TON November 2013

NOVEMBER 2013

www.TheOncologyNurse.com

VOL 6, NO 10

THE WHOLE PATIENT

CANCER CENTER PROFILE

Moffitt Cancer Center Providing Care for Patients With Multiple Myeloma

Camp Bluebird: A Survivorship Program for Life Leslie Verner, RN, BSN, OCN, CCRP, CBCN Cancer Outreach Coordinator, Mission Hospital SECU Cancer Center, Asheville, North Carolina

C

amp Bluebird—is it a special place or a special program or is it just that special feeling you have after you’ve been there? Can you explain Camp Bluebird to others, or do you just have to experience it firsthand? Is it like the camps that we remember as children, rustic and full of splinters, or is it butterflies and fireflies? It is all of these things and more.

Camp Bluebird is a safe place where you can share your hopes, fears, and experiences with others who understand what you are going through, because they have actually walked in your shoes. It is a community of understanding, filled with people with whom you have an immediate bond. At Camp Bluebird, you feel Continued on page 18

GENETIC COUNSELING

Members of the multiple myeloma team at the Moffitt Cancer Center (left to right): Christine Simonelli, RN, BSN, OCN; Kenneth Shain, MD, PhD; Beth Finley, RN, OCN; Rachid Baz, MD; and Sheri Lemanski, RN, BSN, OCN.

T

he Moffitt Cancer Center in Tampa, Florida, is 1 of 41 cancer centers in the United States to receive the National Cancer Institute’s designation as a comprehensive cancer center, and it is the only such center based in the state of Florida. As a center of excellence, Moffitt takes care of patients’ needs starting with diagnosis through cancer treatment on to survivorship. Moffitt is also an active research center, covering basic science, prevention, and clinical research with the goal of translating discoveries into improved patient care. Moffitt is committed to Total Cancer Care—a personalized course of treatment that provides individualized therapies based on a patient’s unique genetic fingerprint.

The Oncology Nurse-APN/PA spoke with Elizabeth (Beth) Finley, RN, OCN, about her role at the Moffitt Cancer Center, where she works exclusively with patients with multiple myeloma.

Inherited Susceptibility to Lung Cancer: What Do We Know?

Cristi Radford, MS, CGC Ambry Genetics

I

n 2013 it is estimated that there will be 228,190 new cases and 159,480 deaths due to lung cancer in the United States,1 making it the leading cause of cancer-related death. In fact, it causes more deaths than colon, breast, and prostate cancer combined.2 Two main lung cancer histologic subtypes exist: small cell and non-small cell, with each having different clinicopathologic characteris-

NOTEWORTHY NUMBERS . . . . . . . . .

Breast Cancer

Lung Cancer in the News

N

ovember is National Lung Cancer Awareness Month. It started in 1995 as Lung Cancer Awareness Day and expanded as the lung cancer community grew and awareness of the disease increased. In this issue, we

2

BREAST CANCER

Alice Goodman

explore some of the lung cancer–related highlights from the European Cancer Congress (ESMO/ECCO/ESTRO), held September 27-October 1, 2013, in Amsterdam, the Netherlands.

Continued on page 12

INSIDE

Continued on page 17

NEWS BRIEFS

tics. The most common type is non-small cell (7 of every 8 people),3 which includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Most often lung cancer occurs when people breathe in dangerous, toxic substances. It is believed that smoking causes lung cancer by damaging the cells lining the lungs; as such, cigarette smoking is the

Greater Attention to Cardiovascular Risk Needed for Breast Cancer Survivors. . . . . . . . . . . . . . . . . . . . . . . . . . 11 Paroxetine Does Not Reduce Tamoxifen’s Effectiveness in Breast Cancer Survivors. . . . . . . . . .

Continued on page 6 ©2013 Green Hill Healthcare Communications, LLC

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SIDE EFFECTS MANAGEMENT

Raising Awareness of Cancer Anorexia-Cachexia Syndrome in Patients With Lung Cancer. . . . . . . .

16

Update on Managing Dyspnea . . . . . . . . . . . . . . . . . . . . . . . . . .

17

LUNG CANCER . . . . . . . . . . . . . . . . . . .

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Paclitaxel in Lung Cancer

NOTEWORTHY NUMBERS

Breast Cancer Throughout the year, many organizations promote breast cancer awareness. Healthcare professionals, public service groups, and government agencies work diligently to provide education and information about the prevention, screening, diagnosis, and treatment of breast cancer. Here are a few statistics to illustrate these efforts.

The American Institute for Cancer Research estimates that 38% of all breast cancer cases in the United

States could be prevented with simple changes to everyday diet and exercise.1

Oncology On Canvas

If followed, these 5 recommendations from the Centers for Disease Control and Prevention can help

SM

“Together they are stronger, brighter and no longer alone

in the journey of survivorship.”

From Creating Connections of Hope and Light by a Healthcare Professional and 2012 entrant

Announcing the 2014 Lilly Oncology On Canvas Art Competition

Call for Entries | Deadline: June 30, 2014 “Some see paint. Others see hope. What do you see?”

In 2004, more than 400 people across 23 countries saw those words and shared their cancer journeys with the world through art and narrative. Today, 10 years later, with more than 4,100 stories shared, many are still waiting to be told by the nearly 14 million cancer survivors today in the U.S.1 — in addition to millions of others who love and care for them.

The 2014 competition marks a year-long commemoration of the 10-year anniversary. Oncology On CanvasSM is a program that was started in 2004 by Lilly Oncology to help address a great, unmet need in cancer care—a need that goes beyond medicine—to help those affected by cancer cope with the emotional toll of the disease.

This biennial competition, presented by Lilly Oncology and the National Coalition for Cancer Survivorship (NCCS), invites people from the United States and Puerto Rico diagnosed with any type of cancer—as well as their families, friends, caregivers, and healthcare providers—to express, through art and narrative, the life-affirming changes that give their cancer journeys meaning.

1. American Cancer Society. Cancer Facts & Figures 2013. American Cancer Society Web site. http://www.cancer.org/Research/CancerFactsStatistics/ CancerFactsFigures2013/index. Accessed July 23, 2013.

ON87677 10/2013 PRINTED IN USA ©2013, LILLY USA, LLC. ALL RIGHTS RESERVED.

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NOVEMBER 2013 I VOL 6, NO 10

Winners’ prizes consist of donations made in their name to the cancer-related charities of their choice.

For further information about Lilly Oncology On Canvas, 2012 winners, an exhibit schedule and details on the competition— in addition to information on 10-year anniversary activities— please visit www.LillyOncologyOnCanvas.com, call 1-866-991-LOOC (5662), or e-mail artdirector@mylooc.com.

Follow us on Find us on Tune in to our Pin our

at twitter.com/LlyOncOnCanvas. at Facebook.com/LillyOncologyOnCanvas. channel at youtube.com/LlyOncOnCanvas.

boards at pinterest.com/LlyOncOnCanvas.

To learn more about cancer survivorship tools and resources, visit the NCCS website at www.canceradvocacy.org.

lower the risk of breast cancer2: • Get screened for breast cancer regularly • Control your weight and increase your physical activity • Know your family history of breast cancer • Find out the risks and benefits of hormone replacement therapy • Limit the amount of alcohol you drink In recent years, mammography screening has generated some controversy, but mammograms have been shown to lower the risk of dying of breast cancer by 35% in women over the age of 50.3 For non-Hispanic white, African American, and Hispanic women in the United States, breast cancer incidence rates differ geographically. Incidence ranges from 110.8 cases per 100,000 women in Arkansas to 140.4 cases per 100,000 in California and the District of Columbia for non-Hispanic white women. Rates for African American women range from 73.2 in New Mexico to 131.0 in Delaware; and for Hispanic women, incidence ranges from 34.1 in Mississippi to 133.3 in Delaware.4 Sources 1. www.aicr.org/learn-more-about-cancer/breast-cancer/? gclid=CISakI6YzLkCFWxyQgodd08AaA#facts.

2. www.cdc.gov/cancer/breast/basic_info/prevention.htm.

3. www.breastcancer.org.

4. www.cancer.org/acs/groups/content/@epidemiologysur veilance/documents/document/acspc-030975.pdf.

www.TheOncologyNurse.com

EDITORIAL BOARD EDITOR-IN-CHIEF

Beth Faiman,

Shannon Hazen, RN, BSN, OCN

PhD(c), MSN, APRNBC, AOCN

Novant Health Presbyterian Cancer Center Charlotte, NC

Catherine Bishop,

Patricia Irouer Hughes, RN, MSN,

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

DNP, NP, AOCNP

Melinda Oberleitner, RN,

Karla Wilson,

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

City of Hope National Medical Center Duarte, CA

Jayshree Shah, NP

Pharmacy John F. Aforismo,

DNS, APRN, CNS

John Theurer Cancer Center Hackensack University Medical Center Hackensack, NJ

Johns Hopkins Kimmel Cancer Center/Sibley Infusion Washington, DC

BSN, OCN

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

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 Biodesix, Inc. Dallas, TX

Piedmont Healthcare Rex, GA

NP, MSN, ACNP-C

MSN, NP, ANP-BC, AOCNP

Sandra E. Kurtin,

Lori Stover, RN,

Arizona Cancer Center Tucson, AZ

Western Pennsylvania Cancer Institute Pittsburgh, PA

Ann McNeill,

Joseph D. Tariman,

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

BSN

PhD, APRN, BC

Northwestern University Myeloma Program Chicago, IL

Jacqueline Marie Toia, RN, MS, DNP

Northwestern University Myeloma Program Chicago, IL

Pamela Hallquist Viale, RN, MS,

CS, ANP, AOCN Saratoga, CA

RN, MSN, FNP-C, CPON

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

Nutrition Karen Connelly, RD, CSO

Somerset Medical Center Somerville, NJ

Patient Advocacy Peg Ford

Ovarian Cancer Alliance San Diego, CA

Social Work Carolyn Messner, DSW, MSW, LCSW-R, BCD CancerCare New York, NY

Genetic Counseling Cristi Radford, MS, CGC

Ambry Genetics Sarasota, FL

Managed Care and Pharmaceutical Management Burt Zweigenhaft, BS

OncoMed Onco360 Great Neck, NY

Sharon S. Gentry, RN, MSN, AOCN

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

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

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

Cassandra J. Hammond, RN,

Dolores “Jeff” Nordquist, RN, MS,

Avid Education Partners, LLC Sharpsburg, MD

Mayo Clinic Rochester, MN

MSN, CRNP

www.TheOncologyNurse.com

CS, FNP

Connie Visovsky,

PhD, RN, ACNP-BC University of South Florida College of Nursing Tampa, FL

Rita Wickham,

PhD, RN, AOCN

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

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

NOVEMBER 2013 I VOL 6, NO 10

3

FROM THE EDITOR 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 Production Manager Stephanie Laudien

A

ccording to the National Cancer Institute, the number of cancer survivors in the United States increased to 11.7 million in 2007—this compares to 3 million cancer survivors in 1971 and 9.8 million in 2001. These statistics show that survivorship is becoming more a part of oncology care, and indicate that oncology nurses Beth Faiman, PhD(c), are playing an increasing role in MSN, APRN-BC, AOCN providing long-term comprehenEditor-in-Chief sive care for cancer survivors.

This care not only encompasses the physical health of survivors, but also their emotional and psychosocial health.

Leslie Verner, an oncology nurse at Mission Hospital in Asheville, North Carolina, tells us about an amazing retreat for adult cancer survivors called Camp Bluebird.

Leslie states that “Being the director of Camp Bluebird has truly been the most challenging and also the most rewarding part of my career as an oncology nurse.” The

President/CEO Brian Tyburski

story of Camp Bluebird illustrates how oncology nurses are meeting the wide-ranging needs of cancer survivors.

Thank you, Leslie, for sharing this inspiring story.

This month’s reader poll asks if you talk to your patients about programs available for survivors. Please go to our website, www.TheOncologyNurse.com, to participate in the poll and tell us about your experiences with survivorship programs.

November is National Lung Cancer Awareness Month.

