 4 capsules to achieve daily dosing.

Capsules are swallowed whole, and can be taken with or without food.

Dose adjustments are permitted for the management of serious adverse events, such as fatigue or bone pain; a reduction to 120 mg daily is suggested in this setting. Of note, in the research

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Steroids Patients presenting for enzalutamide therapy, who are either postdocetaxel or other hormonal manipulations, will likely be taking steroids. Clinical judgment or patient wishes should be addressed. In clinical trials, 48% of patients receiving enzalutamide 160 mg daily took glucocorticoids continuously. Therefore, patients are permitted but not required to continue steroids.

Guidelines suggest that tapering steroids depends on the clinical picture. Patients who have been taking 10 to 20 mg daily of glucocorticoids for longer than 3 weeks, or those who have taken evening doses of steroids for at least 3 weeks, may experience hypothalamic-pituitary-adrenal (HPA) axis suppression if steroids are stopped without tapering. The patient’s previous dosage, the duration of use, and the potency of the steroids taken are important considerations but not good predictors of the consequences of HPA suppression.

The goal of tapering off steroids is to lessen the possible resurgence of the disease for which the steroids were prescribed, to decrease the symptoms of withdrawal, and to lessen the chance of HPA suppression. Guidelines suggest a 5% to 10% reduction of total dose, every 1 to 2 weeks, until completely tapered.10,11

About Enzalutamide With second-line therapy, the patient sitting before us has already had experience with cancer. A common thread connecting many with this disease is their likely reliance on PSA readings.

Because it is an oral medication, enzalutamide reaches steady state in approximately 28 days. A change in PSA should not be expected within this short time frame. In clinical trials, men were taking enzalutamide for 3 months before their PSA levels showed a decrease, which in turn reinforced their commitment to continuing with the new therapy.

Educating patients is key to their quality of life as well as their compliance, especially with oral therapies.

Warnings and Precautions Seizures In clinical trials with enzalutamide, 7 of 800 (0.9%) patients taking 160 mg daily experienced a seizure. Of note, no seizures were diagnosed in patients in the placebo arm. Patients with a known history of seizure, known brain metastasis, or ischemic attacks in the previous 12 months were excluded from trials. All patients who had a seizure were taken off the trial and had no further seizures. Patients considering treatment with enzalutamide should be made aware of the data and have their risk of seizures outlined.

In men with prostate cancer, clinical practice does not often include

Patient education and a keen understanding of anticipatory needs will allow for better compliance with therapy and better patient outcomes.

Drug Interactions Concomitant use with strong cytochrome P (CYP) 2C8 inhibitors (eg, gemfibrozil) or strong CYP3A4 inhibitors (eg, itraconazole) increases the concentration of enzalutamide— decrease the dose of enzalutamide if these medications are coadministered. CYP2C8 (eg, rifampin) and CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin) inducers may alter or decrease plasma exposure and should be avoided. St. John’s wort, a weaker CYP3A4 inducer, should also be avoided.

Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. At steady state, enzalutamide reduced the exposure to midazolam, warfarin, and omeprazole.

Concomitant use of drugs with narrow therapeutic windows should either be avoided or require more frequent monitoring.8

evaluation of a brain scan. Thorough patient and family histories are necessary when considering changes to a patient’s therapy.3,5,7,8,12 Pregnancy Enzalutamide is contraindicated in women and could cause fetal harm, based on its mechanism of action. Men able to father children should practice safe sex with barrier methods while taking, and for up to 3 months posttreatment with, enzalutamide.8 Common Adverse Events With Enzalutamide The most common adverse events of enzalutamide, reported in any grade from clinical trials, were fatigue (34%), diarrhea (21%), hot flashes (20%), musculoskeletal pain (14%), and headaches (12%). Men in the placebo arm experienced the same adverse events, although at a somewhat lower percentage. In

men taking enzalutamide, these effects should be anticipated, and patient education should include strategies aimed at addressing them.3,7,8 Conclusions Advances in therapies aimed at metastatic CRPC have greatly aided our discussions of treatment options, particularly over the past 4 to 5 years. To date, 5 treatment options offer a survival benefit for men living with advanced prostate cancer. Going forward, we will consider not only what to offer our patients, but in what sequence.

Enzalutamide’s current place is in second-line therapy, postdocetaxel, yet ongoing clinical trials may allow for another option in chemo-naive men.

As with all oral therapies, patient education and a keen understanding of anticipatory needs will allow for better compliance with therapy and better patient outcomes. l References

1. American Cancer Society. Cancer Facts and Figures 2013. http://www.cancer.org/research/cancerfacts figures/cancerfactsfigures/cancer-facts-figures-2013.

Accessed March 18, 2013.

2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30.

3. Menon MP, Higano CS. Enzalutamide, a second generation androgen receptor antagonist: development and clinical applications in prostate cancer. Curr Oncol Rep. 2013;15:67-75.

4. Berthold DR, Pond GR, Soban F. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26(2):242-245.

5. Ezzell EE, Chang KS, George BJ. New agents in the arsenal to fight castrate-resistant prostate cancer. Curr Oncol Rep. 2013;16(3):239-248.

6. Taneja SS. Re: increased survival with enzalutamide in prostate cancer after chemotherapy [comment].

J Urol. 2013;189(1):123-124.

7. Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197.

8. Xtandi [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2012.

9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate cancer. Version 1.2013. www. nccn.org/professionals/physician_gls/pdf/prostate.pdf.

Accessed February 19, 2013.

10. Chettle CC. Glucocorticoid drugs: their benefits and risks. http://ce.nurse.com/PrintTopic.aspx?Topi cId=7895. Accessed February 28, 2013.

11. Furst DE, Saag KG, Matteson EL, Romain PL. Glucocorticoid withdrawal. http://www.uptodate.com. ezproxy.med.nyu.edu/contents/glucocorticoid-with drawal?topic. Accessed March 1, 2013.

12. Pal SK, Stein CA, Sartor O. Enzalutamide for the treatment of prostate cancer. Expert Opin Pharmacother.

2013;14(5):679-685.

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May 2013 I VOL 6, NO 4

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Prostate Cancer

setting, there were no dose adjustments for mild or moderate renal or hepatic impairment. Enzalutamide has not been evaluated in men with severe hepatic or renal impairment or in end-stage renal disease.7,8 Prescriptions are written for #120 capsules (four 40-mg capsules daily) per month. Currently, enzalutamide is available through specialty pharmacies. For assistance in locations and for access programs, Astellas Pharma US, Inc., provides the following contact information: www.XTANDIaccess. com, www.XtandiHCP.com, (800) 888-7704, or email at Customer_ Ops@us.astellas.com.

Prostate Cancer The US Food and Drug Administration (FDA) approved an expanded indication for abiraterone acetate (Zytiga Tablets, Janssen Biotech, Inc.) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. This expanded approval was granted on December 10, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm331628.htm.

Abiraterone Acetate: Expanded Indication for Metastatic Prostate Cancer Shawn Bliss, MSN, ARNP, AOCN Florida Cancer Specialists

A

biraterone acetate is a novel antiandrogen agent that has recently received an expanded indication for treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Prostate cancer remains the most common noncutaneous malignancy, accounting for 28% of all cancers, among American men.

According to the American Cancer Societyâ&#x20AC;&#x2122;s estimates, about 238,590 new cases of prostate cancer will be diagnosed and approximately 29,720 men will die of the disease in 2013.1 A growing number of drugs have been developed for the treatment of advanced mCRPC since docetaxel was first approved when it indicated a survival advantage.2 The rapidly emerging field of prostate cancer therapeutics is dramatically changing the mCRPC treatment landscape. With the advent of new medications using different mechanisms of action, options for treatment are becoming more varied and include hormones, intravenous (IV) chemotherapy, and novel agents such as abiraterone acetate. It is imperative that oncology nurses be aware of these multiple treatment options to provide proper care for their patients.

Concomitantly with prednisone, abiraterone acetate attained approval from the US Food and Drug Administration (FDA) in April 2011 for the treatment of mCRPC after docetaxel failure, based on the results of the phase 3 COU-AA-301 trial.3 Those findings indicated that overall survival (OS) was longer in the abiraterone acetate/prednisone group. In 2012, the FDA approved an expanded indication for abiraterone acetate in combination with prednisone,4 the significance of which is that it allowed patients with mCRPC to be treated with this oral agent prior to receiving IV chemotherapy.

Hormones Advanced prostate cancer has been treated by depleting or blocking the action of androgens. This results in a decrease in the concentration of prostate-specific antigen (PSA) as

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well as tumor regression and relief of symptoms. Frequently, these responses do not continue and the disease progresses.5 Secondary hormonal options or chemotherapy may be used when prostate cancer no longer responds to hormone therapy alone. Because androgen receptor activation and autocrine/paracrine synthesis are potential mechanisms of cancer recurrence during androgen deprivation therapy, castrate levels of testosterone should be maintained while additional therapies are employed.6

biosynthesis is inhibited at 3 sources of testosterone production: the testes, adrenal glands, and prostate tumor tissue.3 Androgen-deprivation therapies, such as gonadotropin-releasing hormone (GnRH) analogs or orchiectomy, lower androgen production. This occurs in the testes but not in adrenal glands or in tumors.12 Recent COU-AA-302 Study The most recent approved indication for abiraterone acetate was in combination with prednisone for patients

With the advent of new medications using different mechanisms of action, options for treatment are becoming more varied and include hormones, intravenous chemotherapy, and novel agents such as abiraterone acetate.

The androgen signaling pathway remains important throughout the course of mCRPC. Hormone-refractory (or hormone-resistant) prostate cancer is an imprecise description of metastatic disease that has progressed despite castrate levels of serum testosterone.

Clinical evidence suggests that tumors may remain hormone sensitive.7 There are multiple mechanisms by which tumor cells adapt to a low-androgen environment.8 Prostate cancer tumor cells have enzymatic pathways that produce their own androgen supply. Tumor tissue androgen levels in mCRPC remain sufficient to activate the androgen receptor despite primary androgen-deprivation therapy (surgical or medical castration).9,10 In mCRPC, the tumor may become hypersensitive to even small amounts of androgen.11 Mechanisms of Action Abiraterone acetate is a selective inhibitor of androgen biosynthesis that potently blocks cytochrome P450 c17 (CYP17). Consequently, androgen

with mCRPC. The approval was based on a trial, COU-AA-302, of 1088 men with mCRPC who had not received cytotoxic chemotherapy and were asymptomatic or mildly symptomatic. Participants were randomized to receive either abiraterone acetate plus prednisone (n = 546) or placebo plus prednisone (n = 542). Entry was restricted to those with metastasis to the bone, soft tissue, or lymph nodes. Patients were excluded if they had liver metastases, had moderate to severe pain, or if their aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) was â&#x2030;Ľ2.5 x the upper limit of normal. All patients had either a previous orchiectomy or continued to receive GnRH analog.4 OS and radiographic progression-free survival (rPFS) were the coprimary end points of the study. Compared with placebo, treatment with abiraterone acetate improved rPFS: median rPFS was 8.3 months for those in the placebo arm and had not yet been reached for those receiving abiraterone acetate (hazard ratio = 0.43; 95% CI, 0.35-

0.52; P <.0001). At the prespecified third interim analysis, median OS was 35.3 months in the abiraterone acetate arm and 30.1 months in the placebo arm. Significant improvements in time-to-opiate use and time-to-cytotoxic chemotherapy supported the primary end points.4 Adverse Effects Safety data were evaluated in the 2 pivotal trials of the 1333 men with mCRPC who received abiraterone acetate plus prednisone and the 934 men who received placebo plus prednisone. Fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion were the most commonly reported adverse reactions (â&#x2030;Ľ10%).

Anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST and ALT, hypophosphatemia, and hypokalemia were the most commonly observed laboratory abnormalities (>20%).4 In 55% of patients receiving abiraterone acetate and in 50% of patients receiving placebo, grade 3/4 adverse reactions occurred. There were grade 3/4 increases in ALT or AST in 4% of patients in the abiraterone acetate arm. Grade 3/4 cardiac failure occurred more frequently in patients receiving abiraterone acetate (1.6%) compared with those receiving placebo (0.2%). Adrenal insufficiency occurred in 0.5% and 0.2% of patients receiving abiraterone acetate or placebo, respectively.4 Coadministration of prednisone reduces the incidence and severity of mineralocorticoid-related adverse reactions (hypokalemia, hypertension, and fluid retention). Secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland drives the production of mineralocorticoids, androgens, and glucocorticoids such as cortisone.

