november 2012, vol 5, no 10 the oncology nurse

Early breast cancer patients who gainweight after treatment are atincreased risk for breast cancer

recurrence, according to an Italian studypresented at the European Society forMedical Oncology 2012 Congress, held inVienna, Austria. Saverio Cinieri, MD, of the Hospital

Perrino in Brindisi, Italy, presented theresults of the single-center study of 520patients treated between 1990 and 2012

and followed for a median of 13 years.1Being overweight at the time of early

breast cancer diagnosis has been linked topoorer survival in most studies, and someevidence suggests that women who gainweight after diagnosis are at increased riskof cancer recurrence and death. “But most previous studies on this topic

have relied on retrospective chart re -views,” Cinieri said. “So the aim of this

In a phase 3 head-to-head comparisontrial, the anaplastic lymphoma kinase(ALK) inhibitor crizotinib proved

more effective than standard chemo -therapy with pemetrexed or docetaxel asa second-line treatment for non–smallcell lung cancer (NSCLC) patients withthe ALK genetic abnormality.The results of the global PROFILE

1007 trial were reported by Alice Shaw,MD, of Massachusetts General Hospitalin Boston, at the European Society forMedical Oncology (ESMO) 2012 Con -gress, held in Vienna, Austria.1Rearrangements of the ALK gene are

found in about 5% of all NSCLC. In pre-vious studies, crizotinib was shown to

Side effect ManageMent . . . 20Preventing Chemotherapy-InducedPeripheral Neuropathy RemainsElusive

Medical certificationS . . . . . 22Medical Certification by HealthcareProfessionals for Patients With aHistory of Cancer

caregiving . . . . . . . . . . . . . . . . . . . . . . 26We Faced the Disease Together

coMpliMentary ce . . . . . . . . . . . . 28Considerations in Multiple Myeloma—Ask the Experts:Retreatment Settings

neuroendocrine tuMorS . . . . 36Advances in the Treatment ofPancreatic Neuroendocrine Tumors

noteworthy nuMberS . . . . . . . . 37Family Caregivers

NOvEMBER 2012 www.TheOncologyNurse.com vOL 5, NO 10

©2012 Green Hill Healthcare Communications, LLC

BREAST CANCER

Weight Gain After Breast CancerTreatment Linked to RecurrenceBy Caroline Helwick

Continued on page 7

I N S I D E

Continued on page 11

The mission of the John Theurer Cancer Center is to deliverextraordinary care that is multidisciplinary, personalized, innova-tive, and at the appropriate cost with superior outcomes to the

most satisfied patients. That’s a tall order, but it seems that the centeris fulfilling its mission. The John Theurer Cancer Center at HackensackUniversity Medical Center in New Jersey was ranked as one of the top50 Best Hospitals for cancer, according to U.S. News & World Report.It is the highest-ranked cancer center in New Jersey with this desig-nation. Within its 14 specialized cancer divisions, world-class physi-cians, nurses, and scientists have harnessed the newest technologies

CANCER CENTER PROFILE


Left to right: Andrew Pecora, MD, FACP, CPE; Kevin Barga, RN, BSN, CCRP, clinical trial man-ager; Mary Ann Libby, clerical supervisor; Melinda Weber, RN, APN, advanced practice nursemanager; Eileen Beysel, RN, BSN, OCN, oncology nurse navigator; Jeannie Jones, executiveadministrative assistant; Joan Monaghan, RN, MS, APN, supervisor psychosocial team;William Benham, patient navigator; Bonnie LoGiudice, executive administrative secretary;Rebecca Hirsch, MS, RD, therapeutic dietitian; and James Wittig, MD, chief, Skin andSarcoma Division—Cutaneous Malignancy Program.

Photo from John Theurer Cancer Center.

John Theurer Cancer CenterGold Standard of Care

By Alice Goodman

LUNG CANCER

Crizotinib Superior toChemotherapy in First Head-to-Head ComparisonPROFILE 1007 Was a Headliner at ESMO

By Audrey Andrews

CONFERENCE NEWS

Highlights from the EuropeanSociety for Medical OncologyBy Alice Goodman

Oncology experts from all overthe globe arrived in Vienna,Austria, to attend the Euro -

pean Society for Medical Oncology(ESMO) 2012 Congress. Attendancebroke all records, with 16,394 dele-gates, many of them from outside of

Europe: 1116 from the United States,539 from Japan, 479 from China, 292from Argentina, and 258 from Brazil.Following are some highlights from thePresidential Symposia and papers prof-fered at the meeting.


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Please refer to Black Box Warnings and see Brief Prescribing Informations on back page.

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Docetaxel Injection, USP safely and effectively. See full prescribing information for Docetaxel.

Docetaxel Injection, USPFor intravenous infusion only. Initial U.S. Approval: 1996

WARNING: TOXIC DEATHS, HEPATOTOXICITY, NEUTROPENIA, HYPERSENSITIVITY REACTIONS, and FLUID RETENTION

See full prescribing information for complete boxed warning

• Treatment-related mortality increases with abnormal liver function, at higher doses, and in patients with NSCLC and prior platinum-based therapy receiving docetaxel at 100 mg/m2 (5.1)

• Should not be given if bilirubin > ULN, or if AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN. LFT elevations increase risk of severe or life-threatening complications. Obtain LFTs before each treatment cycle (8.6)

• Should not be given if neutrophil counts are < 1500 cells/mm3. Obtain frequent blood counts to monitor for neutropenia (4)

• Severe hypersensitivity, including very rare fatal anaphylaxis, has been reported in patients who received dexamethasone premedication. Severe reactions require immediate discontinuation of Docetaxel Injection, USP and administration of appropriate therapy (5.4)