In this issue of The Oncology Nurse-APN/PA (TON), we spotlight the lung cancer–related news that came out of the recent European Cancer Congress. In addition, Cristi Radford discusses what is known about the inherited susceptibility to lung cancer in her Genetic Counseling column. As Cristi points out, knowledge about inherited susceptibility “is in its infancy.” Tara L. Plues provides a case-study example of using paclitaxel to treat a patient with non-small cell lung cancer.

Please let us know what you think of this issue of TON. Tell us what topics you want to see covered. We appreciate your feedback—positive and negative—about what you see in print and on the website. Email us at editorial@ greenhillhc.com. l

READER POLL

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore

Do you talk to patients about programs for survivors?

Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

o Yes

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 Trevean Digital Programmer Michael Amundsen Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 fax: 732-656-7938

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NOVEMBER 2013 I VOL 6, NO 10

o No

©iStockphoto.com/Slobodan Vasic

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eslie Verner tells us about Camp Bluebird, a retreat program for adult cancer survivors in western North Carolina. Are there similar programs in your

community? Or supports groups specifically geared for survivors? Let us know if you talk to your patients about programs for survivors and how you decide to do so.

Go to www.TheOncologyNurse.com to answer the question and add your comments.

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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Th

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

2ND ANNUAL

ONQUERING THE C CANCER CARE CONTINUUM

™

A 6-part series 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:

NEXT ISSUE

• Palliation • Pain management • Hospice care • Treatment planning • Survivorship care • Biosimilars in supportive care

FIRST ISSUE IN THE 2013 SERIES

CONQUERING THE CANCER CARE CONTINUUM CONQUERING THE A C N C E R I C O N T C ARE IN SECOND ANNUAL

SECON

D ISSUE ™ IN THE 2013 SE RIES SE C O N D ANN UAL

Changing the Image of Palliative Care Lillie D. Shockney, RN, BS, MAS

vention and relief of suffering by means of early identiam enthusiastic about this 6-part series titled Confication and impeccable assessment and treatment of quering the Cancer Care Continuum. Each edition of pain and other problems, physical, psychosocial, and CCCC will address an important topic in oncology SERIES 13 spiritual.” (http://www.who.int/cancer/ management and offer expert stake20 E TH INTopics UE ISS palliative/en/).

D holder commentaries. will IR TH For too long, however, the image of include: palliative care, pain manageNU AL AN ND O ™ palliative care has been tied exclusively SE Ccare, comprehensive ment, hospice to end-of-life care and focused solely on treatment planning, survivorship care, pain control. and the role of biosimilars in supportLillie D. Sho ckney, RN , BS, MA The articles that follow provide a ive care. In this issue, we address palS n part 2 of clear understanding of the intent of liative care. our Conqu series, the ering the Ca palliative care today, with the primary Palliation in cancer care is a topic focus is on ncer Care ma Continuum pai goal ending its identification that commonly makes people (medical well tic improvements n managem ent.ofDe inabilitysolely as surgical in pharm spite drato overco ace cal care procedure for wh theile dying. providers as well as patients) uncom- we still hav me it effe die agents, provided s designed asuticancer ctivel in gre ea as p con monly res Instead, palliative be pon asso- at pain. Family y, fearing they wil fortable. I recently had the opportunity cessful on beh long way to go to be to hel tro ™ l pain, care should l memb d tha sucD.alf Shockney, of our pat RN, nesscare I wasLillie theirforlov ien ciated with quality-of-life alled t their greatest fea ers, too, comto speak with members of our palliative recentBS, ts.

MAS ly wa r is one in gre tch ute at pain wit having to witcare team at Johns Hopkins and learned ern s of an old, black- ing a few min- cancer patients and survivors, no mat- ease hout a wa and-white the suf movie. A west-clinical outcome. cowboy ter what their that the word “palliative” comes from the fear these fering. Family me y to byword a gun“palliare,” will be the mb slinger, and had been shot ers final image tor att patients may not tell you about the sidewitness before which means to disguise or cloak. Centuries ago, this word as theYour em towncancer s they pted to rem their docove m hisAlthough effects treatment they are experiencing or about their Many organiza loved one dies. was used for the drapes that covered afro casket. theofbul che let tions have oped me the woun st, another discomfort cow asu develdue we continue to drape coffins—most memorably withma the ded tice guidel rement tools an e to their cancer diagnosis or its treatment. n a bottle boy gav to drink d pracof ine and wh s isk In many cases they may simply assume that the discomfor flag—the drape is no longer referred to by this term. a ey knife helping his teeth. providers the purpose of e between I’m sure bac to bit effective age pain with the disease.” However, with the imThe World Health Organizationwamodified k infort s how peoits origly manassociate the “comes day this ple coped provements in medicine and the power of science,itsit treatment. Th d with cancer an inal definition of palliative care as quo follows: “Palliative r to nu mb them with pain – lid e fol pro harthe d toquality to anymore. not wait for your patients vide you with a lowing articles care is an approach that improves life and doesn’t somethhave bite onof. Th toDocall him ing ng ma wealth of aski is is far fro back BS, MAS Today him teinitiate he symptoms; be proac-tion associated inform I wroto rised a discussion about their . all problems asckney, RN, of patients and their families facing the ide surp Sho sank pat t al.

D. an wit how ien hear d guideline Lillie h these too hospitalMy ts wh and said that o ent enviro est thatat the time you are planafter tive s. ls er Th requ soon and initiate this discussion sociatedyou withthe life-threatening through the pret edition ofillness, nm tha a ey did even nex ent to t though also pro He an inp , ond me. wheth atient aterall and tion he to bring to s. This be of the info sure that tful care be taken mote Lillirma or resp meitto e D. Sho a clinic visrateitd all for un wastor t is my privilege cer Care Continuum serie ons, their doc all to ckney, I reite it with journey , by pho Can opti RN, cancer pat of us address wit enaskne. pain me ed to com talk are about the long BS,ther weasu Conquering the ses specifically on hospice HopeMAS me Hill Healthcare Communications, told e ����� �Green ple te a had endLLC focu ured toge experien ients the pain the h our of wheth rement toolhad nt to read. thaand issue, which cing and t prohis y are er they are vitally importa age 30. vidwife he at be s es to im to nosi som eve ple rel pre gre diag beli e be ieve it. Pa ment wa ial expressio e. Patien sentlye in is one I i iys n clinph in steals essed here will sinc herpaiinit her ts have of n, addr tim s on and e, cept ripti wh of tro aw psycholo s at to circle ay social ubl his descto what defully, con it ysical enduran e,dho onwe Base and better way alertness,tua (a hap ver ce and can gical well-bein , intlimi pain was erpted n and e or adopted as newterminally ill cancer I lly absent for g, and reting make qu bad in the py faccal con a ditio gravely ill. y sad facshe som ali an cause the morning ver e) ifwas supporting our r families. ent that theirthe doctord adequate treatme patients. Accur ty of life viry took a evidno was but t ght thei so ate pai me doc and thou bad en n I an ass nt tor pill before t for effect ing essment now be- f that he need to that . Fur patients himcom years ago gett He be priori ive pain himsel ing the cancer viewed by thermore, is thitold ties for all ma I recall several Bill. swinf his so distressetod seeling anyone dur field. as orm of us wo nagea man named on act to theer after I feel and someti ing their d itatidiffi rking in rnet and e-mail from ly re- g this next confident mes visit? Somecultualrega foun via the Inte rdin you will fin provok Certainly it is not. timnes it is, atio had found me ing that his young d these art t he is ing and contai one of the brief convers whawil stat that cer icle me nin And to l gre pat s ass cancan y. te g tho st ate ients is the val Mar wro aist you in st fearsfor exp metastatic brea reassessin uable information ught fear of pai step webut ressed is not a drug oncan ll(He as dev herby g your cur ing wife, Mary, had gressed to her liver, that nnow andplac suffer ren pro ed- hospice. future pat eloping more effe ing and call cer that had ctive ways t patients as n. She was ei ients hav the special program before eie quality and now brai Lilliesleeping rd this term fectively lungs, bone, of life by to help your had not hea n to explain some ofmanaged. Q hospital and D. Shockney, RN having pai bega I , BS, MAS currently in the awake, confused at n ef©ther , he .)3As 201 Greenefits was hospice care RN, of Hil ey, still l ckn He more than she ben “had althcar Co lie, my the key Lillie D. Sho weight, but mmunicati l t and said, e“Lil untifou MAS times, losing chemotherapy he got very upse 8 years old. I ons, LLC rth issue of BS, g doctor been receivin Conquering ot die. We have 2 sons, 6 and him that she wrote that the Colast the Cancer alone.” I then told wife cann yesterday.” He for the ntinuumt hser s thiad n care of her would work with dresse raise them Care staff and Iua mee imies not and nin e can s sit who had take Tr g com ice T to eatment hosp tio ir mTh hrougs.hHethe said omeand asked him Planlosing then.

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NEWS BRIEFS: LUNG CANCER Continued from cover

Second-Generation ALK Inhibitor Regresses CNS Metastases in NSCLC A novel ALK/EGFR (anaplastic lymphoma kinase/epidermal growth factor receptor) inhibitor—AP26113 (ARIAD Pharmaceuticals, Inc.)— achieved good responses in crizotinib-resistant and crizotinib-naive patients with non-small cell lung cancer (NSCLC) as well as radiographic regression of central nervous system (CNS) metastases in these patients.

The results of the first-in-human phase 1/2 dose-finding study of AP26113 were presented by D. Ross Camidge, MD, University of Colorado, Denver.

Half of all ALK-positive patients with NSCLC who develop crizotinib resistance become resistant in the brain, suggesting that crizotinib has inadequate CNS expo-

sure. Systemic progression typically occurs later in the course of disease.

Phase 1 was a 3x3 dose escalation study in 30 to 60 patients with various advanced malignancies. In phase 2, there were 5 cohorts—4 with NSCLC (n = 85 total) and 1 with other cancers amenable to ALK inhibition (n = 20).

The identified dose of 180 mg/day was used in phase 2 initially, but some patients developed pulmonary symptoms at that level, which resolved with steroids over 1 week. The decision was made to use a step-up approach of 90 mg/day for the first week on drug, and then move to 180 mg/day, Camidge said.

Other adverse events included gastro-

intestinal disturbances, and these were mainly mild. Elevated liver enzymes were reported in 12% of patients.

Treatment-emergent grade 3 or higher adverse events were reported in 2% to 4% of patients across all dose levels.

Objective response rate was 65%.

Response rate in patients previously treated with crizotinib was 61%; all 3 crizotinib-naive patients responded (100%), 1 with a complete response.

Eight of 10 patients with CNS metastasis had radiographic evidence of regression, and this improvement lasted from 8 to 40 weeks.

Responses were seen in some patients with the T790M mutation who were treated with the drug. Among 12 treat-

ed patients with the T790M mutation, 5 had stable disease, 4 had progressive disease, and 3 discontinued the study before receiving treatment.

These data are preliminary. More experience is needed to determine if the drug will be an improvement on crizotinib. At least 2 other second-generation ALK inhibitors are in development, and these drugs also appear to achieve radiographic regression in CNS metastases. l

The trial took place in 8 countries at 73 clinical sites and enrolled 532 patients (42 stage IIIA and 490 stage IIIB/IV) with no disease progression after up to 6 cycles of frontline therapy. Four to 17 weeks after chemotherapy, patients were randomized in a 1:1 ratio to receive double-blind therapy with either the vaccine or placebo as maintenance therapy.

Vaccine treatment consisted of 18 monthly injections followed by 2 quar-

terly injections. The primary end point of the trial was overall survival (OS).

Median OS in this group of patients is usually about 10.4 months. The investigators were hoping to achieve 14 months of survival with the vaccine.

At 6 months of follow-up, OS was 20.3 months in the vaccine arm versus 17.8 months in the placebo arm, which was much higher than anticipated for placebo. An exploratory subgroup analysis showed that patients enrolled within 12 weeks of chemotherapy had a trend toward improved survival in the vaccine arm.

Stage IIIB/IV patients had significantly improved survival in the placebo arm if they received radiation, Giaccone said.

“In this study, progression-free survival did not correlate with overall survival,” he said.

The rate of serious adverse events was low, with only 5 patients experiencing 1 of these events. The most common adverse events were immune related and included injection site reaction, erythema, induration, rash, and local effects.