Treatment with abiraterone acetate inhibits the production of cortisone and androgens as a result of CYP17 inhibition. Through the negative feedback

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this drug potentiates dextromethorphan. Strong inhibitors and inducers of CYP3A4 should be avoided or be used with caution.12 Dosing The dosage for abiraterone acetate is 1000 mg (four 250 mg tablets) admin-

Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy Phase 3 study with approximately 3,000 subjects at 500 study sites globally KEY ELIGIBILITY CRITERIA*

PRIMARY ENDPOINT

• Stage IV NSCLC

• Overall survival

• Receiving 1st-line myelosuppressive

SECONDARY ENDPOINTS

chemotherapy

• Progression-free survival

• Hemoglobin (Hb) ≤ 11 g/dL

• Incidence of ≥ 1 red blood cell (RBC) transfusion or Hb ≤ 8.0 g/dL

• ECOG score ≤ 1

S:9.75”

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Continued on page 26

NOW RECRUITING

Mineralocorticoid-Related Adverse Reactions There is a risk of mineralocorticoid excess, and the medication must be used with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. Safety has not been established in patients with left ventricular ejection fraction <50%, New York Heart Association Class III or IV heart failure, or recent myocardial infarction. It is also recommended that hypertension be controlled and hypokalemia be corrected before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical insufficiency has been reported after an interruption of daily steroids and/or with concurrent infection or stress.12

Darbepoetin alfa 500-mcg Q3W

2:1 Randomization (darbepoetin alfa:placebo)

End of Investigational Product

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Week 0

Week 1

Disease progression or end of chemotherapy treatment

*Complete inclusion/exclusion criteria and additional study details can be found in the protocol.

ECOG = Eastern Cooperative Oncology Group; Q3W = once every 3 weeks.

For more information, please email Cory Docken/Getty Images

Drug Interactions Because abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6, drug interactions may occur. Coadministration with CYP2D6 substrates that have a narrow therapeutic index (eg, thioridazine) should be avoided. Note that

tablet 4 times a day rather than all the abiraterone acetate at once. Note that abiraterone acetate is used in combination with prednisone 5 mg orally twice daily.12 Prednisone helps reduce the incidence and severity of mineralocorticoid-related adverse reactions.

S:7.25”

Contraindications Oncology nurses should be familiar with important adverse effects of the medication. Pregnancy is a contraindication for abiraterone acetate, as it may cause fetal harm (Pregnancy Category X).12,16 If the patient’s sexual partner may become pregnant, a condom and another form of birth control must be used. Pregnant women and those of childbearing potential should not handle the medication without protection.16

Hepatotoxicity Hepatotoxicity can occur; increases in liver enzymes have led to drug interruption, dose modification, and/ or discontinuation. Monitor liver function and modify, withhold, or discontinue the drug as necessary.

Monitor liver function enzymes prior to starting treatment, every 2 weeks for the first 3 months, and monthly thereafter.12

istered orally once daily on an empty stomach. Exposure increases are 10to 17-fold higher when administered with a meal compared with a fasting state. Tablets should be swallowed whole with water; patients should not crush or chew tablets. Be aware that many patients will try to take one

Prostate Cancer

mechanism, secreted levels of ACTH increase in response to a decrease in circulating cortisone level. There is a corresponding increase in mineralocorticoid levels that may lead to these adverse reactions.13,14 Prednisone 5 mg orally twice daily in combination with abiraterone acetate preempts the activation of the negative feedback mechanism, because the system no longer perceives a net cortisol deficit.15

Study-20070782@amgen.com or call 1-866-965-0782.

Products under investigational study have not been approved by the FDA for the use under investigation in this trial.

© 2013 Amgen Inc. All rights reserved. Not for Reproduction.

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Prostate Cancer

Abiraterone Acetate: Expanded Indication... Continued from page 25 Adherence In recent years, the term “compliance” has been replaced by “adherence,” a less judgmental expression that refers to how consistently a patient takes a medication exactly as prescribed.17 Adherence to oral agents is critical to their success. Issues related to adherence include limited insurance coverage, comorbid conditions, polypharmacy, and understanding the treatment regimen.

The increased use of oral agents requires that oncology nurses assess and measure patient adherence. This can be achieved by evaluating the percentage of medications taken, the duration

that they are taken, and the timing of medication. Tools to assist with medication adherence include alarm clocks, talking pill bottles, reminder phone calls, medication diaries, online patient portals, and web chats. In addition, medical record audits can be successful.18 Reasons that have been given for poor adherence include cost, forgetfulness, anxiety, denial, illiteracy, complexity of the regimen, and trouble swallowing pills.19 Conclusions Abiraterone acetate is now approved for use in patients with mCRPC, prior to docetaxel treatment. To provide

the best care for patients with cancer, oncology nurses must know the uses and benefits, as well as the adverse effects, of this novel therapy. l References

1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30.

2. El-Amm J, Aragon-Ching JB. The changing landscape in the treatment of metastatic castration-resistant prostate cancer. Adv Med Oncol. 2013;5(1):25-40.

3. de Bono JS, Logothetis CJ, Molina A, et al.

Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

4. US Food and Drug Administration. Abiraterone acetate. http://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm331628.htm. Updated December 11, 2012. Accessed March 10, 2013.

5. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin

Patient Clinical Case

A

70-year-old man had a history of prostate cancer that was originally diagnosed in 1997. He initially was treated with surgery, then required radiation therapy to the prostate bed. He had a rising PSA and was treated with intermittent hormones and triptorelin (Trelstar). In 2010, he developed bone metastasis with activity seen on bone scan. His PSA rapidly climbed to 37. He was again placed on triptorelin and was briefly on bicalutamide, with PSA continuing to climb. Bicalutamide was discontinued and PSA continued to increase. At this point he required additional treatment. However, in February 2011, abiraterone acetate was not indicated before chemotherapy. He therefore was started on docetaxel. He had a rapid decline in performance status, developed severe asthenia, and was also hospitalized for pneumonia. After 3 cycles, his PSA decreased but docetaxel had to be discontinued because of adverse effects. While off the docetaxel, his PSA quickly doubled and he elected to proceed with abiraterone acetate.

At initiation of the medication in May 2011, his PSA was 35, and quickly dropped to 0.7 by July 2011. Within a few weeks, his performance status returned to baseline, his pain improved, and he returned to his active lifestyle. The patient has continued on abiraterone acetate, in addition to triptorelin and monthly zoledronic acid. The plan is to continue the current regimen.

This clinical case is an excellent example of the benefits of abiraterone acetate. With the latest approval for abiraterone acetate, patients can be afforded the opportunity to receive this treatment before chemotherapy.

Oncol. 2005;23(32):8253-8261.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate Cancer. Version 2.2013. http:// www.nccn.org/professionals/physician_gls/f_guide lines.asp. Accessed April 23, 2013.

7. Scher HI, Steineck G, Kelly WK. Hormonerefractory (D3) prostate cancer: refining the concept.

Urology. 1995;46(2):142-148.

8. Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting therapies in prostate cancer: new agents for an established target. Lancet Oncol.

2009;10(10):981-991.

9. Titus MA, Schell MJ, Lih FB, et al. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657.

10. Mohler JL, Gregory CW, Ford OH III, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res. 2004;10(2):440-448.

11. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):6407-6415.

12. Zytiga (package insert). Horsham, PA: Centocor Ortho Biotech Inc. December 2012.

13. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17.

Endocrinol Metab Clin North Am. 2001;30(1):101-119.

14. Janssen Biotech. Zytiga (abirateron acetate) tablets dosing and administration guide for healthcare professionals. Zytiga. http://www.zytigahcp.com/dos age-and-administration. Accessed May 13, 2013.

15. Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treating metastatic prostate cancer. BJU Int. 2005;96(9):1241-1246.

16. Chemotherapy Advisor. Zytiga Rx. http://www. chemotherapyadvisor.com/zytiga/drug/7009. Accessed April 23, 2013.

17. Gangloff JM. Troubling trend: medication adherence. Cure. 2013;(spring suppl):4-8. http://www.cure today.com/index.cfm/fuseaction/article.show/id/2/arti cle_id/2061. Accessed April 23, 2013.

18. Spoelstra SL, Given CW. Assessment and measurement of adherence to oral neoplastic agents. Semin Oncol Nurs. 2011;27(2):116-132.

19. Vaughn D. Taking charge of your cancer treatment. Cure. 2013;(spring suppl):10-15. http://www. curetoday.com/index.cfm/fuseaction/article.show/id/2/ article_id/2062. Accessed April 23, 2013.

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BREAST CANCER The US Food and Drug Administration (FDA) approved pertuzumab (Perjeta; Genentech) for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. This approval was granted on June 8, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm307592.htm.

Pertuzumab for the Treatment of HER2-Positive Breast Cancer Sharon Gentry, RN, MSN, AOCN, CBCN

Novant Health Derrick L. Davis Cancer Center Winston-Salem, North Carolina

W

hen a patient with human epidermal growth factor receptor 2 (HER2)-positive breast cancer is given a personalized treatment plan, she discovers that she is one of the more than 20% of women with the HER2 gene that causes the cancer cells to grow faster, have a higher tendency to metastasize, and recur in the future.1,2 To combat this poorer prognostic breast cancer, the patient commits to a year of trastuzumab treatment, with the vision of continuing the journey as a cancer-free survivor.

JS is a 54-year-old female who was diagnosed with T2N0M0 breast cancer 2 years ago. She is one of the 15% of patients with breast cancer who relapsed after adjuvant trastuzumab treatment.2 After completing her trastuzumab treatment and being diligent in her follow-up visits, JS presented with a persistent cough that she had attributed to an earlier cold. After all other cold symptoms had abated, she followed up with her medical oncologist, who ordered a PET scan, which showed hypermetabolic mediastinal and hilar nodes with sternal bone metastasis.

The oncologist explained the plan for a combined anti-HER2/neu therapy or dual HER2 blockade. JS recalled the mechanism of trastuzumab as a drug that attaches to the HER2 receptors on breast cancer cells and blocks the growth signals from the body as well as directs the immune system to destroy cancer cells onto which the extra HER2 receptors are attached.3 JS was further educated on the concept of dimerization, or pairing together, of HER2 and HER3, thus causing intracellular pathways to develop.4 It was explained that pertuzumab blocks HER2 and HER3 from creating a union that would enable further cancer growth. Trastuzumab used along with pertuzumab blocks any “foot action” between HER2 and HER3 and does not allow them to “hold hands”—further inhibiting interaction between the receptors. To reinforce this information with a visual learning experience, JS watched an educational video about dimerization on Genentech’s pertuzumab website.4 Because the video is

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designed for healthcare professionals, certain terms needed to be explained to JS, but she found the visuals to be helpful. In addition, the pertuzumab website designed for patients and caregivers provides information about a pertuzumab support line with nurse availability as well as access to healthcare coverage information and patient assistance programs.5 After JS completed her restaging and prechemotherapy testing, she was started on docetaxel, pertuzumab, and trastuzumab, the National Comprehensive Cancer Network’s preferred first-line agent for HER2-positive recurrent or metastatic breast disease.6 She has since

for exercise and relaxation. Her blood counts (HgB) have been stable, and her sleep quality is best after the effect of her steroid treatment declines after chemotherapy.

Diarrhea was a concern with the struggle to stay hydrated, and her worst episode has been a grade 2. JS balances the use of loperamide, diet intake, and other strategies with what she calls “intentional hydration,” or focusing on her fluid intake. The diarrhea usually abates within days after treatment, and she has adjusted her work schedule to accommodate this side effect.

Alopecia was an expected effect, and she coped well with it last time by hav-

Each patient with metastatic breast cancer brings an individual emotional response based on her judgment of how she tolerated side effects from the previous treatment. completed 6 cycles, and her primary side effects have been fatigue, diarrhea, alopecia, and a skin rash; all appeared after the first treatment. None of these effects were grade 3 or 4 adverse events as described in the National Cancer Institute’s Common Terminology Criteria for Adverse Events v4.0 (CTCAE).7 The CTCAE is a descriptive tool accepted throughout the oncology community as a standard classification for adverse effects in oncology.

While the side effects have been tolerable enough to allow her to continue working, they have limited her participation in many of her extracurricular activities. Her fatigue was managed by the use of evidence-based interventions provided by the Oncology Nursing Society PEP (Putting Evidence Into Practice) resources.8 JS had set a priority to continue to work, both for her self-esteem and for her emotional needs, so this was set as a base for her energy conservation and activity management. She did allow herself to attend a weekly church service and continue small outdoor walks with her husband

ing different wigs, scarves, and accessories to enhance her appearance. She remembered the tips she received from the Personal Care Products Council Foundation’s Look Good Feel Better program.9 A local program site can be found by going to the Look Good Feel Better website at http://lookgoodfeelbetter.org/programs.

The skin on her dorsal hands, forearms, and abdomen showed a fine macular, reticular rash that presented without itching after her initial treatment.

It subsided with the use of diphenhydramine cream, and adding pre- and posttreatment steroid tapering was also helpful.

JS is aware of the other common side effects with pertuzumab, such as neutropenia, nausea, neuropathy, and cardiac concerns. She continues her heart function monitoring as determined by her oncologist, and she understands the need to communicate any concerns to her healthcare team at the clinic. She is elated that her most recent PET scan results showed improvement and feels like her current treatment allows her

quality time with a balance of family and work.