• Contraindicated if history of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80 (4)

• Severe fluid retention may occur despitedexamethasone (5.5)

CONTRAINDICATIONS• Hypersensitivity to docetaxel or polysorbate 80 (4)• Neutrophil counts of <1500 cells/mm3 (4)

WARNINGS AND PRECAUTIONS • Acute myeloid leukemia: In patients who received docetaxel

doxorubicin and cyclophosphamide, monitor for delayed myelodysplasia or myeloid leukemia (5.6)

• Cutaneous reactions: Reactions including erythema of the extremities with edema followed by desquamation may occur. Severe skin toxicity may require dose adjustment (5.7)

• Neurologic reactions: Reactions including. paresthesia, dysesthesia, and pain may occur. Severe neurosensory symptoms require dose adjustment or discontinuation if persistent. (5.8)

• Asthenia: Severe asthenia may occur and may require treatment discontinuation. (5.9)

• Pregnancy: Fetal harm can occur when administered to a pregnant woman. Women of childbearing potential should be advised not to become pregnant when receiving Docetaxel Injection, USP (5.10, 8.1)

ADVERSE REACTIONSMost common adverse reactions across all docetaxel indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, myalgia (6)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Gemcitabine Injection safely and effectively. See full prescribing information for Gemcitabine Injection.

Gemcitabine InjectionFor Intravenous Infusion Only.Must Be Diluted Before Use.Initial U.S. Approval: 1996

INDICATIONS AND USAGEGemcitabine is a nucleoside metabolic inhibitor indicated for:• Ovarian cancer in combination with carboplatin (1.1)• Breast cancer in combination with paclitaxel (1.2)• Non-small cell lung cancer in combination with cisplatin (1.3)• Pancreatic cancer as a single-agent (1.4)

DOSAGE AND ADMINISTRATIONGemcitabine Injection is for intravenous use only.• Ovarian cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of

each 21-day cycle (2.1)• Breast cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of

each 21-day cycle (2.2)• Non-small cell lung cancer: 4-week schedule, 1000 mg/m2 over

30 minutes on Days 1, 8, and 15 of each 28-day cycle: 3-week schedule; 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.3)

• Pancreatic cancer: 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks (2.4)

• Dose Reductions or discontinuation may be needed based on toxicities (2.1-2.4)

DOSAGE FORMS AND STRENGTHS• 200 mg/5.26 mL injection vial (3)• 1 g/26.3 mL injection vial (3)• 2 g/52.6 mL injection vial (3)

CONTRAINDICATIONSPatients with a known hypersensitivity to gemcitabine (4)

WARNINGS AND PRECAUTIONS • Infusion time and dose frequency: Increased toxicity with

infusion time >60 minutes or dosing more frequently than once weekly. (5.1)

• Hematology: Monitor for myelosuppression, which can be dose-limiting. (5.2, 5.7)

• Pulmonary toxicity: Discontinue Gemcitabine Injection immediately for severe pulmonary toxicity. (5.3)

• Renal: Monitor renal function prior to initiation of therapy and periodically thereafter. Use with caution in patients with renal impairment. Cases of hemolytic uremic syndrome (HUS) and/or renal failure, some fatal, have occurred. Discontinue Gemcitabine Injection for HUS or severe renal toxicity. (5.4)

• Hepatic: Monitor hepatic function prior to initiation of therapy and periodically thereafter. Use with caution in patients with hepatic impairment. Serious hepatotoxicity, including liver failure and death, have occurred. Discontinue Gemcitabine Injection for severe hepatic toxicity. (5.5)

• Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)

• Radiation toxicity. May cause severe and life-threateningtoxicity. (5.8)

ADVERSE REACTIONSThe most common adverse reactions for the single-agent (≥20%) are nausea and vomiting, anemia, ALT, AST, neutropenia, leukopenia, alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or electronically at [email protected], or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION

Revised: 09/2011


HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Oxaliplatin safely and effectively. See full prescribing information for Oxaliplatin.

Oxaliplatin for Injection,powder for solution for intravenous use

Oxaliplatin Injection,solution for intravenous use

Initial U.S. Approval: 2002

WARNING: ANAPHYLACTIC REACTIONSSee full prescribing information for complete boxed warning.

Anaphylactic reactions to Oxaliplatin have been reported, and may occur within minutes of Oxaliplatin administration. Epinephrine, corticosteroids, and antihistamines have been employed to alleviate symptoms. (5.1)

INDICATIONS AND USAGEOxaliplatin is a platinum-based drug used in combination with infusional 5-fluorouracil /leucovorin, which is indicated for:• adjuvant treatment of stage III colon cancer in patients who

have undergone complete resection of the primary tumor. • treatment of advanced colorectal cancer. (1)

CONTRAINDICATIONS• Known allergy to Oxaliplatin or other platinum compounds.

(4, 5.1)

WARNINGS AND PRECAUTIONS• Allergic Reactions: Monitor for development of rash, urticaria,

erythema, pruritis, bronchospasm, and hypotension. (5.1)• Neuropathy: Reduce the dose or discontinue Oxaliplatin if

necessary. (5.2)• Pulmonary Toxicity: May need to discontinue Oxaliplatin until

interstitial lung disease or pulmonary fibrosis are excluded. (5.3)

• Hepatotoxicity: Monitor liver function tests. (5.4)• Pregnancy. Fetal harm can occur when administered to

a pregnant woman. Women should be apprised of the potential harm to the fetus. (5.5, 8.1)

ADVERSE REACTIONSMost common adverse reactions (incidence ≥ 40%) were peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, nausea, increase in transaminases and alkaline phosphatase, diarrhea, emesis, fatigue and stomatitis. Other adverse reactions, including serious adverse reactions, have been reported. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Hospira Inc. at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling.