Prospective studies are planned in stage IIIB/IV patients, he said.

“This is a negative study. The expected difference in survival favoring the vaccine is 3.5 months, but the actual difference between the vaccine and placebo is only 2.5 months,” said formal discussant Rolf A. Stahel, MD, University Hospital Zurich, Switzerland.

“This is another example where a promising phase 2 trial does not have phase 3 confirmation,” he added. l

Reference

Camidge DR, Bazhenova L, Salgia R, et al. Updated results of a first-in-human dose-finding study of the ALK/ EGFR inhibitor AP26113 in patients with advanced malignancies. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3401.

Disappointing Results of Vaccine Maintenance therapy with a therapeutic tumor cell vaccine (belagenpumatucel-L [Lucanix], NovaRx Corporation) failed to improve survival compared with placebo in a phase 3 study of patients with stage IIIA/B and IV non-small cell lung cancer (NSCLC).

The vaccine is composed of 4 different, allogeneic NSCLC cell lines genetically modified to block transforming growth factor beta (TGF-b). The cells are irradi-

ated and cryopreserved until the vaccine is used.

“Most tumors use TGF-b to evade the immune system. Activated T and B cells are refractory to TGF-b inhibition,” explained lead author Giuseppe Giaccone, MD, associate director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC (formerly of the National Cancer Institute).

QOL Improved With Crizotinib Versus Chemotherapy In the ongoing phase 3 PROFILE 1007 study of patients with previously treated anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer, crizotinib improved quality of life (QOL) and key lung cancer symptoms compared with chemotherapy (investigator’s choice: pemetrexed or docetaxel). Crizotinib was associated with a significantly higher improvement rate in global QOL compared with chemotherapy in all domains, said Vera Hirsh, MD, McGill University, Montreal, Canada.

“These improvements in QOL are particularly important for this palliative group of patients. Our findings support the improvement in PFS [progression-free survival] seen in the trial with crizotinib,” she said.

The QOL study randomized 172 patients to receive crizotinib and 171 to standard-of-care chemotherapy with either pemetrexed or docetaxel. Patient-reported outcomes were assessed at baseline, on day 1 of each cycle, and at the end of treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and lung cancer module QLQ-LC13. Scores on these instruments ranged from 0 to 100, with higher scores reflecting higher symptom severity or better functioning/QOL, depending on the instrument and question.

A 10-point or greater change from baseline was deemed clinically meaningful for either improvement or worsening.

As of March 30, 2012, 162 patients in the crizotinib arm and 151 in the chemotherapy arm completed at

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least 1 question at baseline, and this population was analyzed for QOL. Baseline scores were well balanced between the 2 arms and were relatively low. Crizotinib achieved significantly greater improvement in global QOL versus chemotherapy (42.6% vs 20.7%, respectively; P <.001). Crizotinib also significantly improved physical functioning (27.2% vs 11.9%; P <.001), role functioning (30.9% vs 14.6%; P <.001), and emotional functioning (37.0% vs 24.0%; P <.05).

Lung cancer symptoms were significantly improved in the crizotinib arm versus chemotherapy (P <.001 for all comparisons): fatigue (46.3% vs 20.5%, respectively), pain (43.8% vs 20.5%), cough (55.3% vs 33.3%), dyspnea (39.1% vs 17.3%), chest pain (40.0% vs 22.3%), and pain in arm or shoulder (33.5% vs 19.5%).

Domains significantly worsened on crizotinib (P <.001 for both comparisons) were constipation (44.4% vs 22.5%) and diarrhea (41.4% vs 19.2%).

“Deterioration was slowed in a significantly greater proportion of patients in the crizotinib arm versus chemotherapy,” Hirsh reported.

The study was supported by Pfizer Inc. l Reference

Blackhall F, Hirsh V, Kim DW, et al. Impact of crizotinib on patient-reported symptoms and global quality of life (QoL) compared with chemotherapy in a phase III study of advanced alk-positive non-small cell lung cancer (NSCLC).

Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3400.

Reference

Giaccone G, Bazhenova L, Nemunaitis J, et al. A phase III study of belagenpumatucel-L therapeutic tumor cell vaccine for non-small cell lung cancer (NSCLC).

Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. LateBreaking Abstract 2.

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NEWS BRIEFS: LUNG CANCER MPDL3280A in Advanced NSCLC

www.TheOncologyNurse.com

based on very small numbers of patients, ORR was 46% in patients with PD-L1 IHC 2 and IHC 3, and 86% in those with IHC 3.

Responses were sustained over time in all patients except one, Soria said.

Smoking status was a predictor of response; former/current smokers had an ORR of 26% (n = 43) compared with 10% in never-smokers (n = 10).

Reference

and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Abstract 3408.

Continued on page 20

Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety

S:7.25”

NOW RECRUITING

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”

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

For the first time, a therapy for nonsmall cell lung cancer (NSCLC) has achieved more responses in smokers than nonsmokers. The antibody MPDL3280A also achieved good responses in the squamous and adenoma histologic types of NSCLC. These phase 1 study results in patients with metastatic NSCLC were so encouraging that experts suggested bypassing phase 2 and going directly to phase 3 studies.

Genentech’s development program for the monoclonal antibody includes ongoing recruitment for phase 2 and 3 trials in NSCLC. “We are at the beginning of a new era. After 30 years of research in immunotherapy for lung cancer, we have one that works, and it works in smokers,” said lead author Jean-Charles Soria, MD, Institut Gustave Roussy, Paris, France, at the European Cancer Congress. “In this study, smokers responded much better than nonsmokers. This is great news for lung cancer patients—the majority are current or former smokers. The data are preliminary, but the trends are extremely promising,” Soria added.

The study results were based on 85 patients (53 evaluable for efficacy) who received treatment with an intravenous infusion of MPDL3280A every 3 weeks for a median duration of 106 days (range, 1-450 days).

Median duration of therapy was 48 weeks.

Of the 85 patients with NSCLC, 55% were heavily pretreated with 3 or more previous therapies and the majority were smokers or ex-smokers (81%); 19% never smoked.

MPDL3280A was considered safe.

Most adverse events were mild. No dose-limiting toxicities were identified in this trial, nor was any grade 3 to 5 pneumonitis or diarrhea reported. Grade 3 and 4 adverse events were reported in 34%, but these were not necessarily treatment related, as some were cancer related (ie, dyspnea, fatigue).

Objective response rate (ORR) was 24% in the overall population and 23% in patients with NSCLC; 17% of responders were stable over 24 weeks.

The 24-week progression-free survival rate was 44% in squamous cell NSCLC and 46% in nonsquamous cell NSCLC. PD-L1 expression (the target of MPDL3280A) was directly correlated with response, with the best response seen in those with the highest expression of PD-L1 on immunohistochemistry (IHC 3). Those with IHC 3 also had less progressive disease. Although

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.

AOCO3X0071_Recruitment782_AdAsize_r3.indd 1

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NEWS BRIEFS

Breast Cancer in the News Alice Goodman

Predictors of Survival Benefit From Endocrine Therapy Two related studies identified potential predictors of survival benefit from endocrine therapy in women with breast cancer. Both studies were published in a recent issue of the Journal of Clinical Oncology.

The first study found that the presence of vasomotor symptoms (eg, hot flashes) and other specific adverse events (AEs) associated with endocrine therapy, especially during the first year of treatment, predicted improved disease-free survival (DFS) and overall survival (OS).1 The second study showed that women on treatment with endocrine therapy who had a reduction of more than 20% in mammographic density from baseline to the first follow-up mammogram had a 50% reduced risk of breast cancer–specific death.2 In an accompanying editorial, the authors point out that a woman may be more willing to tolerate the considerable AEs of endocrine therapy if this means she will gain a survival advantage.3

Adverse Events, Vasomotor Symptoms A retrospective analysis of the international, randomized, phase 3 TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial looked at the association between survival outcomes and specific AEs.1 The study included 9325 women with postmenopausal estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive breast cancer eligible for endocrine therapy. Participants were randomized to exemestane 25 mg once daily for 5 years or tamoxifen 20 mg once daily for 2.5 to 3 years, followed sequentially by exemestane 25 mg once daily for 2.5 to 3 years.

The specific AEs associated with endocrine therapy and which deplete or block circulating estrogens included vasomotor symptoms (hot flashes and night sweats), musculoskeletal events, and vulvovaginal symptoms (dryness/itching, discharge, painful sexual intercourse, and lack of libido).

Both DFS and OS were improved in patients with specific AEs versus those with nonspecific or no AEs. The incidences of distant metastases, relapse, and death were all reduced in patients with specific AEs. Outcomes were not related to treatment assignment.

The findings from this analysis may provide a potential biomarker of treatment efficacy.

The findings from this analysis may provide a potential biomarker of treatment efficacy. The authors stated that prospective studies are warranted “to advance the personalization of treatment strategies for patients with breast cancer.”

Similar Survival in Early BRCA1-Positive and -Negative Breast Cancer According to a study recently published in the Journal of Clinical Oncology, patients with early-onset BRCA1positive breast cancer have a survival rate similar to that of patients with early-onset BRCA1-negative breast cancer. Among BRCA1 mutation carriers, positive nodal status was a significant predictor of poorer survival, while oophorectomy strongly predicted improved survival.

The study enrolled 3345 women aged 50 years or younger with stage I-III invasive breast cancer diagnosed between 1996 and 2006. Only patients with a first primary cancer were included.

Of the 3345 enrollees, 233 (7%) carried a BRCA1 mutation. Mutation carriers were diagnosed at an earlier age than noncarriers (42 years vs 44 years, respectively; P <.001) and were significantly less likely to be estrogen receptor (ER)-positive, progesterone receptor (PR)positive, and HER2-positive (P <.001 for all 3 comparisons) but significantly more likely to have triple-negative disease (69% vs 13%, respectively; P <.001) and more likely to have undergone oophorectomy (50% vs 14%, respectively), with most having the procedure following their diagnosis of breast cancer.

At a mean follow-up of 7.4 years, the 10-year survival rate was 80.9% for mutation carriers and 82.2% for noncarriers. Among the 485 women with triple-negative breast cancer, overall survival was not inferior among carriers versus noncarriers.

Among BRCA1 mutation carriers, lymph node status was highly predictive of survival, with positive nodal status associated with significantly lower 10-year

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survival (P <.001). Overall, as well as in carriers, survival was similar in women with tumors 0.1 to 1.0 cm and 1.1 to 2 cm. The 10-year survival rate among carriers with small (<2 cm) breast tumors was 89.9% for node-negative patients and 68.6% for node-positive patients. Among carriers with breast tumors ≤1 cm, 27.5% were node positive, and their 10-year survival rate was 81.1%.

Of the 233 BRCA1-positive patients, 101 (43.3%) were deemed high risk (node positive or tumors >5 cm), and their survival was 68.2% at 10 years.

Oophorectomy had a positive effect on prognosis among carriers, and to a smaller extent, in noncarriers.

“Oophorectomy in BRCA1 carriers is beneficial for reducing death after breast cancer. The reduction in death is largely for those occurring as a result of breast cancer, but a number of avoidable deaths will be from secondary primary ovarian cancers,” wrote the authors.

“If these observations are replicated in other populations, oophorectomy should be considered a standard of care for women with breast cancer and a BRCA1 mutation,” they said.

Chemotherapy improved survival among carriers compared with no chemotherapy, even though the tumors of those treated with chemotherapy tended to be larger, node positive, and ER negative. l Reference

Huzarski T, Byrski T, Gronwald J, et al. Ten-year survival in patients with BRCA1negative and BRCA1-positive breast cancer. J Clin Oncol. 2013;31(26):31913196.

Reduction in Mammographic Density According to results of a retrospective population-based case-control study in Sweden, patients taking tamoxifen who experienced a reduction in breast density of more than 20% from their baseline mammogram to their first follow-up mammogram had improved survival versus women with stable mammographic density on tamoxifen treatment.2 Study participants were 974 postmenopausal patients with breast cancer with both a baseline and follow-up mammogram. Of these women, 474 received tamoxifen and 500 did not. The authors measured mammographic density as a percentage change from baseline.