As new therapies are developed, nurses learn about new cancer management options along with their patients. With the application of these therapies to the metastatic setting, the nurse takes her knowledge bank and proactively teaches and looks for possible side effects, acknowledging that each individual patient may have different risks for various effects. For example, patients treated with previous anthracyclines or radiation to the chest may be at higher risk for left ventricular dysfunction; the diabetic patient may be a challenge with peripheral neuropathy; and heavily prior-treated patients for metastatic breast cancer may struggle with fatigue, neutropenia, or nausea and vomiting. Also, each patient with metastatic breast cancer brings an individual emotional response based on her judgment of how she tolerated side effects from the previous treatment and the meaning that is attached to the recurrent cancer.

It will be interesting to watch the future implications and development of metastatic treatment. Will this involve the movement of initial metastatic drugs to the adjuvant setting? Will we see more targeted therapies with less systemic side effects? Hopefully, the evidence-based practice to address side effects will continue to develop.

With the personalized assessment each patient receives prior to starting treatment, and the use of all available tools and resources, the journey for metastatic patients is well supported to enable the best-quality experience with their chronic disease. l References

1. Phillips C. Treatment options for HER2-positive breast cancer expand and evolve. NCI Cancer Bulletin. 2012;9(20):2. http://www.cancer.gov/ncicancerbulletin/101612/page2.

Published October 16, 2012. Accessed March 27, 2013.

2. Nahta R, Esteva F. HER2 therapy: molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 2006;8(6):215.

3. Genentech Inc. Proposed mechanism of action: Herceptin MOA. Herceptin (trastuzumab) Healthcare Professionals Web site. http://www.herceptin.com/hcp/treatment/moa. Accessed March 27, 2013.

4. Genentech Inc. Proposed mechanism of action: inhibit dimerization for more comprehensive HER2 blockade.

PERJETA (pertuzumab) Healthcare Professionals Web site. http://www.perjeta.com/hcp/moa. Accessed March 27, 2013.

5. PERJETA (pertuzumab) Patient & Caregivers Web site. http://www.perjeta.com/patient/index. Accessed March 27, 2013.

6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2013. http://www.nccn.org/professionals/physician_gls/pdf/breast. pdf. Updated March 11, 2013. Accessed April 25, 2013.

7. National Cancer Institute, National Institutes of Health.

Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Bethesda, MD: National Institutes of Health; 2009. NIH publication 09-5410. http://evs.nci.nih.gov/ftp1/ CTCAE/About.html. Revised June 14, 2010. Accessed April 25, 2013.

8. Oncology Nursing Society. ONS PEP®−Putting Evidence Into Practice. http://www.ons.org/Research/PEP. Accessed April 25, 2013.

9. The Personal Care Products Council Foundation. Look Good Feel Better Web site. http://lookgoodfeelbetter.org/.

Accessed April 25, 2013.

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BREAST CANCER The US Food and Drug Administration (FDA) approved everolimus (Afinitor; Novartis Pharmaceuticals Corporation) for the treatment of postmenopausal women with advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. This approval was granted on July 20, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm313008.htm.

Everolimus: A New Treatment for Hormone Receptor–Positive Advanced Breast Cancer Christine M. Rafferty, RN, BSN, OCN Fox Chase Cancer Center Philadelphia, Pennsylvania

Background Breast cancer is the most common cancer diagnosed in women in the United States. It is the second most common cause of cancer deaths among women; only lung cancer accounts for more cancer deaths. It is estimated that 39,620 women will die of breast cancer in 2013.1 The lifetime risk for a woman to develop breast cancer is 1 in 8. In 2008, it was estimated that 2.6 million women had a history of breast cancer. Approximately twothirds of breast cancers are estrogen and/or progesterone positive; this is associated with a favorable prognosis.2 Breast cancer mortality in patients with early-stage disease has been dramatically reduced with the use of adjuvant endocrine, with hormone therapy as the cornerstone of treatment in advanced stages.3 Although most postmenopausal women with estrogen receptor–positive breast cancer benefit from an aromatase inhibitor as first-line endocrine treatment for metastatic disease, ~30% do not respond.4 In patients with breast cancer, resistance to endocrine therapy has been found to be associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway.5 Both in vitro and in vivo studies have shown that inhibition of mTOR by everolimus reduces cell proliferation, angiogenesis, and glucose uptake.6 In July 2012, the US Food and Drug Administration approved everolimus tablets for the treatment of advanced hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer in combination with exemestane, after treatment failure with letrozole or anastrozole, in postmenopausal women. Approval was based on a randomized, double-blind, multicenter, international trial conducted in 724 postmenopausal women who had estrogen receptor–positive, HER2-negative advanced breast can-

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Table 1 Avoid Use of Concomitant Strong Cytochrome P3A4 Inhibitors8 Antibiotics

Clarithromycin Telithromycin

Antidepressants

Nefazodone

Antifungals

Itraconazole Ketoconazole Voriconazole

Anti-HIV agents

Atazanavir Indinavir Nelfinavir Ritonavir Saquinavir

Table 2 Avoid Use of Concomitant Strong Cytochrome P3A4 Inducers8 Anticonvulsants

Carbamazepine Phenobarbital Phenytoin

Antituberculosis agents

Rifabutin Rifampin Rifapentine

Table 3 Requires Dose Modification With Use of Concomitant Moderate Cytochrome P3A4 or P-glycoprotein Inhibitors8 Antibiotics

Erythromycin

Antiemetics

Aprepitant

Antifungals

Fluconazole

Anti-HIV agents

Amprenavir Fosamprenavir

Calcium channel blockers

Diltiazem Verapamil

cer with recurrence or progression after previous treatment with letrozole or anastrozole. Patients were randomly allocated (2:1, in favor of the everolimus/exemestane group) to everolimus 10 mg/day plus exemestane 25 mg/day (n = 485) or to placebo plus exemestane 25 mg/day (n = 239).

Crossover to everolimus at the time of disease progression was not permitted.

The median progression-free survival (PFS) upon final PFS analysis was 7.8 and 3.2 months in the everolimus and

placebo arms, respectively.7 Serious adverse events (AEs) were reported among 23% of patients in the combination-therapy group (11% attributed to study treatment) and 12% in the exemestane-alone group (1% attributed to study treatment).

A higher percentage of patients discontinued everolimus in the combination-therapy group than placebo in the control group because of AEs (19% vs 4%, respectively). In the combination-therapy group, 7

deaths were attributed to AEs during treatment or within 28 days after discontinuing treatment: 2 deaths from sepsis and 1 each from pneumonia, tumor hemorrhage, cerebrovascular incident, renal failure, and suicide. In the exemestane-alone group, 1 death from pneumonia was reported during treatment.5 The most common adverse reactions in patients receiving everolimus plus exemestane were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common (≥2%) grade 3 or 4 AEs were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. Additionally, the most common (≥3%) grade 3 or 4 laboratory abnormalities were lymphopenia, hyperglycemia, anemia, decreased potassium, increased aspartate aminotransferase, increased alanine aminotransferase, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients in the combination group compared with 0.4% of patients in the placebo group.

Dose interruptions or reductions were necessary in 63% of the patients receiving everolimus compared with 14% of the placebo group.7 Management of Adverse Reactions Noninfectious Pneumonitis Noninfectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. It can occur with or without signs and symptoms (pleural effusion, hypoxia, cough, dyspnea, wheezing, shortness of breath, and chest pain). Patients taking everolimus should be educated about the importance of immediately reporting any new or worsening respiratory symptoms. Fatal outcomes have been observed. If symptoms are moderate, consider interrupting everolimus therapy until symptoms improve; steroids may be indicated. Everolimus may be reintroduced at 50% of the previous dose. If symptoms are severe, Continued on page 30

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For postmenopausal women with HR+ breast cancer

It’s breast cancer.

She deserves more.* And you’ve got more to offer with ARIMIDEX Direct.

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ARIMIDEX Direct works with your patients who prefer brand-name ARIMIDEX instead of the generic to get ARIMIDEX delivered to their home, and provides comprehensive patient support.

No insurance issues for you—just the knowledge that your eligible† patients get the #1 most-prescribed branded aromatase inhibitor1 for $40 or less a month.

Visit www.ARIMIDEX.com to find out how you can get more for you and your patients from ARIMIDEX Direct.

DIRECT Not valid for prescriptions purchased under Medicaid or similar medical assistance programs.

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Important Safety Information About ARIMIDEX® • ARIMIDEX is only for postmenopausal women. ARIMIDEX can cause fetal harm when administered to a pregnant woman. Before starting treatment with ARIMIDEX, pregnancy must be excluded. ARIMIDEX is contraindicated in patients with demonstrated hypersensitivity to ARIMIDEX or any of its excipients.

Observed reactions include anaphylaxis, angioedema, and urticaria. (see CONTRAINDICATIONS section of full Prescribing Information) • In women with preexisting ischemic heart disease 465/6186 (7.5%), an increased incidence of ischemic cardiovascular events occurred with ARIMIDEX (17%) vs tamoxifen (10%). In this patient population, angina pectoris was reported in 25/216 (11.6%) vs 13/249 (5.2%) and myocardial infarction was reported in 2/216 (0.9%) vs 8/249 (3.2%) in patients receiving ARIMIDEX and tamoxifen, respectively • Compared to baseline, ARIMIDEX showed a mean decrease in both lumbar spine and total hip bone mineral density. Tamoxifen showed a mean increase in these measurements. Nine percent of patients receiving ARIMIDEX had an elevated serum cholesterol vs 3.5% of patients receiving tamoxifen • In the early breast cancer (ATAC) study, the most common (occurring with an incidence of >10%) side effects occurring in women taking ARIMIDEX included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema and lymphedema, regardless of causality • In the advanced breast cancer studies, the most common (occurring with an incidence of >10%) side effects occurring in women taking ARIMIDEX included hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis, and peripheral edema. Joint pain/stiffness has been reported in association with the use of ARIMIDEX

• Clinical and pharmacokinetic results suggest that tamoxifen should not be administered with ARIMIDEX. Estrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacologic action

Approved Uses ARIMIDEX is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.

ARIMIDEX is indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer and for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy.

Patients with estrogen receptor-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to ARIMIDEX.

Please see brief summary of full Prescribing Information on the next page.

If you can’t afford your medication, AstraZeneca may be able to help. For more information, please visit www.AstraZeneca-us.com You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch, or call 1-800-FDA-1088.

References: 1. Source: IMS NPA Monthly, February 2001-December 2012.

ARIMIDEX is a registered trademark of the AstraZeneca group of companies. ©2013 AstraZeneca. All rights reserved. 2416307 3/13

BREAST CANCER

Everolimus: A New Treatment... Continued from page 28 reinitiation should be based on individual clinical circumstances.8 Infections Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or pro-

tozoal infections (including those with opportunistic pathogens). Viral infections may include reactivation of hepatitis B. Infections may be severe, and can even lead to death.

Management includes watching for signs and symptoms of infection and

treating promptly. Patients should tell their healthcare provider right away if they have a temperature of ≥100.5°F, chills, or do not feel well. If infection occurs, consider interruption or discontinuation of everolimus.8

TRIM: 7.25 x 9.75 ®

TABLETS

Rx only BRIEF SUMMARY of Prescribing Information.

INDICATIONS AND USAGE

Adjuvant Treatment ARIMIDEX is indicated for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer.

First-Line Treatment ARIMIDEX is indicated for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor unknown locally advanced or metastatic breast cancer.

Second-Line Treatment ARIMIDEX is indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following tamoxifen therapy. Patients with ER-negative disease and patients who did not respond to previous tamoxifen therapy rarely responded to ARIMIDEX. RECOMMENDED DOSE The dose of ARIMIDEX is one 1 mg tablet taken once a day. For patients with advanced breast cancer, ARIMIDEX should be continued until tumor progression. ARIMIDEX can be taken with or without food.

No dosage adjustment is necessary for patients with renal impairment or for elderly patients.

No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. ARIMIDEX has not been studied in patients with severe hepatic impairment.

CONTRAINDICATIONS ARIMIDEX may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. ARIMIDEX is contraindicated in women who are or may become pregnant.

ARIMIDEX is contraindicated in any patient who has shown a hypersensitivity reaction to the drug or to any of the excipients. Observed reactions include anaphylaxis, angioedema, and urticaria.

WARNINGS AND PRECAUTIONS In women with pre-existing ischemic heart disease, an increased incidence of ischemic cardiovascular events was observed with ARIMIDEX in the ATAC trial (17% of patients on ARIMIDEX and 10% of patients on tamoxifen). Consider risk and benefits of ARIMIDEX therapy in patients with pre-existing ischemic heart disease.

Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving ARIMIDEX had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline.

