march 2012, vol 5, no 2

Fear of genetic discrimination isoften a stated barrier to referral togenetic counseling services and to

willingness to undergo genetic testing.1,2As a result, when the Genetic Info r -mation Nondiscrimination Act (GINA)was signed almost 4 years ago by

President George W. Bush, many feltthat this would be the panacea for indi-viduals concerned about discrimination.GINA was the first federal legislationproviding protections against geneticdiscrimination by health insurers andemployers. While GINA has granted

Anew quantitative imaging bonebiomarker has been identifiedthat can assess response and is

prognostic for survival in men withmetastatic castration-resistant prostatecancer (mCRPC).Called the bone scintigraphy index

(BSI), it represents the first quantitativeimaging biomarker in prostate cancer. Ina head-to-head comparison, the BSI

was superior to PSA (prostate-specificantigen)—the traditional method—inassessing response to therapy and prog-nosticating for survival after 3 and 6months on therapy for mCRPC, accord-ing to a study published online ahead ofprint in the Journal of Clinical Oncologyon January 9, 2012. Michael Morris, MD,Memorial Sloan-Kettering Cancer

MARCH 2012 www.TheOncologyNurse.com VOL 5, NO 2

©2012 Green Hill Healthcare Communications, LLC

Tina Soo, Karen Julien, and Taline Khoukaz (left to right), GI nurse practitioners at theUniversity of Southern California Norris Comprehensive Cancer Center.

USC Norris ComprehensiveCancer CenterA Comprehensive Approach to Treatment of

Colorectal Cancers

The University of Southern California (USC) Norris Com p re -hensive Cancer Center is part of the Keck School of Medicineand is designated by the National Cancer Institute as one of the

nation’s 40 comprehensive cancer centers. Located in Los Angeles,the USC Norris Comprehensive Cancer Center serves as a regionaland national resource for cancer treatment, research, prevention, andeducation. The staff at the cancer center includes approximately 200basic and population scientists, physicians from the faculty of theUSC Keck School of Medicine, and members of several USC profes-sional schools/departments and the College of Letters, Arts andSciences.

CANCER CENTER PROFILE

Continued on page 24

NEWS BRIEFS

Bone Biomarker Identified forMetastatic Prostate Cancer By Alice Goodman

THE PATIENT’S VOICE

What Doctors Can Learn FromNursesBy MMA


Supportive and

palliative Care . . . . . . . . . . . . . . . . 22Assessing Pain in a Geriatric

Oncology Population

Side effeCt ManageMent . . 24Long-term Implications of

Oophorectomy

BaSal Cell CarCinoMa . . . . 26Vismodegib: A New Treatment

Option for Basal Cell Carcinoma

perSonalized MediCine in

onCology . . . . . . . . . . . . . . . . . . . . 28Crizotinib Miracle: A Nursing

Perspective

BreaSt CanCer . . . . . . . . . . . . . . 28BOLERO-2: Practice-Changing Results

With Exemestane Plus Everolimus in

Advanced Breast Cancer

leukeMiaS . . . . . . . . . . . . . . . . . . . . 29Minimal Residual Disease to Monitor

Therapy in Acute Leukemia

I N S I D E

“Are you crazy, yet?”I heard a voice floating through the

early morning air. I stirred out of mysleep, turned my head to the source of thevoice, and mumbled, “Not any more thanusual.” After a moment, though, as I triedto focus despite the tumor sitting on myoptic nerve, which left my vision blurred,I realized the question came from the

doctor assigned to see me during my in-hospital chemotherapy sessions. I knewthat if I did not snap into reality quicklydespite the fact that it was only 7:30 AM

and I had been kept up most of the nightwith nausea, he would simply ask me ifeverything was alright and literally sprintout my door. So, remembering throughthe blur that I had important questions I



GENETIC COUNSELING

Genetic Discrimination: WhatOncology Nurses Need to KnowAbout GINA and Health InsuranceBy Cristi Radford, MS, CGCSarasota Memorial Health Care System, Sarasota, Florida

Anya Prince, EsqCancer Legal Resource Center, Los Angeles, California

TON_March2012_v8_TON 3/16/12 8:33 AM

VELCADE and Millennium are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139

Copyright © 2010, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-10-0196 11/10

*The VELCADE Reimbursement Assistance Program does not file claims or appeal claims for callers, nor can it guarantee that you will be successful in obtaining reimbursement

VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1VRAP_10.875x13.875.indd 1

9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM9/9/11 5:04 PM

TON_March2012_v8_TON 3/15/12 11:02 AM

March 2012 I VOL 5, NO 2 3www.TheOncologyNurse.com

Editorial Board

EDITOR-IN-CHIEFBeth Faiman,PhD(c), MSN, APRN-BC, AOCNCleveland Clinic TaussigCancer InstituteCleveland, OH

Elizabeth Bilotti,RN, MSN, APRN,BC, OCNJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Catherine Bishop,DNP, NP, AOCNPVirginia Cancer CareLansdowne, VA

Deena DamskyDell, MSN, RN-BC,AOCN, LNCFox Chase Cancer CenterPhiladelphia, PA

Wendy DiSalvo,DNP, APRN, AOCNGenentechNew London, NH

DeniceEconomou, RN,MN, CNS, AOCNCity of Hope NationalMedical CenterDuarte, CA

ConstanceEngelking, RN,MS, CNS, OCNThe CHE ConsultingGroup, Inc.Mt. Kisco, NY

Amy Ford, RN,BSN, OCNInnovexDallas, TX

Sharon S. Gentry,RN, MSN, AOCNDerrick L. Davis ForsythRegional Cancer CenterWinston-Salem, NC

Cassandra J.Hammond, RN,MSN, CRNPAvid Education Partners,LLCSharpsburg, MD

Shannon Hazen,RN, BSN, OCNNovant HealthPresbyterian CancerCenterCharlotte, NC

Patricia IrouerHughes, RN, MSN,BSN, OCNPiedmont HealthcareRex, GA

Taline Khoukaz,NP, MSN, ACNP-CUniversity of SouthernCaliforniaNorris Cancer Center &HospitalLos Angeles, CA

Sandra E. Kurtin,RN, MS, AOCN,ANP-CArizona Cancer CenterTucson, AZ

Ann McNeill,MSN, RN, NP-C,OCNJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Kena C. Miller,RN, MSN, FNPRoswell Park CancerInstituteBuffalo, NY

Patricia Molinelli,MS, RN, APN-C,AOCNSSomerset Medical CenterSomerville, NJ

Dolores “Jeff”Nordquist, RN, MS,CS, FNPMayo ClinicRochester, MN

MelindaOberleitner, RN,DNS, APRN, CNSCollege of Nursing andAllied Health ProfessionsUniversity of LouisianaLafayette, LA

Jayshree Shah, NPJohn Theurer Cancer CenterHackensack UniversityMedical CenterHackensack, NJ

Gary Shelton,MSN, NP, ANP-BC,AOCNPNYU Clinical CancerCenterNew York, NY

Lori Stover, RN,BSNWestern PennsylvaniaCancer Institute Pittsburgh, PA

Joseph D.Tariman, PhD,APRN, BCNorthwestern UniversityMyeloma ProgramChicago, IL

Jacqueline MarieToia, RN, MS, DNPNorthwestern UniversityMyeloma ProgramChicago, IL

Pamela HallquistViale, RN, MS,CS, ANP, AOCNSaratoga, CA

Connie Visovsky,RN, PhD, APRNUniversity of South Florida College of Nursing Tampa, FL

Rita Wickham,PhD, RN, AOCNNorthern MichiganUniversity Independent Oncology &Palliative Care ConsultantMarquette, MI

Karla Wilson, RN,MSN, FNP-C, CPONCity of Hope NationalMedical CenterDuarte, CA

PharmacyJohn F. Aforismo,BSc Pharm, RPh,FASCPRJ Health SystemsInternational, LLCWethersfield, CT

NutritionKaren Connelly,RD, CSOSomerset Medical CenterSomerville, NJ

Patient AdvocatePeg FordOvarian Cancer AdvocacyAllianceCoronado, CA

Social WorkCarolyn Messner,DSW, MSW, LCSW-R, BCDCancerCareNew York, NY

Managed Care andPharmaceuticalManagementBurt Zweigenhaft,BSBioPharma Partners LLCNew York, NY

Isabell Castellano, RNBristol-Myers Squibb Children’s HospitalRobert Wood Johnson University HospitalNew Brunswick, NJ

Jeanne Westphal, RNMeeker County Memorial HospitalLitchfield, MN

TON_March2012_v8_TON 3/15/12 11:02 AM

PUBLISHING STAFF

Senior Vice President, Sales & MarketingPhilip Pawelko

[email protected]

PublisherJohn W. Hennessy

[email protected]

Director, Client ServicesJoe Chanley

[email protected]

Editorial DirectorKristin Siyahian

[email protected]

Managing EditorKristen Olafson

[email protected]

Quality Control DirectorBarbara Marino

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Business ManagerBlanche Marchitto

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Editorial Contact:Telephone: 732.992.1891

Fax: 732.656.7938

The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print);ISSN 1944-9801 (online) is published 11 times a year byGreen Hill Healthcare Communications, LLC, 241Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831.Telephone: 732.656.7935. Fax: 732.656.7938. Copyright©2012 by Green Hill Health care Com munications,LLC. All rights reserved. The Oncology Nurse-APN/PA®

logo is a registered trademark of Green Hill HealthcareCommunications, LLC. No part of this publication maybe reproduced or transmitted in any form or by any meansnow or hereafter known, electronic or mechanical, includ-ing photocopy, recording, or any informational storageand retrieval system, without written permission from thePublisher. Printed in the United States of America.

EDITORIAL CORRESPONDENCE should beaddressed to EDITORIAL DIRECTOR, The OncologyNurse-APN/PA®, 241 Forsgate Drive, Suite 205C,Monroe Twp, NJ 08831. E-mail: [email protected]. YEARLY SUBSCRIPTION RATES: UnitedStates and possessions: individuals, $105.00; institutions,$135.00; single issues, $17.00. Orders will be billed atindividual rate until proof of status is confirmed. Pricesare subject to change without notice. Correspondenceregarding permission to reprint all or part of any articlepublished in this journal should be addressed toREPRINT PERMISSIONS DEPARTMENT, GreenHill Healthcare Communications, LLC, 241 ForsgateDrive, Suite 205C, Monroe Twp, NJ 08831. The ideasand opinions expressed in The Oncology Nurse-APN/PA®

do not necessarily reflect those of the Editorial Board, theEditorial Director, or the Publisher. Publication of anadvertisement or other product mention in The OncologyNurse-APN/PA® should not be construed as an endorse-ment of the product or the manufacturer’s claims.Readers are encouraged to contact the manufacturer withquestions about the features or limitations of the productsmentioned. Neither the Editorial Board nor the Publisherassumes any responsibility for any injury and/or damageto persons or property arising out of or related to any useof the material contained in this periodical. The reader isadvised to check the appropriate medical literature andthe product information currently provided by the manu-facturer of each drug to be administered to verify thedosage, the method and duration of administration, orcontraindications. It is the responsibility of the treatingphysician or other healthcare professional, relying onindependent experience and knowledge of the patient, todetermine drug dosages and the best treatment for thepatient. Every effort has been made to check generic andtrade names, and to verify dosages. The ultimate respon-sibility, however, lies with the prescribing physician.Please convey any errors to the Editorial Director.

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4 March 2012 I VOL 5, NO 2 www.TheOncologyNurse.com

From the Editor

With this issue of TheOncology Nurse-APN/PA(TON), we cover every-

thing from issues related to geneticdiscrimination to how a patient feelsabout her interaction with a doctor.Cristi Radford and Anya Prince pro-vide specific information about the2008 Genetic Info rmation Non -discrimination Act so oncology nurs-es can help their patients navigatethe concerns about their medicalrecords and health insurance cov-erage. In the Patient’s Voice arti-cle, MMA tells us about how she

feels when a doctor asks her if she’s “crazy yet,” giving usall insight into how our actions as healthcare providersare perceived by patients. We hope to provide you withmore perspectives from MMA as she journeys throughher cancer treatment, which at this point includes astem cell transplant in the near future. MMA would like

to remain anonymous, but we welcome her contributionsto TON.March is national colorectal cancer awareness month. To

acknowledge this, Noteworthy Numbers focuses on the sta-tistics of this disease, which is the second leading cause ofcancer-related death in the United States. Our CancerCenter Profile this month is an interview with TalineKhoukaz, an oncology nurse specializing in colorectal can-cer at the USC Norris Comprehensive Cancer Center inLos Angeles. Taline tells us about the changes she’s seen inthe field and makes it clear that she likes chocolate! Pleasenote Tara Rich’s article discussing the “crizotinib miracle,”which demonstrates some of the promise that personalizedmedicine can bring to oncology care. Be sure to visit our Web site, www.TheOncology

Nurse.com. You’ll find a delicious quinoa recipe from KarenConnelly, and you can respond to this month’s Reader Pollabout genetic discrimination. Let us know your thoughtsabout The Patient’s Voice—we want to hear your reactionsto MMA’s experience. And, as always, let us know whattopics you want to see covered in TON. �

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

Editor-in-Chief

Drug Shortage ActionsOn February 21, 2012, the FDA announced a series ofactions to deal with the severe shortages of Doxil (doxoru-bicin hydrochloride liposome injection; Janssen Research &Development, LLC) and preservative-free formulations ofmethotrexate. Doxorubicin is used to treat patients withovarian cancer, multiple myeloma, and Kaposi’s sarcomawhen first-line therapies have failed. Methotrexate is anantimetabolite used in both adults and children for the treat-ment of osteosarcoma, acute lymphoid leukemia, and lungcancer. It is also used to treat adults with gestational troph -oblastic tumors, meningeal leukemia, breast cancer, head andneck cancer, advanced mycosis fungoides, and advancednon-Hodgkin lymphomas.

Doxorubicin Hydrochloride Liposome InjectionJanssen, the sole supplier of Doxil in the United States,reported that the shortage is a result of manufacturing issuesat its contracted manufacturer, Ben Venue Laboratories,which voluntarily suspended production on November 19,2011, after problems occurred at its manufacturing facility inBedford, Ohio. A Janssen spokeswoman stated there was“unplanned downtime due to equipment failure” at the facil-ity. The facility had been cited by regulators for manufactur-ing deficiencies.To increase the supplies of doxorubicin, the FDA is

allowing the temporary importation and distribution ofLipodox. The FDA’s action is limited to Sun PharmaGlobal FZE and its authorized distributor, CaracoPharmaceutical Laboratories Ltd—no other entities willbe allowed to import or distribute doxorubicin. SunPharma’s Lipodox contains the same active ingredient

and concentration as the doxorubicin hydrochloride lipo-some injection manufactured in the US (Doxil). Lipodoxis manufactured at an FDA-inspected facility in India, andCaraco Pharmaceutical Laboratories is working with FDAto make Lipodox available to wholesalers in the US. TheFDA stated Sun Pharma Global’s Lipodox remains unap-proved for marketing in the US.According to the FDA, “Temporary importation of foreign

drugs is considered in rare cases when a shortage of anapproved critical US drug exists and the shortage cannot beresolved by manufacturers of the approved drug in the imme-diate future.”

Preservative-Free MethotrexateThe FDA has approved a preservative-free methotrexategeneric drug manufactured by APP Pharmaceuticals after aprioritized review. APP has a generic drug already approvedby the FDA, and the approval for preservative-freemethotrexate was based on a supplemental application.The pharmaceutical companies that manufacture

methotrexate slowed or stopped manufacturing for a vari-ety of reasons, citing increased demand and manufactur-ing delays. Ben Venue Laboratories, one of the suppliers ofthe preservative-free formulation of methotrexate, volun-tarily shut down production and distribution at its Ohiofacility for issues related to maintenance and requalifica-tion of equipment. After confirming the safety of thealready-manufactured preservative-free methotrexate, theFDA worked with Ben Venue to release its supply of theproduct. This supply is available for emergency distribu-tion while APP and other manufacturers work to increasethe production of preservative-free methotrexate. �

Recent FDA Updates

Check out our user-friendly Web site

www.TheOncologyNurse.comIn addition to Web-only exclusives, news coverage, and journal articles,

you’ll have the opportunity to participate in our current reader poll.

TON_March2012_v8_TON 3/16/12 11:07 AM

Your determination to educate patients on how they can benefi t from therapy is what makes you a vital part of the treatment team

©2011 Cephalon, Inc. All rights reserved. TRE-2354 August 2011 Printed in USA.

DISCOVER THE MANY WAYS TREANDA® SUPPORTS NURSES IN THE CONTINUED FIGHT AGAINST CANCER.Patient brochures and treatment diaries Everything patients need to know about their disease and treatment in an easy-to-read format Patients can track their progress, blood counts, and report side effects

Learn more about all of these resources at www.TREANDA.com.

IndicationsTREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Ef� cacy relative to � rst-line therapies other than chlorambucil has not been established. TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.Important Safety Information Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA The most common non-hematologic adverse reactions associated with TREANDA (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. The most common hematologic abnormalities associated with TREANDA (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia

Cephalon Oncology Reimbursement Expertise (CORE) A service that helps patients and providers with the reimbursement process and accessing TREANDA

CephalonCares® Foundation A program that provides patients who qualify with FDA-approved Cephalon products free of charge

Additional disease education tools and useful patient resources

Real Patients. Real Passions. Real Practices.

We want to hear about your patients’ success with TREANDA. Help them share their story today!

From Where I Stand is a program in which patients who have bene� tted from treatment with TREANDA share their experiences

TON_March2012_v8_TON 3/15/12 11:02 AM

Brief Summary of Prescribing Information

INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions]

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

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

Number (%) of patients TREANDA Chlorambucil (N=153) (N=143)System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17)Gastrointestinal disordersNausea 31 (20) 1 (<1) 21 (15) 1 (<1)Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued)

Number (%) of patients TREANDA Chlorambucil

(N=153) (N=143)System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditionsPyrexia 36 (24) 6 (4) 8 (6) 2 (1)Fatigue 14 (9) 2 (1) 8 (6) 0Asthenia 13 (8) 0 6 (4) 0Chills 9 (6) 0 1 (<1) 0Immune system disordersHypersensitivity 7 (5) 2 (1) 3 (2) 0Infections and infestationsNasopharyngitis 10 (7) 0 12 (8) 0Infection 9 (6) 3 (2) 1 (<1) 1 (<1)Herpes simplex 5 (3) 0 7 (5) 0Investigations Weight decreased 11 (7) 0 5 (3) 0Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1)Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

TREANDA Chlorambucil (N=150) (N=141)

Laboratory Abnormality All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) n (%)Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9)Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10)Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3)Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4)Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176)

System organ class Number (%) of patients*Preferred term All Grades Grade 3/4Total number of patients with 176 (100) 94 (53)at least 1 adverse reaction Cardiac disordersTachycardia 13 (7) 0Gastrointestinal disordersNausea 132 (75) 7 (4)Vomiting 71 (40) 5 (3)Diarrhea 65 (37) 6 (3)Constipation 51 (29) 1 (<1)Stomatitis 27 (15) 1 (<1)Abdominal pain 22 (13) 2 (1)Dyspepsia 20 (11) 0Gastroesophageal reflux disease 18 (10) 0Dry mouth 15 (9) 1 (<1)Abdominal pain upper 8 (5) 0Abdominal distension 8 (5) 0General disorders and administration site conditionsFatigue 101 (57) 19 (11)Pyrexia 59 (34) 3 (2)Chills 24 (14) 0Edema peripheral 23 (13) 1 (<1)Asthenia 19 (11) 4 (2)Chest pain 11 (6) 1 (<1)Infusion site pain 11 (6) 0Pain 10 (6) 0Catheter site pain 8 (5) 0

TON_March2012_v8_TON 3/15/12 11:02 AM

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued)

System organ class Number (%) of patients*Preferred term All Grades Grade 3/4 Infections and infestationsHerpes zoster 18 (10) 5 (3)Upper respiratory tract infection 18 (10) 0Urinary tract infection 17 (10) 4 (2)Sinusitis 15 (9) 0Pneumonia 14 (8) 9 (5)Febrile Neutropenia 11 (6) 11 (6)Oral Candidiasis 11 (6) 2 (1)Nasopharyngitis 11 (6) 0InvestigationsWeight decreased 31 (18) 3 (2) Metabolism and nutrition disordersAnorexia 40 (23) 3 (2)Dehydration 24 (14) 8 (5)Decreased appetite 22 (13) 1 (<1)Hypokalemia 15 (9) 9 (5)Musculoskeletal and connective tissue disordersBack pain 25 (14) 5 (3)Arthralgia 11 (6) 0Pain in extremity 8 (5) 2 (1)Bone pain 8 (5) 0Nervous system disordersHeadache 36 (21) 0Dizziness 25 (14) 0Dysgeusia 13 (7) 0Psychiatric disordersInsomnia 23 (13) 0Anxiety 14 (8) 1 (<1)Depression 10 (6) 0Respiratory, thoracic and mediastinal disordersCough 38 (22) 1 (<1)Dyspnea 28 (16) 3 (2)Pharyngolaryngeal pain 14 (8) 1 (<1)Wheezing 8 (5) 0Nasal congestion 8 (5) 0Skin and subcutaneous tissue disordersRash 28 (16) 1 (<1)Pruritus 11 (6) 0Dry skin 9 (5) 0Night sweats 9 (5) 0Hyperhidrosis 8 (5) 0Vascular disordersHypotension 10 (6) 2 (1)

*Patients may have reported more than 1 adverse reaction.NOTE: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).

Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies

Percent of patientsHematology Variable All Grades Grade 3/4Lymphocytes Decreased 99 94Leukocytes Decreased 94 56Hemoglobin Decreased 88 11Neutrophils Decreased 86 60Platelets Decreased 86 25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions]

OVERDOSAGE: The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

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

TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration.

Sterile Water for Injection, USP Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used.

and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture

for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown

discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.

DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Manufactured by: Manufactured for:Pharmachemie B.V. Cephalon, Inc.The Netherlands Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates.

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

TON_March2012_v8_TON 3/15/12 11:02 AM

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1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM


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1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM1/18/12 3:59 PM


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ome.cSeaGenSecurGEN (855.473.2436)855.4SEA


GEN (855.473.2436)

1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM1/19/12 10:22 AM


Overall, the lifetime risk ofdeveloping colorectal canceris approximately 1 in 20(5.1%), and the risk is slightlylower for women than men.

The risk of developing colorectal cancer increaseswith age. More than 90% of cases develop in people aged 50 or older.

It is estimated there will be103,170 new cases of coloncancer and 40,290 new casesof rectal cancer in the US in2012.


Noteworthy Numbers

ADCETRIS, SeaGen Secure and their logos are trademarks and Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2012 Seattle Genetics, Inc., Bothell, WA 98021

All rights reserved. Printed in USA US/BVP/2011/0150

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

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

Indications and usageThese indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS.

ADCETRIS (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.

ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

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

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

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

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

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

Progressive multifocal leukoencephalopathy JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression.

Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

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

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

Adverse reactionsADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased.

ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting. The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

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

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

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

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

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

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

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

Pediatric useThe safety and effectiveness of ADCETRIS have not been established in the pediatric population. Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

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

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

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

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

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

Dose modificationPeripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.

Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

Colorectal cancer is the second leading cause of cancer-related deaths in the United States among men and women. As we recognize colorectal cancer awareness month, let’s examine the statistics.

From 2004 to 2008, 75years was the medianage at death for patientswith cancer of the colonand rectum.

The disease is expected tocause approximately51,690 deaths during 2012(26,470 in men and 25,220in women).

As of 2010, 1 in 3 adultsbetween the ages of 50and 75 were not up-to-date with recommendedcolorectal cancer screening.

The death rate fromcolorectal cancer hasbeen declining over thepast 20 years.

If patients aged 50 yearsand older were screenedregularly, as many as 60% of colorectal cancerdeaths could be prevented.

Between 2003 and 2007,approximately 66,000 co lorectal cancer caseswere prevented and32,000 lives were saved(compared with 2002).Half of the preventedcases and deaths wereavoided as a result of colorectal cancer screening.

From 2004 to 2008, theaverage age at the timeof colorectal cancer diagnosis was approxi-mately 70 years.

Today, there are morethan 1 million colorectalcancer survivors in theUS.

Sources: www.cdc.gov/features/colorectalawareness/; www.cancer.org/Cancer/ColonandRectumCancer/DetailedGuide/colorectal-cancer-key-statistics;http://seer.cancer.gov/statfacts/html/colorect.html#incidence-mortality; www.cancer.net/patient/Cancer+Types/Colorectal+Cancer?sectionTitle=Statistics.

TON_March2012_v8_TON 3/15/12 8:28 PM Page 13

many important protections, the law isonly as good as its interpretation andenforcement. This is especially true inthe oncology setting.Oncology nurses interact with patients

at all stages of the genetic testing process:prior to being identified as at-risk for ahereditary cancer syndrome, duringgenetic counseling and testing, and afterbeing diagnosed with a hereditary cancersyndrome. Therefore, it is important foroncology nurses to have a basic under-standing of GINA as it applies to patientsin the various stages of identification.Not only can oncology nurses help mini-mize misconceptions about genetic dis-crimination, they can also assist patientsin being proactive after undergoing can-cer genetic testing to fully maximize theprotections GINA provides.

Overview of GINAGINA was signed into law on May 21,2008.3 It is a federal law and as such pro-vides a basic level of protection for allAmericans. It prohibits health insurersand employers from discriminatingagainst individuals on the basis of genet-ic information. It also prohibits theseactors from collecting genetic informa-tion except in limited circumstances dis-cussed below. Some states have provi-sions for genetic discrimination that aremore protective than GINA.4 In suchsituations, entities must comply withGINA and the more protective statelaws. The definition of genetic informa-tion in GINA is not limited to genetictest results. It is defined broadly andincludes family medical history, genetictest results, participation in geneticresearch, and use of genetic services.5GINA does not apply to Tricare, theVeterans Health Administration, theIndian Health Service, or the FederalEmployees Health Benefits Program.However, many of these programs haveprotections similar to GINA. AlthoughGINA does provide protection for themajority of individuals against geneticdiscrimination for health insurance andemployment, it is important to note thatGINA does not apply to life, long-termcare, or disability insurance.The only circumstance under which a

health insurance company can requestgenetic information is when trying todetermine if a procedure is medicallynecessary. For example, if a patient isseeking to undergo prophylactic surgery,the insurance company can gather infor-mation about genetic test results andfamily history to determine if that is anecessary procedure. The insurancecompany does not have to cover theprocedure, but it cannot use the geneticinformation to raise rates, cancel a poli-cy, or otherwise discriminate. UnderGINA, if it is reasonable for an employ-

er or insurance company to expect thatgenetic information could be gatheredin a request for medical records, the col-lection request must explicitly state thatgenetic information should not be pro-vided. If healthcare professionals orpatients do not comply with the noticeby handing over genetic information,then insurance companies will not haveviolated the law by receiving geneticinformation.

Applying Knowledge to ClinicalPracticeScenario 1: Patient is consideringgenetic servicesSamantha is a 38-year-old female recentlydiagnosed with breast cancer. Additionally,she has a family history of numerous can-cers. She was previously referred for genet-ic counseling, and you notice she did notkeep her appointment. When you inquireabout the reason, she responds, “If I have apositive genetic test, I will lose my healthinsurance.” How can you encourageSamantha to undergo genetic counseling?Genetic counseling is a multifaceted

process. One component of the processis empowering patients to make aninformed decision regarding genetictesting. Therefore, undergoing geneticcounseling does not translate into auto-matic genetic testing. The practitionerproviding the genetic counseling willdiscuss the benefits, limitations, andrisks of genetic testing. Additionally, heor she will discuss current legislationregarding genetic discrimination.6,7Under GINA, the definition of genetic

information includes use of genetic ser -vices, such as genetic counseling. Thus,a health insurer or employer cannot dis-criminate against an individual based onundergoing genetic counseling. There -fore, you can encourage Samantha tomeet with a genetics provider to obtainadditional information. It is the respon-sibility of the individual providing thegenetic counseling to discuss state andfederal laws as they apply to genetic test-ing in more detail.As Samantha has expressed that her

concern is loss of health insurance witha positive test result, educating herabout the benefits of genetic counselingmay not be enough. To encourage her toattend the appointment, you can reas-sure her that under GINA a healthinsurer cannot use the results of a genet-ic test to discriminate. Additionally, shemay not be aware that her test resultsmay have implications in her currenttreatment and future medical manage-ment, as well as medical managementfor her family members. Her actual riskof genetic discrimination is most likely

much less than the chance she wouldhave an additional cancer if she testedpositive. In the unlikely situation thatSamantha has an insurance plan thatdoes not fall under GINA’s protections,she would need to look at state laws tosee if her plan is covered under them orlook to the rules of the plan itself. Forexample, the Federal EmployeesHealth Benefits Program has rulesagainst genetic discrimination that aresimilar to many aspects of GINA.

Scenario 2: Patient has been identified as having a hereditarycancer syndromeJohn is a 40-year-old male who was foundto have over 50 adenomatous polyps on ascreening colonoscopy. Due to numerousadenomatous colonic polyps, he underwenta colectomy and was found to have an addi-tional 83 adenomatous polyps. Genetictesting revealed a mutation in the APCgene and confirmed a diagnosis of familialadenomatous polyposis. You receive arequest for medical records from his insur-ance company as it is reviewing the claim todetermine if colectomy was indicated. Whatshould you do?One of the most notable parts of

GINA is prohibition of both healthinsurers and employers gaining access toan individual’s genetic information.Discriminatory intent can often be diffi-cult to prove, and this provision helpsensure that a person cannot discriminate,even subconsciously, against the individ-ual. However, the provision is only com-pletely effective if these companies trulydo not get the information. Medicalrecords are rife with genetic information,including family history and genetic testresults. Therefore, in order to ensure fullprotection of the law, healthcareproviders and individuals with hereditarycancer syndromes should be aware of howmedical records are handled.If healthcare professionals receive a

medical records request, they should besure to redact the genetic information ofa patient to help ensure the full protec-tion of the law. This includes redactionnot just of genetic test results but also offamily medical history, use of geneticservices, and participation in geneticresearch. However, manifested diseasesare not included in the definition ofgenetic information.In John’s case, the presence of the ade-

nomatous polyps would not be redactedbecause those are manifest in the patient.However, any information about familymembers who have had cancer in thepast or John’s APC gene mutation shouldnot be passed to the insurance company.As the person receiving the request formedical records, you should make sure toremove information about John’s APCtest results, family history, genetic coun-seling services, and/or participation ingenetic research. If you send this infor-mation and the insurance company stat-ed this information should not be includ-ed, then John may not be fully protectedunder GINA.

Tabatha is a 58-year-old female diagnosedwith colorectal cancer at age 56. She has agermline mutation in the MSH2 gene and,thus, a diagnosis of Lynch syndrome.Tabatha is worried about what her diagnosismeans for her children. Additionally, she

Genetic Counseling

14 March 2012 I VOL 5, NO 2 www.TheOncologyNurse.com

Cristi Radford, MS, CGC Anya Prince, Esq

GINA was signed into law on May 21, 2008. It is a

federal law and as such provides a basic level

of protection for all Americans.

Genetic Discrimination: What Oncology Nurses Need to Know... Continued from cover


confides that she doesn’t think they shouldbe tested for the MSH2 mutation becauseshe is worried that they won’t be able to getlife insurance.Under GINA, the medical history of

family members cannot be used byhealth insurers to discriminate againstan individual. This fact is important tomention to patients such as Tabatha,who are worried about their children’swell-being. If Tabatha’s children areapplying for health insurance, they donot need to disclose their mother’s co l-orectal orMSH2 diagnosis on the appli-cation. If the health insurer somehowgets information about the colorectalcancer or MSH2 mutation, they cannotuse this information to change premiumamounts, deny coverage, change bene-fits, or otherwise discriminate.GINA does not apply to life, long-

term care, and disability insurance.Therefore, Tabatha’s concerns abouther children’s ability to get life insur-ance may be well-founded; however,this depends on where her children aretrying to get insurance. Life, long-termcare, and disability insurances are regu-lated at the state level, and the extentof protection varies greatly among thestates. As Tabatha’s nurse, you canpoint her to resources that can help herdetermine how her children are pro-tected across state lines. It is important

to keep in mind that not only the pro-tections but also the definition ofgenetic information may vary amongstate laws. For example, Connecticuthas no state-level protections for theseinsurances, while Vermont prohibitsinsurers from basing a policy of insur-ance on genetic test results. Ad -ditionally, some states, such as Cali -fornia, define genetic informationbroadly to include family history, whileothers in clude only genetic test resultsin the definition. Oncology nursesshould inform patients such as Tabathathat these laws may vary but be clearthat this is an area where there may begaps in the law.Despite possible gaps, overall, you

can encourage Tabatha to have herchildren undergo genetic counseling.The definition of genetic informationin many state laws regarding life, dis-ability, and long-term care insurance

only includes information about genetictest results, not family history. There -fore, if the insurer wants to take geneticpredispositions into account for enroll-ment, they unfortunately probablyalready have the information throughfamily medical history. Therefore, addi-tional information from a genetic testmay not change the outcome of insur-ance, but it can greatly assist medicaltreatment options. In fact, a negativetest result may even help an individualget these insurances despite a family his-tory of a disease.