After a 15-year follow-up, 121 patients (12.4%) had died of breast cancer. Among women who had received tamoxifen, 35% of the breast cancer–associated deaths occurred in women who had had a reduction in mammographic density of 20% or more, compared with a 48% reduction in women who did not die from breast cancer. Women treated with tamoxifen who had a 20% or more reduction in mammographic density had a 50% reduced risk of death compared with women who had stable mammographic density from baseline mammogram to first follow-up mammogram. Although the relationship between density change on mammogram and survival was not statistically significant, it trended toward improved survival for those with reduced breast density.

The authors suggested that change in breast density from baseline to first follow-up mammogram in patients treated with tamoxifen could be a biomarker for response. If change in mammographic density on treatment is validated as an early marker for response to endocrine therapy, it could be a cost-effective tool for routine clinical use, the authors said. l References

1. Fontein DB, Seynaeve C, Hadji P, et al. Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis. J Clin Oncol. 2013;31(18):22572264.

2. Li J, Humphreys K, Eriksson L, et al. Mammographic density reduction is a prognostic marker of response to adjuvant tamoxifen therapy in postmenopausal patients with breast cancer. J Clin Oncol. 2013;31(18):22492256.

3. Henry NL, Stearns V. Treatment-emergent effects may predict benefit from endocrine therapy. J Clin Oncol. 2013;31(18):2233-2235.

Continued on page 10

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

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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%) 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 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. 2633500 5/13

NEWS BRIEFS: BREAST CANCER Continued from page 8

1 in 5 Women Do Not Believe Their Breast Cancer Risk Assessment A recent study reported that nearly 20% of women who participated in a risk-assessment study did not believe the breast cancer risk they were assigned. Most of the women who distrusted their numbers stated that they felt that the risk-assess-

ment tool did not fully incorporate their family history of cancer or their personal health habits.

If women don’t believe their actual risk of developing breast cancer, then they cannot make informed medical decisions, 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. Consider bone mineral density monitoring in patients treated with ARIMIDEX. 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.

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stated senior author of the study Angela Fagerlin, PhD. This goes both ways—if they believe their risk is not high when it is, they might not seek chemoprevention strategies that could significantly reduce their risk; if, on the other hand, they have

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 These adverse reactions are reported voluntarily from a population of uncertain size. Therefore, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. The following have been reported in post-approval use of Arimidex: • Hepatobiliary events including increases in alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma-GT, and bilirubin; hepatitis; • Rash including cases of mucocutaneous disorders such as erythema multiforme and StevensJohnson syndrome; • Cases of allergic reactions including angioedema, urticaria and anaphylaxis; • Myalgia, trigger finger and hypercalcemia (with or without an increase in parathyroid hormone).

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.

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been assigned a low risk and they believe their risk assessment should be higher, they may seek out medically inappropriate treatments that can cause long-term problems, she explained.

The findings, which are part of a larger study that provides information about medications that can reduce risk of breast cancer, were published in Patient Education and Counseling.

The study included 690 women at above-average risk of developing breast cancer. They completed a web-based decision aid that included questions about age, ethnicity, personal history of breast cancer, and the number of first-degree relatives with breast cancer. Based on their answers, they were assigned a 5-year risk of developing breast cancer and were given information on prevention strategies. They then were asked to recall their 5-year risk of developing breast cancer, and those who gave an incorrect answer were asked why they forgot or disagreed with the number.

If women don’t believe their actual risk of developing breast cancer, then they cannot make informed medical decisions.

Among participants, 22% who incorrectly reported their risk said that they disagreed with the numbers. The most common reason for disagreement was that their family history made them either more or less likely to develop breast cancer. Other participants believed that having no family history of breast cancer should place them in the low-risk category. One-third of women said their “gut instinct” told them that their risk numbers were either too high or too low.

Lead author of the study, Laura D. Scherer, PhD, said that fear could account for some of this distrust. Many women assumed certain factors would affect their risk, but these factors did not place them at increased risk.

Both Scherer and Fagerlin found the study results of concern, since they suggest that a proportion of women who are given a risk assessment for developing cancer will not seek the most appropriate medical care. l Reference

Scherer LD, Ubel PA, McClure J, et al. Belief in numbers: when and why women disbelieve tailored breast cancer risk specifics. Patient Educ Couns.

2013;92(2):253-259.

www.TheOncologyNurse.com

NEWS BRIEFS: BREAST CANCER DCIS Overdiagnosed and Overtreated in the United States The increased use of screening leads to detection of more cancers that are potentially clinically insignificant, including ductal carcinoma in situ (DCIS) and Barrett esophagus, according to a recent report published in the Journal of the American Medical Association.

The detection and removal of these specific precancerous lesions have not led to a lower incidence of invasive cancer, stated the authors.

The authors noted that the word cancer carries associations of “an inexorably lethal process,” but lesions like DCIS and Barrett esophagus often represent indolent diseases that will not cause harm during a patient’s lifetime if left untreated. Naming them cancers can lead to unnecessary anxiety, incorrect expectations of risk, and unnecessary treatment.

In March 2012, the National Cancer Institute (NCI) convened a meeting to evaluate the overdiagnosis of tumors that would not cause harm if left untreated. Overdiagnosis, the panel noted, necessarily often leads to overtreatment if not recognized. Overdiagnosis of indolent cancer is common and is a consequence of screening programs, they state.

A working group was formed to develop a strategy related to the current approach to cancer screening and prevention. The panel noted that an ideal screening intervention should focus on detection of diseases that are ultimately harmful and more likely to be cured if detected early. Going forward, avoiding overtreatment will require better screening programs that incorporate improved characterization of the biology of the disease detected and use disease dynamics (ie, how the disease will behave over time) as well as molecular diagnostics that can determine whether a cancer is aggressive or indolent.

The working group called for a change in cancer terminology based on companion diagnostics and avoiding the use of the word cancer for lesions that are unlikely to be lethal if left untreated. They stated that premalignant conditions such as DCIS or highgrade prostatic intraepithelial neoplasia should not be designated as cancer by name. They also recommended that molecular diagnostics that can identify indolent and low-risk lesions be adopted and validated. The working group emphasized the necessity for a new taxonomy and classification system for indolent lesions of epithelial origin (IDLE).

The creation of observational patient registries for IDLE would be useful to trace the course of these lesions over time. The data from such registries

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In March 2012, the National Cancer Institute convened a meeting to evaluate the overdiagnosis of tumors that would not cause harm if left untreated. would provide a link between disease dynamics (growth rate over time) and disease diagnostics that could support the use of less invasive interventions for these lesions.

The strategies called for by the working group include reducing frequency of screening for IDLE lesions, focusing screening on high-risk populations, raising the threshold for recall

and biopsy, and testing the safety and efficacy of risk-based screening approaches to help select appropriate patients for cancer screening. The goal is to detect potentially lethal lesions while avoiding detection of inconsequential disease.

The authors stated that physicians and patients should engage in open discussion about these complex issues. l Reference

Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA. 2013;310(8):797-798.

BREAST CANCER

Greater Attention to Cardiovascular Risk Needed for Breast Cancer Survivors Audrey Andrews

Oncology providers need to increase their awareness of cardiovascular disease risk in breast cancer survivors, according to studies presented at the 2013 Breast Cancer Symposium, held September 7-9, 2013, in San Francisco, California.1,2 “Cardiovascular disease is a significant risk among breast cancer survivors. While the risk of breast cancer death decreases for survivors over time, the risk of death related to cardiovascular disease increases,” said Julia White, MD, of the Ohio State University, who discussed the studies.

Cardiovascular risk factors increase as a result of many breast cancer treatments, and referrals to cardiologists may be warranted, but many such women are neglected in this regard, she said.

A study from the Ville Marie Medical and Women’s Health Centre in Montreal, Canada, evaluated whether the type of treatment a patient with breast cancer received affected cardiovascular risk factor development, based on pre- and posttreatment anthropometric and vital sign measurements. The population included 3674 nononcology female patients and 740 breast cancer survivors who received 1 of 8 different treatment regimens (ie, combinations of surgery, chemotherapy, radiotherapy, and hormonal therapy).

John R. Keyserlingk, MD, reported that compared with nononcology controls, patients undergoing breast cancer surgery alone had significantly higher blood pressure values, greater amounts of body fat, and larger waist circumferences. Adding 2 additional therapies, such as hormonal therapy, radiotherapy, or chemotherapy, tended to be related to worsening parameters. Significant differences were also seen between the cancer survivors in terms of body mass index, resting heart rate, and lean muscle mass.

“This information is important for the medical team to consider when directing the cancer survivors on healthy lifestyle choices posttreatment,” Keyserlingk said.

In her discussion, White noted, “The investigators concluded that number of unfavorable body characteristics seemed to be associated with the completion of treatment for breast cancer, and many changes in body composition led to an increased risk of developing cardiac and metabolic problems.”

She pointed out that previous studies found that patients with breast cancer are less likely to exercise after treatment than before their diagnosis. “This is important when you think about the increased number of risk factors following therapy…putting this into perspective with regard to lifetime cardiac risk. The risk of cardiovascular death increases dramatically with additional risk factors,” she emphasized.

Outcomes of Cardio-Oncology Referrals A second study evaluated the outcomes of 356 breast cancer survivors referred through a survivorship clinic for a consultation with a cardio-oncologist. Researchers identified patients with ≥3 cardiovascular risk factors, either preexisting or treatment related, and explored the proportion referred to cardio-oncology and their outcomes.

They found that only 21% of these patients were referred to specialists, 13% were already being followed by a specialist, and 66% were not referred.

Patients who were referred to cardio-oncology had an average of 5.7 risk factors versus 4.4 for those not referred.

The most common risk factors associated with referral was a body mass index >25 kg/m2, elevated high-density lipoprotein, exercise <150 minutes per week, and exposure to anthracyclines.

The most common outcomes for those seen by cardio-oncology were further diagnostic testing, medication changes, or a return visit to the cardiologist or a nurse practitioner, according to the study by Jennifer R. Klemp, PhD, MPH, of the University of Kansas Cancer Center in Westwood.

“These findings demonstrate the need to determine how to include treatment-related risk factors along with traditional cardiovascular risk factors in assessing and managing cardiovascular risk in breast cancer survivors,” Klemp said.

References

1. Keyserlingk JR, Jones DH, Nestore M, et al. The impact treatment has on cardiovascular risks factors for breast cancer survivors. J Clin Oncol. 2013;31(suppl 26). Abstract 106. Presented at: 2013 Breast Cancer Symposium; September 7-9, 2013; San Francisco, CA. 2. Klemp JR, Ranallo L, Knight C, et al. Evaluating the prevalence of cardiovascular risk factors among breast cancer survivors and the outcomes of cardio-oncology referrals by a breast cancer survivorship clinic. J Clin Oncol. 2013;31(suppl 26).

Abstract 107. Presented at: 2013 Breast Cancer Symposium; September 7-9, 2013; San Francisco, CA

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Inherited Susceptibility to Lung Cancer... Continued from cover primary risk factor for lung cancer.

Other risk factors include exposure to radon or secondhand smoke, certain smoking-related diseases, and occupational exposure to lung carcinogens, such as asbestos, arsenic, nickel, and chromium.4,5 For many years, scientific evidence has strongly demonstrated the association of cigarette smoking with lung cancer. It is well established that the risk increases based on the number of years an individual smokes as well as the quantity he or she smokes. For never-smokers (typically defined as individuals who have not smoked 100 cigarettes in their lifetime), exposure to secondhand smoke and workplace carcinogens are the 2 biggest risk factors; however, approximately a fourth of never-smokers with lung cancer worldwide report no exposure to either.6 Of note, although most patients with lung cancer (at least 80%) have used tobacco products, only about 20% of long-term heavy smokers will develop the disease.7 Moreover, many people with lung cancer have never smoked, and having a family history of lung cancer increases a person’s risk as well. This tells us that genetic factors may make certain individuals more prone to developing lung cancer—even in the smoking population.

An association between family history and lung cancer risk has been reported since at least the 1960s8 and continues to be demonstrated.

Individuals with a first-degree relative with lung cancer are at an approximate 50% increased risk of developing lung cancer compared with those without a family history.9 The association appears to be greater when a sibling rather than a parent is affected. For those who have ever smoked and have a first-degree relative with lung cancer, the increased risk is approximately 3.19 compared with never-smokers without a first-degree relative with the disease. The risk also appears to increase when lung cancer has been diagnosed in an affected family member under age 50 years and when multiple family members are affected. Thus, a positive family history may be one inclusion criteria for studies focused on lung cancer screening.