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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, AOCNPJohns Hopkins KimmelCancer Center/SibleyInfusionWashington, DC

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, OCNQuintilesDallas, 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

Ellen A. Neylon,MSN, FNP-BC,CCRP, OCNColumbia UniversityMedical CenterCenter for LymphoidMalignanciesNew York, NY

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

Editorial Board

4 NOvEMbER 2012 I vOL 5, NO 10 www.TheOncologyNurse.com

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139

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The Oncology Nurse-APN/PA®, ISSN 1944-9798 (print);ISSN 1944-9801 (online) is published 11 times a year byGreen Hill Healthcare Communications, LLC, 1249South River Road, Suite 202A, Cranbury, NJ 08512.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®

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From the Editor

In this month’s issue of The Oncology Nurse-APN/PA(TON), we bring you the news

from the European Society forMedical Oncology 2012 Con -gress. Some of the most excitingnews came from the update of thePROFILE 1007 trial, with resultsshowing that crizotinib was moreeffective than standard chemo -therapy with pemetrexed or doce -taxel as a second-line treatmentfor non–small cell lung cancer.We also cover the latest treatment

information about pancreatic neuroendocrine tumors,which, as one presenter noted, is “not a rare disease any longer.”With all the research news, it’s important to recognize

the role oncology nurses play in direct patient care andacknowledge that this care often goes beyond the strictlymedical. We present an article from the Cancer LegalResource Center that covers the basics of how healthcareprofessionals can provide documentation to certify theirpatients’ medical conditions. Patients confront manynonmedical situations that relate to their cancer diagno-sis, including how to deal with employment and publicbenefits issues, and we as oncology nurses are often askedto provide guidance. Please read the article by Rich Devlin, where he tells us

about the journey he and his wife made after her diagnosisof breast cancer. Oncology nurses regularly interact withfamily caregivers and we know how central they are to thewell-being of patients. Noteworthy Numbers presents someof the statistics related to family caregivers. We want to hear from you. Please tell us what you want

to see in TON. Contact us at [email protected]

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

Editor-in-Chief

Recent FDA News

Omacetaxine Mepesuccinate Approved to Treat CMLThe US Food and Drug Administration (FDA) has

approved omacetaxine mepesuccinate subcutaneous injec-tion (Synribo, Teva Pharmaceutical Industries) for thetreatment of adult patients with chronic myeloid leukemia(CML) with resistance and/or intolerance to 2 or moretyrosine kinase inhibitors (TKIs). Approval for omacetax-ine mepesuccinate was granted on October 26, 2012.The FDA approval was based on the combined results of

2 open-label, single-arm trials that enrolled patients withCML in chronic phase or accelerated phase. Patients in thetrials had received 2 or more prior TKIs, including imat -inib. The end points for the studies were major cytogenet-ic response for chronic-phase CML and major hematologicresponse for accelerated-phase CML. For those with chron-ic-phase CML, major cytogenetic response was achieved in18.4% of patients (median response duration of 12.5months). For patients with accelerated-phase CML, 14.3%achieved major hematologic response (median responseduration of 4.7 months).Thrombocytopenia, anemia, neutropenia, diarrhea, nau-

sea, fatigue, asthenia, injection-site reaction, pyrexia, infec-tion, and lymphopenia were the most common (≥20%)grades 1 to 4 adverse drug reactions. Thrombocytopenia,anemia, neutropenia, febrile neutropenia, asthenia/fatigue,pyrexia, and diarrhea were the most common (≥5%) grades3 to 4 adverse drug reactions. Among the patients in thetrials, 10 died within 30 days of the last omacetaxine mepe-succinate dose: 4 deaths were attributed to progressive dis-ease, 4 to cerebral hemorrhage, 1 to multiorgan failure, and1 to unknown causes.Omacetaxine mepesuccinate was reviewed under the

FDA’s accelerated approval review program that providesan expedited 6-month review for drugs that offer majoradvances in treatment or that provide treatment when noadequate therapy exists. In addition, the FDA designatedomacetaxine mepesuccinate as an orphan product becauseit is intended to treat a rare disease or condition. Richard Pazdur, MD, director of the Office of

Hematology and Oncology Products in the FDA’s Centerfor Drug Evaluation and Research, stated that the approvalof omacetaxine mepesuccinate “provides a new treatmentoption for patients who are resistant to or cannot tolerateother FDA-approved drugs for chronic or accelerated phas-es of CML.” He also noted that it “is the second drugapproved to treat CML in the past two months.”

Expanded Labeling for PemetrexedThe FDA expanded the labeling of pemetrexed

(Alimta, Eli Lilly and Company) to include the results ofan additional trial evaluating its safety and efficacy for theinitial treatment of patients with locally advanced ormetastatic, nonsquamous, non‒small cell lung cancer fol-lowed by pemetrexed maintenance in patients with dis-ease that has not progressed after 4 cycles of platinum andpemetrexed as first-line chemotherapy. The approval forexpanded labeling was granted on October 17, 2012.The expanded labeling describes the results of a multi-

center, randomized (2:1), double-blind, placebo-con-trolled trial that evaluated pemetrexed maintenance inpatients with stage IIIB/IV nonsquamous, non‒small celllung cancer whose initial treatment was 4 cycles of peme-trexed plus cisplatin. There were 539 patients randomizedto receive 500 mg/m2 pemetrexed intravenously on day 1of each 21-day cycle (359 patients) or matching placebo(180 patients). All patients had an ECOG performancestatus of 0 or 1 and had completed 4 cycles of pemetrexedplus cisplatin with a best response of stable disease, partialresponse, or complete response.Investigator-assessed progression-free survival (PFS)

was significantly improved in patients randomized toreceive pemetrexed maintenance, compared with thosewho received placebo. Median PFS was 4.1 months forpatients in the pemetrexed arm and 2.8 months forpatients receiving placebo. Overall survival, a secondaryend point, also was significantly improved for patientsreceiving pemetrexed maintenance, with median survivaltime of 13.9 months, compared with 11.0 months forpatients receiving placebo.Neutropenia, anemia, fatigue, nausea, vomiting, stoma -

titis, and edema were the most common (>5%) adverseevents for patients in the pemetrexed arm. Anemia andneutropenia were the most common severe adverse reac-tions. Approximately 25% of patients receiving peme-trexed maintenance had treatment reduced or delayedbecause of toxicity. l