Take-Home Messages• Under GINA, the definition ofgenetic information includes geneticcounseling, family medical history,and genetic test results. Thus, ahealth insurer cannot discriminateagainst an individual based onundergoing genetic counseling, their

family’s manifested diseases (such ascancer), or genetic test results

• Medical records are rife withgenetic information. When receiv-ing a request for medical records,pro viders should make sure toremove information on genetictest results, family medical history,use of genetic services, and partici-pation in genetic research toensure that their patients have thefullest protections of the law

• GINA does not apply to life, long-term care, and disability insurance.However, state laws may providesome protection. Providers shouldknow where to direct patients foradditional information �

References1. Ader T, Susswein LR, Callanan NP, et al. Attitudesand practice of genetic counselors regarding anonymoustesting for BRCA1/2. J Genet Couns. 2009;18:606-617.2. Nedelcu R, Blazer K, Schwerin B, et al. Genetic dis-crimination: the clinician perspective. Clin Genet.2004;66:311-317.3. GINA§101. Genetic Information NondiscriminationAct, H. R. 493, 110th Congress of United States ofAmerica. 2008.4. State laws on genetic privacy. www.councilforresponsiblegenetics.org/geneticprivacy/map_statelaw.html.Accessed February 15, 2012.5. GINA overview. www.ginahelp.org/. AccessedFebruary 15, 2012.6. American Society of Clinical Oncology. Statement ofthe American Society of Clinical Oncology: genetictesting for cancer susceptibility. J Clin Oncol.1996;14:1730-1736.7. American College of Obstetricians and Gyneco -logists. Hereditary breast and ovarian syndrome. ACOGPractice Bulletin. Number 103, April 2009.


Genetic Counseling

Life, long-term care, and disability insurances

are regulated at the state level, and the extent

of protection varies greatly among the states.

Have patients talked to you about the issue of genetic discrimination?

Go to www.TheOncologyNurse.com to cast your vote and add your comments.

Please tell us what you think and what your patients are saying.

Reader Poll

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Subcutaneous VELCADE Demonstrated Efficacy Consistent With IV for the Primary Endpoint

Difference in Incidence of Peripheral Neuropathy With Subcutaneous VELCADE

PERIPHERAL NEUROPATHY (PN) IN RELAPSED MM: SUBCUTANEOUS AND IVRESPONSE RATES† IN RELAPSED MULTIPLE MYELOMA (MM): SUBCUTANEOUS AND IV

Please see Brief Summary for VELCADE on next page.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.comReference: 1. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440.

▼ The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE retained at least 60% of the overall response rate after 4 cycles relative to single-agent IV VELCADE

SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed MM. The primary endpoint was overall response rate at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival (OS), and safety.

* INDICATIONS: VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

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

VELCADE IMPORTANT SAFETY INFORMATIONCONTRAINDICATIONSVELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients

with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope,

and those who are dehydrated▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal

medications or fluid replacement▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

▼ Starting VELCADE® (bortezomib) subcutaneously may be considered for patients with preexisting PN or patients at high risk for PN. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment

▼ Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness

▼ Patients experiencing new or worsening PN during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see full Prescribing Information for dose modification guidelines for PN

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS CONTINUED▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the

potential harm to the fetus

▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported

AT 24 WEEKS (AFTER 8 CYCLES) VELCADE±dexamethasone

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

NOW APPROVED FOR SUBCUTANEOUS ADMINISTRATION IN ALL INDICATIONS*

003399_milpro_schcp_vbcc_fa2.indd 1 3/7/12 10:56 AM


www.TheOncologyNurse.com18 March 2012 I VOL 5, NO 2

Bone Biomarker Identified for Metastatic Prostate Cancer Continued from cover

News Briefs

Center, New York City, was senior authorof the paper.

Bone scintigraphy is an older technol-ogy that images bone but not the cancer-ous lesions themselves. It shows the effecton the bone surrounding the metastasis,and, as such, is considered an imperfecttool on its own.

BSI is a method of expressing thetumor burden in bone as a percent ofthe total skeletal mass based on refer-ence man skeletal masses. The studyincluded 88 men enrolled in 4 differentclinical trials who had bone scintigra-phy done at baseline, 3 months, and 6months on therapy.

The percent change in BSI frombaseline to 3 and 6 months was prog-nostic for survival. Doubling of the BSIwas associated with an almost 2-foldincrease in risk of death. When com-pared head-to-head with PSA, changein PSA from baseline was not prognos-tic for survival.

“BSI tells us about response to therapyand survival. When the BSI goes up, sur-vival is shorter, and when it goes down,survival will be longer,” Morris explained.

He and his colleagues are developing acomputer-generated BSI that will havewide applicability. At present, the BSI iscomputed manually. �

Brief Summary

INDICATIONS:VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS:VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been

isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

(continued)

003399_milpro_schcp_ahdb_fa1.indd 2 3/5/12 2:18 PM


In patients with chronic kidney disease(CKD), decreasing glomerular filtra-tion rate (GFR) is associated with

increased risk of kidney and urothelialcancer in a step-wise fashion, accordingto a large community-based study. Anadjusted multivariate analysis found a 2-

fold increase in risk of renal cancer and asubstantially increased risk of urothelialcancer at GFR <30 mL/min/1.73 m2. Thestudy was presented at the 2012 ASCOGenitourinary Cancers Symp osium, heldFebruary 2-4 in San Francisco,California.

“Our study found an increased risk ofrenal and urothelial cancer with lowerGFR rates. This suggests that estimatedGFR may play a role in identifyingpatients with CKD at higher risk of thesecancers. We need to assess whether thereis a clinical benefit for targeted cancer

screenings in this population,” statedWilliam Thomas Lowrance, MD,Huntsman Cancer Institute, Universityof Utah, who presented the study.The association between dialysis

patients with end-stage renal disease(ESRD) and kidney cancer is well estab-lished, with a 3 to 4 times greater risk ofkidney cancer. The link between CKDand kidney cancer has been less wellstudied, Lowrance noted. About 11.5% of people in the United

States have CKD or proteinuria, and 13.5million Americans have stage 3 CKD orworse. CKD is an independent risk factorfor death, cardiovascular events, and hos-pitalization. About 65,000 new cases ofkidney cancer and about 75,000 newcases of urothelial cancer are reportedeach year. These diseases pose a majorhealth concern.

Using the SEER (Surveillance,Epidemiology, and End Results) registryto capture data from 2000 through 2008,Lowrance and colleagues analyzed KaiserPermanente members of their renal reg-istry, excluding members with preexistingcancer or ESRD. Just under 1.2 million adults were

included, with a median follow-up of 5.3years. During that time, more than76,000 had a new cancer diagnosis.Median age was 55 years, and median ageincreased with decreasing GFR. Increasein comorbidities was associated withdecreasing GFR.The crude rate of renal cancer

increased in a step-wise fashion as GFRdecreased.The same was true for urothelial can-

cers. In a multivariate analysis adjustedfor confounding factors, these results per-sisted for kidney and urothelial cancers,but no association was seen with breast,lung, colorectal, or prostate cancer. Lowrance said that one limitation of

this study is potential selection bias, sincesubjects with worse renal function may befollowed more closely. Also, there was noadjustment for severity of comorbiditiesor dosages of medication. “More study is needed to elucidate the

mechanism by which decreased GFRmay play a role in development of kidneyand urothelial cancers,” he said. � —AG


News Briefs

About 11.5% of people in

the United States have

CKD or proteinuria, and

13.5 million Americans

have stage 3 CKD

or worse.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE (bortezomib). Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA:Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs

were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group.

DRUG INTERACTIONS:Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE (bortezomib) is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

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

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0017 3/12

003399_milpro_schcp_ahdb_fa1.indd 3 3/5/12 2:18 PM

Chronic Kidney Disease and Risk of Kidney Cancer



News Briefs

Colonoscopy screening and re -moval of adenomatous polypsreduced the risk of colorectal

cancer death by 53% in a recent studyreported in the New England Journal ofMedicine (2012;366:687-696).According to the authors, the find-

ings demonstrate that adenomas iden-tified and removed at colon oscopy areclinically important, because theyhave the potential to develop into carcinomas.Colorectal cancer is common, with

an expected 143,000 new cases and51,000 deaths due to colorectal cancerin the United States this year. Al -though polypectomy via colo n oscopyhas been shown to prevent the devel-opment of colorectal cancer, the long-term cancer-specific mortality amongpeople who have had adenomatouspolyps removed via colonoscopy is notwell studied.Study subjects (N = 2602) were par-

ticipants in the National Polyp Studywho had adenomatous polyps removedduring colonoscopy. The NationalPolyp Study was a randomized trial ofsubjects referred for colonoscopybetween 1980 and 1990 because ofpositive findings on a barium enematest, sigmoidoscopy, fecal occult bloodtests, or other tests, or because they

had symptoms or a family history ofcolon cancer. Subjects were followedfor a median of 16 years, with a maxi-mum follow-up of 23 years. Among the 2602 patients with ade-

nomas removed during the study, aftera median follow-up of 15.8 years, 1246

study subjects (48%) died, including12 deaths due to colorectal cancer.Using data from the SEER

(Surveillance, Epidemiology, and EndResults) registry, the authors determinedthe expected number of deaths in thegeneral population among peoplematched for age, sex, and race. The esti-mated percentage of cumulative deathsfrom colorectal cancer in the generalpopulation over 20 years was 1.5%, com-pared with a cumulative mortality of0.8% in the adenoma cohort treatedwith polypectomy.

The cancer mortality rate of the ade-noma cohort was also compared with agroup of 773 participants in theNational Polyp Study who had beenfound to have nonadenomatous polypson initial colonoscopy. Over the first 10years after the index colonoscopy, the

mortality rate was 0.15% in the non-adenomatous polyp group versus 0.19%in those with adenomas.These findings show that the risk of

mortality due to colorectal cancer wassimilar between patients with adeno-mas removed at first colonoscopy andthose with nonadenomatous polypsremoved at that time. The authors used a model to estimate

mortality if the adenomas had not beenremoved and no intervention had inter-fered with the natural history of adeno-mas developing into carcinoma.

“The model showed an even largerreduction in mortality [after] polypecto-my than the comparison with the SEER incidence-based mortality rates,”noted lead author Ann Zauber, PhD,Memorial Sloan-Kettering CancerCenter, New York City.For colonoscopy to be effective,

adults who are candidates must complywith screening guidelines. But severalstudies have shown poor compliance inthe United States, as well as a generalreluctance to undergo colonoscopy.The compliance problem is not limitedto the US. In the same issue of theNew England Journal of Medicine, astudy from Spain found that only24.6% of adults offered colonoscopyagreed to undergo the test. � —AG

Colonoscopy With Polypectomy Saves Lives

Patients with metastatic renal cellcarcinoma (mRCC) who do notmeet eligibility criteria for clinical

trials have worse outcomes on targetedtherapy compared with eligible pa -tients. In fact, extrapolating results ofclinical trials to ineligible patientsleads to inferior response rates (RRs),progression-free survival (PFS), andoverall survival (OS).“Many patients in everyday practice

do not meet eligibility for clinical trials,yet they receive the same targeted thera-pies as those in clinical trials. Our studyshows that ineligible patients have worseoutcomes and 1.5 times greater risk ofdeath on the same therapies comparedwith eligible patients. These findingssuggest that these discrepancies shouldbe taken into account when we considerusing protocol therapies in protocol-inel-igible patients. We need to temper ourenthusiasm,” said lead author DanielYick Chin Heng, MD, Tom Baker

Cancer Centre, University of Calgary,Alberta, Canada. Heng presented thestudy results at the 2012 ASCOGenitourinary Cancers Symposium.The study included 894 ineligible

patients and 1182 eligible patients withmRCC consecutively treated withVEGF-targeted therapy at 17 interna-tional cancer centers. Patients weredeemed ineligible retrospectively

according to common exclusion criteriafor clinical trials. All other patientswere assumed to be eligible.Patients received a variety of anti-

VEGF tyrosine kinase inhibitors,including sunitinib, sorafenib, beva-cizumab, pazopanib, and axitinib. Themost common exclusion criteria wereKarnofsky performance status <70%(13.4%), nonclear cell histology

(11.2%), brain metastasis (8.3%), andhemoglobin 9 g/dL (7.4%). Patients inthe ineligible group were much morelikely to be poor risk, and fewer hadundergone nephrectomy compared witheligible patients.Overall response rate was 27%. RR

was 34% in favorable-risk patients, 28%in intermediate-risk patients, and 19%in poor-risk patients. RRs were uniform-ly lower in ineligible patients than eligi-ble patients for every risk category.Median PFS was 8.6 months for eligi-

ble patients and 5.2 for ineligiblepatients (P <.0001); median PFS whenthese drugs were used as second-linetherapy was 4.4 months and 3.2months, respectively (P = .0074).Median OS was 28.8 months versus14.5 months, respectively (P <.0001).“Specific trials should be undertaken

to address the needs of protocol-ineligi-ble patients and assess overall survival,”he said. � —AG

Protocol-Ineligible Patients With Metastatic Renal Cell Carcinoma Fare Worse Than Those Eligible for Clinical Trials

“Many patients in everyday

practice do not meet

eligibility for clinical trials,

yet they receive the same

targeted therapies as those

in clinical trials.”

—Daniel Yick Chin Heng, MD

© A

SC

O/T

odd B

uchanan 2

012.

Colorectal cancer is common, with an expected

143,000 new cases and 51,000 deaths due to

colorectal cancer in the United States this year.

Diabetes is associated with an in creased risk of colon and rectal

cancers, even in studies thatcontrolled for the common

risk factors of smoking, obesity, and exercise.

—Am J Gastroenterol. 2011;106:1911-1921.

Did You Know?


Longer follow-up of a phase 2 trialshows that vemurafenib (Zelboraf)extends overall survival (OS) for

patients with BRAF-positive metastat-ic melanoma. Median OS was 16months, compared with the medianOS of 6 to 10 months typically report-ed for advanced melanoma (N Engl JMed. 2012;366:707-714).First reports from the phase 2 trial

showed that vemurafenib inducedmeaningful responses in a significantnumber of BRAF-positive patients, butthe study was not long enough to showan effect on OS at the time thoseresults were presented. The latest dataare an update on the effect of the drugon survival.

About 50% of patients with advancedmelanoma are BRAF-positive. “Thisstudy shows that vemurafenib changesthe natural history of the disease. Theseresults tell us that the drug is having avery big impact and this changes theway we treat metastatic melanoma,” saidcoprincipal investigator, Antoni Ribas,MD, UCLA Jonsson ComprehensiveCancer Center, Los Angeles, California.Jeffrey Sosman, MD, Vanderbilt-IngramCancer Center, Nashville, Tennessee,was coprincipal investigator as well.The study enrolled 132 patients with

stage IV BRAF-positive melanomapreviously treated with at least 1 sys-temic therapy. The rate of partialresponse was 47%, and completeresponse was 6%. Overall response ratewas 53% in these advanced patients.The majority of patients had at least

1 adverse event that was attributed tovemurafenib. The most commonadverse events were arthralgia, rash,

sun sensitivity, alopecia, and fatigue.Twenty-six percent developed cuta-neous squamous cell carcinoma, whichwas treated with surgical excision. Vemurafenib has also been studied

in a phase 3 trial. An interim analysisshowed that vemurafenib achieved a

significant improvement in both pro-gression-free survival and OS versuschemotherapy. The phase 2 trial is thefirst to confirm the durability of response.Vemurafenib is approved for metastat-

ic melanoma in the United States,Europe, and elsewhere. � —AG

Vemurafenib Extends Survival in PatientsWith BRAF-Positive Metastatic Melanoma


News Briefs

www.AONNonline.orgAONNKsize_81911

Best Practices

��

A selection of member-submitted best practicesfor others to learn from and comment on.

��

Nurse & Patient Navigator Association

Continuing EducationLearn how to advance your understanding of the complexities of cancer care through our live, online, and printed educational activities.

Networking OpportunitiesCoordinated events throughout the year both in person and online to help you connect withmembers and leaders.

Expert Opinion BlogsThought-provoking articles from the leadersin navigation and survivorship on varioussubject areas.

Community ResourcesA collection of resources to help you and yourpatients better navigate their cancer treatment.

PublicationsSubscriptions to the Journal of Oncology Navigation & Survivorship® and The OncologyNurse®-APN/PA.

��

“This study shows that

vemurafenib changes

the natural history of

the disease. …the drug

is having a very big

impact and this changes

the way we treat

metastatic melanoma.”

—Antoni Ribas, MD

A recent study showed that peoplewith systemic lupus erythematosus

may be at increased risk forpotentially viral-related

malignancies, especially thosecancers associated with the human

papilloma virus.

—Arthritis Rheum. 2011;63:3032-3037.

Did You Know?