Although a relationship has been demonstrated between family history and lung cancer for 50 years, little is known about the genetic influences involved. Familial studies display high heterogeneity, and it is challenging for researchers to account for environmental exposures such as smoking. Not only does an individual’s exposure influence the

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risk of developing lung cancer, it also likely affects his or her genetic capacity to activate or inactivate tobacco carcinogens.10 Furthermore, the overall 5-year

n tio a dic n I L TC P ine L d 2n

survival rate is much lower than other cancers, around 16.6%, and only approximately 15% of cases are diagnosed at an early, localized stage.11 As a result, it is

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

• Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131)1 • Studied in a pretreated, histologically diverse PTCL population1 • Patients could be treated until disease progression at their discretion and that of the investigator1

Important Safety Information WARNINGS AND PRECAUTIONS • Treatment with ISTODAX® (romidepsin) has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX. The risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D)

ADVERSE REACTIONS Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

ISTODAX® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 07/13 US-IST130001a

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difficult to ascertain survivors for research studies, especially families with multiple lung cancer survivors.

In the past several years, chromosome

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GENETIC COUNSELING regions that may help explain variation in lung cancer risk have been identified.

Genome-wide association studies have reported chromosomal region 15q2425.1 as associated with an increased risk of lung cancer,12-15 as well as 5p15, 6p21-

6p22, and 12p13.12 Linkage analyses in families with lung cancer have also shown a region of 6q23-25 as associated with an increased risk.10,16,17 In addition, variation in 9p21.3 may be associated with squamous cell lung cancer risk.12

However, none of these regions have yet proven useful in a clinical setting.

To date, there isn’t one specific susceptibility gene that explains most cases of familial lung cancer. However, there are several genetic syndromes that

may place an individual at an increased risk of developing lung as well as other cancers. These include Li-Fraumeni syndrome, retinoblastoma, xeroderma pigmentosum, and Peutz-Jeghers syndrome.

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Demonstrated efficacy in PTCL after at least 1 prior therapy in Study 3a1

15% ~60% 25%

(19/130) Complete Response Rate (CR+CRu) by independent central review (95% CI: 9.0, 21.9) • Similar complete response rates in the 3 major PTCL subtypes (NOS, AITL, ALCL)

9.2 months

(11/19) of Complete Responses (CR+CRu) exceeded • Follow-up was discontinued in the remaining 8 patients prior to 9.2 months (33/130) Objective Response Rate (CR+CRu+PR) by independent central review (95% CI: 18.2, 33.8)

1.8 months a

(~2 cycles) median time to Objective Response

Efficacy based on 130 patients with histological confirmation by independent central review.1

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Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

DRUG INTERACTIONS • Monitor prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX (romidepsin) and warfarin sodium derivatives • Romidepsin is metabolized by CYP3A4 Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors Avoid co-administration of ISTODAX with rifampin and other potent inducers of CYP3A4 • Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

USE IN SPECIFIC POPULATIONS • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see Brief Summary of Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, on the following pages.

Reference: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2013.

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Inherited Susceptibility to Lung Cancer... Continued from page 13 Of the syndromes, Li-Fraumeni has the most well-documented association with lung cancer risk. This syndrome is associated with mutations in the TP53 gene. Individuals are primarily at an increased risk for sarcomas, breast cancer, brain tumors, adrenocortical carcinoma, and leukemias. Other reported cancers include lung, gastrointestinal,

genitourinary, skin, thyroid, and neuroblastoma.18,19 Retinoblastoma is associated with mutations or deletion of the RB1 gene.

Like Li-Fraumeni syndrome, this condition is transmitted in an autosomal dominant manner. Individuals are at high risk of developing retinoblastoma before age 5 years and also at increased risk for

melanoma.20,21 Other reported cancers have included osteosarcomas, soft tissue sarcomas, brain tumors, lymphoma, and breast as well as lung cancer.21,22 Xeroderma pigmentosum is associated with mutations in several genes and is inherited in an autosomal recessive manner.23 It causes extreme sensitivity to ultraviolet rays and results in a T:7”

high risk of developing skin cancer.

Other reported associated cancers have included brain and lung (in smokers).24 Peutz-Jeghers syndrome is associated with mutations in the STK11 gene and is inherited in an autosomal dominant fashion. Individuals are at increased risk for gastrointestinal polyposis, mucocutaneous pigmentation, and a variety of

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monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary of the Prescribing Information for the peripheral T-cell lymphoma indication only; see Full Prescribing Information for complete product information.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

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1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle.

Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5° C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely

GENETIC COUNSELING cancers including colorectal, gastric, pancreatic, breast, ovarian, and adenoma malignum of the cervix.25 Somatic mutations in STK11 are common in lung cancer.25,26 Some studies and/or case reports have shown an association with STK11 germline mutations and lung cancer risk. However, similar to retinoblastoma and xeroderma pigmentosum, the association has not been routinely replicated and/or did not account for

cigarette smoking and, thus, the true association remains unclear.

involved. Gene variants involved in lung cancer have been identified in the past several years; however, the significance of these findings to increased risk remains unclear and a single “lung cancer gene” has not been identified • Because identifying individuals who are at increased risk of lung cancer is imperative for prevention and screening studies, encourage patients

Take-Home Messages • Knowledge surrounding inherited lung cancer susceptibility is in its infancy • Although studies have shown an association between family history and risk of lung cancer, little is known about the genetic influences T:7”

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2013 Celgene Corporation. All Rights Reserved.

U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBSPTCL.005 06/13

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References

1. National Cancer Institute. Lung cancer. http://www. cancer.gov/cancertopics/types/lung. Accessed October 11, 2013.

2. American Lung Association. Understanding lung cancer. http://www.lung.org/lung-disease/lung-can cer/learning-more-about-lung-cancer/understand ing-lung-cancer/. Accessed October 11, 2013.

3. National Cancer Institute. What you need to know about lung cancer. http://www.cancer.gov/cancertopics/ wyntk/lung/page4. Accessed October 11, 2013.

4. Mayo Clinic. Lung cancer. http://www.mayoclinic. com/health/lung-cancer/DS00038/DSECTION=causes.

Accessed October 11, 2013.

5. National Cancer Institute. Cigarette smoking: health risks and how to quit. http://www.cancer.gov/ cancertopics/pdq/prevention/control-of-tobacco-use/ HealthProfessional/page2. Accessed October 11, 2013.

6. Couraud S, Zalcman G, Milleron B, et al. Lung cancer in never smokers—a review. Eur J Cancer.

2012;48:1299-1311.

7. Mayo Clinic. Lung cancer research update. http:// www.mayo.edu/research/documents/newsletter-1pdf/ DOC-10027463. Accessed October 11, 2013.

8. Tokuhata GK, Lilienfeld AM. Familial aggregation of lung cancer among hospital patients. Public Health Rep. 1963;78:277-283.

9. Cote ML, Liu M, Bonassi S, et al. Increased risk of lung cancer in individuals with a family history of the disease: a pooled analysis from the International Lung Cancer Consortium. Eur J Cancer. 2012;48:1957-1968.

10. Irshad S, Maryum M. Genetic susceptibility and risk factors associated with familial lung cancer.

Public Health Res. 2012;2:1-8. http://article.sapub.org/ pdf/10.5923.j.phr.20120202.01.pdf. Accessed October 11, 2013.

11. National Cancer Institute: SEER stat fact sheets: lung and bronchus. http://seer.cancer.gov/statfacts/html/ lungb.html#survival. Accessed October 11, 2013.

12. Timofeeva MN, Hung RJ, Rafnar T, et al; for TRICL Research Team. Influence of common genetic variation on lung cancer risk: meta-analysis of 14,900 cases and 29,485 controls. Hum Mol Genet. 2012;21:4980-4995.

13. Amos CI, Wu X, Broderick P, et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nat Genet.

2008;40:616-622.

14. Hung RJ, McKay JD, Gaborieau V, et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature.

2008;452:633-637.

15. Thorgeirsson TE, Geller F, Sulem P, et al. A variant associated with nicotine dependence, lung cancer, and peripheral arterial disease. Nature. 2008;452:638-642.

16. Bailey-Wilson JE, Amos CI, Pinney SM, et al. A major lung cancer susceptibility locus maps to chromosome 6q23-25. Am J Hum Genet. 2004;75:460-474.

17. You M, Wang D, Liu P, et al. Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene. Clin Cancer Res. 2009;15:2666-2674.

18. National Center for Biotechnology Information.

GeneReviews. Li-Fraumeni syndrome. http://www.ncbi. nlm.nih.gov/books/NBK1311/. Updated April 11, 2013.

Accessed October 11, 2013.

19. Hwang SJ, Cheng LS, Lozano G, et al. Lung cancer risk in germline p53 mutation carriers: association between an inherited cancer predisposition, cigarette smoking and cancer risk. Hum Genet.

2003;113:238-243.

20. Kleinerman RA, Yu CL, Little MP, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30:950957.

21. National Center for Biotechnology Information.

GeneReviews. Retinoblastoma. http://www.ncbi.nlm. nih.gov/books/NBK1452/. Updated March 28, 2013.

Accessed October 11, 2013.

22. American Cancer Society. Second cancers. http:// www.cancer.org/cancer/retinoblastoma/detailedguide/ retinoblastoma-after-second-cancers. Accessed October 11, 2013.

23. National Center for Biotechnology Information.

GeneReviews. Xeroderma pigmentosum. http://www. ncbi.nlm.nih.gov/books/NBK1397/. Accessed October 11, 2013.

24. Genetics Home Reference. Xeroderma pigmentosum. http://ghr.nlm.nih.gov/condition/xeroderma-pig mentosum. Published September 23, 2013. Accessed October 11, 2013.

25. National Center for Biotechnology Information.

GeneReviews. Peutz-Jegher syndrome. http://www.ncbi. nlm.nih.gov/books/NBK1266/. Accessed October 11, 2013.

26. Sanchez-Cespedes M, Parrella P, Esteller M, et al. Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 2002;62:3659-3662.

T:9.875”

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25% [See Clinical Pharmacology (12.3)]. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).

7.3 Drugs that Induce Cytochrome P450 3A4 Enzymes Avoid co-administration of ISTODAX with rifampin. In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively [See Clinical Pharmacology (12.3)].

Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.

7.4 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

with lung cancer and their family members to participate in research studies assessing inherited risk factors

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SIDE EFFECTS MANAGEMENT

Raising Awareness of Cancer Anorexia-Cachexia Syndrome in Patients With Lung Cancer Alice Goodman

C

ancer anorexia-cachexia syndrome (CACS) is underrecognized and underreported in patients with advanced lung cancer receiving routine clinical care, according to a retrospective, single-institution study presented at the 2013 annual meeting of the Multinational Association of Supportive Care in Cancer. The study found that 62% of patients with stage IV metastatic non-small cell lung cancer (mNSCLC) met at least 1 of 4 defining criteria for CACS. The investigators from Duke Clinical Research Institute and Duke Cancer Institute, Durham, North Carolina, said that the underreporting of CACS “demonstrates a substantial opportunity for clinical and patient education as to the presence and impact of the condition, especially as new therapies become available.”

CACS, a multifactorial condition leading to muscle wasting, affects up to 80% of patients with advanced malignancies, said the investigators. The presence of CACS impairs quality of life and compromises response to chemotherapy. Patients with CACS have more frequent and severe toxicity and require more dose reductions and treatment delays than those without the syndrome, thus interfering with the beneficial effect of anticancer therapy.

Reasons for the underrecognition and

undertreatment of CACS include lack of a standardized definition, lack of effective treatments, and poor education about CACS and its impact. As new treatment options become available, it is important to look at how CACS is identified and addressed in the current clinical landscape.

To look at the prevalence of CACS in patients with mNSCLC, the Duke investigators gathered data from an

(ICD-9) codes assigned by healthcare providers.