Sourceshttp://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm325990.htmhttp://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm325895.htmhttp://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm324239.htm

NOvEMbER 2012 I vOL 5, NO 10 7www.TheOncologyNurse.com

Breast Cancer

prospective observational single-centerstudy was to determine whether weightat diagnosis and/or weight gain after earlybreast cancer treatment is associatedwith breast cancer recurrence.”Weight and body mass index (BMI)

were recorded at baseline and 24months after completion of treatment(radiotherapy and/or chemotherapy,but not endocrine therapy). Three cat-egories of BMI were used: BMI <25kg/m2 (lean), BMI 25-30 kg/m2 (over-weight), and >30 kg/m2 (obese).Patients’ mean BMI at study entry

was 26.8 and 24 months posttreatmentwas 27.7. Almost 60% of the patientswere postmenopausal. The study docu-mented recurrences in 194 patients. Weight at diagnosis was not associ-

ated with recurrences, the studyfound. In both the lean and over-weight groups, 40% of patients hadrecurrences; in the obese group, 31%recurred.There was also no correlation

between breast cancer recurrence andweight loss. This included moderateweight loss (<1 kg/m2), where 47% ofwomen recurred, or greater weight loss(>1 kg/m2), where 31% recurred. “However, weight gain was rather

significantly related to recurrences,”Cinieri reported. This was most strik-ing for weight gain of more than 2kg/m2, a group in which 48% ofwomen had recurrences. In those withmoderate gain (<2 kg/m2), 34%recurred. “Our findings show that early breast

cancer patients do gain weight aftertreatment, and moderate or largeweight gain postdiagnosis is signifi-cantly associated with an increased riskof breast cancer recurrence,” he said.“Medical oncologists should monitorweight carefully in their patients andoffer intervention strategies to thosewho gain weight.”Abstract discussant Michael Baum,

MD, of University College London inthe United Kingdom, commented that“the weight of the evidence suggeststhat if you are overweight at diagnosis,the outcome is worse.” The currentstudy did not find this, but did showthat weight gain after treatment affectsoutcome. Therefore, the issue is notyet settled.Rowan Chlebowski, MD, of the

University of California Los Angeles,who has conducted seminal studies ondietary and hormonal influences inbreast cancer, added that theWomen’s Intervention NutritionStudy, a randomized study he spear-headed,2 showed dietary fat to be sig-nificantly lower in a group that under-went an intervention program, andthis was accompanied by an average

6-pound weight loss. The interven-tion paid off in another way: relapsesoccurred in 9.8% of the dietarygroup, versus 12.4% of the controlgroup, for a 24% statistically signifi-cant reduction in risk. Somewhatsurprisingly, the result was most strik-ing in the estrogen receptor–negativegroup, he said.

Baum agreed with the recommen-dation for intervention to preventweight gain. “We must emphasizestrongly to our patients that not gain-ing (or losing) weight after treatmentis an important, and very resource-efficient, way to reduce the risk ofrecurrence, in addition to adjuvanttherapy, of course,” he said. l

References1. Fedele P, Nacci A, Lapolla A, et al. Analysis of corre-lation between weight at diagnosis, weight gain afterbreast cancer treatment and recurrence in women withearly stage breast cancer (ebc). Presented at: EuropeanSociety for Medical Oncology 2012 Congress;September 30, 2012; Vienna, Austria. Abstract 2480.2. Chlebowski RT, Blackburn GL, Thomson CA, et al.Dietary fat reduction and breast cancer outcome: inter-im efficacy results from the Women’s InterventionNutrition Study. J Natl Cancer Inst. 2006;98(24):1767-1776.

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Weight Gain After Breast Cancer... Continued from cover

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

S

August 2012

D

Single-agent TREANDA tripled median PFS*

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Effi cacy relative to fi rst-line therapies other than chlorambucil has not been established.

20100 30 4025155

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

35

TREANDA(n=153)

Chlorambucil(n=148)18 months

median PFS

45

0.10.20.30.40.5

Surv

ival

dis

tribu

tion

func

tion

0.60.70.80.91.0

Months

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

6 monthsmedian PFS

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

2

≥≥

Important Safety Information

≥ ≥

LEARN MORE AT WWW.TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

©2012 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-2510a August 2012

Discover the elements of ef� cacy and safety

1-2 9 11:57 AM

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions]WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 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 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment 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 patientsTREANDA Chlorambucil(N=153) (N=143)

System organ classPreferred term All Grades Grade 3/4 All Grades Grade 3/4Total number of patients with atleast 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) 0Diarrhea 14 (9) 2 (1) 5 (3)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) 0InvestigationsWeight decreased 11 (7) 0 5 (3) 0Metabolism and nutrition disordersHyperuricemia 11 (7) 3 (2) 2 (1) 0Respiratory, thoracic and mediastinal disordersCough 6 (4) 1 (<1) 7 (5) 1 (<1)Skin and subcutaneous tissue disordersRash 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 AbnormalityAll 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. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions]OVERDOSAGE: The intravenous 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. Reconstitution/Preparation for Intravenous Administration. Aseptically

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

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

reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride

drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°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.