Supportive and Palliative Care

Pain is a frequent and pervasiveproblem for older persons withcancer, affecting approximately

80% of this population.1 Treating olderadults with cancer can be complexbecause of the presence of comorbidconditions that may impact chronicpain.2 Once pain is identified and thecause is known, it is sometimes neces-sary to target specific pain mecha-nisms.3 Hence, a comprehensive assess-ment of each individual patient isessential in order to identify all of theconditions contributing to pain.Older persons with cancer also expe-

rience pain directly related to diseaseor treatment modalities, such as radia-tion therapy or surgery. Cancer-relatedchronic pain is not limited to thosewho are receiving end-of-life care butmay be present in patients for whomcure or control of the underlying can-cer is the treatment goal. With contin-uing advances in cancer treatment,patients can be expected to live longer,thus requiring ongoing extended painmanagement. Despite the many advances in pain

management over the past fewdecades, and the numerous guidelinesand evidenced-based measures avail-able to physicians and practitioners fortreating cancer-related pain, under-treatment of pain in cancer patientscontinues to be a problem.4

AssessmentIt is through a thorough pain assess-ment that clinicians can understandhow to help their patients. Since painis subjective and there is no objectiveway to measure it, a satisfactorymethod of pain assessment is the foun-dation needed to properly control painin older patients with cancer.

Methods of Pain AssessmentWhen it comes to assessing pain inten-sity, there are many different scalesavailable that have proven to be valid.In a cross-sectional multicenter studyof 240 advanced cancer patients withpain, background pain and currentpain intensity were assessed using a 6-point verbal rating scale as well as an11-point (0-10) numeric rating scale.During this study, the numeric ratingscale was shown to be most consistentand reproducible, suggesting that dur-ing cancer pain exacerbations, patientsuse numeric rating scales more appro-priately and effectively.5 According toHerr and colleagues, older adults, par-ticularly those with cognitive impair-ment, tend to prefer vertical rather

than horizontal scales.6 When everpain is assessed, no matter which scaleis used, it is important to ensure thatthe scale is well understood by the cli-nician who is presenting the scale tothe patient.

Pain Assessment in Older AdultsA study reviewing emergency depart-ment records of older adult patientsfound that 34% had no objectiveassessment of pain documented.7 Painassessment and reassessment are essen-tial to managing and treating painappropriately; however, such reassess-ments are often lacking. When apatient is able to self-report, simplyusing a pain scale to determine painintensity is not the completion of painassessment. One obstacle in this popu-lation is the inability of older adults toself-report with accuracy.

Pain Assessment in IndividualsWith CancerThorough pain assessment is done byboth the nurse and the clinician todetermine all aspects of the patient’spain. As self-report is the standard ofcare, this assessment is obtained fromthe patient. It is important for clini-cians to determine the location andintensity of the pain; whether the paininterferes with daily activities; thetiming (onset, duration, course, per-sistent or intermittent), quality, and

description of the pain; any aggravat-ing and alleviating factors; any otherassociated symptoms; and any currentor past treatments and why these werestarted or stopped and by whom. It isimportant to obtain a complete histo-ry and physical so that polypharmacycan be avoided. At the end of theassessment, a pain diagnosis and anindividualized pain treatment planshould be established, based on mutu-ally agreed upon goals.8

Treatment of Chronic Cancer PainMany studies on the treatment of painspecifically related to older adultswith cancer pain have been conduct-ed. For example, one cross-sectionalstudy in 2004 by the National NursingHome Society of 1174 nursing homesin the United States examined painprevalence, pain treatment, and asso-ciated factors in 303 older residentsassigned to a hospice specialty unit.Of these residents, 11.4% had a can-cer diagnosis, 36.63% had experi-enced pain in the past 7 days, and ofthose with observed or reported pain,86.4% had received analgesics, with65.5% receiving an opiate prepara-tion. While it is clear that residentswith pain are receiving some pharma-cologic intervention, the lack of painmedication in the prior 24-hour periodsuggests the potential for inadequatepain control overall.9 With the knowl-edge that 45% to 80% of nursing homeresidents endure substantial pain, it isdisconcerting to know that these med-ications are not being provided to clientson a more regular basis.2 These studieshighlight the need for more diligentassessment and reassessment of pain toensure that patients’ pain is continuallyaddressed and managed. Nonpharmacologic treatments for

cancer pain are also available; however,there are fewer rigorous clinical trialsinvestigating the use and effectiveness ofnonpharmacologic therapies in manag-ing cancer pain, and these treatmentsneed additional research before recom-mendations for practice can be made.The Cancer Health Empower ment forLiving without Pain (Ca-HELP) studywas a randomized trial sponsored by theAmerican Cancer Society that was com-pleted in Sacramento, California. Thisstudy included 265 cancer patients withpain of at least moderate severity whowere randomly assigned to receive eithereducationally enhanced usual care(EUC) or tailored education and coach-ing (TEC), to demonstrate that a brief,tailored patient activation intervention

may promote better cancer pain care andoutcomes.10 This study showed thatTEC, compared with EUC, resulted inimproved pain communication self-effi-cacy and temporary improvement inpain-related impairment, but no im -provement in the pain severity itself.11A quasi-experimental, comparative

study in 187 ambulatory-care cancerpatients tested an educational interven-tion called “Passport to Comfort,” whichfocused on reducing barriers to pain andfatigue management through education-al sessions. To be included, patients withbreast, lung, colon, or prostate cancershad to report pain and/or fatigue of atleast 4 or greater on an 11-point (0-10)numeric scale. The intervention, whichincluded 4 educational sessions, wasshown to be effective in both reducingpatient barriers to pain and fatigue man-agement as well as increasing patientknowledge regarding pain and fatigue.12When treating chronic cancer pain, weshould continue to explore educationalinterventions in the older adult popula-tion, as these might be beneficial to ourpatients.

Barriers to Cancer PainManagementThere are numerous barriers to treatingpain in older adults, including thatthey are more tolerant of pain, thatthey cannot tolerate the use of opioidsfor cancer pain, and that they experi-ence less pain and/or are less sensitiveto pain.13 Also, it is a common miscon-ception that older adults withdecreased cognitive function experi-ence less pain or are completelyunaware of pain. In a cross-sectional,correlational study, Allen and col-leagues explored the associationsbetween pain and cognitive functionamong cancer patients and their fami-ly caregivers.14 What they found wasthat, contrary to expectations, patientswith cognitive impairment reportedmore intense pain than did patientswith intact cognitive function.Barriers that can be common to all

adults have been documented well inthe literature. Patients’ beliefs andactions lead to underreporting and thusundertreatment of pain. Some patientsare reluctant to report pain because theyare fearful of side effects from pain med-ications; they feel pain control is not arealistic goal; they do not want to dis-tract their physicians from continuingto treat their cancer; or they might feelthat the pain means their disease is pro-gressing. Physicians and practitionersface barriers as well. These include fail-

Assessing Pain in a Geriatric Oncology PopulationBy Rachelle Rodriguez, MS, ARNP, AOCNPUniversity of South Florida, College of Nursing, Tampa, Florida

Rachelle Rodriguez, MS, ARNP, AOCNP

It is through a thorough

pain assessment

that clinicians can

understand how to help

their patients.



Supportive and Palliative Care

ing to adequately assess pain or recog-nize barriers the patient is experiencing;lack of knowledge regarding treatmentoptions for pain or side effects; and notunderstanding key concepts such as addiction, tolerance, dosing, andcommunication.12

Implications for Research andNursing PracticeThere is a gap in the literature in regardto pain control in long-term cancercases. More research is needed to deter-mine how much more effective an inter-disciplinary team is at not only managingbut also assessing pain in cancer patients.More research is also needed specificallyrelated to chronic cancer pain and howoften practitioners are assessing this painin both inpatient and outpatient settings.Nurses are also vital in the assessment

of pain, and this is a core competencythat must be mastered in all clinical set-tings. Individualized, comp rehensive,continued assessment allows the nurse torelay vital information to the clinicianregarding the patient, which is why it isso important that nurses receive contin-ued education on pain assessment andthat there be continued research todetermine best nursing practices forassessment in various settings.When patients are confronted with

a diagnosis of cancer, they are fearful ofthe future and what life now holds forthem. Despite practitioners’ bestattempts to reassure patients andanswer their questions, patients cannothelp but think they are about toembark on a long painful road. Aspractitioners, we must not only reas-sure patients that there are options forpain treatment but also ensure thatthorough assessment and reassessmentof pain continues and is integrated intoall aspects of care. In order to givepatients the best possible pain control,it is important to continue to imple-ment evidence-based treatment proto-cols and utilize guidelines for pain, spe-cific not only to cancer patients butalso to the older adult. This is a specialpopulation, one that will have specialpsychological needs and will, in manycircumstances, be dealing with thisdiagnosis for the rest of their life, thusrequiring ongoing long-term manage-ment of pain. �

References1. Rao A, Cohen HJ. Symptom management in the eld-erly cancer patient: fatigue, pain, and depression. J Natl Cancer Inst Monogr. 2004;32:150-157. 2. Miaskowski C. Effective management of pain inolder adults with cancer. Oncol Nurs Forum. 2010;37(suppl):5-6.3. American Geriatrics Society Panel on Phar -macological Management of Persistent Pain in OlderPersons. Pharmacological management of persistent painin older persons. J Am Geriatr Soc. 2009;57:1331-1346. 4. Deandrea S, Montanari M, Moja L, et al. Prevalenceof undertreatment in cancer pain: a review of publishedliterature. Ann Oncol. 2008;19:1985-1991.5. Brunelli C, Zecca E, Martini C, et al. Comparisonof numerical and verbal rating scales to measure pain

exacerbations in patients with chronic cancer pain.Health Qual Life Outcomes. 2010;22:42.6. Herr K, Spratt KF, Garand L, et al. Evaluation of theIowa pain thermometer and other selected pain inten-sity scales in younger and older adult cohorts usingcontrolled clinical pain: a preliminary study. Pain Med.2007;8:585-600. 7. Herr K, Titler M. Acute pain assessment and phar-macological management practices for the older adultwith a hip fracture: review of ED trends. J Emerg Nurs.2009;35:312-320.8. National Comprehensive Cancer Network. NCCNClinical Practice Guidelines in Oncology: Adult Cancer

Pain. Version 2.2011. www.nccn.org/professionals/physician_gls/PDF/pain.pdf. Accessed September 6,2011.9. Hanlon JT, Perera S, Sevick MA, et al. Pain and itstreatment in older nursing home hospice/palliativecare residents. J Am Med Dir Assoc. 2010;11:579-583.10. Kravitz RL, Tancredi DJ, Street RL Jr, et al. CancerHealth Empowerment for Living without Pain (Ca-HELP): study design and rationale for a tailored edu-cation and coaching intervention to enhance care ofcancer-related pain. BMC Cancer. 2009;9:319.11. Kravitz RL, Tancredi DJ, Grennan T, et al. CancerHealth Empowerment for Living without Pain (Ca-

HELP): effects of a tailored education and coachingintervention on pain and impairment. Pain. 2011;152:1572-1582.12. Borneman T, Koczywas M, Sun VC, et al.Reducing patient barriers to pain and fatigue manage-ment. J Pain Symptom Manage. 2010;39:486-501.13. Miaskowski C, Cleary J, Burney R, et al. Guidelinefor the Management of Cancer Pain in Adults andChildren. 3rd ed. Glenview, IL: American Pain Society;2005.14. Allen RS, Haley WE, Small BJ, et al. Pain reportsby older hospice cancer patients and family caregivers:the role of cognitive functioning. Gerontologist.2002;42:507-514.

“Quality care iseveryone’s business.”

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Cancer Center Profile

The USC Norris Comp re -hensive Cancer Center pro-vides patient care throughinpatient and outpatient ser - vices at several affiliated hos-pitals (USC Norris CancerHospital, Child ren’s HospitalLos Angeles, USC Uni -versity Hospital, and LosAngeles County + USCMedical Center) and outpa-tient clinics.

Taline Khoukaz, NP, MSN,ACNP-C, works in theGastrointestinal Oncology Program atthe USC Norris Comprehensive CancerCenter. She answered our questionsabout colorectal cancer care and workingas part of a multidisciplinary team.

As an oncology nurse specializing incolorectal cancer, can you describeyour interaction with the multidisci-plinary team at USC Norris Comp re -hensive Cancer Center and how itrelates to patient outcomes?

Taline Khoukaz (TK): At USCNorris Comprehensive Oncology

Department, we have 4 GIoncologists and 3 nursepractitioners. The multidis-ciplinary group consists ofspecialized colorectal sur-geons, hepatobiliary sur-geons, radiation oncolo-gists, a patient advocate, anostomy nurse, dietitians,and genetic counselors.Working as a team, weprovide effective andseamless outcomes for ourpatients. In addition, our

delegated social worker provides emo-tional support for patients and theirfamily members and assists in makingappropriate referrals to home services.

What types of outreach programs forcolon cancer management is the USCNorris Cancer Center involved in?

TK: Every year in the month of March,which is colorectal cancer awarenessmonth, we at USC celebrate with ourpatients at a reception. Throughout theyear, we provide lectures to patientadvocacy groups and wellness commu-

nities, write blogs on a colon cancerWeb site, and post to a novel biomark-er-driven Web site called CollabRx(www.collabrx.com/) that we created.

Can you describe the role of geneticcounseling as part of your patients’care?

TK: The genetic counselor is an integralpart of our team, seeing all patients whomay have any kind of genetic predisposi-tion based on their age, pathology, orfamily history of cancer. She works close-ly with us to develop screening guide-lines for patients with familial adenomatous or hereditary nonpolyposiscolorectal cancer.

What are you most excited about inthe field of colorectal cancer?

TK: I have been an oncology nursepractitioner for over 11 years. Since Ihave been in this field, we have had 4new agents, including targeted agents,approved by the FDA for the treatmentof colon cancer. Patients have been liv-ing years past the survival statistics given

to them for stage IV colon cancer. AtUSC, we are very proud to be on theforefront on individualized chemothera-py. Our patients are screened for muta-tions in Kras, Braf, PI3K, and Nras, andgene expression levels of TS, ERCC-1,EGFR, VEGF, and VEGFR, which willguide us to select the most effective ther-apy for our patients.

What inspired you to become anoncology nurse?

TK: Initially, I did not consider becom-ing an oncology nurse. I used to work asan RN in the ICU, and then interviewedfor a neurosurgical nurse practitionerjob. By chance, I was offered anoncology nurse practitioner positioninstead. After much debate withmyself, I decided I would try it and seehow I felt. Immediately, I was drawnto this patient population and theirfight to live! I have found this to be amost rewarding job—with its share oftears. The patients and their familiesare always showing their gratitudewith hugs, kisses, and, at times, withchocolates! �

USC Norris Comprehensive Cancer Center Continued from cover

Oophorectomy in younger womenleads to decreased bone mineraldensity (BMD) and a higher

prevalence of arthritis, according to astudy reported at the 2011 CTRC-AACR San Antonio Breast CancerSymposium.

An estimated 300,000 women under-go oophorectomy each year in theUnited States for a variety of reasons.Women at high risk of breast cancer arerecommended to have their ovariesremoved at a younger age, and removalof the ovaries is often done togetherwith hysterectomy, which is performedfor several benign conditions, includingfibroid tumors, explained lead authorAnne Marie McCarthy, PhD, JohnsHopkins Bloomberg School of PublicHealth and Sidney Kimmel Com -prehensive Cancer Center in Balti more,Maryland. She and her colleagues want-ed to explore the effect of oophorectomyat a younger age on bone health.

“To our knowledge, this has not beenreported before. Our study suggests thatwomen who undergo oophorectomy ata younger age may have significantbone loss and may develop arthritis.

These women should have their BMDclosely monitored to prevent the devel-opment of osteoporosis. Longitudinalstudies are needed to assess bone lossover time and the incidence of arthritisin women who undergo oophorectomy,”she told listeners.

The study was based on data from thethird National Health and NutritionExamination Survey (NHANES III)from 1988 to 1994. This study focusedon women aged 40 years and older whoanswered detailed questionnaires thatincluded questions about diagnosis ofarthritis and BMD test results. Total hys-terectomy and removal of ovaries wasperformed in 98% of the oophorectomy

group. The BMD analysis included 3660women and the arthritis analysis includ-ed 4039 women. Oophorectomy wasperformed in 560 women for a variety ofreasons, excluding cancer surgery; theremaining women had intact ovaries.Low BMD was defined as BMD >2.0standard deviations below the mean.

Among women who had never usedhormone replacement therapy (HRT),those who had an oophorectomy beforethe age of 45 were more than twice aslikely as those with intact ovaries tohave low BMD. The odds of arthritiswere similar with and without HRT.

Low BMD was reported in 28.8% ofthe oophorectomy group younger than45 years, in 26% of those who had anoophorectomy after reaching 45 years,and in 23.3% of those with intactovaries. Arthritis was diagnosed in47.9% of younger women withoophorectomy, 41.5% of women olderthan 45 with oophorectomy, and 32% ofthose with intact ovaries. When HRTwas excluded, the rates of low BMD inthese 3 groups, respectively, were 50.7%,33%, and 22.9%. The rates of arthritis innon-HRT users were 54%, 50.5%, and

28.7%, respectively. A multivariateanalysis adjusted for age, race, smoking,alcohol, body mass index, parity, mater-nal history of osteoporosis, osteoporosistreatment, physical activity, calcium, andvitamin D found that age <45 at the timeof oophorectomy was the strongest pre-dictor for low BMD in the total studypopulation. When HRT users wereexcluded, oophorectomy at a youngerage remained a significant predictor oflow BMD.