During the ATAC trial, more patients receiving ARIMIDEX were reported to have elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively).

ADVERSE REACTIONS Serious adverse reactions with ARIMIDEX occurring in less than 1 in 10,000 patients are: 1) skin reactions such as lesions, ulcers, or blisters; 2) allergic reactions with swelling of the face, lips, tongue, and/or throat. This may cause difficulty in swallowing and/or breathing; and 3) changes in blood tests of the liver function, including inflammation of the liver with symptoms that may include a general feeling of not being well, with or without jaundice, liver pain or liver swelling.

In the early breast cancer (ATAC) study, the most common (occurring with an incidence of >10%) side effects occurring in women taking ARIMIDEX included: hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea and vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema and lymphedema, regardless of causality.

In the advanced breast cancer studies, the most common (occurring with an incidence of >10%) side effects occurring in women taking ARIMIDEX included: hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, increased cough, dyspnea, pharyngitis and peripheral edema.

Ischemic Cardiovascular Events Between treatment arms in the overall population of 6186 patients, there was no statistical difference in ischemic cardiovascular events (4% ARIMIDEX vs. 3% tamoxifen). In the overall population, angina pectoris was reported in 71/3092 (2.3%) patients in the ARIMIDEX arm and 51/3094 (1.6%) patients in the tamoxifen arm; myocardial infarction was reported in 37/3092 (1.2%) patients in the ARIMIDEX arm and 34/3094 (1.1%) patients in the tamoxifen arm. In women with preexisting ischemic heart disease 465/6186 (7.5%), the incidence of ischemic cardiovascular events was 17% in patients on ARIMIDEX and 10% in patients on tamoxifen. In this patient population, angina pectoris was reported in 25/216 (11.6%) patients receiving ARIMIDEX and 13/249 (5.2%) patients receiving tamoxifen; myocardial infarction was reported in 2/216 (0.9%) patients receiving ARIMIDEX and 8/249 (3.2%) patients receiving tamoxifen.

Bone Mineral Density Findings Results from the ATAC trial bone substudy at 12 and 24 months demonstrated that patients receiving ARIMIDEX had a mean decrease in both lumbar spine and total hip bone mineral density (BMD) compared to baseline. Patients receiving tamoxifen had a mean increase in both lumbar spine and total hip BMD compared to baseline. Because ARIMIDEX lowers circulating estrogen levels it may cause a reduction in bone mineral density. A post-marketing trial assessed the combined effects of ARIMIDEX and the bisphosphonate risedronate on changes from baseline in BMD and markers of bone resorption and formation in postmenopausal women with hormone receptor-positive early breast cancer. All patients received calcium and vitamin D supplementation. At 12 months, small reductions in lumbar spine bone mineral density were noted in patients not receiving bisphosphonates. Bisphosphonate treatment preserved bone density in most patients at risk of fracture. Postmenopausal women with early breast cancer scheduled to be treated with ARIMIDEX should have their bone status managed according to treatment guidelines already available for postmenopausal women at similar risk of fragility fracture.

Cholesterol During the ATAC trial, more patients receiving ARIMIDEX were reported to have an elevated serum cholesterol compared to patients receiving tamoxifen (9% versus 3.5%, respectively). A post-marketing trial also evaluated any potential effects of ARIMIDEX on lipid profile. In the primary analysis population for lipids (ARIMIDEX alone), there was no clinically significant change in LDL-C from baseline to 12 months and HDL-C from baseline to 12 months. In secondary population for lipids (ARIMIDEX+risedronate), there also was no clinically significant change in LDL-C and HDL-C from baseline to 12 months.

In both populations for lipids, there was no clinically significant difference in total cholesterol (TC) or serum triglycerides (TG) at 12 months compared with baseline. In this trial, treatment for 12 months with ARIMIDEX alone had a neutral effect on lipid profile. Combination treatment with ARIMIDEX and risedronate also had a neutral effect on lipid profile. The trial provides evidence that postmenopausal women with early breast cancer scheduled to be treated with ARIMIDEX should be managed using the current National Cholesterol Education Program guidelines for cardiovascular risk-based management of individual patients with LDL elevations.

Second-Line Therapy ARIMIDEX was tolerated in two controlled clinical trials (i.e., Trials 0004 and 0005), with less than 3.3% of the ARIMIDEX-treated patients and 4.0% of the megestrol acetate-treated patients withdrawing due to an adverse reaction. The principal adverse reaction more common with ARIMIDEX than megestrol acetate was diarrhea.

30

May 2013 I VOL 6, NO 4

The incidences of the following adverse reaction groups potentially causally related to one or both of the therapies because of their pharmacology, were statistically analyzed: weight gain, edema, thromboembolic disease, gastrointestinal disturbance, hot flushes, and vaginal dryness. These six groups, and the adverse reactions captured in the groups, were prospectively defined. The results are shown in the following table.

Table 1 – Number (n) and Percentage of Patients with Pre-specified Adverse Reactions in Trials 0004 and 0005 ARIMIDEX 1 mg ARIMIDEX 10 mg Megestrol Acetate 160 mg (N=262) (N=246) (N=253) Adverse Reaction Group N (%) N (%) N (%) Gastrointestinal Disturbance 77 (29) 81 (33) 54 (21) Hot Flushes 33 (13) 29 (12) 35 (14) Edema 19 (7) 28 (11) 35 (14) Thromboembolic Disease 9 (3) 4 (2) 12 (5) Vaginal Dryness 5 (2) 3 (1) 2 (1) Weight Gain 4 (2) 10 (4) 30 (12)

Post-Marketing Experience Hepatobiliary events including increases in alkaline phosphatase, alanine amino-transferase, aspartate aminotransferase have been reported commonly (≥1% and <10%) and gamma-GT, bilirubin and hepatitis have been reported uncommonly (≥0.1% and <1%) in patients receiving ARIMIDEX. ARIMIDEX may also be associated with rash including cases of mucocutaneous disorders such as erythema multiforme and Stevens-Johnson syndrome. Cases of allergic reactions including angioedema, urticaria and anaphylaxis have been reported in patients receiving ARIMIDEX. Trigger finger and hypercalcemia (with or without an increase in parathyroid hormone) have been reported (≥0.1% and <1%) in patients receiving ARIMIDEX. Myalgia has been reported (≥1% and <10%) in patients receiving ARIMIDEX. DRUG INTERACTIONS

Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27%. However, the coadministration of anastrozole and tamoxifen did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen. At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor-positive subpopulation. This treatment arm was discontinued from the trial [see Clinical Studies (14.1) in Full Prescribing Information ]. Based on clinical and pharmacokinetic results from the ATAC trial, tamoxifen should not be administered with anastrozole.

Estrogen-containing therapies should not be used with ARIMIDEX as they may diminish its pharmacological action.

USE IN SPECIFIC POPULATIONS Pregnancy PREGNANCY CATEGORY X ARIMIDEX may cause fetal harm when administered to a pregnant woman and offers no clinical benefit to premenopausal women with breast cancer. ARIMIDEX is contraindicated in women who are or may become pregnant. If ARIMIDEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and potential risk for pregnancy loss.

Nursing Mothers It is not known if anastrozole is excreted in human milk. Because many drugs are excreted in human milk and because of the tumorigenicity shown for anastrozole in animal studies, or the potential for serious adverse reactions in nursing infants, 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 Clinical studies in pediatric patients included a placebo-controlled trial in pubertal boys of adolescent age with gynecomastia and a single-arm trial in girls with McCune-Albright Syndrome and progressive precocious puberty. The efficacy of ARIMIDEX in the treatment of pubertal gynecomastia in adolescent boys and in the treatment of precocious puberty in girls with McCune-Albright Syndrome has not been demonstrated.

Geriatric Use In studies 0030 and 0027 about 50% of patients were 65 or older. Patients ≥65 years of age had moderately better tumor response and time to tumor progression than patients <65 years of age regardless of randomized treatment. In studies 0004 and 0005 50% of patients were 65 or older. Response rates and time to progression were similar for the over 65 and younger patients. In the ATAC study 45% of patients were 65 years of age or older. The efficacy of ARIMIDEX compared to tamoxifen in patients who were 65 years or older (N=1413 for ARIMIDEX and N=1410 for tamoxifen, the hazard ratio for disease-free survival was 0.93 [95% CI: 0.80, 1.08]) was less than efficacy observed in patients who were less than 65 years of age (N=1712 for ARIMIDEX and N=1706 for tamoxifen, the hazard ratio for disease-free survival was 0.79 [95% CI: 0.67, 0.94]). The pharmacokinetics of anastrozole are not affected by age.

Renal Impairment Since only about 10% of anastrozole is excreted unchanged in the urine, the renal impairment does not influence the total body clearance. Dosage adjustment in patients with renal impairment is not necessary [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in Full Prescribing Information].

Hepatic Impairment The plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials. Therefore, dosage adjustment is also not necessary in patients with stable hepatic cirrhosis. ARIMIDEX has not been studied in patients with severe hepatic impairment [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in Full Prescribing Information].

OVERDOSAGE Clinical trials have been conducted with ARIMIDEX, up to 60 mg in a single dose given to healthy male volunteers and up to 10 mg daily given to postmenopausal women with advanced breast cancer; these dosages were tolerated. A single dose of ARIMIDEX that results in life-threatening symptoms has not been established. There is no specific antidote to overdosage and treatment must be symptomatic. In the management of an overdose, consider that multiple agents may have been taken. Vomiting may be induced if the patient is alert. Dialysis may be helpful because ARIMIDEX is not highly protein bound. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

These highlights do not include all the information needed to use ARIMIDEX safely and effectively. See full Prescribing Information for ARIMIDEX. To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca Pharmaceuticals LP at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ARIMIDEX is a registered trademark of the AstraZeneca group of companies. © 2009 AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850.

All rights reserved.

Rev 3/13 2416307 3/13

Stomatitis Mouth ulcers, stomatitis, and oral mucositis occur in patients treated with everolimus, at an incidence ranging from 44% to 86%. Grade 3 or 4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments such as mouthwashes or mouth gels are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Patients should be instructed on good oral hygiene.

Unless a fungal infection has been diagnosed, antifungal agents should not be used.8 Laboratory Abnormalities Laboratory abnormalities have been reported with everolimus, including electrolyte imbalances and hematologic, renal function, and glucose and lipid abnormalities. Laboratory testing should be performed prior to the initiation of therapy and periodically thereafter, and should include renal function, fasting glucose and lipid panels, and complete blood cell count.

Whenever possible, optimal glucose and lipid control should be achieved before a patient starts everolimus.8 Other Nursing Considerations Everolimus is available in 2.5-, 5-, 7.5-, and 10-mg tablets. It should be taken daily at the same time of day and consistently with or without food. The tablet cannot be crushed, chewed, or broken. It should be swallowed whole with a glass of water.

The recommended dose and schedule for everolimus for this indication is 10 mg orally daily. Patients with severe or intolerable adverse reactions may require dose reduction or interruption. A missed dose can be taken up to 6 hours later. If it is past the 6 hours, the dose should be skipped until the next day. Patients should not take 2 tablets to make up for the missed dose. Each tablet is packaged in a foil-wrapped blister pack to protect it from light. The tablets should be kept in the original container and opened with scissors before taking the medication.8 Decreased effectiveness was noted when pills were taken out of the blister pack and kept in a pillbox.

Patients taking everolimus should avoid live vaccines and close contact with those who have recently been vaccinated with a live vaccine.8 Agents that inhibit cytochrome P (CYP) 3A4 (Table 1) can increase everolimus blood concentrations, whereas CYP3A4 inducers (Table 2) can decrease blood concentrations.

Patients should report all medications

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inhibitors in breast cancer: a systematic review. Gynecol Oncol. 2012;127(3):662-672.

5. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529.

6. CenterWatch. Afinitor (everolimus). http://www.cen terwatch.com/drug-information/fda-approvals/drug-de tails.aspx?DrugID=1199. Accessed April 26, 2013.

7. US Food and Drug Administration. Everolimus 2012. Updated July 23, 2012. http://www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm313008.htm.

Accessed April 1, 2013.

8. Afinitor [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2012.

Clinical Trials With Everolimus Everolimus combined with an aromatase inhibitor has been found to improve PFS in patients with hormone receptorâ&#x20AC;&#x201C;positive advanced breast cancer who were previously treated with a nonsteroidal aromatase inhibitor.5 Other clinical trials are ongoing, including a study adding everolimus with letrozole, tamoxifen, and trastuzumab, and another study using letrozole and everolimus in the neoadjuvant setting. l

References

1. American Cancer Society. Cancer Facts & Figures 2013. http://www.cancer.org/research/cancerfactsfigures/ cancerfactsfigures/cancer-facts-figures-2013. Accessed April 1, 2013.