3. A score of ≥7 on patient-reported questions related to weight loss or lack of appetite.

4. A prescription for drugs that treat CACS (eg, megesterol acetate, dronabinol).

Of the 495 patients identified with mNSCLC between May 2007 and April 2012, 307 (62%) met at least 1 of the 4

Cancer anorexia-cachexia syndrome, a multifactorial condition leading to muscle wasting, affects up to 80% of patients with advanced malignancies.

electronic patient-reported outcomes (ePRO) database combined with other electronic data systems and paper case notes available at Duke.

CACS was identified according to the following 4 criteria: 1. Weight loss ≥5% or weight loss >2% with a body mass index (BMI) <20 kg/m2 within 3 to 6 months of diagnosis.

2. CACS-related International Classification of Diseases, Ninth Revision

criteria for CACS. For example, among patients with weight loss data available at 3 and 6 months (n = 215), 51% met the criteria. Healthcare providers assigned the ICD-9 code for CACS to 22% of patients. Among patients completing the ePRO survey (n = 202) during the course of treatment, 32% met the predefined threshold for severe loss of weight or appetite. Finally, 5% of patients (n = 26) received either megesterol acetate or dronabinol.

Of the 109 patients who fulfilled weight loss criteria for CACS, less than 50% were captured by ePRO, ICD-9 code, or medication adherence. The prevalence of CACS was 42% and 17% in patients with weight loss ≥5% at 3 months and 6 months, respectively. Weight loss criteria of ≥2% with a BMI ≤20 kg/m2 were met by 1% of patients at 3 months and 2% at 6 months.

The study’s senior author, Amy Abernethy, MD, commented on the importance of the findings: “In the setting of advanced cancer, anorexia-cachexia syndrome is woefully underrecognized.

Over half of the patients with available weight data could have met the criteria for CACS by weight loss criteria alone.

In this single setting, over 60% met at least 1 criterion. If we aren’t identifying people burdened by this syndrome, then we cannot initiate approaches to help them. Simple maneuvers like education will help patients and families know what to expect. And, we anticipate that our treatment toolbox will soon be filled with new efficacious medications. We need to learn how to identify the red flags of CACS so that we can be ready to treat people who suffer from the syndrome.” l Reference

Benner A, Hirsch B, Abernethy A. Cancer anorexia-cachexia syndrome (CACS) is under-recognized among patients with metastatic non-small cell lung cancer (mNSCLC). Support Care Cancer. 2013;21(suppl 1):S33. Abstract 0808.

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CANCER CENTER PROFILE

Moffitt Cancer Center... Continued from cover Tell me about your position at Moffitt.

Beth Finley (BF): I am part of a team of physicians, oncologic pharmacists, and nurses who specialize in the management of patients with multiple myeloma. The myeloma team within the department of malignant hematology includes 3 nurses (Sheri Lemanski, RN, BSN, OCN; Christine Simonelli, RN, BSN, OCN; Lisa Nodzon, PhD, ARNP, AOCNP) and myself; 1 pharmacist; and 2 physicians. I educate patients about their disease and the management of side effects of therapies, and coordinate their care within a multidisciplinary approach. In addition, given that myeloma is not curable, the primary focus of therapy is to improve quality of life, decrease complications of the disease, and extend survival.

When deciding on treatment options, we always consider a clinical trial, as patients who present to our center are often interested in considering a novel approach to manage their disease, including recently approved therapies such as carfilzomib and pomalidomide.

What are some of the challenges in your job?

BF: Caring for patients with a noncurable cancer can be challenging on many levels: helping patients cope with a new diagnosis, navigating the patient through financial constraints of modern healthcare, ensuring adherence to therapy, and helping patients with end-of-life decisions.

What are some of the rewards of your job?

BF: Patients with advanced cancers have tremendous resilience and optimism in the face of adversity. This adds perspective to our handling of everyday problems we face. I am grateful to be part of their lives and often their families’ lives.

What are you excited about in the field of myeloma right now?

BF: Research in the field of myeloma has led to approval of several new drugs, including carfilzomib and pomalidomide in the last year. We participated in the clinical trials that led to approval of those drugs. Having more drugs available to treat myeloma means that patients are living longer and better, and we are moving toward making this a chronic disease. Our patients benefit from these drugs and also from our multidisciplinary approach, which can include a neurosurgeon, orthopedist, radiation and medical oncologists, and oncology nurses, as well as the expertise of a social worker, nutritionist, physical therapist, and home healthcare when needed.

www.TheOncologyNurse.com

What inspired you to be an oncology nurse, and how long have you been in the field?

BF: I’ve always wanted to be a nurse.

I had a dear family member who was affected by esophageal cancer. Going through the process with my family dealing with a diagnosis, treatment, and end of life was very difficult. This led me to the field of oncology. I was a nursing assistant while attending nursing school at Moffitt Cancer Center. I’ve spent 7 years in oncology, 2 years in leukemia, and the last 5 years in myeloma. I have found my home with myeloma patients.

I love the elderly population. I am currently working toward my nurse practitioner license while working full time and attending school part time.

Beth Finley, RN, OCN (left), and Lisa Nodzon, PhD, ARNP, AOCNP.

Has the role of oncology nurse evolved over the past 5 years?

BF: Yes. We have more of a voice than we had in the past 5 years. At Moffitt we

are now committed to a shared governance model. Nurses participate in decision-making about daily care of patients.

What advice would you give to a person entering the field of oncology nursing?

BF: Taking care of oncology patients is a rewarding job. The patients are very appreciative of the support they get through the disease process. The supportive care given by oncology nurses begins at diagnosis and continues past death to the patient’s family.

What would you do if you weren’t an oncology nurse?

BF: Even if I won the lottery, I would still be a myeloma nurse. But since I love to take care of children, the elderly, and animals, I could work with any of those groups. l

SIDE EFFECTS MANAGEMENT

Update on Managing Dyspnea Alice Goodman

D

yspnea is the most prevalent symptom in patients with cancer, occurring in 22% to 55% of all affected individuals, and up to 79% at the end of life. Most patients with advanced lung cancer will have dyspnea. It is challenging to manage, and the only evidence-based intervention is opioids once dyspnea becomes disabling.

“Dyspnea is one of the most frightening symptoms in patients with cancer. There is no road map for treating dyspnea. Opioids are the only recommended therapy, and many physicians as well as nurses are reticent to use these drugs. This is probably based on fear of failure,” stated Awni Awad Daibes, Master, Institute Jules Bordet, Brussels, Belgium, at the European Cancer Congress (ESMO/ECCO/ESTRO), held September 27-October 1, 2013, in Amsterdam, the Netherlands.

The causes of dyspnea are multifactorial, and optimal measurement is unclear, he continued. Dyspnea is a subjective feeling of not being able to breathe, often associated in a symptom cluster with fatigue, anxiety, and depression.

Dyspnea can be caused by medical problems that should be treated promptly. These include plural effusion, pneumothorax, pulmonary edema or embolism, chronic obstructive pulmonary disease, congestive heart failure, cardiac tamponade, lung obstruction, and pulmonary hypertension.

Refractory dyspnea occurs mainly in advanced lung cancer and is defined as difficulty breathing. Sensations vary in intensity and it is frequently debilitating, he said.

Daibes noted that many cancer patients with dyspnea are referred too late to the palliative setting. Patients with advanced lung cancer should be referred for palliation at the outset of dyspnea, so the symptom can be controlled.

Although the visual analog scale is the simplest way to measure dyspnea, there is no validated agreed-upon standard measure. Measures of respiration include oxygen

saturation and pulmonary function tests, but the results of these measures are unlikely to affect management, he said.

The goal of treatment is to improve the sensation of breathing and empower the patient to control the symptom. In advanced lung cancer, it is not possible to target the underlying etiology.

“Nurses are not always aware of the latest evidence.

There is a huge amount of published materials, and some of it can be difficult to interpret. Putting evidence-based medicine into practice is a must,” Daibes stated.

To this end, the European Oncology Nursing Society and the Oncology Nursing Society in the United States have initiated a joint project called Putting Evidence Into Practice (PEP). Nurses will be able to go online to the PEP website and get evidence-based guidance on how to manage cancer-related symptoms, including dyspnea. PEP uses traffic-light colors for its recommendations: green = go (strong evidence from rigorously designed studies); yellow = caution (effectiveness not established); red = stop (don’t use; can cause harm).

The only green-light recommendation for dyspnea is immediate-release oral and parenteral opioids. Yellowlight recommendations include extended-release morphine, anxiolytics, transmucosal fentanyl, and nebulized furosemide; nonpharmacologic interventions include a fan, acupuncture, and psychoeducation. Palliative oxygen is a red-light recommendation (can cause harm).

“The management of dyspnea is not writ in stone.

Evidence-based practice is alive, and it is an ongoing process. Interventions we currently use may be deemed ineffective, and new effective ones may be identified. You must use sound judgment in your daily practice,” he told listeners. l Reference

Daibes A. Dyspnoea—an oncological challenge. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands.

Abstract 361.

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THE WHOLE PATIENT

Camp Bluebird: A Survivorship Program for Life Continued from cover that you have been given permission to enjoy life again and not let cancer consume your thoughts. It is a place where tears can flow freely and laughter bubbles up at any moment—the kind of laughter that you haven’t let yourself experience in a long time, like everything is going to be alright—the kind of laughter that gives you hope again.

That is part of what Camp Bluebird is all about, but it is also so much more.

First of all, simply put, Camp Bluebird is a 2-night, 3-day retreat for adult cancer survivors, held each spring and fall in the beautiful mountains of North Carolina. It is sponsored by Mission Hospital in Asheville and the AT&T Telephone Pioneers, the volunteer organization of our local telephone company. Anyone 18 years or older with a past or current diagnosis of cancer may attend. This year our Camp Bluebird is joyfully celebrating its 20th anniversary.

Camp Bluebird came to be in 1985, when a cancer survivor in Birmingham, Alabama, decided to start a retreat for adult cancer survivors. He approached the Foundation at St Vincent’s Hospital, and with help from their local Telephone Pioneers, America’s first adult cancer camp was born. It was named after the bluebird, which is known as the “symbol of hope.” This first 3-day retreat was so well received by cancer survivors in the area that St Vincent’s Hospital decided to share the idea with other hospital systems in the Southeast. Franchises were sold, using the Camp Bluebird name, and 36 cancer retreats were started in various parts of the country. Unfortunately, as the years went by, some of these retreats were discontinued due to lack of funding, but others continued to grow and prosper. Now, 28 years later, the first Camp Bluebird from St Vincent’s Hospital is still going strong. It is offered each fall at Camp Sumatanga near Birmingham. Jeffrey Scott Powell, Administrative Director of Development for St Vincent’s Hospital Foundation, estimates that there are at least 23 of the original 36 Camp Bluebirds still in existence, extending from Florida to North Carolina to Michigan to Texas.

Our Camp Bluebird was started in 1993, when an oncology nurse from Mission Hospital in Asheville, North Carolina, and a representative from BellSouth, our local telephone company at the time, traveled to Birmingham to buy a Camp Bluebird franchise. We have been extremely fortunate with funding since our inception 20 years ago. Our Mission Healthcare Foundation has always supported Camp Bluebird financially when our operating budget was running low. Although registration fees

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The Camp Bluebird quilt.

A costume party at Camp Bluebird.

cover some of the cost for each camp, both private and corporate donations are always greatly appreciated. For 10 of the last 20 years, our local American Cancer Society has donated $10,000 per year, for a total gift of $100,000. Our ultimate goal is for Camp Bluebird to one day be financially self-sustaining, with all future camps paid for by interest from an endowment. This would be an incredible gift for the cancer survivors of western North Carolina.

We have always held our retreats at the Bonclarken Conference Center in historic Flat Rock, situated in the beautiful mountains of North Carolina about a 40-minute drive from Mission Hospital. Accommodations are very comfortable, each room hav-

ing 2 beds and a private bathroom. The Bonclarken staff have always made us feel welcome, and they are proud to have hosted Camp Bluebird at their facility for these last 20 years.