The odds of arthritis were similarwith and without HRT in those whohad oophorectomy, with youngerwomen being twice as likely to get adiagnosis of arthritis as those with intactovaries. McCarthy speculated that theexplanation for an increased risk ofarthritis found in this study might berelated to deleterious effects on thejoints and cartilage occurring withestrogen deprivation.

Future studies by these investigatorswill address pre- and post-oophorecto-my effects on BMD and arthritis. Thesestudies will involve collaboration withbasic scientists, McCarthy said, notingthat she is an epidemiologist. �

Long-term Implications of OophorectomyBy Alice Goodman

Taline Khoukaz, NP,MSN, ACNP-C

Side Effect Management

An estimated 300,000

women undergo

oophorectomy each

year in the United States.


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Who Will BetheONE?

The OncologyNurse ExcellenceAward Winner

The Oncology Nurse-APN/PA Nurse Excellence awardwill recognize an oncology nurse nominated byhis/her peers for an outstanding contribution to oncology nursing practice, patient care, research, or education in 2011.

The four leading nominees will be profiled in the Aprilissue of The Oncology Nurse-APN/PA. Readers willhave an opportunity to vote for the winner online atwww.TheOncologyNurse.com/award or by visitingThe Oncology Nurse-APN/PA booth at the 2012 ONS Congress. The winner will be announced in the Juneissue of The Oncology Nurse-APN/PA.

TREANDA is manufactured by Cephalon, Inc., a whollyowned subsidiary of Teva Pharmaceutical Industries Ltd.

The Oncology Nurse-APN/PA is pleased to announce the Second Annual Oncology NurseExcellence award sponsored by TREANDA.

�� TON_March2012_v8_TON 3/15/12 11:04 AM Page 25

Basal cell carcinoma (BCC) andsquamous cell carcinoma (SCC),commonly referred to as non-

melanoma skin cancers (NMSCs), arethe most common types of cancers inthe United States. These 2 cancersaccount for approximately 2 millioncases of skin cancer annually.1 BCC isapproximately 4 to 5 times more com-mon than SCC.2 Although rarelymetastatic, BCC and SCC can causesubstantial local destruction involvingextensive areas of soft tissue, cartilage,and bone, as well as disfigurement. It isestimated that the cost of treatingthese NMSCs in the Medicare popula-tion exceeds $400 million annually.3

The Management of BCCThe goal of primary treatment for BCCof the skin is curing the tumor. Surgicalapproaches are the most commontreatment and offer the most effectivemethod for achieving cure for this con-dition; however, considerations relatedto preserving function; preservation,restoration, or physical appearance;and patient preference all may lead tothe choice of radiation therapy as theprimary treatment to achieve optimaloverall results.4

For patients who have low-risk, super-ficial BCC, or for those in whom surgeryor radiation is contraindicated or unfea-sible, topical therapies or vigorouscryotherapy may be considered, althoughthe cure rate with these options may belower. In addition, for patients at highrisk for multiple primary skin tumors,increased surveillance and prophylacticmeasures may be indicated.4

Postoperative radiation has beenwidely accepted as a valuable approachfor high-risk patients to reduce the rateof recurrence. Adjuvant radiotherapyis recommended by the NationalComprehensive Cancer Networkpanel for any NMSC that shows evi-dence of substantial perineural in -volvement; that is, involvement ofmore than a few small or large nerves.4

All patients with BCC of the trunkand extremities who have undergonelymph node dissection should be con-sidered for adjuvant radiation therapy;despite resection followed by radiationtherapy, patients at high risk oftenexperience locoregional recurrenceand distant metastasis. The behavior ofcutaneous BCC is characteristicallyindolent, but it rarely metastasizes todistant areas. When the disease doesmetastasize to distant sites, systemictherapy is indicated.4

A New Treatment Option forAdvanced DiseaseExtensive research has led to advances inthe understanding of the genetics ofNMSCs.5 Among these advances, anunderstanding of the role of the sonichedgehog pathway has played a pivotalrole in understanding the pathogenesisof BCCs. We now know that muta-tions in PTCH, the patched genelocated on chromosome 9q that codesfor the sonic hedgehog receptor, arethe underlying cause of nevoid BCCsyndrome. These mutations are alsocommon in sporadic BCCs. In addi-tion, specific mutations in the tumorsuppressor gene p53 appear to beinvolved in the development ofNMSCs.5

On January 30, 2012, the FDAapproved vismodegib (Erivedge), ahedgehog pathway inhibitor, for thetreatment of BCC in adults withlocally advanced or metastatic diseasewho are not candidates for surgery orradiotherapy. The FDA used its prior-ity review process for the approval ofvismodegib; this approval was basedon the results of an international,open-label, single-arm trial that eval-uated the efficacy and safety of vis-

modegib in 104 patients with locallyadvanced or metastatic BCC.

The approval of vismodegib repre-sents the first approved therapy forpatients with locally advanced ormetastatic BCC whose disease was notamenable to surgery or radiation thera-py, which are the standard treatmentsfor this serious condition. In addition,vismodegib’s oral formulation may beviewed as more convenient for patientsand may increase patient adherence totherapy. Some type of assistance pro-gram may be necessary to increasepatients’ ability to obtain the drug.

Clinical Pharmacology andPharmacokineticsVismodegib binds to and inhibitssmoothened, a transmembrane pro-tein involved in hedgehog signaltransduction.6

Vismodegib is eliminated via multiplepathways, but it is predominantly excret-ed unchanged. Inhibition of thecytochrome (CY) P450 is not predictedto alter vismodegib’s systemic exposure,because steady-state plasma concentra-tions of vismodegib were observed inpatients enrolled in vismodegib’s clinicaltrials who were being treated concomi-tantly with CYP3A4 inducers orCYP3A4 inhibitors.6

The results of in vitro studies indi-cate that vismodegib is a substrate ofthe efflux transporter P-glycoprotein;therefore, when vismodegib is coad-ministered with drugs that inhibit P-glycoprotein, such as clarithromycin,erythromycin, and azithromycin, sys-temic exposure to vismodegib and theincidence of adverse events may beincreased.6

Drugs that alter the pH of the uppergastrointestinal tract may alter the sol-

ubility of vismodegib and reduce itsbioavailability, but no formal studieshave been conducted to evaluate theeffect of gastric pH-altering drugs onthe systemic exposure of vismodegib.Therefore, if vismodegib is coadminis-tered with proton pump inhibitors, H2-receptor antagonists, or antacids, thesystemic exposure of vismodegib maybe decreased, and the effect of vismo -degib on efficacy is unknown.6

The single-dose bioavailability ofvismodegib is 31.8%. The systemicexposure of vismodegib is not affectedby food; therefore, vismodegib may betaken with or without food. The vol-ume of distribution of vismodegibranges from 16.4 L to 26.6 L. The plas-ma protein binding of the drug inpatients is >99%. The primary route ofelimination of vismodegib and itsmetabolites is hepatic, with 82% of thedose administered recovered in thefeces and 4.4% recovered in urine. Thevismodegib estimated elimination half-life is 4 days after continuous once-daily dosing and 12 days after adminis-tration of a single dose.6

Clinical Trial Evidence and EfficacyThe efficacy and safety of vismodegibwas evaluated in an international, single-arm, open-label trial of 104 patients withmetastatic BCC (n = 33) or with locallyadvanced BCC (n = 71). Enrolledpatients with locally advanced BCC hadto have lesions that recurred after radio-therapy, unless radiotherapy was con-traindicated or inappropriate (ie, Gorlinsyndrome, limitations because of thelocation of the tumor, or in cases wherethe lesion was unresectable or when sur-gical resection would result in substantialdeformity).

Patients received vismodegib 150mg/day orally until disease progression orunacceptable toxicity occurred. The pri-mary efficacy outcome of this study wasdetermination of objective response rate(ORR), which was assessed by an inde-pendent review facility. In the cohort ofpatients with metastatic BCC, tumorresponse was evaluated using theResponse Evaluation Criteria in SolidTumors (RECIST) Version 1.0. In thecohort of patients with locally advancedBCC, evaluation of tumor responseincluded measurement of externallyassessable tumor (including scarring) andassessment for ulceration in photographs,radiographic assessment of target lesionswhen appropriate, and tumor biopsy.6

Of the 104 patients enrolled in thisstudy, 96 patients were evaluable for


Basal Cell Carcinoma

Vismodegib: A New Treatment Option for Basal CellCarcinomaBy Rhonda Williams

Table 1 Objective Response Rate With Vismodegib: Efficacy in Evaluable Patients6

ResponseMetastatic BCC

(n = 33)Locally advanced BCC

(n = 63)

Objective response rate,N (%)*

10 (30.3) 27 (42.9)

95% CI 15.6-48.2 30.5-56.0

Complete response 0 (0) 13 (20.6)

Partial response 10 (30.3) 14 (22.2)

Median response duration, months

7.6 7.6

95% CI 5.6-nonestimable 5.7-9.7

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

The ORR was 30.3%

in patients with metastatic

BCC and 42.9% in

patients with locally

advanced BCC.



Basal Cell Carcinoma

ORR: 33 patients in the metastaticBCC cohort and 63 patients in thelocally advanced BCC cohort. Themedian age of all patients evaluable forefficacy was 62 years; 46% of patientswere aged ≥65 years. Of the patients inthe metastatic BCC cohort, 97% ofpatients had received previous thera-pies, including surgery (97%), radio-therapy (58%), and systemic therapies(30%). Among the patients with local-ly advanced BCC, 94% had previoustherapies, including surgery (89%),radiotherapy (27%), and systemic/topi-cal therapies (11%).6

The ORR was 30.3% in patientswith metastatic BCC and 42.9% inpatients with locally advanced BCC.There were no complete responses inthe metastatic BCC cohort comparedwith 20.6% of patients in the locallyadvanced BCC cohort who had a com-plete response. The median duration ofresponse in the metastatic and thelocally advanced BCC cohorts was 7.6months.6 Table 1 outlines the responserates in both cohorts.

Safety ProfileWhen vismodegib monotherapy wasadministered at daily oral doses of≥150 mg in 4 open-label, uncon-trolled, dose-ranging or fixed single-dose clinical trials enrolling a total of138 patients with advanced BCC, themost common adverse reactions(≥10% of patients) included musclespasms, alopecia, dysgeusia, and oth-ers, as shown in Table 2.

Furthermore, 3 of 10 premenopausalwomen developed amenorrhea whilebeing treated with vismodegib. In addi-tion, treatment-emergent grade 3 labo-ratory abnormalities were observed in11 patients in clinical trials; 6 (4%)patients experienced hyponatremia, 2(1%) patients experienced hypo -kalemia, and azotemia was reported in3 (2%) patients.6

The safety and effectiveness of vis-modegib has not been established inpatients with renal or hepatic impair-ment. In addition, clinical trials of vis-modegib did not include sufficientnumbers of patients aged ≥65 years to establish whether this patient popu-lation responded differently to vismo - degib than younger patients. The safe-ty and effectiveness of vismodegibhave not been established in pediatricpatients.6

Warnings and PrecautionsAssociated With VismodegibBlack Box Warning: Embryo-FetalDeath and Severe Birth DefectsVismodegib can result in severe birthdefects or embryo-fetal death.Vismodegib is embryotoxic and terato-genic in animals. Teratogenic effectswith this medication included severe

midline defects, missing digits, andother irreversible malformation. In ratsat maternal exposures lower thanhuman exposures of the recommendeddose (150 mg/day), vismodegib was ter-atogenic, embryotoxic, and fetotoxic.Malformations in rats included cranio-facial anomalies, open perineum, andabsent or fused digits. Fetal retardationand variations were also observed.

Pregnancy status should be verifiedbefore initiation of treatment with vis-modegib. Both male and female patientsshould be made aware of these risks.Female patients should be advised of theneed for contraception, and malepatients should be advised of the poten-tial risk to the fetus of vismodegib expo-sure through semen. Patients should beadvised to notify their healthcareprovider immediately if they suspect thatthey or their female partner may be preg-nant. Patients exposed to vismodegibduring pregnancy, either directly orthrough seminal fluid, should be encour-aged to participate in the vismodegibpregnancy pharmacovigilance program.6

Blood DonationPatients should be advised not todonate blood or blood products whilereceiving vismodegib and for at least 7

months after the last dose of vismodeg-ib is received.6

DosingThe recommended dose of vismodegib is150 mg orally once daily until evidenceof disease progression exists or until unac-ceptable toxicity is noted. If a dose of vis-modegib is missed, the dose should not bemade up. Dosing should resume with thenext scheduled dose.6

Vismodegib may be taken with orwithout food. The capsule should betaken whole and not be opened orcrushed.

Vismodegib is not available at localdrugstores and is only distributedthrough specialty pharmacies.

ConclusionVismodegib, a hedgehog pathway in -hibitor, was approved by the FDA earlierthis year for the treatment of BCC inadults with locally advanced or metastat-ic disease who are not candidates for sur-gery or radiotherapy. This approval,which was done under the FDA’s priorityreview process, was based on the results ofan international, open-label, single-armtrial that evaluated the efficacy and safe-ty of vismodegib in 104 patients withlocally advanced or metastatic BCC.

Vismodegib is the first FDA-approvedagent for the treatment of this seriouscondition. Although BCC is usually cur-able if lesions are contained to a smallarea of skin, in rare cases the lesions canbecome disfiguring, invade surroundingtissue, and/or metastasize. In theseinstances of advanced BCC, the diseasecannot be effectively managed with sur-gery or radiation, the standard treatmentsfor this common skin cancer. This recentapproval of vismodegib fills a gap and anunmet need in the treatment paradigm ofthis serious condition. �

References1. American Cancer Society. Cancer Facts & Figures2011. Atlanta, GA: American Cancer Society; 2011.www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-029771.pdf.Accessed February 17, 2012.2. Miller SJ, Alam M, Andersen J, et al. Basal cell andsquamous cell skin cancers. J Natl Compr Cancer Netw.2010;8:836-864.3. Mudigonda T, Pearce DJ, Yentzer BA, et al. The eco-nomic impact of non-melanoma skin cancer: a review.J Natl Compr Canc Netw. 2010;8:888-896.4. National Comprehensive Cancer Network(NCCN). NCCN Clinical Practice Guidelines inOncology: Basal Cell and Squamous Cell Skin Cancers.Version 1.2012. www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf. Accessed February 3, 2012.5. Benjamin CL, Melnikova VO, Ananthaswamy HN.P53 protein and pathogenesis of melanoma and non-melanoma skin cancer. Adv Exp Med Biol. 2008;624:265-282. 6. Erivedge [prescribing information]. South SanFrancisco, CA: Genentech, Inc; 2012.