2. American Cancer Society. Breast Cancer Facts & Figures 2011-2012. http://www.cancer.org/research/can cerfactsfigures/breastcancerfactsfigures/breast-cancerfacts-and-figures-2011-2012. Accessed April 1, 2013.

3. Paplomata E, Oâ&#x20AC;&#x2122;Regan R. New and emerging treatments for estrogen receptor-positive breast cancer: focus on everolimus. Ther Clin Risk Manag. 2013;9:27-36.

4. Zagouri F, Sergentanis TN, Chrysikos, et al. mTOR

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GBC2013Asize20813_Layout 1 2/8/13 11:12 AM Page 1

ANNUAL CONFERENCE

"! !

!

!

Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

*

3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

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

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management â&#x20AC;˘ Reimbursement Challenges

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. 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 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 Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

*Agenda is subject to change.

PMPMERSONALIZED EDICINE IN ONCOLOGY O

May 2013 I VOL 6, NO 4

31

BREAST CANCER

including dietary supplements and should not start any new medications without contacting their healthcare professionals. Coadministration with strong CYP3A4 inhibitors and inducers should be avoided. When coadministering with a moderate CYP3A4 inhibitor (Table 3), dose adjustments are recommended. Everolimus should be reduced to 2.5 mg daily if coadministration is required. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the everolimus dose is increased. If the moderate inhibitor is discontinued, the everolimus dose should be returned to the dose used prior to initiation of the moderate CYP3A4 inhibitor. Grapefruit, grapefruit juice, and other foods that are known to inhibit CYP450 and P-glycoprotein activity may increase everolimus exposure and should be avoided during treatment. An increase in everolimus is recommended if use with a strong CYP3A4 inducer is required; it should be increased from 10 mg daily up to 20 mg daily, using 5-mg increments.8 Everolimus requires insurance verification and prior authorization.

Novartis, the manufacturer of Afinitor (everolimus), offers Patient Assistance NOW oncology support programs that make prescribing easier and can help with patient education, insurance verification, assistance with denial and/ or appeals, copays, and out-of-pocket costs. When everolimus is prescribed, a 14-day free supply can be shipped directly to patients so they can start treatment while waiting for insurance approval. This resource can be used with new prescriptions and also with changes in dosage.

HEMATOLOGIC MALIGNANCIES The US Food and Drug Administration (FDA) approved carfilzomib (Kyprolis; Onyx Pharmaceuticals, Inc.) for the treatment of patients with multiple myeloma who have received at least 2 prior therapies and who have demonstrated disease progression. This approval was granted on July 20, 2012.

For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm312945.htm.

Carfilzomib in the Treatment of Multiple Myeloma Sandra Kurtin, RN, MS, AOCN, ANP-C Arizona Cancer Center Tucson, Arizona

M

ultiple myeloma (MM) is not the most common hematologic malignancy, representing approximately 10% of all such malignancies. Roughly 21,700 new cases and 10,710 deaths were reported in the United States in 2012.1 It remains an incurable disease with multiple relapses over the course of the illness, each relapse

generally characterized by a diminished depth of response and shorter time to progression.2 Mortality rates have declined over the past decade, primarily attributed to the introduction of the immunomodulatory agents thalidomide and lenalidomide and the first proteasome inhibitor, bortezomib.2,3 Supportive care strategies including growth fac-

tors, transfusion medicine, stem cell mobilization agents, anti-infective agents, and bisphosphonate therapies have improved the ability to manage patients in the outpatient setting and keep them on therapy for longer periods of time. As a result, more patients have been eligible for hematopoietic stem cell transplants, which is still an important treatment option for MM.

Table 1 Selected Clinical Trials With Carfilzomib in Newly Diagnosed or Relapsed/Refractory Multiple Myeloma5 Study

Patients

CRd

Transplant eligible Newly diagnosed

CCd

Carfilzomib 20/36 mg/m

Other Agents

Further Treatment

Lenalidomide 25 mg/d days 1-21 Dexamethasone 20/10 mg days 1, 2, 8, 9, 16, 22, 23

Maintenance Lenalidomide 10 mg/d days 1-21

Aged â&#x2030;Ľ65 years or 20/36 mg/m2 transplant ineligible Newly diagnosed

Cyclophosphamide 300 mg/m2 days 1, 8, 15 Dexamethasone 40 mg days 1, 8, 15, 22

Maintenance Carfilzomib 36 mg/m2 days 1, 2, 15, 16

CYCLONE

Transplant eligible Newly diagnosed

Thalidomide 100 mg daily Cyclophosphamide 300 mg/m2 days 1, 8, 15 Dexamethasone 40 mg days 1, 8, 15, 22

None

C + Pan

Relapsed/Refractory 20/27 mg/m2 to 20/45 mg/m2

Panobinostat 20-30 mg days 1, 3, 5, 15, 17, 19

None

C + Pan

Relapsed/Refractory 20/27 mg/m2 to 20/45 mg/m2

Panobinostat 15-30 mg days 1, 3, 5, 8, 10, 12 Dexamethasone 4 mg days 1, 2, 8, 9, 15, 16

None

Car-Pom-d

Relapsed/Refractory 20/27 mg/m2 to 20/36 mg/m2 to 20/45 mg/m2 to 20/56 mg/m2

Pomalidomide 3 mg cohort 1, 4 mg cohorts 1-4, days 1-21 Dexamethasone 40 mg cycles 1-4, 20 mg after cycle 4

Maintenance Cycle 7 on: carfilzomib days 1, 2, 15, 16; pomalidomide/dexamethasone as before

C + ARRY-520

Relapsed/Refractory 20/27 mg/m2

ARRY-520 escalated from 0.5 to 1.5 mg/m2/d days 1, 2, 15, 16 Dexamethasone 4 mg days 1, 2, 8, 9, 15, 16

None

32

May 2013 I VOL 6, NO 4

2

15/20 mg/m2 to 20/45 mg/m2; 20/36 mg/m2 expansion

However, relapsed disease is still inevitable for most patients, and those who relapse during treatment with novel agents have a poor prognosis with an estimated survival of <9 months, indicating the need for additional treatment options.2,3 Overview On July 20, 2012, the US Food and Drug Administration (FDA) granted accelerated approval to carfilzomib injection (Kyprolis), which is indicated for the treatment of patients with MM who have received at least 2 previous therapies, including bortezomib and an immunomodulatory agent (thalidomide or lenalidomide), and have demonstrated disease progression on or within 60 days of the completion of the last therapy.4 The approval of carfilzomib was based on the response rate determined in a single-arm, multicenter clinical trial, and was not based on survival. Additional clinical trials are in process to investigate combination therapies and the use of carfilzomib in the early stages of MM (Table 1).5 Familiarity with the drugâ&#x20AC;&#x2122;s mechanism of action, pharmacokinetics, safety profile, and administration, as well as common treatment-emergent adverse events and the strategies to prevent or manage them, is necessary to safely incorporate carfilzomib into the treatment paradigm for eligible patients.

Carfilzomib is an irreversible proteasome inhibitor that binds with high affinity to the substrate binding sites of the 20S core particle of the proteasome, selectively inhibiting the chymotrypsin-like catalytic activity of the b5 subunit, which promotes the accumulation of ubiquinated proteins. Most intracellular proteins are degraded by the ubiquitin-proteasome pathway, resulting in cell arrest and apoptosis.6-8 Preclinical studies showed consecutive daily dosing of carfilzomib was optimal for inhibition of the proteasome. In addition, irreversible binding of carfilzomib to the proteasome binding sites required renewed proteasome

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Clinical Trials The FDA approval of carfilzomib was based on 4 phase 2 trials including 526 patients with relapsed and/or refractory MM: PX-171-003-A0 (n = 46), PX-171-003-A1 (the pivotal registration trial; n = 266), PX-171004 (n = 164), and PX-171-005 (n = 50). Most patients received carfilzomib at the approved dose and schedule (20 mg/m2 for cycle 1, escalated to 27 mg/m2 for subsequent cycles, dosed on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle). The patients in study PX-171-005, who had various degrees of renal insufficiency, received carfilzomib 15 mg/m2 in cycle 1, then 20 mg/m2 in cycle 2, and 27 mg/m2 in cycle 3 and beyond. Data from these trials (Table 1) established the safety and efficacy of carfilzomib in a population of heavily pretreated patients with relapsed and/or refractory MM. Updated results from a phase 2 extension study (PX-171-010) of prolonged carfilzomib therapy in patients with MM who were previously enrolled in phase 1 and 2 clinical trials were presented at the American Society of Hematology annual meeting in December 2012 by Siegel and colleagues.11,12 As of October 2012, 28 of 100 patients enrolled in the continuation trial remained in the study, with a median of 22.5 cycles and a maximum of 51 cycles. Carfilzomib was administered in combination with another drug—most commonly dexamethasone, lenalidomide, or cyclophosphamide—in 43% of patients. Although some patients required dose reductions or increases, overall response rates (ORRs) ranged from 24.2% to 45.2% depending on the regimen, and clinical benefit response (CBR = ORR + MR [minimal response]) ranged from 33.3% to 52.4%. Toxicity profiles were similar to those previously reported in the registration trial, with 63% of patients experiencing grade 3 or greater treatment-emergent adverse events (TEAEs), the most common being cytopenias and pneumonia.

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Table 2 Practical Considerations in the Administration of Carfilzomib in Patients With Relapsed/Refractory Multiple Myeloma9 Carfilzomib Mechanism of Action: Proteasome Inhibitor FDA-Approved Indication: Treatment of patients with multiple myeloma who have received at least 2 prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Reconstitution: Carfilzomib is supplied in a 60 mg vial containing lyophilized powder and should be stored at 4ºC. To reconstitute: Slowly inject 29 mL sterile water to inside wall, swirl gently and/or invert for ~1 minute. If foam is present in the vial, let rest for 2 to 5 minutes until foaming subsides. Solution should be clear and colorless prior to use; if not, don’t use the solution.

Pretreatment Assessment: 1. CBC, differential, and platelet counts. Evaluate bone marrow status and capacity to recover to establish guidelines for posttreatment monitoring of blood counts.

2. Assess patient for preexisting cardiopulmonary disease including echocardiogram for any patient with known history of cardiopulmonary disease. Avoid dosing prior to weekend to avoid need for emergent care.

3. Allopurinol should be considered for patients at increased risk for tumor lysis syndrome.

4. Antiviral therapy (shingles prophylaxis) is recommended.

Sample Orders/Dosage and Administration Premedication: Dexamethasone 4 mg po; normal saline 250 mL (use caution in patients with preexisting cardiopulmonary disease).

Cycle 1: Carfilzomib: 20 mg/m2 IVB over 2 to 10 minutes, days 1, 2, 8, 9, 15, and 16, every 28 days. May administer over 30 minutes if needed for any evidence of infusion intolerance.

Cycle 2 and beyond: If cycle 1 is well tolerated, 27 mg/m2 IV over 2 to 10 minutes, days 1, 2, 8, 9, 15, and 16, every 28 days. May administer over 30 minutes if needed for any evidence of infusion intolerance. Premedication with dexamethasone and normal saline based on tolerance of cycle 1.

Laboratory Monitoring: 1. CBC, differential, and platelet counts weekly prior to treatment in cycle 1 to assess bone marrow status and indications for supportive care. Repeat at start of each subsequent cycle or more frequently as clinically indicated.

2. Complete metabolic panel, LDH, PO4, calcium, uric acid at baseline and repeated on days 2, 3, 8, and 15 for patients at risk for tumor lysis in cycle 1. Repeat prior to each subsequent cycle or as clinically indicated.

Adverse Events Profile: All grades (grade ≥3) 1. Thrombocytopenia and neutropenia—thrombocytopenia (cyclic): 36.3% (23.4%); neutropenia: 20.7% (10.3%) 2. Peripheral neuropathy—overall: 14% (1% grade 3, no grade 4) 3. Fatigue—overall: 55.5% (7.6%) 4. Gastrointestinal—constipation: 20.9% (0.2%); diarrhea: 32.7% (1.0%); nausea: 44.9% (1.3%) 5. Cardiopulmonary—dyspnea: 34.6% (5.0%); hypertension: 14.3% (3.3%); peripheral edema: 24.0% (0.6%) 6. Infectious disease—varicella zoster: 2%; pneumonia: 12.7% (10.5%) 7. Renal dose modifications—renal dose adjustment recommended for creatinine ≥2 x baseline 8. Thromboembolic events—not reported 9. Rash—not reported 10. Contraindications—none Abbreviations: CBC, complete blood cell count; FDA, US Food and Drug Administration; IV, intravenous; IVB, intravenous bolus; LDH, lactate dehydrogenase; po, orally; PO4, phosphate.

Patients discontinued treatment most often because of progression of disease; only 11% of these patients discontinued because of TEAEs. A total of 6 patients died while participating in the study: 1 of myocardial infarction, 1 of pneumonia, 1 with both an infarction and pneumonia, and 3 because of progressive disease. The incidence of peripheral neuropathy (PN) was low (12% all grades, 2% grade ≥3).