Distributed by:Cephalon, Inc.Frazer, PA 19355TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved.©2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 April 2012(Label Code: 00016287.06) This brief summary is based on TRE-006 TREANDA full Prescribing Information.

TRE-2511a August 2012

This brief summary is based on TRE-2527 TREANDA full Prescribing Information.


Lung Cancer

induce significant clinical responses inpatients with advanced ALK-positiveNSCLC, but this is the first phase 3 studyto directly compare the novel agent withstandard chemotherapy. The study com-pared crizotinib with pemetrexed ordoce taxel (by physician choice) in 347patients with ALK-positive, stageIIIB/IV NSCLC who had already beentreated with chemotherapy. Crizotinib was superior to standard

single-agent chemotherapy in terms ofresponse, progression-free survival(PFS), and quality of life in ALK-posi-tive patients who progressed after first-line, platinum-based chemotherapy,Shaw reported.“These results establish crizotinib as

the standard of care for patients withadvanced, previously treated, ALK-pos-itive NSCLC,” she maintained.

Doubling in PFSAt 12 months’ median follow-up, crizo-tinib prolonged median PFS to 7.7months, compared with 3.0 monthswith chemotherapy, a highly significant51% reduction in the risk of progression(P <.0001). By type of chemotherapy,median PFS was 4.2 months with peme-trexed (P = .0004) and 2.6 months withdocetaxel (P <.0001).The overall response rate was also sig-

nificantly higher with crizotinib (65%vs 20%; P <.0001).All subgroups experienced a PFS ben-

efit with crizotinib, with the greatestadvantages seen in patients with non-adenoma histology (hazard ratio [HR],0.12).

Survival, TolerabilityAt this point, overall survival (OS) dif-ferences have not been observed, butthe survival analysis is immature, withonly 40% of events occurring. Also,87% of chemotherapy-treated patientshave crossed over to receive crizotinibupon progression, and this would diluteany OS differences, Shaw said.Median OS at this point is approxi-

mately 22 months in each arm. Whenadjusted for confounding by crossovers,there was still a 17% reduced risk ofdying from the disease for patients whoreceived ALK inhibitor, she pointed out.Side effects were more frequent with

crizotinib, but Shaw pointed out thatcrizotinib-treated patients received anaverage of 11 cycles, compared with 4with pemetrexed or docetaxel, whichpartly explains these differences.Toxicities with crizotinib are, however,distinct from those observed withchemotherapy, but are “generally toler-able and manageable,” she noted.The most common treatment-related

adverse events with crizotinib were diar-

rhea (60%), vision disturbance (60%),nausea (55%), and vomiting (47%), butfew grade 3 or 4 toxicities were reported,except for elevated transaminases, whichoccurred in 16% of this arm. Patientsreceiving chemotherapy had morefatigue, alopecia, dyspnea, and rash. Six percent of crizotinib patients,

compared with 10% of pemetrexed/doce taxel patients, discontinued the trialdue to treatment-related adverse events.

Better Quality of Life With CrizotinibPatients on crizotinib also reportedimproved quality of life, compared withchemotherapy. “They reported greater improvement

from baseline in cough, dyspnea,fatigue, alopecia, insomnia, and painwith crizotinib,” Shaw said, “and all ofthese were statistically significant (P <.0001).”They also showed greater improve-

ment from baseline in global quality oflife (P <.0001). Furthermore, “time todeterioration in lung cancer symptoms”was significantly extended with crizo-tinib treatment, to 5.6 months, com-pared with 1.4 months with chemother-apy (HR, 0.54; P <.0001).

Crizotinib “Changes the NaturalHistory” of Lung CancerDiscussing the paper at the meeting,Jean-Charles Soria, MD, of the Institut

Gustave Roussy in Villejuif, France,noted that 2 months’ extended sur-vival in advanced NSCLC is essential-ly “unheard of ” in the general popula-tion of NSCLC patients.“Comparison with historical data

suggests that crizotinib has changedthe natural history of the disease, witha median OS now of 22 months, versus9 months in the past,” he said, “andthis is accomplished with very mildtoxicity.”Even patients in the trial who initial-

ly received chemotherapy had a medianOS of nearly 23 months “because theyreceived crizotinib,” he added. Soria suggested that clinicians

become familiar with the toxicity pro-file, which is quite distinct fromchemotherapy, but is generally man-ageable with the exception of “somerare side effects you need to be awareof,” he told attendees. l

Reference1. Shaw AT, Kim DW, Nakagawa K, et al. Phase III studyof crizotinib versus pemetrexed or docetaxel chemother-apy in patients with advanced ALK-positive non-smallcell lung cancer (NSCLC) (PROFILE 1007). Presentedat: European Society for Medical Oncology 2012Congress; September 30, 2012; Vienna, Austria.Abstract LBA1 PR.

“These results establish crizotinib

as the standard of care for patients

with advanced, previously treated,

ALK-positive NSCLC.”

—Alice Shaw, MD

Photo © ESMO 2012.

Crizotinib Superior to Chemotherapy... Continued from cover

SAVE THE DATE

July 26-28, 2013Hyatt Regency La Jolla at Aventine3777 La Jolla Village Drive San Diego, California

Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

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SECOND ANNUAL CONFERENCE

The median age of patientsin the VISTA‡ trial was 71 years (range: 48-91).