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

MedDRA Preferred Term

All Patients With Advanced BCC (N = 138)

All grades,* N (%) Grade 3, N (%) Grade 4, N (%)

Gastrointestinal disorders

Nausea 42 (30.4) 1 (0.7) –

Diarrhea 40 (29) 1 (0.7) –

Constipation 29 (21) – –

Vomiting 19 (13.8) – –

General disorders and administration site conditions

Fatigue 55 (39.9) 7 (5.1) 1 (0.7)

Investigations

Weight loss 62 (44.9) 10 (7.2) –

Metabolism and nutrition disorders

Decreased appetite 35 (25.4) 3 (2.2) –

Musculoskeletal and connective tissue disorders

Muscle spasms 99 (71.7) 5 (3.6) –

Arthralgias 22 (15.9) 1 (0.7) –

Nervous system disorders

Dysgeusia 76 (55.1) – –

Ageusia 15 (10.9) – –

Skin and subcutaneous disorders

Alopecia 88 (63.8) – –

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



Personalized Medicine in Oncology: Lung Cancer

Crizotinib Miracle: A Nursing PerspectiveBy Tara L. Rich, MSN, RN, CNPTaussig Cancer Institute, Cleveland Clinic, Ohio

For every nurse there is apatient who you willnever forget; the details

of that story will not blur overtime. In the developing era ofpersonalized medicine, there isthat one patient whose story Iwill not easily forget. It is thestory of a 24-year-old malemedical student who present-ed for initial consultation thesame week that crizotinib wasapproved by the FDA for thetreatment of anaplastic lym-phoma kinase (ALK)-positive non–small cell lung cancer.This young never smoker was blissful-

ly unaware of the recent advances inidentifying the echinoderm microtubule-associated protein-like 4 (EML4)-ALKoncogene and the associated response to

crizotinib. Upon initialevaluation, his tissue wassent for epidermal growthfactor receptor andEML4-ALK testing, butdue to the urgent natureof his symptoms, the deci-sion was made to startstandard platinum dou-blet chemotherapy. Thisis when I first met him—he was sitting in thechemo chair waiting fortreatment to start. He was

quickly becoming symptomatic and wasadmitted to the hospital that day forevaluation. Over the course of the nextcouple days he acutely developed a peri-cardial effusion that tamponaded,requiring emergent bedside pericardio-centesis. He proceeded to develop pul-

monary emboli, atrial fibrillation, andpleural effusions requiring bilateralchest tubes. The second day he was inthe ICU we received the news that histumor was ALK positive. He was toosick to understand the news, and hisfamily was too scared to understand thepossible utility of this information.Our patient assistance team worked

feverishly with the pharmaceutical com-pany and his insurance company sincethe drug was brand new. Twenty-fourhours later he was taking crizotinib. Hisresponse was immediate and miraculous.He was discharged home 20 days later;he walked out of the hospital withoutany assistance or medical equipment.Within 1 month of leaving the hospitalhe had resumed his normal activities ofweekend outings and visiting his friendsfrom med school. I remember the day he

called the office to inquire whether hewas allowed to have a beer, a once typi-cal social activity for a 24-year-old stu-dent. We all smiled with relief, knowingthat without crizotinib the outcomewould not have been the same. He con-tinues to do well and has become active-ly involved in educating people aboutlung cancer and crizotinib. Speaking tothe public has given him a purpose andfocus while he decides whether to con-tinue with medical school.As a nurse practitioner, being able to

witness the life-altering effects of crizo-tinib reminds me of the progress that isbeing made each day in cancerresearch. We hope that these advancesin genomic testing and targeted agentscontinue to provide patients not onlywith individualized care but withincreased treatment options. �

Breast Cancer

Tara L. Rich, MSN,RN, CNP

Updated results of the phase 3BOLERO-2 trial demonstratedthat adding everolimus to hor-

monal therapy extends progression-free survival (PFS) in hormone recep-tor–positive (HR+) metastatic breastcancer that progressed on hormonaltherapy with anastrozole or letrozole.The positive outcomes observed inthis study suggest that everolimus plusexemestane will be a new option for postmenopausal metastatic HR+breast cancer.First results of this study, called

BOLERO-2, were presented in Sep t em -ber 2011 at ECCO/ESMO/ESTRO.Up dated results with additional follow-up, presented at the 2011 CTRC-AACR San Antonio Breast CancerSymposium, confirm the PFS benefit ofadding everolimus to exemestane inthis group of women. Overall survivaldata are not yet mature.“We believe these results underline

that everolimus is the first agent to significantly enhance the efficacy ofhormonal therapy in patients withHR+ breast cancer. The addition ofeverolimus in advanced breast cancercould represent a paradigm shift in themanagement of this patient popula-

tion,” stated Gabriel N. Hortobagyi,MD, professor of medicine and directorof the Multidisciplinary Breast CancerResearch Program at the University ofTexas MD Anderson Cancer Center inHouston, Texas.

“Endocrine therapy is the treatmentof choice for the majority of breast can-cers that express the estrogen receptor,which represents about 75% of pa -tients over age 50. The standard is touse multiple endocrine regimens insequence to get multiple mileage. Butthe sad truth is that after a few monthsof suppression of tumor cells on one

agent, tumor cells become smarter andresistant and we need to changeagents,” Hortobagyi explained.Everolimus is an mTOR inhibitor.

This pathway is activated in hormone-resistant advanced breast cancer. Phase2 clinical trials of everolimus mono ther-apy and in combination with endocrinetherapy were encouraging in advancedHR+ breast cancer, Hortobagyi ex -plained. Positive results of phase 2 trialswith everolimus added to hormonaltherapy led to the strategy tested inBOLERO-2, he said.BOLERO-2 was a prospective, dou-

ble-blind, placebo-controlled, phase 3trial. The study population included724 postmenopausal women with HR+metastatic breast cancer with diseaseprogression on previous hormonaltherapy (ie, resistance). Patients wererandomized 2:1 to exemestane pluseverolimus (n = 485) versus exemes-tane plus placebo (n = 279).Baseline demographics and disease

characteristics were similar betweenthe arms. At baseline, median age was62 years, 56% had visceral metastases,and 84% had documented benefitfrom previous endocrine therapy withletrozole or anastrozole (100%),

tamoxifen (48%), fulvestrant (16%),and chemo therapy for advanced dis-ease (25%). Sixty percent had excel-lent performance status. The studypopulation reflects a variety of ethnicgroups, he said.At a median follow-up of 12.5

months, median PFS was 7.4 monthsfor the combination versus 3.2 monthsfor exemestane plus placebo. The per-centage of patients who experiencedclinical benefit (complete response,partial response, stable disease, amountof pain, and overall benefit of the drug)was almost double in the combinationarm: 50.5% for the combination versus25.5% for exemestane plus placebo.The combination of exemestane

plus everolimus was well tolerated,Hortobagyi told listeners. The mostcommon grade 3 or higher adverseevents for the combination versusexemestane plus placebo, respectively,were stomatitis (8% vs 1%), anemia(7% vs 1%), hyperglycemia (5% vs<1%), dyspnea (4% vs 1%), andfatigue (4% vs 1%). Adverse eventswere manageable with dose delays ordose reductions. Quality of life was almost identical

in both arms of the study. �

BOLERO-2: Practice-Changing Results With ExemestanePlus Everolimus in Advanced Breast CancerBy Alice Goodman

Everolimus is an mTOR

inhibitor. This pathway is

activated in hormone-

resistant advanced

breast cancer.



Leukemias

Treatment response in patientswith acute leukemia is tradition-ally measured by searching for

leukemic cells that persist duringchemotherapy. This is done by screeningsmears of bone marrow aspirates andperipheral blood samples using lightmicroscopy, striving to identify leukemiccells by their morphologic fea-tures. However, leukemic cellsin most cases closely resem-ble normal bone marrow andblood cells: acute lymphoblas-tic leukemia (ALL) lym-phoblasts can be confusedwith normal immature lym-phoid cells and activatedlymphocytes; acute myeloidleukemia (AML) myelo -blasts are similar to normalimmature myeloid cells.Hence, the identification ofleukemic cells among normal cells is adifficult task even for an experiencedhematopathologist, and the cutoff todefine leukemia remission is thereforerather lax; at most centers it is 5%.However, patients with <5% leukemicblasts in the bone marrow and in com-plete remission by this criterion may stillhave a large total number of residualleukemic cells (potentially up to 1010).Measuring treatment response

more accurately is important becausethe degree of initial leukemia cytore-duction is strongly associated withrisk of subsequent relapse. It is wellknown that patients who have a poorresponse to remission induction ther-apy and fail to achieve morphologicremission have a high risk of relapse.However, with contemporary therapy,the majority of patients with ALLand AML do achieve complete remis-sion as defined by the above criterion,yet a substantial number subsequentlyrelapse. The hypothesis underlyingstudies of minimal residual disease(MRD), which denotes leukemia notdetectable by conventional morpho-logic analysis, is that among “goodresponders” there may be substantialheterogeneity in residual leukemiaburden that is unappreciated by mor-phologic analysis. Studies reportedduring the past 2 decades are in linewith this hypothesis, and the prog-nostic importance of MRD has beendemonstrated unequivocally.1,2 There -fore, the more stringent definition ofremission provided by MRD assays isprogressively replacing that definedby morphologic analysis.

Methods to Measure MRDLeukemic cells have several distinguish-ing features that can be used to trackthem during chemotherapy. ALL cellshave unique clonal rearrangement of thegenes encoding immunoglobulin (Ig)and T-cell receptor (TCR) proteins thatcan be identified in the majority of

cases.3 The leukemia-spe-cific rearrangements areelucidated in each patientat diagnosis, and specificprimers are synthesized andthen incorporated into apolymerase chain reaction(PCR) assay. After deter-mining the optimal condi-tions of the assay, these areapplied to follow-up sam-ples to monitor MRD.PCR analysis of Ig andTCR genes allows for the

routine detection of 1 leukemic cell in10,000 to 100,000 normal cells.3 In astudy by the AIEOP-BFM ALL group,only 305 of the 3341 (9.1%) diagnosticsamples examined either lacked suitablegene rearrangements for PCR analysis orhad rearrangements with sequences notsufficiently distinct to reach a sensitivityof 0.01%.4 In a study performed at St.Jude Children’s Research Hospital, 475of 539 (88.1%) bone marrow samplesfrom patients with newly diagnosed B-lineage ALL had clonal antigen receptorgene rearrangements suitable for PCR

monitoring of MRD with a sensitivity ofat least 0.001%.5 Ig and TCR genes arerarely rearranged in AML and thereforetheir contribution to the range of poten-tial targets is negligible.3Another feature that can be used to

distinguish leukemic from normal cellsconsists of chromosomal abnormalitiesand their resulting gene fusions.3 Fusiontranscripts, such as BCR-ABL1, MLL-AFF1, TCF3-PBX1, and ETV6-RUNX1in ALL, and RUNX1-RUNX1T1,CBFB-MYH11, and PML-RARA inAML can be used as targets for amplifi-cation.2,3 Real-time PCR provides themost accurate way to measure their lev-els. Overall, up to one-thirdof patients with ALL orAML have leukemic cellswith genetic abnormalitiesthat currently can be per-formed as routine assays inmolecular pathology labora-tories, allowing the detectionof 1 leukemic cell in 1000 to100,000 normal bone mar-row cells.2,3 Abnormal fusiontranscripts may persist longinto clinical remission.Therefore, positive results,particularly at low levels, aredifficult to interpret for some of thefusion transcripts such as ETV6-RUNX1, RUNX1-RUNX1T1, andCBFB-MYH11 as they often do not indi-cate a higher risk of relapse, but sequen-

tial monitoring may be informative.6-8 Inaddition to gene fusions, NPM1 genemutations, when present, can be used astargets for MRD studies.9Leukemic cells can also be identified

by the expression of unique combina-tions of cell markers that are best detect-ed with monoclonal antibodies and flowcytometry (Figure).10 The most currentflow cytometers allow the detection of 8or more markers. Leukemia-associatedimmunophenotypes are identified atdiagnosis in each patient by comparingthe cell marker profile of leukemic blaststo that of reference bone marrow samplesfrom healthy donors and from patients

during and after chemother-apy or transplant.10 If a suffi-cient number of cells areanalyzed (eg, 100,000mononuclear cells per anti-body combination), flowcytometry has a routine sen-sitivity of detection of0.01% in ALL.10 Among2143 patients with B-lin-eage ALL enrolled on 9900series treatment protocols ofthe Children’s OncologyGroup, a test with the sensi-tivity of at least 0.01% on

day 29 could be performed in 92% ofpatients.11 In the St. Jude Total XV study,MRD could be monitored by flowcytometry with a 0.01% sensitivity in

Minimal Residual Disease to Monitor Therapy inAcute Leukemia By Sally Blair, MD; Elaine Coustan-Smith, MS; Dario Campana, MD, PhDDepartment of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore

Figure. Detection of MRD by flow cytometry. Flow cytometric dot plots show results obtained in bone marrow samplesfrom 4 patients (2 with ALL and 2 with AML) at diagnosis and during chemotherapy. Each axis indicates intensity ofexpression of the markers used; the dashes areas enclose signals from leukemic cells. The percentage of MRD in eachfollow-up sample is shown.

CD10

CD58 CD7

CD34

Pt. 1

Pt. 2

0.4%

<0.01%

Pt. 3

Pt. 4

0.3%

<0.1%

ALLDiagnosis Follow-up

AMLDiagnosis Follow-up


105

104

103

0-5

17

-2080 103 104 105

105

104

103

0-5

17

-2080 103 104 105

105

104

103

0-5

17

-2080 103 104 105

105

104

103

0-5

17

-2080 103 104 105

105

104

0-7

,396

-2060 103 104 105

105

104

0-7

,396

-2060 103 104 105

105

104

0-7

,396

-2060 103 104 105

105

104

0-7

,396

-2060 103 104 105

Sally Blair, MD

Elaine Coustan-Smith,MS



Leukemias

482 of 492 patients (98%).12 In AML,distinctive markers can also be identifiedin most patients, although in approxi-mately 40% of patients the routine sensi-tivity that can be achieved is not higherthan 1 in 1000, a consequence of partialoverlap between the phenotype ofleukemic cells and those of normalhematopoietic cells.13 In the studies per-formed in the St. Jude AML02 trial, wefound immunophenotypes suitable forMRD studies with a sensitivity of at least0.1% in 200 of 210 (95%) patients.13The number of antibody combinationsused to identify leukemic cells, the sta-bility of the markers targeted, and theskill of the investigator interpreting theresults are key to the reliability of MRDmonitoring by flow cytometry.

Prognostic Significance of MRD in ALLMany studies have demonstrated theclinical significance of MRD monitoringin children and adolescents with ALL.MRD tests performed during the earlyphases of treatment appear to be particu-larly informative and often outweigh theprognostic impact of clinical and biolog-ical features previously associated withtreatment outcome (reviewed inCampana1). For example, a recentlyreported study of 3184 B-lineage ALLpatients enrolled in the AIEOP-BFMALL 2000 protocol showed that MRDmeasurements by PCR amplification ofantigen-receptor gene rearrangementson days 33 and 78 of treatment weresuperior to previous stratification criteriabased on leukocyte count, age, earlyresponse to prednisone, and genetic sub-type.14 Other recent studies also pointedto the predictive value of MRD for oth-erwise homogeneous subgroups ofpatients, such as infants,15 those with T-ALL,16 and those with specific geneticabnormalities.17 Another study from thesame group measured MRD by flowcytometry on day 15 of treatment in 815patients and found a strongcorrelation between higherMRD levels and subsequentrelapse.18 A high level ofMRD (ie, ≥1%) at the end ofremission induction predictsa particularly poor outcome,and it remained an unfavor-able predictor of outcome inthe St. Jude Total XV study(the only independent ad -verse predictor together withCNS3 status), despite MRD-based treatment intensifica-tion.12 Conversely, patientswho attain MRD <0.01% early duringtherapy have excellent chances toremain in continuous complete remis-sion with contemporary postremissiontherapy. In our early study with patients

enrolled in the Total XIII study, thosewith early leukemia cell clearance (ie,MRD <0.01% on day 19 of treatment;46%) had a 5-year cumulative incidenceof relapse of 6.0% ± 3.4%.19 Likewise, inthe AIEOP-BFM ALL 2000 study,patients with MRD <0.01% on day 33(42%) had a 5-year event-free survival of92.3% ± 0.9%.14

It is also clinically useful to monitorMRD in children and adolescents withfirst-relapse ALL who achieve a secondremission,20 and in those undergoingallogeneic hematopoietic stem cell trans-plantation, as the level of MRD beforetransplant is associated with risk ofrelapse posttransplant.21,22 Finally, con-vincing evidence is emerging that MRDis clinically important in adult patientswith ALL. In studies by the German

Multicenter Study Groupfor Adult Acute Lymph -oblastic Leukemia, MRDon days 11 and 24 of treat-ment predicted outcome in adult patients with “standard-risk” ALL,23 andsequential studies of MRDwere also informative.24

Other studies also demon-strated the predictive valueof MRD in different sub-groups of adult ALL(reviewed in Campana1).

Prognostic Significance of MRD in AMLIn an early study, Children’s OncologyGroup investigators showed that chil-dren with AML in remission who were

MRD positive had a 4.8 times higher riskof relapse than those who were MRDnegative and that MRD was thestrongest prognostic factor among thevariables considered.25 Likewise, a studyperformed in the St. Jude Children’sResearch Hospital AML97 cohortshowed that the mean 2-year survivalestimates for patients with MRD positiv-ity (≥0.1%) after induction therapy was

33%, compared with 72% for those withlower levels or no detectable MRD;MRD was also the strongest predictor ofoutcome in this cohort.26 Subsequentstudies in children with AML consoli-dated these early findings.27,28 In the St.Jude AML02 study, we used MRD toguide treatment schedule and intensity.Patients with MRD ≥1% at the end ofremission induction therapy were classi-fied as high risk and offered transplant;patients with MRD 0.1% to <1%received gemtuzumab ozogamicin and, ifMRD persisted, became candidates fortransplant. MRD remained a predictiveprognostic factor, although patients withlower levels of MRD (0.1%-<1%)appeared to benefit from this strategy.13

Early studies in adult patients with

AML showed that MRD detected in thefirst bone marrow obtained after induc-tion treatment was highly predictive ofrelapse.29 Others reported that the rate ofdecrease in cells expressing aberrantimmunophenotypes during treatmentwas significantly and independentlyrelated to treatment outcome.30 Morerecently, Maurillo and colleagues31

reported that levels of MRD after consol-idation therapy were particularly inform-ative: MRD-negative patients had a sig-nificantly better outcome, regardless ofwhether they underwent autologous orallogeneic stem cell transplantation.