Practical Management of the Patient Receiving Carfilzomib Carfilzomib is supplied in a 60 mg vial containing lyophilized powder and

should be stored at 4ºC. To reconstitute: slowly inject 29 mL of sterile water to the inside wall, swirl gently and/or invert for ~1 minute. If foam is present in the vial, let rest for 2 to 5 minutes until foaming subsides.

Solution should be clear and colorless before use; if not, don’t use the solution. The FDA-approved dosing for carfilzomib is based on the PX-171003-A1 pivotal, phase 2 noncomparative trial in which patients received 20 mg/m2 for the first 28-day cycle with dose escalation to 27 mg/m2 in the second and subsequent cycles if cycle 1 dosing was well tolerat-

ed. Once reconstituted, carfilzomib is administered intravenously over 2 to 10 minutes on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17-28). If signs of dose intolerance occur, extension of the infusion time up to 30 minutes can be considered (Table 2). The titrated dosing from cycle 1 (20 mg/m2) to cycle 2 (27 mg/m2 if cycle 1 was tolerated) is based on data obtained in the phase 1 trials in which initial dosing with 27 mg/m2 was associated with an infusion-like reaction (reversible Continued on page 34

May 2013 I VOL 6, NO 4

33

HEMATOLOGIC MALIGNANCIES

synthesis after drug administration, thus leading to the eventual clinical schedule of 2 consecutive days of dosing once weekly for 3 consecutive weeks using a 28-day cycle.9 Carfilzomib is distributed widely in tissues: metabolized extrahepatically, with 97% being bound to proteins, it is rapidly cleared from the circulation by biliary and renal excretion (t1/2 =15-30 minutes) with less than 1% excreted intact. Carfilzomib does not appear to be dependent on the cytochrome P450 enzyme pathway, and renal function had no effect on carfilzomib clearance in preclinical pharmacokinetic trials.10

HEMATOLOGIC MALIGNANCIES

Carfilzomib in the Treatment of Multiple Myeloma Continued from page 33 fevers, chills, and rigors, with a grade filzomib is not unlike most thera- iting toxicity for bortezomib when bortezomib administered subcutane1-2 increase in creatinine) in some pies for MM, with myelosuppression administered intravenously using the ously showed a significant reduction in patients in the presence of high tumor being most common. Importantly, original dosing schedule of 1.3 mg/m2 the incidence and severity of PN com1 5/9/13 3:03 Pagefor 1 carfilzomib is days 1, 4, 8, and 11, every 21 days. A pared with the original intravenous burden and dehydration.13 The admin-Project1_Layout the incidence ofPMPN istration of 250 mL of normal saline very low. PN is a potential dose-lim- subsequent noninferiority trial using dosing schedule.14 before each dose in cycle 1 is recommended as a result of these findings, with consideration of the individual patient profile and tolerance of these fluids. In addition, premedication with 4 mg of dexamethasone before administration of carfilzomib in cycle 1 of treatment is recommended as standard practice. It may also be prudent to include this premedication for the first dose escalation. The premedication may be omitted in patients who tolerate the initial cycles of 2:30 pm - 3:15 pm General Session 7: Oncology Medical Home PRELIMINARY AGENDA* therapy without difficulty. Blood 3:15 pm - 3:45 pm BREAK IN THE EXHIBIT HALL chemistries should be monitored 3:50 pm - 4:35 pm General Session 8: Meeting the Needs of FRIDAY, NOVEMBER 15 the Adult and Child Survivor Throughout closely in cycle 1 for those patients 12:00 pm - 12:30 pm Welcome the Life Span at increased risk of dehydration or • Conference Co-Chairs: • Christy Roberts, RN, BSN, OCN tumor lysis. Kortuem and Stewart Sharon Gentry, RN, MSN, AOCN, CBCN 4:35 pm - 5:20 pm General Session 9: The Role of Complementary Lillie D. Shockney, RN, BS, MAS suggest obtaining serum chemTherapies in Navigation 12:30 pm 2:00 pm PRE-CONFERENCE WORKSHOPS • Linda Lee, MD, AGAF istries on days 1, 2, 3, 8, and Basic Navigation Track 5:30 pm 7:30 pm Poster Award Reception 15 in cycle 1 and on days 1, 8, • Tricia Strusowski, MS, RN 8 and 15 thereafter. Additionally, • Nicole Messier, RN, BSN SUNDAY, NOVEMBER 17 OR the authors suggest oral hydra6:30 am - 7:30 am Breakfast/Product Theater Advanced Navigation Track tion is likely adequate for most (non–CME-certified activity) • Elaine Sein, RN, BSN, OCN, CBCN patients beyond cycle 1 of thera7:45 am 8:00 am Welcome and Introductions • Danelle Johnston, RN, MSN, OCN, CBCN • Conference Co-Chairs: py. Allopurinol prophylaxis is also 2:00 pm - 2:45 pm BREAK IN THE EXHIBIT HALL Sharon Gentry, RN, MSN, AOCN, CBCN 2:45 pm 3:30 pm General Session 1: Top 10 Best Practices recommended for any patient at Lillie D. Shockney, RN, BS, MAS • Moderators – Conference Co-Chairs: risk for tumor lysis (bulky dis8:30 am - 8:45 am General Session 10: Navigator’s Role Sharon Gentry, RN, MSN, AOCN, CBCN ease, rapidly progressive disease, in Tumor Boards Lillie D. Shockney, RN, BS, MAS • Laurie Mathis, RN, BS, MAS or aggressive histology). A small 3:30 pm - 5:00 pm Administrator’s Track 8:45 am 10:30 am DISEASE SITE–SPECIFIC BREAKOUTS number of patients in these trials • Mandi Pratt-Chapman, MA • Breast Cancer Navigation & Survivorship • Michele O’Brien, MSN, ACNS-BC, RN, BA reported dyspnea within 48 hours • Karen Dow Meneses, PhD, RN, FAAN OR of drug administration, echoing • Vinnie Myers Case Manager’s Track the careful assessment of preex• Thoracic Oncology Navigation 5:00 pm - 6:00 pm FREE TIME • Gean Brown, RN, OCN isting cardiopulmonary disease or 6:00 pm - 8:00 pm Welcome Reception/Posters in the Exhibit Hall • GI & Colorectal Cancer Navigation other predisposition to intrave• Darcy Doege, RN, BSN SATURDAY, NOVEMBER 16 nous hydration. It is important to • Kristen Vogel, MS, CGC 6:30 am - 7:30 am Breakfast/Product Theater remember that patients with New • GYN Cancers Navigation (non–CME-certified activity) • Penny Daugherty, BSN, RN, OCN York Heart Association Class III 7:45 am - 8:00 am Welcome and Introductions • Prostate Cancer Navigation and IV heart failure were not • Conference Co-Chairs: • Head, Neck, & Neuro Navigation Sharon Gentry, RN, MSN, AOCN, CBCN eligible for the clinical trials, and • Tamara Bowen, RN, BSN, MHA Lillie D. Shockney, RN, BS, MAS thus safety in this population has • Pediatric Oncology 8:00 am - 8:30 am General Session 2: The Future of AONN • Kathy Ruble, RN, CPNP, PhD not been evaluated. Given the (The AONN Business Meeting) • Hematology/Oncology Navigation increased incidence of herpes zos• Sharon Gentry, RN, MSN, AOCN, CBCN • Melanoma Navigation ter and hepatitis reactivation in • Lillie D. Shockney, RN, BS, MAS • Sherry Riggins, RN, BSN, OCN 8:30 am - 9:15 am General Session 3: Community Needs trials using bortezomib, pretreat10:30 am - 11:15 am BREAK IN THE EXHIBIT HALL and Navigation 11:15 am - 12:00 pm General Session 11: Understanding the Role ment evaluation and prevention • Lillie D. Shockney, RN, BS, MAS, on behalf of of the Primary Care Physician of shingles are recommended. the Global Breast Health Initiative • Michael Kolodziej, MD Ongoing clinical trials are evalu• Jennifer Klemp, PhD, MPH, MS 12:15 pm - 1:15 pm Lunch/Product Theater 9:15 am - 10:00 am General Session 4: Development and Application ating the dose escalation sched(non–CME-certified activity) of Evidence-Based Guidelines in Cancer Care: ule, maximum tolerated dose, pre1:30 pm - 2:15 pm General Session 12: Navigator’s Role The NCCN Perspective in End-of-Life Care medication requirements, and the • Liz Danielson, MHA • Lillie D. Shockney, RN, BS, MAS need for additional hydration in 10:00 am - 10:45 am BREAK IN THE EXHIBIT HALL 2:15 pm - 3:00 pm General Session 13: Music & Medicine: 10:45 am - 11:30 am Keynote: Update on Guidelines patients who are not considered at A Dynamic Partnership • Linda Ferris, PhD risk for tumor lysis.

• Deforia Lane, PhD, MT-BC 11:45 am - 12:45 pm Lunch/Product Theater 3:00 pm - 3:15 pm Conclusion of the Conference/Final Remarks As is the case in all therapies for (non–CME-certified activity) • Conference Co-Chairs: cancer treatment, efficacy is only 1:00 pm - 1:45 pm General Session 5: Onco-Politic Barriers Sharon Gentry, RN, MSN, AOCN, CBCN one side of the story. An estab• Dan O’Connor Lillie D. Shockney, RN, BS, MAS 1:45 pm - 2:30 pm General Session 6: Addressing Disparities of Care lished safety profile, including the • Swann Arp Adams, PhD, MS *Preliminary agenda, subject to change. absence of severe or potential• Michelle Weaver Knowles, RNC, BSN ly irreversible TEAEs that may exclude future treatment options, is key. The TEAE profile of car-

Fourth Annual Navigation and

November 15-17, 2013 • The Peabo

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May 2013 I VOL 6, NO 4

www.TheOncologyNurse.com

the arsenal for treatment of MM. The reduced incidence in PN is an attractive property of this agent. Ongoing clinical trials will provide the data necessary to refine the role of carfilzomib in combination with other agents or in patients with an earlier stage of dis-

ease. Familiarity with the administration protocol based on the mechanism of action, awareness of the recommendations for premedication and prehydration, and assessment of patient risk for tumor lysis or cardiopulmonary toxicity are recommended. l

Survivorship Conference

ody Memphis • Memphis, Tennessee CONFERENCE CO-CHAIRS Program Director: Lillie D. Shockney, RN, BS, MAS University Distinguished Service Associate Professor of Breast Cancer Depts of Surgery and Oncology Adm Director, Johns Hopkins Breast Center Adm Director, Johns Hopkins Cancer Survivorship Programs Associate Professor, JHU School of Medicine Depts of Surgery, Oncology & Gynecology and Obstetrics Associate Professor, JHU School of Nursing Baltimore, MD

FACULTY* Swann Arp Adams, PhD, MS Tamara Bowen, RN, BSN, MHA Gean Brown, RN, OCN

Penny Daugherty, BSN, RN, OCN Darcy Doege, RN, BSN Karen Dow Meneses, PhD, RN, FAAN Linda Ferris, PhD Sharon Gentry, RN, MSN, AOCN, CBCN

Jennifer Klemp, PhD, MPH, MS Michael Kolodziej, MD Deforia Lane, PhD, MT-BC Linda Lee, MD, AGAF

CONFERENCE OVERVIEW

AONN’s Fourth 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.

TARGET AUDIENCE

This activity was developed for oncology nurse navigators, patient navigators, social workers, and case managers.

CONTINUING EDUCATION INFORMATION

Learning Objectives Upon completion of this activity, the participant will be able to: • 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.

Nicole Messier, RN, BSN Vinnie Myers Michele O’Brien, MSN, ACNS-BC, RN, BA

Liz Danielson, MHA

Danelle Johnston, RN, MSN, OCN, CBCN

Sharon Gentry, RN, MSN, AOCN, CBCN Breast Nurse Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

Laurie Mathis, RN, CBCN, OCN

Dan O’Connor Mandi Pratt-Chapman, MA Sherry Riggens, RN, BSN, OCN Christy Roberts, RN, BSN, OCN Kathy Ruble, RN, CPNP, PhD Elaine Sein, RN, BSN, OCN, CBCN Lillie D. Shockney, RN, BS, MAS Tricia Strusowski, MS, RN Kristen Vogel, MS, CGC Michelle Weaver Knowles, RNC, BSN *For full information visit www.aonnonline.org

1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.

2. Kumar SK, Rakjumar SV, Dispenzieri A, et al.

Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.

3. Kumar SK, Dispenzieri A, Gertz MA, et al.

Continued improvement in survival in multiple myeloma and the impact of novel agents.

Blood. 2012;120:Abstract 3972. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. 4. US Food and Drug Administration. Kyprolis (carfilzomib) for injection: US prescribing information. http://www.accessdata.fda.gov/drugsat fda_docs/label/2012/202714lbl.pdf. Accessed March 25, 2013.