Mission Hospital has encouraged their oncology nurses to serve as counselors at Camp Bluebird, as have private oncology offices. As an oncology nurse, I personally became involved with Camp Bluebird in 1994 when I was asked to serve as a counselor at the fall camp. Then a year later, the “director’s baton” was passed over to me. Being the director of Camp Bluebird has truly been the most challenging and also the most rewarding part of my career as an oncology nurse. It has always been my desire to make the cancer journey as

easy as possible for my patients. Camp Bluebird is a special program that can benefit survivors at any point in their cancer journey: newly diagnosed, going through treatment, at the end of their treatment and unsure of what to do next, dealing with a recurrence, or in the final stages of their disease. Camp Bluebird has something to offer EVERY survivor at ANY time.

At each of our 3-day retreats, we have 50 to 60 adult cancer survivors (about half returning campers and half first-timers) paired with 30 to 35 counselors, comprising a wonderful combination of oncology nurses from either the hospital setting or private oncology offices, plus social workers, physical therapists, chaplains, and the Telephone Pioneer volunteers. It always amazes me to watch the return campers make the first-time campers feel immediately at home. Each counselor’s job is to make his or her 2 campers feel special and pampered while at Camp Bluebird, by sharing meals with them, participating in free-time activities together, and keeping an eye on them to be sure they are feeling well and are not in need of medical attention. At each camp, in addition to the 6 to 8 oncology nurse counselors, there is also a “dedicated” camp nurse whose role is to ensure that all of the campers’ medical needs are met. We also have a “dedicated” camp chaplain available for spiritual support.

But by far, the biggest source of support at camp is the emotional support the cancer survivors give to each other, and it is truly magical to see how each retreat takes on its own personality because of the mix of people that attend each camp. To watch the first-time campers transform from scared little “first graders” into confident “seniors” by the third day of camp is like watching a miracle unfold in front of your very eyes.

Through the years, I have had many campers tell me that Camp Bluebird has changed their life. Through the tears and the laughter they share with other survivors at camp and with their counselors, they reach a point where they don’t fear the future quite so much. They may still fear recurrence of their cancer, but through conversations with other campers and advice from trained facilitators in the small groups they attend, our campers learn coping skills that allow them to enjoy each day rather than dread what might happen.

With 2 camps offered each year, it is always a challenge to come up with activities that are fresh and new. Campers can choose from a variety of activities offered during free time between 1:00 and 5:30 pm on the first 2 days of camp. They are always encouraged to pick and choose those that interest them most, to avoid fatigue from overscheduling themselves.

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THE WHOLE PATIENT Some take this advice, and others want to participate in everything! Many of the activities allow both the campers and their counselors to participate together.

Other activities, such as the Healing Touch Reiki Therapy, are provided specifically for the campers themselves.

We also offer more serious, contemplative activities, such as the Service of Remembrance, which is held on the second morning of camp in a very special memorial garden, outside under the trees. At this spiritual service, we remember past campers who are no longer with us, by symbolically putting a scoop of dirt into the base of a potted tree that will be planted on the Bonclarken property in their memory.

The camp chaplain leads this service, and it is always very emotional.

Immediately following this memorial service, campers are encouraged to attend small group sessions, where they can choose from several topics that may be pertinent to their situations. Each group is led by a welltrained facilitator, whether it be an oncology nurse, social worker, or the camp chaplain. Some of the topics include Fear of Recurrence, Helping Your Family Deal With Your Cancer, Spirituality Issues, Healthy Eating for the Cancer Survivor, Dealing With Chemotherapy and/or Radiation Side Effects, and Survivorship Issues. We offer these small group sessions twice during each camp.

Mealtime is always very special at Camp Bluebird, not only because the food is delicious, but also because it is a time to relax with new and old friends and reflect over the day. Many friendships have been made and strengthened around the dining room tables at Camp Bluebird. We always take a full hour for each meal, because it is such an important time for sharing. After dinner, we all let our hair down and our free spirits come out to play, with live musical entertainment. In recent years, I have seen a lot of dancing in the aisles, and that is always encouraged! When we have a live band combined with a costume party, everyone is encouraged to dress up, but it is not required. Each party has a theme, such as a Hawaiian Luau, a ’50s Sock Hop, a ’60s Hippie Party, a Country Western Party, an Olympics Party, or a Come Dressed as Your Favorite Movie Star/Sports Personality Party. I mail a letter to each camper about 6 to 8 weeks before the next camp to let them know the theme of the costume party so they have plenty of time to put together a costume if they want to dress up. Prizes are often awarded for the most creative costumes.

On the last day of each camp, after the counselors help the campers take their suitcases to the cars, we offer either a small group or a panel discussion. At

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A fishing party at Camp Bluebird.

our spring camp in May, we had a panel of experts discussing pertinent survivorship issues such as long-term disability, Medicare/Medicaid, healthcare power of attorney, living wills, and hospice/palliative care. Then for the final lunch, campers are encouraged to invite friends and/or family to join us. At the closing ceremony, we show a slideshow of photos taken throughout the last 3 days. Seeing the expressions on the faces of the campers—enjoying themselves and feeling free to just be who they are, accepted by all, wig or not, hair or no hair—is exhilarating. The pictures in that final slideshow say it all: Camp Bluebird is a place where you can just relax, throw your troubles away, and go home with a renewed zest for life. The immediate friendships made

Making a birdhouse at Camp Bluebird.

peace and serenity they have felt here.

The good news is that many campers have told me that this peace has stayed with them long after leaving Camp

“Camp Bluebird allows us to try new things, to stretch ourselves. I remember at my first camp, I reluctantly signed up for Reiki Therapy and didn’t know how this could possibly make me feel better.

Well, one hour later, I staggered, completely in a state of bliss, from the Reiki room and was a firm believer in this healing touch therapy modality.”

Carolyn Comeau, a breast cancer survivor who has attended Camp Bluebird several times, speaks of her first experience at Camp Bluebird

at Camp Bluebird may be some of the most meaningful friendships you have ever had. While we nurses can express our compassion and educate you about your cancer and try to calm your fears, we can’t know deep down in our souls how you are truly feeling, like another cancer survivor can. As the camp chaplain says the closing prayer, some of the campers seem afraid to leave this safe place, thinking they might lose the

Bluebird and that their newly acquired coping skills have helped sustain them during times of worry and stress.

These “graduates” of Camp Bluebird are always invited to attend again in the future. However, since survivors are living longer due to early detection and better treatment options, about 10 years ago I had to make the difficult decision to let campers return to only one camp per year. Every January, past campers

receive a questionnaire, asking if they would like to attend the spring or fall camp that year. I always give priority to first-time campers and to those who are dealing with a recurrence of disease. If a return camper has been to more than 5 previous camps, I automatically put them on a waiting list until I know we’ll have a spot for them. Fortunately, a camper has NEVER been turned away from our Camp Bluebird because of inability to pay. For many years, the registration fee for first-time campers has stayed at $40, but if that is a problem, we ALWAYS have partial or full scholarships available to cover the registration fee. The fee for return campers has been set at $75 for the last 5 years or so, and if that is a problem, scholarships are available, no questions asked.

In closing, I want to tell the story of a woman with breast cancer who attended Camp Bluebird for many years back in the mid-1990s. Unfortunately, her disease progressed, and each time her husband brought her to camp, she appeared more frail. The final camp she attended, she stayed in a wheelchair most of the time because of weakness and bone pain. However, during the costume party while the band was playing, she got up out of that wheelchair and danced for a couple of minutes.

You should have seen the look of joy on her face. The rest of us were smiling too, through our tears. And when her husband came to pick her up on the last day of camp, she had the energy to walk out to him without assistance. We lost her to breast cancer a few months later, but we were all truly inspired by the incredible courage she displayed. Now her husband is a survivor too, and he comes to camp and always talks about his precious wife and how she loved Camp Bluebird.

We will never forget these special patients who pass through our lives and find a permanent place in our hearts. As oncology nurses, we do all that we can to make their cancer journey as easy as possible, and in return they teach us so much more than we could ever teach them. They have all figured out the secret of life and what is truly important, living in the moment and being with the ones you love. Camp Bluebird is like that…living in the moment and being with the ones you love. It is so much more than a place or a program… it is a feeling that you carry with you after you leave. It is permission to enjoy the rest of your life. Camp Bluebird is hope for your future, no matter how short or long that future might be. l For more information about starting a survivorship program like Camp Bluebird, please contact Leslie Verner at 828-213-4656 or leslie.verner@msj.org.

NOVEMBER 2013 I VOL 6, NO 10

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NEWS BRIEFS: LUNG CANCER Continued from page 7

Who Should Get CT Screening Computed tomography (CT) screening is expensive and should be targeted to high-risk patients when the benefits exceed the harms. A late-breaking abstract used modeling based on a hypothetical US cohort of 100,000 people from an analysis by the National Lung Screening Trial. That study found a

20% reduction in mortality with CT screening of high-risk populations.

In 100,000 people, the most efficient use of annual lung cancer CT screening was for those individuals between the ages of 55 and 80 with at least 30 packyears of smoking and who quit within 15 years, reported Harry J. de Koning, MD,

Erasmus Medical Center, Rotterdam, the Netherlands.

“If you go above that strategy, you exceed the harms, with more radiation exposure, more overdiagnosis and overtreatment, and higher cost,” he said.

De Koning and his coinvestigators used 5 different models to estimate the

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harms and benefits in this population born in 1950 and followed up from ages 45 to 90 years. They evaluated 576 possible scenarios and found that triennial screening programs reduced lung cancer mortality by 5% to 6%, biennial screening programs by 7% to 10%, and annual screening programs by 11% to 21%.

If screening were limited to the group they identified (age 55-80 years; 30 pack-years, quitting within the past 15 years), this would result in 19.3% of the cohort being screened at least once, 287,000 CT screens, 1971 screen-detected cases, 50% of lung cancers being detected at an early and treatable stage, a 14% reduction in lung cancer mortality (avoiding 520 deaths), and 5500 life-years gained. To avoid 1 lung cancer death, 550 screens are needed.

In 100,000 people, the most efficient use of annual lung cancer CT screening was for those individuals between the ages of 55 and 80 with at least 30 pack-years of smoking and who quit within 15 years.

These benefits must be balanced against 330,000 CT exams, 66,000 false-positive results, and an estimated overdiagnosis rate of 4% (190 lung cancers), as well as 24 deaths due to radiation exposure.

Formal discussant of this trial, Dirk de Ruysscher, MD, University Hospitals Leuven, Belgium, said that lung cancer survivors are also in the highest risk group, even after 18 years of survivorship.

“Five years later, survivors are in the highest risk group of developing lung cancer. After 10 years, 23% of those survivors will die of lung cancers [probably a second primary]; after 15 years, 35% will die of lung cancer; and after 18 years, 40% will die of lung cancer. That is about 2% per year,” de Ruysscher said.

Perhaps this type of modeling could be used to follow up patients treated for primary lung cancer, and be extended to survivors, he suggested. l

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Reference

De Koning HJ, Plevritis SK, Meza R, et al. Benefits and harms of computed tomography lung cancer screening programs for high risk populations—using evidence from the 2 largest randomized controlled trials on lung cancer screening worldwide. Presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, the Netherlands. Late-Breaking Abstract 14.

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BREAST CANCER

Paroxetine Does Not Reduce Tamoxifen’s Effectiveness in Breast Cancer Survivors

safety of using SSRIs and tamoxifen together,” Haque stated. “This study has implications for clinical decision-making and improving quality of life among breast cancer survivors,” she said. l

Alice Goodman

B

reast cancer survivors who suffer from depression can safely take both tamoxifen and a concomitant selective serotonin reuptake inhibitor (SSRI) antidepressant, according to a large population-based observational study presented at the 2013 annual meeting of the Multinational Association of Supportive Care in Cancer.

Depression affects about half of all women with breast cancer, and many of them take antidepressants to alleviate their mood symptoms. Depressed mood is a potential side effect in women with estrogen receptor–positive (ER+) breast cancer who are typically treated with hormonal therapy to prevent recurrence.

So, while tamoxifen reduces the risk of breast cancer, it can also have effects on mood that lead women to use antidepressants. SSRIs, however, are known to inhibit CYP2D6, an enzyme needed to metabolize tamoxifen, raising concerns about whether concomitant SSRIs interfere with the protective effects of tamoxifen. However, no large studies had previously addressed breast cancer recurrence in women who take both tamoxifen and antidepressants.