Practical Considerations for theClinical Application of MRDIn patients with ALL, MRD resultsobtained by PCR amplification of Ig andTCR genes or by flow cytometry are gen-erally concordant when MRD is presentat levels of ≥0.01%.32,33 Each method hasunique strengths (Table).10 Flow cytome-try is more likely to be readily available asit is routinely used for leukemia profilingfor diagnostic purposes. For studies atearly time points during therapy, such ason day 15, flow cytometry has an edgeover PCR because the development of aPCR assay currently requires more than2 weeks. By contrast, the higher sensitiv-ity of PCR can be advantageous for stud-ies at the end of therapy or after trans-plant, where it may uncover MRDundetectable by flow cytometry. PCR hasoften been said to be more expensive,but many variables must be factored intothis calculation including equipment

costs, consumables, and staff support. Inour experience, the costs of the 2 meth-ods are similar. Both assays must be per-formed in laboratories with provenexpertise; therefore the type of expertlaboratory available to a cancer center orcooperative group may ultimately be thedecisive factor in selecting the method tobe used to monitor MRD in ALL. Flowcytometry is the only method that canstudy MRD in most patients with AML.Studies of MRD by PCR amplification offusion transcripts are also an option, butthey are obviously limited to specificleukemic subtypes and are generally usedon an ad hoc basis.

MRD is most commonly tested inbone marrow aspirates, as the bone mar-row is the site where leukemic cells grow

Table Main Properties of MRD Assays in Acute Leukemia

Property

MRD AssayPCR Ig/TCR

GenesPCR FusionTranscripts Flow Cytometry

Use in ALL Yes (~90%) Yes (~40%) Yes (>95%)

Use in AML No Yes (~40%) Yes (95%)

Sensitivity 0.01%-0.001% 0.01%-0.001% 0.01% (ALL); 0.1%-0.01% (AML)

Potential for wide availability?

No No Yes

Specific expertisein MRD required?

Yes Yes Yes

Analysis of diagnostic samplerequired?

Yes Yes Yes

Development of patient-specificassay?

Yes No No*

MRD positivitystrongly correlatedwith outcome?

Yes No Yes

*The best markers for each patient should be selected at diagnosis.

Minimal Residual Disease to Monitor Therapy in Acute Leukemia Continued from page 29

Dario Campana, MD, PhD

MRD is most commonly tested in bone marrow

aspirates, as the bone marrow is the site where

leukemic cells grow and are typically found in

higher proportions.



Leukemias

and are typically found in higher propor-tions. Some studies examined the poten-tial for using peripheral blood instead. Itwas found that in patients with T-lineageALL, MRD levels in peripheral bloodwere similar to those in bone marrow.34,35Interestingly, this was also the case inpatients with T-cell lymphoblastic lym-phoma.36 Thus, in patients with T-cellmalignancies, sequential MRD testingcan be performed in blood. In patientswith B-lineage ALL, early MRD meas-urements in peripheral blood (eg, on day8) may be clinically informative.11

The clinical significance of MRD andits use for treatment stratificationdepends on protocol design. Thereforethere is considerable variability in thetime points during treatment at whichMRD studies are performed and in the levels of MRD considered to bemost informative. The current COGAALL08B1 protocol for children withB-lineage ALL includes MRD measure-ments in peripheral blood on day 8 oftreatment and in bone marrow at theend of remission induction therapy (day29), and the cutoff levels used to assignrisk are 1% and 0.01%, respectively. Inthe Dana-Farber Cancer Institute study0501 for childhood ALL, the MRDthreshold of 0.001% at the end of remis-sion induction therapy (day 28) is usedfor risk assignment. In the St. JudeChildren’s Research Hospital Total XVIstudy, MRD levels on day 15 and day 42are used for treatment assignment.Patients with MRD of ≥1% on day 15receive intensified remission inductiontherapy; further intensification is re -served for patients with ≥5% leukemiccells. Patients with MRD <0.01% on day15 receive a slightly less intensive rein-duction therapy and lower cumulativedoses of anthracycline. Patients withstandard-risk ALL who have MRD of≥0.01% on day 42 are reclassified ashigh-risk; patients with MRD ≥1% areeligible for allogeneic transplant in firstremission. For patients with AML, MRDis typically measured after each block ofchemotherapy, as well as before andafter transplant. In the current St.Jude AML08 study for children andadolescents with AML, 0.1% is thethreshold used to define MRD positiv-ity, while levels of MRD ≥1% indicatehigh-risk AML.

The prevalence of MRD varies amongdifferent genetic subtypes of ALL andAML.1,12,13,37,38 Other presenting featuresthat have been shown to be associatedwith MRD are gene profiles of leukemiccells,39,40 and germline- or leukemia-asso-ciated gene polymorphisms.41 Theseassociations raise the question whetherMRD studies can be replaced by thesepresenting features. However, in virtual-ly all correlative studies performed todate, MRD was an independent prognos-tic factor, and it could dissect subgroups

of patients with different outcomesamong those with apparently identicalleukemia subtype.

In addition to measuring initialresponse to chemotherapy, MRD assayshave many other uses in the manage-ment of patients with acute leukemia.For patients who achieve MRD-negativestatus after remission induction therapy,conversion to MRD positivity alerts ofthe possibility of relapse; a subsequentincrease in MRD levels usually indicatesimpending relapse. Therefore, such afinding can give a head start in thepreparation for salvage therapy and/ortransplant. Because levels of MRD beforetransplant are strongly related to the suc-cess of the procedure, it is increasinglycommon to attempt to reduce them withchemotherapy before initiating thetransplant conditioning, although evi-dence that this practice is effective is notyet available. MRD measurements canalso be used to guide intervention post-transplant, such as reduction of immuno-suppression, administration of donorlymphocyte infusions, or preparation fora second transplant.

The Future of MRD StudiesEvidence for the prognostic importanceof MRD in both ALL and AML is solid.One could argue that the collective datasupporting the clinical use of MRD areconsiderably more compelling thanthose provided in the past in support ofestablished parameters widely used forrisk stratification. Moreover, as discussedin this article, MRD testing has multipleapplications during the course of treat-ment that go beyond prognostication.Clinical studies have shown that MRDresults can be applied to most patientswith ALL and AML and can be deliv-ered in a timely fashion.12,13 Some believethat, with time, MRD studies maybecome obsolete in the context of theever-increasing knowledge of the biologyand genetics of leukemic cells, but wethink it unlikely as MRD measurementsreflect the composite influence of multi-ple factors, such as drug dosage, druginteraction, pharmacokinetic and phar-macogenomic variable, and compliancewith the scheduled treatment plan,which cannot be captured by examiningthe leukemic cells alone.

Methods to study MRD are continual-ly being refined.42 MRD studies can berelatively expensive in relation to other

routine diagnostic laboratory assays but,overall, are not significantly more expen-sive than high-complexity tests, such ascytogenetics or molecular pathology.Moreover, when one considers thepotential benefits of avoiding undertreat-ment and relapse, or overtr eatment andits sequelae, the cost of MRD testing isfully justified as it can ultimately reducethe cost of patient care. Regardless, cur-rent MRD assays remain too expensiveand complex for many centers to imple-ment. Thus, the potential benefits ofcareful leukemia monitoring are limitedto a minority of patients. The approachof having reference centers performingthe tests in the context of multicenterstudies can help in this regard, as it savescostly and time-consuming setup andstandardization efforts in peripheral cen-ters while ensuring an expert sample pro-cessing and analysis. Ultimately, howev-er, it would be desirable to make MRD

testing simpler and less expensive. Tothis end, we developed a simplified flowcytometric assay to study MRD inpatients with B-lineage ALL duringremission induction therapy.43 Whenapplied to samples collected on day 19 oftreatment, the results of the simplifiedassay correlated well with those of themore complex flow cytometric assay andthose of PCR amplification of antigen-receptor genes. This assay is currentlybeing used in international protocols toidentify patients with good initialresponse to therapy who are then offereda low-intensity, low-toxicity treatmentregimen, an approach that has producedencouraging preliminary results.

It is sometimes disputed that only afew leukemic cells have long-term repop-ulating capacity (“leukemia stem cells”)and that current MRD assays cannotdetermine whether the signals detectedoriginate from these or more differentiat-

ed cells incapable of driving relapse. Thisis a rather controversial topic. Evidencethat such “stem cells,” defined asleukemic subsets that preferentially growin immunodeficient mice, also have agrowth advantage in humans is lacking.Data indicating that such subsets aremore resistant to chemotherapy are lessthan compelling. In any case, the strongcorrelation between MRD levels andrelapse indicates that MRD positivityshould be interpreted as evidence for thepersistence of leukemic cells that areresistant to further chemotherapy andare capable of driving the recurrence ofclinically overt disease.

Besides their use in clinical manage-ment, MRD studies are likely to be usedmore often as a surrogate marker tomeasure the effectiveness of novelantileukemic therapies. For example,MRD levels during and at the end ofremission induction therapy can be usedto develop a stopping rule when compar-ing the efficacy of a new remission induc-tion regimen in relation to that of itspredecessor. In addition, MRD testingcould be used to quickly determinewhether a new agent exerts significantantileukemic effects in vivo, thus sparingthe need for lengthy trials with ineffec-tive agents. �

References1. Campana D. Minimal residual disease in acute lym-phoblastic leukemia. Hematology Am Soc Hematol EducProgram. 2010;2010:7-12.2. Shook D, Coustan-Smith E, Ribeiro RC, et al.Minimal residual disease quantitation in acute myeloidleukemia. Clin Lymphoma Myeloma. 2009;9(suppl 3):S281-S285.3. Brüggemann M, Schrauder A, Raff T, et al.Standardized MRD quantification in European ALL tri-als: proceedings of the Second International Symposiumon MRD assessment in Kiel, Germany, 18-20 September2008. Leukemia. 2010;24:521-535.4. Flohr T, Schrauder A, Cazzaniga G, et al. Minimalresidual disease-directed risk stratification using real-timequantitative PCR analysis of immunoglobulin and T-cellreceptor gene rearrangements in the international multi-center trial AIEOP-BFM ALL 2000 for childhood acutelymphoblastic leukemia. Leukemia. 2008;22:771-782.5. Stow P, Key L, Chen X, et al. Clinical significance oflow levels of minimal residual disease at the end of remis-sion induction therapy in childhood acute lymphoblasticleukemia. Blood. 2010;115:4657-4663.6. Zelent A, Greaves M, Enver T. Role of the TEL-AML1 fusion gene in the molecular pathogenesis ofchildhood acute lymphoblastic leukaemia. Oncogene.2004;23:4275-4283.7. Lane S, Saal R, Mollee P, et al. A >or=1 log rise in RQ-PCR transcript levels defines molecular relapse in corebinding factor acute myeloid leukemia and predicts subsequent morphologic relapse. Leuk Lymphoma.2008;49:517-523.8. Corbacioglu A, Scholl C, Schlenk RF, et al. Prognosticimpact of minimal residual disease in CBFB-MYH11-pos-itive acute myeloid leukemia. J Clin Oncol.2010;28:3724-3729.9. Krönke J, Schlenk RF, Jensen KO, et al. Monitoring ofminimal residual disease in NPM1-mutated acutemyeloid leukemia: a study from the German-Austrianacute myeloid leukemia study group. J Clin Oncol.2011;29:2709-2716.10. Coustan-Smith E, Campana D. Immunologic mini-mal residual disease detection in acute lymphoblasticleukemia: a comparative approach to molecular testing.Best Pract Res Clin Haematol. 2010;23:347-358.11. Borowitz MJ, Devidas M, Hunger SP, et al. Clinicalsignificance of minimal residual disease in childhoodacute lymphoblastic leukemia and its relationship toother prognostic factors. a Children’s Oncology Groupstudy. Blood. 2008;111:5477-5485.12. Pui CH, Campana D, Pei D, et al. Treating childhoodacute lymphoblastic leukemia without cranial irradiation.N Engl J Med. 2009;360:2730-2741.

The clinical significance

of MRD and its use for

treatment stratification

depends on

protocol design.

Clinical studies have shown that MRD results can

be applied to most patients with ALL and AML

and can be delivered in a timely fashion.



13. Rubnitz JE, Inaba H, Dahl G, et al. Minimal residualdisease-directed therapy for childhood acute myeloidleukaemia: results of the AML02 multicentre trial. LancetOncol. 2010;11:543-552.14. Conter V, Bartram CR, Valsecchi MG, et al.Molecular response to treatment redefines all prognos-tic factors in children and adolescents with B-cell pre-cursor acute lymphoblastic leukemia: results in 3184patients of the AIEOP-BFM ALL 2000 study. Blood.2010;115:3206-3214.15. Van der Velden VH, Corral L, Valsecchi MG, et al.Prognostic significance of minimal residual disease ininfants with acute lymphoblastic leukemia treated withinthe Interfant-99 protocol. Leukemia. 2009;23:1073-1079.

16. Schrappe M, Valsecchi MG, Bartram CR, et al. LateMRD response determines relapse risk overall and in sub-sets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118:2077-2084.17. Attarbaschi A, Mann G, Panzer-Grümayer R, etal. Minimal residual disease values discriminatebetween low and high relapse risk in children with B-cell precursor acute lymphoblastic leukemia and anintrachromosomal amplification of chromosome 21:the Austrian and German acute lymphoblasticleukemia Berlin-Frankfurt-Munster (ALL-BFM) trials.J Clin Oncol. 2008;26:3046-3050.18. Basso G, Veltroni M, Valsecchi MG, et al. Risk ofrelapse of childhood acute lymphoblastic leukemia is pre-

dicted by flow cytometric measurement of residual diseaseon day 15 bone marrow. J Clin Oncol. 2009;27:5168-5174.19. Coustan-Smith E, Sancho J, Behm FG, et al.Prognostic importance of measuring early clearance ofleukemic cells by flow cytometry in childhood acute lym-phoblastic leukemia. Blood. 2002;100:52-58.20. Raetz EA, Borowitz MJ, Devidas M, et al.Reinduction platform for children with first marrowrelapse of acute lymphoblastic leukemia: A Children’sOncology Group Study. J Clin Oncol. 2008;26:3971-3978.21. Bader P, Kreyenberg H, Henze GH, et al. Prognosticvalue of minimal residual disease quantification beforeallogeneic stem-cell transplantation in relapsed child-hood acute lymphoblastic leukemia: the ALL-REZ BFM

Study Group. J Clin Oncol. 2009;27:377-384.22. Leung W, Campana D, Yang J, et al. High success rateof hematopoietic cell transplantation regardless of donorsource in children with very high-risk leukemia. Blood.2011;118:223-230.23. Bruggemann M, Raff T, Flohr T, et al; GermanMulticenter Study Group for Adult Acute Lymph -oblastic Leukemia. Clinical significance of minimalresidual disease quantification in adult patients withstandard-risk acute lymphoblastic leukemia. Blood.2006;107:1116-1123.24. Raff T, Gökbuget N, Lüschen S, et al; GMALL StudyGroup. Molecular relapse in adult standard-risk ALLpatients detected by prospective MRD monitoring duringand after maintenance treatment: data from the GMALL06/99 and 07/03 trials. Blood. 2007;109:910-915.25. Sievers EL, Lange BJ, Buckley JD, et al. Prediction ofrelapse of pediatric acute myeloid leukemia by use of mul-tidimensional flow cytometry. J Natl Cancer Inst.1996;88:1483-1488.26. Coustan-Smith E, Ribeiro RC, Rubnitz JE, et al.Clinical significance of residual disease during treatmentin childhood acute myeloid leukemia. Br J Haematol.2003;123:243-252.27. MRD-AML-BFM Study Group; Langebrake C,Creutzig U, Dworzak M, et al. Residual disease monitor-ing in childhood acute myeloid leukemia by multipa -rameter flow cytometry: the MRD-AML-BFM StudyGroup. J Clin Oncol. 2006;24:3686-3692.28. van der Velden VH, van der Sluijs-Geling A, GibsonBE, et al. Clinical significance of flowcytometric minimalresidual disease detection in pediatric acute myeloidleukemia patients treated according to the DCOGANLL97/MRC AML12 protocol. Leukemia. 2010;24:1599-1606.29. San Miguel JF, Vidriales MB, Lopez-Berges C, et al.Early immunophenotypical evaluation of minimal resid-ual disease in acute myeloid leukemia identifies differentpatient risk groups and may contribute to postinductiontreatment stratification. Blood. 2001;98:1746-1751.30. Kern W, Voskova D, Schoch C, et al. Determinationof relapse risk based on assessment of minimal residualdisease during complete remission by multiparameterflow cytometry in unselected patients with acute myeloidleukemia. Blood. 2004;104:3078-3085.31. Maurillo L, Buccisano F, Del Principe MI, et al.Toward optimization of postremission therapy for residualdisease-positive patients with acute myeloid leukemia.J Clin Oncol. 2008;26:4944-4951.32. Neale GA, Coustan-Smith E, Stow P, et al.Comparative analysis of flow cytometry and polymerasechain reaction for the detection of minimal residual dis-ease in childhood acute lymphoblastic leukemia.Leukemia. 2004;18:934-938.33. Kerst G, Kreyenberg H, Roth C, et al. Concurrentdetection of minimal residual disease (MRD) in child-hood acute lymphoblastic leukaemia by flow cytometryand real-time PCR. Br J Haematol. 2005;128:774-782.34. Coustan-Smith E, Sancho J, Hancock ML, et al. Useof peripheral blood instead of bone marrow to monitorresidual disease in children with acute lymphoblasticleukemia. Blood. 2002;100:2399-2402.35. van der Velden V, Jacobs DC, Wijkhuijs AJ, et al.Minimal residual disease levels in bone marrow andperipheral blood are comparable in children with T cellacute lymphoblastic leukemia (ALL), but not in precur-sor-B-ALL. Leukemia. 2002;16:1432-1436.36. Coustan-Smith E, Sandlund JT, Perkins SL, et al.Minimal disseminated disease in childhood T-cell lym-phoblastic lymphoma: a report from the children’s oncol-ogy group. J Clin Oncol. 2009;27:3533-3539.37. Coustan-Smith E, Mullighan CG, Onciu M, et al.Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol.2009;10:147-156.38. Mullighan CG, Su X, Zhang J, et al; Children’sOncology Group. Deletion of IKZF1 and prognosis inacute lymphoblastic leukemia. N Engl J Med.2009;360:470-480.39. Cario G, Stanulla M, Fine BM, et al. Distinct geneexpression profiles determine molecular treatmentresponse in childhood acute lymphoblastic leukemia.Blood. 2005;105:821-826.40. Flotho C, Coustan-Smith E, Pei D, et al. A set ofgenes that regulate cell proliferation predicts treatmentoutcome in childhood acute lymphoblastic leukemia.Blood. 2007;110:1271-1277.41. Yang JJ, Cheng C, Yang W, et al. Genome-wide inter-rogation of germline genetic variation associated withtreatment response in childhood acute lymphoblasticleukemia. JAMA. 2009;301:393-403.42.Coustan-Smith E, Song G, Clark C, et al. New mark-ers for minimal residual disease detection in acute lym-phoblastic leukemia. Blood. 2011;117:6267-6276.43. Coustan-Smith E, Ribeiro RC, Stow P, et al. A sim-plified flow cytometric assay identifies children withacute lymphoblastic leukemia who have a superior clini-cal outcome. Blood. 2006;108:97-102.