5. US National Institutes of Health. ClinicalTrials. gov. http://clinicaltrials.gov/. Accessed April 11, 2013.

6. Demo SD, Kirk CJ, Aujay MA, et al.

Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391.

7. Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011;17:2734-2743.

8. Kortuem KM, Stewart K. Carfilzomib. Blood.

2013;121(6):893-897.

9. Kyprolis (carfilzomib) for Injection [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc; July 2012.

10. McCormack PL. Carfilzomib: in relapsed, or relapsed and refractory, multiple myeloma. Drugs.

2012;72(15):2023-2032.

11. Siegel DS, Wang M, Martin TG, et al. A phase 2 study of prolonged carfilzomib therapy in patients with multiple myeloma previously enrolled in carfilzomib clinical trials.

Blood. 2012;120:Abstract 2962. Presented at: 54th American Society of Hematology Annual Meeting; December 8-11, 2012; Atlanta, GA. 12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):28172825.

13. Alsina M, Trudel S, Furman RR, et al. A phase 1 single agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012;18(17):4830-4840.

14. Moreau P, Pylypenko H, Grosicki S, et al.

Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440.

COE_vertical_fish_62212_Layout 1 7/9/12 12:47 PM Pa

SPONSORS

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

COMMERCIAL SUPPORT ACKNOWLEDGMENT

Grant requests are currently being reviewed by numerous supporters.

Support will be acknowledged prior to the start of the educational activities.

REGISTERED NURSE DESIGNATION

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 16.25 contact hours.

FREE Continuing Education

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References

HEMATOLOGIC MALIGNANCIES

Summary As an important treatment strategy for MM, proteasome inhibitors exploit the vulnerability in the pathobiology of the disease. Carfilzomib, the most recently approved proteasome inhibitor, offers an important addition to

REGISTER TODAY AT www.COEXM.com May 2013 I VOL 6, NO 4

35

HEMATOLOGIC MALIGNANCIES The US Food and Drug Administration (FDA) approved bosutinib (Bosulif; Pfizer, Inc) for the treatment of chronic, accelerated, or blast phase Philadelphia chromosome–positive chronic myeloid leukemia in adult patients with resistance or intolerance to previous therapy. This approval was granted on September 4, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm318203.htm.

Bosutinib for the Treatment of Chronic Myeloid Leukemia: A Nursing Perspective Ann Q. Shen, BSc, BScN

Katharine F. Lord, PA-C, MMSc

Emory University Atlanta, Georgia

C

hronic myeloid leukemia (CML) is a clonal proliferative disorder of the hematopoietic cells of myeloid lineage1-3 driven by a reciprocal translocation between chromosomes 9 and 22, resulting in the so-called Philadelphia (Ph) chromosome. This translocation consists of a head-to-tail fusion of the breakpoint cluster region (BCR) on chromosome 22 and the Abelson gene (ABL) on chromosome 9 that results in the formation of the BCR-ABL hybrid oncogene,1,3 and is the hallmark of this disease. BCR-ABL is the major driver of leukemogenesis in CML, largely through a deregulated activity in ABL’s intrinsic tyrosine kinase activity.3 CML is a relatively rare disease (accounting for only 15% of adult leukemias4) that affects mainly older patients (median age at diagnosis, 65 years4). Most patients with CML are asymptomatic, receive their diagnosis after a routine complete blood cell count (CBC), and present clinically in the initial and indolent form of this triphasic disease, the chronic phase (CP). Untreated or with ineffective treatment, CP-CML progresses within 3 to 5 years to the symptomatic and aggressive phases of the disease,

Texas Oncology Austin, Texas

ie, the accelerated phase (AP) and the rapidly fatal blast phase (BP).3 Better understanding of the pathophysiology of this disease has led to the development and the first successful clinical application of targeted therapy in cancer. Five tyrosine kinase inhibitors (TKIs) are now commercially available, and these agents have dramatically improved the outcomes of

Physical evaluation revealed splenomegaly, which led to a CBC that showed hyperleukocytosis with a white blood cell count of 92,000/µL. A bone marrow aspirate and biopsy showed a hypercellular marrow (100%) with no increase in blasts, and cytogenetic analyses confirmed the presence of the Ph+ in 20 metaphases. The diagnosis of CP-CML was therefore

Bosutinib has activity in all phases of CML that is resistant or intolerant to imatinib and/or dasatinib or nilotinib.

patients with CML.5 This article focuses on the SRC-ABL inhibitor bosutinib (Bosulif), and reviews practical aspects for the management of patients treated with this drug.

Clinical Presentation A 23-year-old patient presented with a 4-week history of abdominal pain, bloating, early satiety, anorexia, night sweats, and dramatic weight loss.

confirmed and the patient started imatinib (Gleevec) at the dose of 800 mg daily. Treatment with imatinib was complicated by diarrhea, pleural effusions requiring thoracentesis, myalgias, arthralgias, facial rash, and pancytopenia requiring a temporary hold of imatinib. With recurrence of these adverse events despite dose reduction to 400 mg daily the patient was deemed imatinib intolerant and

Table 1 Treatment Response With Second- or Third-Line Bosutinib in Patients With CP-CML Second-Line Treatment

Response

IM resistant (n = 200)

IM intolerant (n = 88)

Third-Line Treatment IM + DAS resistant (n = 38)

IM + DAS intolerant (n = 50)

IM + NIL resistant (n = 27)

Cytogenetic Response (%) MCyR

54

49

33

48

39

CCyR

41

41

19

43

27

80

76

Hematologic Response (%) CHR

86

85

62

Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; CP-CML, chronic phase chronic myeloid leukemia; DAS, dasatinib; IM, imatinib; MCyR, major cytogenetic response; NIL, nilotinib.

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May 2013 I VOL 6, NO 4

was offered enrollment in a trial, the Phase 1/2 Study of SKI-606 [or bosutinib] in Philadelphia Chromosome Positive Leukemias (ClinicalTrials. gov identifier: NCT00261846). The patient started bosutinib at 500 mg daily on March 12, 2008.

Treatment with bosutinib was associated with early onset of gastrointestinal adverse events (nausea, vomiting, and diarrhea) and transient facial rash, both of which resolved without dose interruptions or reduction. The patient promptly achieved a complete hematologic remission (CHR) and a major cytogenetic remission (MCyR) that became complete (CCyR) at 6 months. BCR-ABL mRNA levels were no longer detected by quantitative real-time polymerase chain reaction (qPCR), and therefore the patient also achieved a complete molecular remission (CMR). More than 4 years later, the patient is still receiving bosutinib and remains in CHR, CCyR, and CMR. Treatment of CML Previously, allogeneic hematopoietic stem cell transplantation was considered the only “curative” option for CML, and was offered up front to young and otherwise healthy patients who had a suitable donor.2,3 However, given the high responses with firstline TKI treatment, the sustainability of these responses, the excellent tolerability of these oral agents, and the availability of effective second-line TKIs, transplants are no longer recommended as a first-line option. Three TKIs are approved for first-line treatment for patients with CML: imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna). Both dasatinib and nilotinib were previously approved as second-line agents,6,7 and more recently ponatinib (Iclusig) was approved for the treatment of adults with CML and Ph+ acute lymphoblastic leukemia.8 However, and despite spectacular responses, a subgroup of patients are intolerant or develop resistance to these agents, often due to the development of ABL kinase domain mutations.

On September 4, 2012, the US Food and Drug Administration (FDA) approved bosutinib tablets for the treatment of CP, AP, or BP Ph+ CML

www.TheOncologyNurse.com

Response Monitoring Response to treatment in CML is initially determined by the resolution of splenomegaly, normalization of both the CBC and marrow cellularity (CHR), and subsequently by quantitative assessments of blood or marrow samples for the presence of BCR-ABL mRNA. Cytogenetic response is determined by the number of marrow Ph+ metaphases: minor response when the Ph+ is detected in 36% to 65% of the metaphases, major when the number of Ph+ metaphases decreases to <35%, and the absence of Ph+ metaphases defines CCyR.1 Molecular methods that can also be reliably performed on blood samples include fluorescence in situ hybridization (FISH) and the very sensitive qPCR.13 Major molecular response (MMR) is defined as a â&#x2030;Ľ3-log reduction (International Scale) of the BCR-ABL mRNA and CMR by the absence of detectable BCR-ABL mRNA.1 Efficacy of Bosutinib in CML Bosutinib has activity in all phases of CML that is resistant or intolerant to imatinib and/or dasatinib or nilotinib.

Overall, 86% of imatinib-resistant and 85% of imatinib-intolerant CP patients achieved CHR14; 55% of AP and 28% of BP patients achieved an overall hematologic response defined as either CHR, a return to a second CP, or no evidence of leukemia.15 Additionally, 41% of imatinib-resistant CP, 41% of imatinib-intolerant CP, 33% of AP, and 29% of BP patients achieved CCyR.14,15 The overall survival at 2 years for imatinib-resistant and -intolerant CP patients was 88% and 98% with a progression-free survival of 72% and 89%, respectively.14 Bosutinib was also effective when administered as a third-line agent to 119 patients with CP-CML resistant or intolerant to imatinib, dasatinib, or nilotinib16; of

www.TheOncologyNurse.com

these patients, 62% to 80% achieved bosutinib.18 The primary end point CHR and 33% to 48% achieved was to determine the proportion of MCyR that was complete in 19% to patients who achieved CCyR at 12 43%.17 Table 1 summarizes the activ- months in both arms of the trial. ity of bosutinib in previously treated Results of this trial showed compapatients with CP-CML. Data from rable rates of CCyR in both arms, this trial led to the FDA approval of achieved in 68% and 70% of imatibosutinib for the treatment of resis- nib- and bosutinib-treated patients, tant CP-CML. respectively. However, the MMR rate A phase 3 trial, Bosutinib Efficacy at 12 months was higher with bosuand Safety in Newly Diagnosed tinib than imatinib (41% vs 27%), Chronic Myeloid Leukemia, was4:34 PM andPage median time to achieve CCyR Bendamustine Asize_030413_TON0210 3/13/13 2 conducted comparing imatinib with and MMR was significantly faster for

bosutinib-treated patients compared with imatinib-treated patients (12.9 weeks vs 24.6 weeks and 37.1 weeks vs 72.3 weeks, respectively).18 Adverse Events and Management Common adverse events associated with the use of bosutinib are summarized in Table 2. Overall, bosutinib is well tolerated, and adverse events are often transient, manageable, and rarely result in drug discontinuation.

Continued on page 38

Th

eO seri Vie nc es w olo on the gy line Nu a rse t .co m

Faculty Perspectives

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Faculty Perspectives

Part 1 of a 4-Part Serie s

DECEMBER

2012 â&#x20AC;˘ VOL UME 4 â&#x20AC;˘ NUM BER 1

â&#x201E;˘

A Retrospectiv

e Review of th of Bendamus e Characterization tine

CONTRIBUT

ING FACULTY

Julie M. Vos e, MD, MBA

University of Nebraska Medical Cen ter

Colleen Ros s, RN, MSN, MHA, OC

Susanne Liew er, PharmD, BCO

N University of Nebraska Medical Cen ter

PMP M O

ERSONALIZED EDICINE IN ONCOLOGY

P University of Nebraska Medical Cen ter

Supported

through fund ing by

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37

HEMATOLOGIC MALIGNANCIES

in adult patients with resistance or intolerance to previous TKI therapy.9 Formally known as SKI-606, bosutinib is an effective TKI that competitively inhibits both the BCR-ABL and SRC kinases.10,11 Furthermore, bosutinib demonstrates greater inhibition as well as increased selectivity for the tyrosine kinase domains, thus resulting in minimal inhibitory activity against c-KIT or platelet-derived growth factor.

Bosutinib is bioavailable orally in 100 mg or 500 mg tablets. The recommended dose is 500 mg once daily with food for optimal absorption.12 Bosutinib is metabolized by the cytochrome P3A4 enzyme and cleared by the liver; therefore, dose reductions are required for preexisting hepatic impairment.

HEMATOLOGIC MALIGNANCIES

Bosutinib for the Treatment of Chronic Myeloid Leukemia... Continued from page 37 The most common nonhematologic adverse events are gastrointestinal, and include diarrhea (84%), nausea (44%), and vomiting (35%).14 The mechanisms that lead to diarrhea are unknown; however, the pattern is very predictable: early onset (median of 2 days) after initiation of bosutinib in the majority of cases is grade 1 to 2 (75%) and lasts a median of 2

days. Antidiarrheals (ie, loperamide or diphenoxylate atropine) are very effective. If bosutinib needs to be temporarily held, resumption of the drug is usually not associated with diarrhea recurrence. Diarrhea is rarely grade 3 to 4 (9%), is very infrequently chronic, and led to bosutinib discontinuation in only 1% of patients in clinical trials.