Peripheral neuropathy, including severe cases, may occur – m

Hypotension can occur. Use caution when treating patients r

Closely monitor patients with risk factors for, or existing h

Acute diffuse infiltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred a

Thrombocytopenia or neutropenia can occur; complete blood c

Tumor Lysis Syndrome, Reversible Posterior L

Women should avoid becoming pregnant while being treated w

Closely monitor patients receiving VELCADE in combination w

Living Proof

INDICATIONVELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE 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

▼ Women should avoid becoming pregnant while being treated with VELCADE (bortezomib). Pregnant women should be apprised of the potential harm to the fetus

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

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

Please see Brief Summary for VELCADE on next page.*Melphalan+prednisone.†HR=0.695 (95% CI, 0.57-0.85); p<0.05.‡ VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma (MM). The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed.

§The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL).

Survival never gets old

VELCADE (bortezomib) Indication and Important Safety Information

Approved for subcutaneous and IV administration§

VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP* vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months†; 60.1-month median follow-up‡)

LEARN MORE AT THE 2012 AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING AND EXPOSITION

1-2 1 3:23 PM

Brief Summary

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

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

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc.All rights reserved. Printed in USA V-12-0209 8/12

3:23 PM


Cancer Center Profile

to serve the patients who come throughits doors. The Oncology Nurse-APN/PAspoke with Melinda Weber, RN, APN,about what it is like to work at the JohnTheurer Cancer Center.

What is your role at the JohnTheurer Cancer Center?Melinda Weber (MW): I am theadvanced practice nurse manager. Iwear many hats. First and foremost, mymanagerial responsibilities focus oncollaboration with my immediate teamof advanced practice nurses, educators,and nurse navigators. I also work “inthe trenches” with my administrative,financial, ancillary, legal, pharmacy,radiation, laboratory, dietary, psy-chosocial, and physician team toachieve the best possible outcomes forour patients and the institution. Thisincludes maintaining compliance withJCAHO [Joint Commission onAccreditation of Healthcare Org a -nizations], ACS [American College ofSurgeons], Magnet, and all nationalaccrediting agency mandates andlicensure requirements. Additionally, I maintain all day-to-

day activities of the all-division–specif-ic advanced practice nursing team,with emphasis on scheduling all areasfor patient safety outcomes. I alsocover the solid tumor division whenneeded as a “float” to act in a cliniciancapacity to ensure patient care. I amalso the clinical advanced practicenurse for the Skin and SarcomaDivision and act as a direct patientcaregiver for the division.

What are you excited about rightnow in the field of oncology?MW: I am very excited about value-based medicine. We are providing theappropriate individualized gold standardof care that meets and exceeds allnational standards, whether diagnosticor therapeutic, without the need forundue diagnostic studies or redundant,unwarranted interventions. This ap -proach is critical, not only because of ourcurrent healthcare economy, but becauseof quality and ethical issues as well. I am also very enthusiastic about evi-

dence-based practice and its applicability

to oncology. We have created evidence-based guidelines for toxicities andadverse events such as nausea/vomiting,diarrhea, and mucositis. We have devel-oped written guidelines/order sets on asingle page via NCI [National CancerInstitute] standards using the CommonTerminology Criteria for Adverse Eventsto grade toxicities; provide an immediateteaching tool for patients about that tox-icity; and suggest the immediate evi-dence-based gold standard inter ventionfor that toxicity. We are working onbuilding this 1-page tool into the elec-tronic medical record for all patientswho are treated at our center andthroughout the entire medical centeras well. This will enable any practi-tioner who is seeing that patient toaccess the entire record of toxicitiesand interventions for that patient.

What is the approach to treatingpatients at the John TheurerCancer Center?MW: Our goal is to provide comprehen-sive, individualized extraordinary care forevery patient. Throughout our 14 cancerdivisions, we employ a multidisciplinaryapproach with medical oncologists, sur-geons, nurse navigators, clinical nursingstaff, advanced practice nursing team,patient navigators, other specialty physi-cians, social workers, and support staff.We offer complimentary yoga, exercise,and cooking classes. We have a librarianwho provides complimentary literaturesearches for patients. We are committed

to clinical research, including phase 1 tri-als, working today to provide tomorrow’scures. We also have an active tumorbank of blood and tissue samples for per-sonalized cancer therapy development.We have one of the nation’s largestblood and bone marrow transplant pro-grams. We offer “TrueBeam”-specificradiosurgery, and TomoTherapy radia-tion, as well as da Vinci surgical robots.

How does your approach improvepatient outcomes?MW: All of our physicians are board-certified oncology experts. Each divisionactively participates in multidisciplinarytumor boards, presenting patients todetermine the best plan of care. We arecertified by ACS; JCAHO, includingDSC [disease-specific care] certificationfor our Breast, Gynecology, Gastro -intestinal, and Bone Marrow Transplantprograms; and are Magnet certified as

well. We follow NCCN [National Com -prehensive Cancer Network] guidelines,and patients have access to evidence-based clinical care. For example, todaymy physician colleague and I consultedwith a new patient with breast cancerand incidentally discovered a spot on herlung. Her pathology slides from a previ-ous institution were reviewed the sameday, with additional pathology markersordered, and she was immediatelyreferred to our lung cancer expert andpulmonary care expert. She receivedindividualized patient education, and,after we obtained insurance authoriza-tion, she received her diagnostic scansthe same day as her consult, and her planof care was created.

What inspired you to become anoncology nurse?MW: As a junior volunteer, I workedwith a very young patient who wasdying of metastatic pancreatic cancer.I was deeply touched by the level ofcompassion and dignity provided bythe oncology nurses.