“Depression is commonly treated with antidepressants, especially SSRIs. Women and their providers can gain reassurance from this study that using an SSRI and tamoxifen at the same time does not pose a greater risk of breast cancer recurrence,” stated lead author Reina Haque, PhD, of Kaiser Permanente Southern California.

About 7000 women in the Kaiser Permanente managed care system are diagnosed with breast cancer each year, she explained. “Nearly 50% of women with a recent breast cancer diagnosis experience depression, and the incidence of depression increased 4-fold in breast cancer survivors compared to women with no history of breast cancer,” she said.

The present study, Antidepressants and Breast Cancer Pharmacoepidemiology (ABC2), examined this association in a cohort of 16,887 breast cancer survivors diagnosed between 1996 and 2007, and followed through 2009. The study was based on electronic health records of these survivors. Median age at diagnosis was 63 years; about 6% had ductal carcinoma in situ; 50% had stage I disease; and 44% had stage II. Subsequent breast cancer was reported in 2946 women; 2504 developed recurrent or metastatic disease, and 457 developed contralateral breast cancer.

A multivariate analysis found no increased risk of subsequent breast cancer among 16,887 women who took both paroxetine and tamoxifen for at least

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25% of the days for each of the 5 years on tamoxifen. The same results were found among 12,076 women with good adherence to tamoxifen who also took paroxetine for at least 25% of the 5 years of tamoxifen treatment.

“Using one of the most complete pharmacologic databases of insured patients, we observed no significantly increased risk of subsequent breast cancer in women who used paroxetine and tamoxifen concurrently. This study demonstrates the

Reference

Haque R, Shi J, Fletcher SW, et al. Tamoxifen & antidepressant drug interactions in a cohort of breast cancer survivors cared for in large healthcare delivery systems in California. Support Care Cancer. 2013;21(suppl 1):S205. Abstract 0586. Presented at: 2013 Multinational Association of Supportive Care in Cancer Annual Meeting; June 27-29, 2013; Berlin, Germany.

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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.

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LUNG CANCER

Paclitaxel in Lung Cancer Tara L. Plues, MSN, RN, CNP Taussig Cancer Institute, Cleveland Clinic Cleveland, Ohio

litaxel include HSRs, neurotoxicity, and hematologic toxicities.

Case Study A 66-year-old female with newly diagnosed non-small cell lung cancer (NSCLC) presents to clinic. She is diagnosed with a stage IV adenocarcinoma.

She was previously treated at an outside institution with pemetrexed in a clinical trial. She is epidermal growth factor receptor (EGFR) mutant and anaplastic lymphoma kinase (ALK) fusion oncogene negative. With an Eastern Cooperative Oncology Group (ECOG) performance status of 2, we decided against the use of cisplatin. We know standard of care is a platinum doublet and decide on a carboplatin and paclitaxel combination. She receives her first dose without incident, but develops a hypersensitivity reaction (HSR) with the second dose, as evidenced by some hives and back pain during the infusion. She also starts developing some arthralgias and myalgias for about 4 to 5 days after each dose. She finds these painful and lies in bed for most of this time period. What measures can be taken to get her safely and comfortably through chemotherapy?

Paclitaxel Paclitaxel was discovered as part of the National Cancer Institute program in which thousands of plants were screened for anticancer activity. In 1963, preclinical studies found that taxol, a crude extract from the bark of the Pacific yew, Taxus brevifolia, a scarce and slow-growing evergreen found in the old-growth forests of the Pacific Northwest, has cytotoxic activity against many tumors.1 Paclitaxel was identified as the active constituent of this extract in 1971. Paclitaxel promotes the polymerization of tubulin, disrupting normal microtubule dynamics essential to cell division and vital interphase processes, thereby causing cell death.2 Paclitaxel has demonstrated cytotoxicity in a broad range of tumor types, including breast, ovarian, lung, and head and neck cancers, as well as malignancies refractory to conventional chemotherapy, such as previously treated lymphoma, small cell lung cancer, and esophageal, gastric, endometrial, bladder, and germ cell tumors. Paclitaxel is also active against AIDS-associated Kaposi sarcoma. Toxicities associated with pac-

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Paclitaxel in NSCLC In 2002, the ECOG 1594 was published, looking at a comparison of platinum doublets in the treatment of patients with advanced NSCLC.3 The 4 doublets in the trial included cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel. There was no difference in overall survival (OS) between the 4 doublets. The overall similarity of these results suggests that treatment decisions should be made based on other parameters, such as cost, adverse events, and scheduling.

In 2004, several studies looked at the efficacy of platinum doublets in the setting of adjuvant use. The International Adjuvant Lung Cancer Trial compared platinum doublets (cisplatin plus either etoposide, vinorelbine, vinblastine, or vindesine) versus observation in postoperative stage I-IIIA patients.4 The result was a 5% improvement in both disease-free survival and 5-year OS. That same year, the JBR.10 study compared cisplatin/vinorelbine to observation in patients with stage I-II NSCLC and confirmed the benefit of receiving adjuvant cisplatin-based chemotherapy.5 The results were grossly positive, with a difference of 15% in 5-year survival between the 2 arms (69% cisplatin/vinorelbine vs

HSRs observed during preclinical and early phase 1 studies, Cremophor EL, by inducing the direct release of histamines from circulating cells, has generally been felt to be the causative agent.7 The incidence of major HSRs in early phase 1 trials approached 25% to 30%. 8,9 Most affected patients had type I HSRs, including dyspnea, bronchospasm, urticaria, and hypotension. HSRs usually occurred within 2 to 3 minutes after treatment and are almost always noticed within the first 10 minutes; most occur with the first or second dose, indicating that prior sensitization is not necessary.

For this reason these reactions are thought to be non-IgE mediated.10-14 Most major HSRs resolve completely after stopping the paclitaxel infusion and administering histamine receptor (H 1) antagonists, fluids, and occasionally vasopressors. Minor HSRs, such as flushing and rashes, have also been reported in as many as 40% of patients. Minor HSRs do not predict the development of major reactions. Patients with major HSRs have been successfully rechallenged with paclitaxel, using substantially lower infusion rates along with treatment with dexamethasone 20 mg IV every 6 hours for 4 doses, although this approach is not always successful.14

Paclitaxel has demonstrated cytotoxicity in a broad range of tumor types, including breast, ovarian, lung, and head and neck cancers, as well as malignancies refractory to conventional chemotherapy.

54% observation). Based on the results of previous trials, carboplatin is used frequently in patients who may not be able to tolerate cisplatin.

Toxicities

Hypersensitivity reactions In addition to a limited supply of drug from Pacific yew tree bark, paclitaxel’s aqueous insolubility requires the use of a pharmaceutical vehicle consisting of 50% Cremophor EL (polyoxyethylated castor oil) and 50% ethanol.6 Although it was initially unclear whether paclitaxel or Cremophor EL was responsible for the relatively high incidence of major

Hematologic toxicity Neutropenia is the most common toxicity of paclitaxel.15 Onset is usually 8 to 10 days after treatment, and recovery is usually complete by days 15 to 21. In most patients, particularly in those who have received prior chemotherapy, the maximum tolerated dose of paclitaxel without granulocyte colony-stimulating factor is 175 to 200 mg/m2. The most critical pharmacologic determinant of the severity of neutropenia seems to be the length of time that paclitaxel plasma concentrations are higher than biologically active concentrations, a fact that may explain the increased incidence of

neutropenia with longer infusions.16,17 Paclitaxel alone rarely causes thrombocytopenia and anemia.

Neurotoxicity A peripheral neuropathy characterized by sensory symptoms such as numbness and paresthesia in a glove and stocking distribution is the principal neurotoxic effect of paclitaxel.15,18-21 Symptoms may begin as soon as 24 to 72 hours after treatment with higher doses (≥250 mg/ m2) but usually occur only after multiple courses at 135 to 250 mg/m2. It appears that patients treated with paclitaxel over shorter (3-hour) schedules are more prone to the neurotoxic effect of paclitaxel than those treated with longer (24 or 96 hours) schedules, which argues that peak concentrations may be a principal pharmacologic determinant of neurotoxicity. The incidence of neurotoxicity has been particularly high in patients who receive paclitaxel as a 3-hour infusion combined with cisplatin.

A number of factors influence the incidence of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving neurotoxic chemotherapy, including patient age, dose intensity, cumulative dose, therapy duration, coadministration of other neurotoxic chemotherapy agents, and preexisting conditions such as diabetes and alcohol abuse.

While symptoms may resolve completely, in some instances CIPN is only partly reversible, and in other cases it does not appear to be reversible at all.21,22 There is a separate paclitaxel-induced toxicity that is a bothersome syndrome of subacute aches and pains—commonly referred to as arthralgias and myalgias—described in up to 58% of patients receiving paclitaxel.6,23,24 These symptoms generally begin 1 to 3 days after drug administration and are usually self-limited, often resolving within 7 days.

Symptoms have been described in large axial muscular and joint regions and generally are not accompanied by objective musculoskeletal or neurologic changes.

Based on the nature and temporal occurrence of paclitaxel-induced acute pain syndrome symptoms, it is hypothesized that the acute pain syndrome occurs as a result of sensitization of nociceptors, their fibers, or the spinothalamic system, as opposed to a musculoskeletal injury.24 The paclitaxel-induced acute pain syndrome following paclitaxel infusion has commonly been treated with nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and/or opioid pain medications, among others. Few studwww.TheOncologyNurse.com

LUNG CANCER ies, mostly case series, have investigated the role of other medications in both treatment and prevention. Studies using Shakuyaku-kanzo-to (a Japanese herb),25 antihistamines,26 corticosteroids,27 opioid analgesics,28 and amifostine20 have not yielded enough evidence to establish a standard practice.

Case Study Discussion In regard to the HSR our female patient experienced, I would recommend a rechallenge of paclitaxel. Based on the data presented above, I would decrease the infusion rate to a 24-hour rate and increase the rate as tolerated. I would also give her dexamethasone and diphenhydramine premedications in repeated doses prior to infusion. In regard to the arthralgias and myalgias she experienced, there is a lack of significant data showing how to treat these. In my personal clinical experience, I have found corticosteroids to be very effective for patients. I typically use 4 mg of oral dexamethasone with breakfast and lunch for 3 to 5 days, starting the day after chemotherapy. The IV premedication dose typically wears off about 36 hours after the administration. I always remind patients to take their oral dose of dexamethasone with food and to take it earlier in the day to help with the side effect of insomnia as well. With some adjustments to the paclitaxel administration rate, the premedication schedule, and the management of side effects, it is likely we can safely and comfortably deliver the optimal chemotherapy choice of paclitaxel and carboplatin doublet. l

13. Castells MC, Tennant NM, Sloane DE, et al.

Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol. 2008;122(3):574-580.

14. Lee C, Gianos M, Klaustermeyer WB. Diagnosis and management of hypersensitivity reactions related to common chemotherapy agents. Ann Allergy Asthma Immunol.

2009;102(3):179-187.

15. Rowinsky EK, Eisenhauer EA, Chaudhry V, et al.

Clinical toxicities encountered with paclitaxel (Taxol).

Semin Oncol. 1993;20(4 suppl 3):1-15.

16. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol.

1994;12(12):2654-2666.

17. Huizing MT, Keung AC, Rosing H, et al.

Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian

cancer patients. J Clin Oncol. 1993;11(11):2127-2135.

18. Rowinsky EK, Chaudhry V, Cornblath DR, et al.

Neurotoxicity of Taxol. J Natl Cancer Inst Monogr.

1993;15:107-115.

19. Chaudhry V, Rowinsky EK, Sartorius SE, et al.

Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol. 1994;35(3):304-311.

20. Gelmon K, Eisenhauer E, Bryce C, et al. Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer. J Clin Oncol. 1999;17(10):3038-3047.

21. Kannarkat G, Lasher EE, Schiff D. Neurologic complications of chemotherapy agents. Curr Opin Neurol.

2007;20(6):719-725.

22. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249(1):9-17.

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toxicities of paclitaxel 210 mg m(-2) by 3-hour infusion.

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Navigation and Survivorship Conference september 18-21, 2014 Walt disney World sWan hotel orlando, Florida

www.AONNonline.org NOVEMBER 2013 I VOL 6, NO 10

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Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.