Myelosuppression is the main hematologic adverse effect associated with bosutinib, with anemia occurring in 90%, thrombocytopenia in 66%, and neutropenia in 40% of patients.14 Median onset of myelosuppression is 22 days, and median duration is 14 days. Hematologic adverse effects are generally managed with transfusions as indicated and standard supportive

Table 2 Common Adverse Events and Symptoms Associated With Bosutinib and Suggested Management Options Adverse Event Gastrointestinal Diarrhea, nausea, vomiting Diagnostic test History: early onset (median of 2 days) after starting the drug, and short duration (median of 2 days); if late onset and recent antibiotic usage, consider obtaining Clostridium difficile toxin. Obtain orthostatic blood pressure and weight to evaluate for dehydration Suggested management Diarrhea: loperamide or diphenoxylate atropine, fluid replacement if needed; if severe diarrhea (≥7 stools/d), hold BOS until recovery; resuming at same dose is successful in 95% of cases; otherwise, decrease dose to 400 mg/d Nausea/vomiting: antiemetics including ondansetron, prochlorperazine, and promethazine; if possible, avoid antacids, H2 blockers, or proton pump inhibitors to avoid reduction in BOS exposure Hematologic Anemia, thrombocytopenia, leucopenia, or pancytopenia Diagnostic test History: usually occurs in the first month (median onset is 22 days); anemia symptoms include shortness of breath, fatigue, chest pain, roaring in the ears, and orthostatic dizziness; thrombocytopenia symptoms include bleeding, bruising Physical examination: petechiae, low-grade fever Laboratory: CBC Suggested management Transfusions as per institutional standards; if ANC <1000/mm3 and/or platelets <50,000/mm3: hold drug until ANC ≥1000/mm3 and platelets ≥50,000/mm3; resume at same dose if recovery occurs within 2 weeks; if counts remain low for >2 weeks, reduce dose by 100 mg and resume treatment upon count recovery; consider starting prophylactic antibiotics if ANC <500/mm3 Hepatic Elevation of ALT and/or AST Diagnostic test Laboratory: abnormal liver enzymes; tends to occur in the first month (median onset is 29 days) in the course of therapy, lasts 4 weeks in general; monitor and evaluate liver transaminases in the first months of therapy Suggested management If elevated ALT/AST ≥5 x ULN, hold drug until recovery to ≤2.5 x ULN and resume at 400 400 mg/d; if recovery takes ≥4 weeks, consider discontinuing BOS Dermatologic Rash Diagnostic test Physical examination: can happen at any time during therapy; visual inspection to assess extent; assess concomitant medications for the addition of other drugs that can lead to rashes Suggested management Supportive care (diphenhydramine); no dose interruption needed if mild and asymptomatic; otherwise, hold the drug, resume at same dose after resolution of the rash; rechallenge often successful with no recurrence of the rash Abbreviations: ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; BOS, bosutinib; CBC, complete blood cell count; ULN, upper limit of normal.

Gambacorti-Passerini C, Brummendorf TH, Cortes JE, et al. Evolution of bosutinib toxicity in patients with Philadelphia chromosome-positive leukemia after resistance/intolerance to prior therapy. Abstract to be presented at: 2013 ASCO Annual Meeting; May 31-June 4, 2013; Chicago, IL.

38

May 2013 I VOL 6, NO 4

care measures. Hematopoietic growth factors are rarely used in CP patients; however, dose interruptions, reductions, or discontinuations are at times required in the management of severe myelosuppression. The mechanisms that lead to myelosuppression are multifactorial and include direct marrow drug toxicity and possibly effective suppression of a predominantly Ph+ driven hematopoiesis.19 Elevation of liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) occurs in 59% and 49% of patients, respectively.14 Median time to onset of liver enzymes elevation is 31 days, and median duration is 20 days. These abnormalities usually resolve with dose reduction or transient drug interruption, and rarely recur with reintroduction of the drug. No cases of liver failure were reported, and abnormal liver function tests led to drug discontinuation in 2% of patients in clinical trials. Overall, adverse events that led to discontinuation of bosutinib in clinical trials included thrombocytopenia, neutropenia, and elevated ALT. Predictors of Resistance to Bosutinib Baseline factors predicting resistance to bosutinib include the presence of ABL-domain mutations that include the detection of V299L and T315I.20 Responses to bosutinib are observed regardless of the presence of ABL domain mutations. Indeed, impressive response rates are observed, with 75% achieving CHR and 43% achieving MCyR among patients with CP-CML and ≥1 baseline mutation. Furthermore, resistance to previous TKI therapies is also associated with lower response rates to bosutinib. At the time of progression while receiving bosutinib therapy, new emergent mutations were reported in 24% of patients with CP-CML, with V299L and T315I mutations detected in 11% and 5%, respectively.20 Development of resistance is suspected in the setting of progressive rise in BCR-ABL as measured by qPCR, loss of cytogenetic response, or loss of hematologic response.1,21 Monitoring response by qPCR can be challenging because benign minor fluctuations often occur.22 Unless there is a steady rise in qPCR mRNA levels (which is a prelude for a loss of cytogenetic response) and progression is observed, treatment rarely needs to be altered.

Conclusions Although 3 very effective and overall well-tolerated TKIs are available for the upfront treatment of CML, failure

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17. Khoury HJ, Gambacorti-Passerini C, Kantarjian HM, et al. Bosutinib as therapy for chronic phase chronic myeloid leukemia following failure with imatinib plus dasatinib and/or nilotinib: 24-month minimum follow-up update. Presented at: 54th American Society of Hematology Annual Meeting and Exposition; December 8-11, 2012; Atlanta, GA. Abstract 3785.

18. Cortes JE, Kim DW, Kantarjian HM, et al.

Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30(28):3486-3492.

19. Lima LM, Sampat K, Assouline S, et al. Does pretreatment fluorescence in situ hybridization for BCR-ABL predict imatinib-associated hematologic toxicity in chronic myeloid leukemia? Leuk Lymphoma.

2011;52(6):1010-1016.

20. Gambacorti-Passerini C, Khoury HJ, Pinczowski H, et al. Clinical activity of bosutinib by mutational status in patients with previously treated Philadelphia chromosome-positive leukemias. Blood.

2010;116:Abstract 3434.

21. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041-6051.

22. Kantarjian HM, Shan J, Jones D, et al.

Significance of increasing levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic response. J Clin Oncol. 2009; 27(22):3659-3663.

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Acknowledgments The authors thank Dr H. Jean Khoury for providing guidance, suggestions, and review of this paper.

References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Chronic Myelogenous Leukemia. Version 4.2013. http://www.nccn.org/professionals/physician_gls/ pdf/cml.pdf. Accessed March 13, 2013.

2. Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet. Chronic myeloid leukaemia. Lancet.

2007;370(9584):342-350.

3. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340(17):1330-1340.

4. American Cancer Society. Leukemia—Chronic Myeloid (Myelogenous). http://www.cancer.org/acs/ groups/cid/documents/webcontent/003112-pdf.pdf.

Accessed March 13, 2013.

5. Björkholm M, Ohm L, Eloranta S, et al. Success story of targeted therapy in chronic myeloid leukemia: a population-based study of patients diagnosed in Sweden from 1973 to 2008. J Clin Oncol. 2011;29(18):2514-2520.

6. US Food and Drug Administration. Nilotinib (Tasigna). http://www.fda.gov/AboutFDA/Centers Offices/OfficeofMedicalProductsandTobacco/CDER/ ucm216218.htm. Accessed March 19, 2013.

7. US Food and Drug Administration. Dasatinib. http://www.fda.gov/AboutFDA/CentersOffices/ OfficeofMedicalProductsandTobacco/CDER/ ucm129236.htm. Accessed March 19, 2013.

8. US Food and Drug Administration. Ponatinib. http://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm332368.htm. Accessed March 23, 2013.

9. US Food and Drug Administration. Bosutinib tablets. http://www.fda.gov/Drugs/InformationOnDrugs/ ApprovedDrugs/ucm318203.htm. Accessed March 17, 2013.

10. Hsyu PH, Mould DR, Upton RN, et al.

Pharmacokinetic-pharmacodynamic relationship of bosutinib in patients with chronic phase chronic myeloid leukemia. Cancer Chemother Pharmacol. 2013; 71(1):209-218.

11. Konig H, Holyoake TL, Bhatia R. Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606. Blood. 2008;111(4):2329-2338.

12. Pfizer Labs. Dosing guide for Bosulif (bosutinib). http://www.pfizerpro.com/resources/minisites/bosulif/ docs/Dosing_Guide.pdf. Accessed March 19, 2013.

13. Lima L, Bernal-Mizrachi L, Saxe D, et al.

Peripheral blood monitoring of chronic myeloid leukemia during treatment with imatinib, second-line agents, and beyond. Cancer. 2011;117(6):1245-1252.

14. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118(17):4567-4576.

15. Gambacorti-Passerini C, Cortes JE, Khoury HJ, et al. Safety and efficacy of bosutinib in patients with AP and BP CML and ph+ ALL following resistance/intolerance to imatinib and other TKIs: update from study SKI-200. Presented at: 2010 ASCO Annual Meeting; June 4-8, 2010; Chicago, IL. Abstract 6509.

16. Khoury HJ, Cortes JE, Kantarjian HM, et al.

Bosutinib is active in chronic phase myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119(15):3403-3412.

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too. When I first I worried about this, I felt a complete arrived back in my city, turmoil and comdisconnect from the being a cancer motion associated with treatment center. patient at a major cancer cancer patient that I did not want to be go back to my life to wanted I anymore. my career, energy precancer—progress in to and from their children my to shuttle to actually activities, enough resources freedom to eat the and money, save some Though many at my favorite restaurants. page 7

in a city far from spent 8 long months intense chemomy own, undergoing autologous stem therapy and then an after a longercell transplant. Eventually, in the hosstay than-I-would-have-liked weeks living close pital and another few of emergency, I was to the hospital in case of medicines bagful a with home sent back ith what and instructions on how/when/w them. to take around the issue Much discussion exists to adhere to their of how to get patients home. I must admit treatment regimen at

I

Continued on

ELING GENETIC COUNS Cole, RN, OCN; Carol Lynn Gansauer, RN, MSN, nurses at the Gibbs MSN, OCN; Lucy Sharon Bartelt, RN, CBN (left to right), oncology Beeker, RN, BSN, OCN, BSN, OCN; Kristen Carolina.

Cancer Center in South

g (South Carolina) part of the Spartanbur Cancer Institute he Gibbs Cancer Center, System, is 1 of 21 National Recognizing in Regional Healthcare cancer centers.

(NCI)-designated community receive their care in the commucancer patients care in the community 2007 that 85% of all s for elevating cancer nity, NCI set benchmark Center and other NCI-designated commuCancer on reducing healthcare setting. The Gibbs have to meet standards cancer screening and centers cancer for nity community outreach quality disparities, enhancing high-quality biospecimens, improving of technology, surfollow-up, collection and expanding information are of cancer care, research,care. Approximately 1700 cancer patients of many vivorship, and palliative the Gibbs Cancer Center each year, at diagnosed and treated levels of literacy. or uninsured, with low Continued on page 9 them underinsured

T

n Cancer: Inherited Colo e, Juvenile Polyposis Peutz-Jeghers Syndrom Syndrome Syndrome, and Cowden

By Cristi Radford, MS,

CGC

is the olorectal cancer (CRC) non– of third most common type men and skin cancer in both cancers, the women. As with other are familial, 15% majority are sporadic, hereditary. Thus, in and 5% to 10% are familial clustering 25% of CRC cases a assessment risk further is present, and testing are indicatand possibly genetic ed forms of ed. The 2 most well-describ

C

adenomatous inherited CRC are familial syndrome, Lynch polyposis (FAP) and nonpolyposis also known as hereditary d by 100s syndrome. FAP is characterize whereas polyps, to 1000s of colonic a more diverse Lynch syndrome has with at least phenotype and is associated have been Both 10 extracolonic cancers. articles. discussed in previous on page 12 Continued

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the experimental biology, of the tion about and he 2012 Annual Meeting prevention, diagnosis, Antonio etiology, cancer and preCTRC-AACR San therapy of breast breast disease. Following Breast Cancer Symposium wealth of news malignantof the highlights from the (SABCS) offered a the world. are some to attendees from around conference.

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HEMATOLOGIC MALIGNANCIES

of first-line therapy remains a challenge. The selection of the second- or third-line agent is affected by several factors, predominantly the detection of specific ABL-kinase domain mutations, physician’s preference, dose schedule, timing of drug administration (food restrictions), baseline comorbidities that may increase the risk of drug-specific adverse effects, and risks for cross-intolerance. Given the significant and sustained activity in settings of second-line treatment and beyond, bosutinib is an effective addition to the armamentarium for the treatment of CML, that with the exception of V299L and T315I, has shown activity across all ABL domain mutations. l

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