What advice would you give tonurses just entering the field?MW: Select the best baccalaureate andgraduate nursing program you can find,and be sure you are in an environmentthat fosters love of learning. After nurs-ing school you will continue to learn,because the field of cancer is constantlyevolving, and what was considered thebest care management 5 years ago haschanged dramatically. Be sure to networkwith great colleagues. The OncologyNursing Society is a guiding light forevery oncology nurse and offers a bastionof opportunity for networking and alsofor certification. For me, the most impor-tant principles of oncology nursing areintelligence, diligence, grace, and humil-ity. To be kind, respectful, and approach-able to patients, their significant others,and our entire team is absolute. We needto be agents of change. Remember, agenuine smile goes a long way for some-one with cancer.

What would you be if you were notan oncology nurse?MW: A stand-up comedian. l

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Adding bevacizumab to chemo therapyregimens improved response rates andprogression-free survival (PFS) inpatients with platinum-resistantrecurrent ovarian cancer, accordingto an exploratory analysis of thephase 3 AURELIA trial (AbstractLBA26).1 The study design allowedtreatment with 1 of 3 chemo therapyregimens (weekly paclitaxel, pegylat-ed liposomal doxorubicin [PLD], ortopotecan). Bevacizumab improved PFS in the

overall analysis of the trial (poolingdata from the 3 different regimens).Median PFS was 10.4 months for beva-cizumab plus chemotherapy versus 3.9months for chemotherapy alone.

“Bevacizumab combined with chemo -therapy should be considered a newstandard option for platinum-resistantrecurrent ovarian cancer,” stated leadauthor Andres M. Poveda, MD,Fundación Instituto Valenciano deOncología, Valencia, Spain. The exploratory analysis looked at

each of the 3 regimens and found thatweekly paclitaxel plus bevacizumab hadsuperior results. As stated above, medi-an PFS was 10.4 months when beva-cizumab was added to weekly paclitaxelversus 3.9 months for weekly paclitaxelalone. In the PLD cohort, median PFSwas 5.4 months versus 3.4 months,respectively. In the topotecan cohort,median PFS was 5.8 months versus 2.1months, respectively. AURELIA randomized 361 patients

with platinum-resistant recurrent ovar-ian cancer treated with up to 2 prioranticancer regimens to chemotherapyalone or chemotherapy plus bevacizu -mab. The chemotherapy regimen wasthe investigator’s choice among the 3regimens. Treatment was continueduntil unacceptable toxicity or progres-

sive disease occurred.Overall response rates (ORRs) were

superior with the addition of bevacizu -mab, with the highest response ratesobserved in the weekly paclitaxel

cohort: 51.7% versus 28.8% forchemotherapy alone. ORR was 18.3%and 7.9%, respectively, for the PLDcohort and 22.8% and 3.3%, respective-ly, for the topotecan cohort.

No significant differences in toxicitywere observed, with the exception ofmore peripheral neuropathy in the week-ly paclitaxel cohort and more hand-footsyndrome in the PLD cohort.

www.TheOncologyNurse.com16 NOvEMbER 2012 I vOL 5, NO 10

Conference News: ESMO

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Hodgkin lymphoma (HL) after failure of autologous s

Systemic anaplastic large cell lymphoma (

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Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad.REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012.US/BVP/2011/0104d

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

Overall response

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Bevacizumab Plus Chemotherapy Extends Survival in Platinum-Resistant Ovarian Cancer



57%complete remission(95% CI: 44%-70%)1

29%partial remission(95% CI: 18%-41%)1

sALCL: 86% ORR (95% CI: 77%-95%)1

32% complete remission(95% CI: 23%-42%)1

40%partial remission(95% CI: 32%-49%)1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)1

Important Safety Information• Progressive multifocal leukoencephalopathy (PML): JC

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

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

• Use in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.Drug Interactions:Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

BOXED WARNINGProgressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS.

Contraindication:Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.Warnings and Precautions:• Peripheral neuropathy: ADCETRIS treatment causes a peripheral

neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifi cations accordingly.

• Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.

• Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS.

• Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1

• HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

Indicated for the treatment of:• Systemic anaplastic large cell lymphoma

(sALCL) after failure of at least 1 multiagent chemotherapy regimen1

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

After multiple failures,

single-agent responseC

N = 102, 15-77 years (median: 31 years)1 N = 58, 14-76 years (median: 52 years)1

2:39 PM

Standard of Care for Soft Tissue CarcinomaSingle-agent doxorubicin remains thestandard of care as first-line treatmentfor unresectable or metastatic soft tis-sue sarcomas, according to results of a phase 3 trial conducted by EORTCand presented at the PresidentialSymposium during the ESMO 2012

Congress (Abstract LBA7).2,3 Thisstudy is the latest in a string of trialsattempting to improve outcomes withdoxorubicin by adding other agents. Soft-tissue sarcomas are a heteroge-

neous group of tumors that are relative-ly rare. Overall incidence is approxi-

mately 5 per 100,000, said Winette van der Graaf, MD, University ofNijmegen, the Netherlands. The com-plexity of the tumor types and the rela-tive rarity of the tumors have made itchallenging to conduct clinical trials,she added.

This study compared doxorubicin todoxorubicin/ifosfamide plus growth fac-tor support in 455 patients aged 18 to60 years with locally advanced ormetastatic soft tissue sarcomas. Thisstudy used a higher dose of ifosfamide


(10 g/m2 over 4 days with growth factorsupport) than previous studies thatevaluated this combination.Treatment was continued every 3

weeks for a maximum of 6 cycles oruntil the development of progressivedisease. At a median follow-up of 56

months, there was no significant differ-ence between the 2 treatment arms inoverall survival (OS). Median OS was14.3 months with the combination ofdoxorubicin/ifosfamide versus 12.8months with doxorubicin alone; OS at1 year was 60% and 51% for the 2

arms, respectively. Doxorubicin/ifos-famide achieved a longer progression-free survival: 7.4 months versus 4.6months, respectively (P = .003), andhigher overall response rates—26.5%versus 13.6%, re spectively—but thiscame with a host of increased toxicity.