Leukemias

�� Editor in ChiefSagar Lonial, MDAssociate Professor of Hematology and Oncology Emory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Section of HematologyRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Therapy• Transplant-Eligible Patients• Retreatment• Transplant-Ineligible Patients• Cytogenetics• Side-Effect Management• Bone Health

Newsletter Series

��

��

Topics include:• Hodgkin Lymphoma• Follicular Lymphoma• Mantle Cell Lymphoma• Waldenstrom’s Macroglobulinemia• Diffuse Large B-Cell Lymphoma• T-Cell Lymphoma

��

��

Target AudienceThese activities were developed for physicians, nurses, and pharmacists.

AccreditationThis activity has been approved for 1.0 AMA PRA Category 1 Credit™ (a total of 14.0 credit hours will be issued for completion of all activities). Nursing and Pharmacy credit hours will also be provided.For complete learning objectives and accreditation information, please refer to each activity.

This activity is jointly sponsored by Global EducationGroup and Medical Learning Institute, Inc.

Coordination for this activity provided by Center of Excellence Media, LLC.

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YOUR QUESTIONS ANSWERED

COEAsize40611MM

For information about the physician accreditation of this activity, please contact Global at 303-395-1782 or [email protected].

This activity is supported by educational grant from Cephalon Oncology,Millennium Pharmaceuticals, Inc., and Seattle Genetics, Inc.

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

��

Minimal Residual Disease to Monitor Therapy in Acute Leukemia Continued from page 31



Quinoa, the ancient “grain” of the Andes, culti-vated for over 7000 years, has transitioneditself into our present-day kitchens and the

title of a modern-day superfood. The Incas believedquinoa to be a sacred food and referred to the “grain” asthe “mother seed.” Many years later, this superfoodwould make its way to the United States, where its pop-ularity continues to grow as its numerous nutritionalbenefits are spotlighted.How do you say that strange name? Quinoa, or

“keen-wah” as is it properly pronounced, will have a fewpeople looking twice and asking, “Are you sure that ishow you say that?”Quinoa is often referred to as a grain but is actually the

seed of a plant. It belongs tothe same plant family as beets,chard, and spinach. Quinoacooks up just like a grain, so itis often grouped in this catego-ry. One distinguishing qualityof quinoa is that it is a com-plete protein. It is unusual for aplant food to provide all theessential amino acids that ourbodies cannot make on theirown. This makes quinoa a fan-tastic protein source for veg-ans, vegetarians, and thoselooking to replace an animalprotein meal with a plant-based protein meal. One of theamino acids in high concentration in quinoa is lysine.This amino acid is particularly important in tissuegrowth, tissue repair, and collagen formation. Due to thisbenefit, quinoa is a good choice for anyone goingthrough chemotherapy, radiation, or postsurgical recov-ery to help the body heal and generate new cells. In addition to the superior protein content of quinoa,

it is also abundant in a variety of vitamins and miner-als, as well as naturally occurring compounds such aspolyphenols, phytosterols, and flavonoids with possiblenutraceutical benefits.1 Quinoa is a good source of mag-nesium, manganese, folate, phosphorus, and potassi-um.2 The minerals present in quinoa work as cofactorsin antioxidant enzymes.3 Antioxidants help to protect

cells from damage by free radicals that are created fromsuch things as smoking and pollution, as well as the by-products of normal metabolism. Free radical damage isassociated with an increased risk of many chronic dis-eases. Vitamin E is a strong antioxidant that can protectcells against free radicals, and quinoa is an ideal foodchoice to add to your menu to increase your intake ofthis important vitamin. Quinoa is also a good source ofB vitamins such as thiamin, folic acid, and riboflavin,and it provides about 15% of your daily recommendedamount of iron.2 Add a food item that is high in vita-min C such as tomatoes, broccoli, or peppers to cookedquinoa to help improve the body’s absorption of plant-based non-heme iron.

Diet and lifestyle changesmay help to reduce the risk ofcertain types of cancer. In par-ticular, increasing fiber-richfoods in the diet may help toreduce the risk of colorectalcancer.4 Quinoa is an excel-lent source of fiber, providing5 grams of fiber per 1-cup serv-ing.2 In corporating fiber-richfoods from a variety of differ-ent food groups en hances theprotective effect against can-cer and other chronic diseases.It is not well understood at

this time if the protective benefit lies solely within thefiber content or if it is how the fiber content of a partic-ular food interacts with the other naturally occurringcompounds that helps to reduce the risk of disease. By including quinoa in your everyday menu, you

will also be receiving a serving of whole grain. The2010 Dietary Guidelines for Americans recommendsthat all Americans make half or more of the grainsthey consume be whole grains—about 3 to 5 servingsof whole grain per day. A half-cup serving of quinoaprovides 1 serving of whole grain. The Whole GrainsCouncil is an invaluable resource to help peopleidentify whole grain foods and understand their healthbenefits, as well as to provide health professionals withscientific studies supporting the health benefits ofwhole grains. The Whole Grains Council also devel-oped the Whole Grain Stamp found on many foodproducts in your local supermarket. This stamp identi-fies a food item as whole grain and tells consumersexactly how much whole grain it contains. The WholeGrain Stamp and the wealth of information on theirWeb site help take the mystery out of eating healthy.5Quinoa is so versatile it can become a part of your

regular diet from breakfast to dessert. It can be madeinto savory or sweet dishes. Cooked quinoa is smoothand fluffy yet slightly chewy with a nutty flavor. It issimilar to couscous and rice, so it is easy to substitute

quinoa in these recipes. Quinoa can also be used as ahot cereal in the morning—just add the toppings youwould typically add to oatmeal, and you will have anutrient-packed breakfast. The quinoa seed is tiny andround. The yellow seed is the most common variety, butit also comes in red, black, pink, orange, and purple.Quinoa is also gluten free, making it a superb, highlynutritious choice for people with celiac disease or any-one with a wheat allergy or intolerance.Before cooking quinoa, the seeds need to be rinsed to

remove the soapy saponins that will give the seed a bit-ter taste if not removed. Commercial brands of quinoaare sometimes sold prerinsed, but it is still good to rinsethese seeds one more time before cooking.Quinoa is the tiny “grain” with a funny name that

packs a huge nutritional punch. The advantages ofadding quinoa to your diet are numerous. The excellentprotein content, vitamin and mineral profile, as well asimpressive antioxidant and phytonutrient activity makeit an exceptional food choice to incorporate into thediet. Quinoa is low in fat and is cholesterol free, anotheradded bonus. This is a food item that I regularly recom-mend people introduce into their diet. It is a great choicefor people on active chemotherapy and radiation treat-ment because of its mild flavor and the ability to adjust itto their particular taste, while at the same time providingmore nutrition than plain white rice or pasta. It is alsoperfect for those patients who have completed treatmentand are looking to improve the quality of their diet orperhaps move toward a plant-based diet. Quinoa is aperfect food for people to start this new journey. It isnot an intimidating grain or so strange that it may dis-courage some from making a change to a healthierway of eating. Another recommendation is to encour-age people to go their local health food stores or super-markets and look for prepared quinoa or whole grainsalads in the deli section to give them an idea of whatthese grains should look and taste like once they makeit on their own. Making small changes is ultimatelywhat will motivate most people into following ahealthier diet and overall healthier lifestyle; quinoacan be that first stepping-stone. �

References1. Abugoch James LE. Quinoa (Chenopodium quinoa Willd.): composition,chemistry, nutritional, and functional properties. Adv Food Nutr Res.2009;58:1-31.2. US Department of Agriculture. Quinoa, cooked. Nutrition FactInformation. http://ndb.nal.usda.gov/ndb/foods/show/6430. Accessed Feb -ruary 25, 2012.3. Vega-Galvez A, Miranda M, Vergara J, et al. Nutrition facts and function-al potential of quinoa (Chenopodium quinoa willd.), an ancient Andeangrain: a review. J Sci Food Agric. 2010;90:2541-2547.4. Chan AT, Giovannucci EL. Primary prevention of colorectal cancer.Gastroenterology. 2010;138:2029-2043.5. Whole Grains Council. Identifying whole grain products. www.wholegrainscouncil.org. Accessed February 25, 2012.

Visit www.TheOncologyNurse.com for Karen’s quinoarecipe.

Nutri ionwithKaren

Ms Connelly is a Registered

Dietitian and Certified Specialist

in Oncology Nutrition at the

Steeplechase Cancer Center in

Somerville, New Jersey. As

part of her responsibilities, she

provides nutrition counseling,

group classes, and monthly

cooking classes for patients

and families.

Quintessential QuinoaBy Karen Connelly, RD, CSO

The excellent protein

content, vitamin and

mineral profile, as well

as impressive antioxidant

and phytonutrient activity

make it an exceptional

food choice.

©iStockphoto.com/Stephanie Timmermann


needed answered (What did it meanthat I had a high platelet count? Whenwould I know if this round ofchemotherapy worked? What alterna-tives existed if it did not?), I fuddledaround until I found the button on myelectronic bed, pushed it, and waiteduntil the small, humming motor slowlyraised my head so I could carry on adecent conversation.

“Oh, good morning, Dr F,” I said.“Why would I be crazy?”

“The steroids we are giving you willmake you crazy!” he stated forcefully.

Dr F represents an entire cadre of doc-tors who could learn from the nurses whosurround them how to approach a real,live patient. Certainly, I understand thehierarchy in the hospital. I understandthat many demands seemingly muchmore important than visiting me, or anyother patient, clutter the days of doctors.I understand what a nurse explained tome: the doctors give the orders and thenurses carry them out; the doctor comesup with the treatment plan, the nurseapplies it and comforts the patientthrough it; the doctor does a round onthe floor at given intervals, while thenurse actually works on the floor, spend-ing his/her days with patients. However,in my mind, none of that gives the doc-tor a right to be curt, sarcastic, and dis-orienting in his/her interaction with me!

So how would I suggest to Dr F thathe enter a patient’s room, even if it is7:30 in the morning, and the patient hasgotten literally no sleep after a difficultnight? The same way the nurses did allduring the night!

“Hi, Ms M,” she (in this case) wouldgently say to me as I drifted in and out ofsleep interrupted by nausea, exhaustion,blurry vision, and confusion. “I am justhere to see if you need more medi-cine…” or “I am just here to let youknow that someone is around…” or “Iam just here to answer any questions youmay have…” or “I am just here to check

up on you…” or “I am just here.…”Yes, Dr F, use my name! Talk to me in

a calm voice (you already know I amsomewhat disoriented because of thetime of day and the characteristics ofmy illness). Tell me what you wantfrom me or have to offer me. Do not besarcastic. Do not speak loudly whenyou see me lying with my eyes closed.

Do not ask me disorienting questions.In short, Dr F, act like a nurse aroundme! It would do both of us a world ofgood in your job as a doctor! �

MMA is undergoing treatment forcancer. She wishes to use her initials.


The Patient’s Voice

PROVENGE® (sipuleucel-T)Suspension for Intravenous Infusion Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION For Autologous Use Only.

diphenhydramine.

the infusion bag.Do Not Initiate Infusion of Expired Product.

Do Not Use a Cell Filter.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS

PROVENGE is intended solely for autologous use.

Acute infusion reactions

following the third infusion. Some (1.2%) patients in the PROVENGE group were

PROVENGE group.

administered as needed.

Handling Precautions for Control of Infectious Disease. PROVENGE is notleukapheresis material and PROVENGE may carry the risk of transmitting infectious

should be followed.

Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either

with PROVENGE.

Product Safety Testing. PROVENGE is released for infusion based on the microbial

Dendreon will notify the treating physician. Dendreon will attempt to identify the

and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONS

mononuclear cells.

included acute infusion reactions (see Warnings and Precautions)

tumor flare.

number of these patients discontinued treatment as a result. Monitoring for infectious

were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

Any Adverse EventChillsFatigue

NauseaJoint acheHeadacheCitrate toxicityParesthesiaVomiting

ConstipationPainParesthesia oralPain in extremity

Muscle ache

Diarrhea

Musculoskeletal painDyspneaEdema peripheralHot flushHematuriaMuscle spasms

591 (98.3)

247 (41.1)

186 (30.9)

7 (1.2)

291 (96.0) 97 (32.0)

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

(Table 1 continued on next page.)

What Doctors Can Learn From Nurses Continued from cover

Tell me what you want

from me or have to offer

me. Do not be sarcastic.

Do not speak loudly

when you see me lying

with my eyes closed.

Prospective data from a recentstudy link the long-term use of non-aspirin non steroidal anti-

inflammatory drugs to increasedrisk for renal cell carcinoma. The

use of acetaminophen and aspirinwas not associated with the risk

for renal cell carcinoma.

—Arch Intern Med. 2011;171:1487-1493.

Did You Know?


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


Reader Survey

Cerebrovascular Events.

(See Adverse Reactions [6] of full Prescribing Information.)

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

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE

Hypertension

Upper respiratory tract infection

Musculoskeletal chest painCoughNeck painWeight decreasedUrinary tract infectionRashSweatingTremor

All Gradesn (%)

All Gradesn (%)

Grade 3-5n (%)

Grade 3-5n (%)

PROVENGE (N = 601) Control* (N = 303)

Dendreon Corporation Seattle, Washington 98101

PROVENGE are registered trademarks of Dendreon Corporation.P-A-11.10-073.02(b)

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

Should everyone be required to purchase health insurance?

Our thanks to all who participated in this survey. If you want to participate in this month’s survey, see page 15 for details.

www.TheOncologyNurse.com

We asked our online reading community about this subject, and here arethe results:• 64% said people should be required to purchase health insurance• 36% didn’t think people should be required to purchase health insurance


Prostate cancer cell

Resting T cell PROVENGE

Activated T cell attacks prostate cancer

PROVENGE-activated T cell

ACTIVATE THE POWER OF THE IMMUNE SYSTEM. EXTEND SURVIVAL.

PROVENGEIN ADVANCED PROSTATE CANCER...

www.PROVENGE.com©2012 Dendreon Corporation. All rights reserved. February 2012. P-A-02.12-025.00

PROVENGE extends median survival beyond 2 years1

Only 1.5% of patients treated with PROVENGE in the pivotal trial discontinued treatment due to adverse events2

— The most common adverse events in PROVENGE trials were chills, fatigue, fever, back pain, nausea, joint ache, and headache2

PROVENGE is the first and only FDA-approved immunotherapy for advanced prostate cancer The NCCN recommends PROVENGE as a first-line treatment for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (NCCN Category 1 recommendation)3

INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases. In controlled clinical trials, serious adverse events reported in the PROVENGE group include acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent page.

5392_Onc_Nurse_APN-PA_L1.indd 1 2/21/12 2:32 PM


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