Based on these results, van derGraaf said that single-agent doxoru-bicin should remain the standard ofcare in the palliative setting. Thecombination might be useful forselected patients 60 years and youngerwith large tumors.



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

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

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

Drug 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.

Standard of Care for Soft Tissue Carcinoma Continued from page 17

T-DM1 SurvivalBenefit Confirmedin Advanced HER2+Breast Cancer

T-DM1, an antibody-drug conjugatelinking trastuzumab to potent chemo -therapy, extended survival, comparedwith lapatinib plus capecitabine, inadvanced HER2+ breast cancer in anupdated analysis from the phase 3 EMILIA trial (Abstract LBA12).4At a median follow-up of about 20

months, T-DM1 reduced the risk ofdying by 32%, with a 6-month differ-ence favoring T-DM1. Median overallsurvival (OS) (death from any cause)was 30.9 months for T-DM1 versus25.1 months for lapatinib pluscapecitabine (P <.0001).Lead author Sunil Verma, MD,

Sunnybrook Odette Cancer Centre,Toronto, Ontario, Canada, predictedthat T-DM1 would be an importanttreatment option for unresectable locallyadvanced or metastatic breast cancer. EMILIA was conducted at 213 sites in

26 countries. The study randomized 991patients with HER2+ advanced breastcancer who had been treated withtrastuzumab and a taxane in a 1:1 ratio toT-DM1 or lapatinib plus capecitabine. Final progression-free survival (PFS),

presented earlier at the 2012 AnnualMeeting of the American Society ofClinical Oncology, showed median PFSof 9.6 months with T-DM1 versus 6.4months with lapatinib plus capecitabine,a 35% reduction in the risk of progres-sion favoring T-DM1 (P <.0001).The OS data presented at ESMO

were from the second interim analysis,with a data cutoff of July 31, 2012,when more than 50% of targeted sur-vival events had occurred. Final OSdata are expected in 2014.Grade 3 or higher adverse events

occurred more frequently with lapatinibplus capecitabine: 57% versus 41% for T-DM1. Patients in the T-DM1 arm hada higher incidence of thrombocytopeniaand increased serum aminotransferaselevels, whereas those treated with lapa-tinib plus capecitabine had higher ratesof diarrhea, nausea, vomiting, and hand-foot syndrome. The rates of cardiac dys-function were very low and similar inboth treatment arms.

The major barriers to implementing ade-quate pain control for cancer patients ona global scale are restrictive governmentregulations and lack of access to suppliesof morphine. Individual countries maylack morphine suppliers, and regulationsin countries where morphine is availablemay prevent doctors from prescribingdoses strong enough to alleviate pain andsuffering. Although a number of international

organizations have made strong state-ments hoping to address the problem ofinadequate pain control in cancerpatients, this has not led to widespreadreform in allowing access to standardcare, said Kathleen Foley, MD,Memorial Sloan-Kettering CancerCenter in New York City, at the ESMO2012 Congress.6 These organizationsinclude the Council of Europe,International Narcotics Control Board,United Nations, World Health Or g a -nization, Commission on NarcoticDrugs, and Human Rights Watch,among others.Foley believes that the problems are

solvable, but mainly on a country-by-country basis. She reported success storiesfor programs funded by the InternationalPalliative Care Initiative. The model forthese programs is to identify a “nationalchampion” for cancer pain control with-in a country, perform a needs assessment,hold a stakeholders meeting, develop taskforces, and then formulate a palliativecare concept for that country. So far, thishas been done in 20 countries. “We use international documents with

symbolic language to guide this policy ata country level. These passionate cham-

pions are driving this movement withineach country,” she told listeners.In 2012, the International Palliative

Care Initiative funded fellowships inIndia, Bangladesh, Sri Lanka, Albania,Kyrgyzstan, and Ukraine. Fellows work atthe University of Wisconsin in Madisonto learn the model described above.

Success Stories In Romania, 35-year-old restrictive poli-cies were changed. Now there are no lim-its on daily morphine dose or patientdiagnosis. “Past policies were burdensomefor patients, and physicians, and these arenew beginnings,” Foley said.

In Colombia, a new palliative care lawwas passed in 2009, and as a result of thatlaw, each district of the country has 1pharmacy that can provide opioids 24hours a day.In Guatemala, efforts are ongoing to

bring a morphine supply from GuatemalaCity to rural areas and to provide furthereducation to legislators, physicians, andpatients.“It’s hard to believe, but in 2012, the

first injectable morphine prescriptionwas written in Guatemala, at a hospital

where bone marrow transplant is avail-able,” she said. In Nigeria, the government is now sup-

portive of getting cancer patients accessto pain control. In Serbia, a pain policyfellow is working with the government,which has adopted a pain policy statingthat opioids are essential for pain relief.In Armenia, a policy is in place, but asupplier still needs to be found. “Uganda is a great success story,”

she continued. The initiative created astrategic health plan, added liquid mor-phine to the essential list, adopted newguidelines, and authorized prescriptionby nurses. Seventy-nine providers havebeen trained.“We argue that no country should be

allowed to enter the EU [EuropeanUnion] unless they have opioids and apain policy for cancer care. The solutionis to identify champions at a country leveland work with them. We can do this,”Foley said. l

References1. Poveda A, Selle F, Hilpert F, et al. Weekly paclitaxel,pegylated liposomal doxorubicin or topotecan ± beva-cizumab in platinum-resistant recurrent ovarian cancer:analysis by chemotherapy cohort in the GCIG AURE-LIA randomised phase III trial. Presented at: EuropeanSociety for Medical Oncology 2012 Congress;September 30, 2012; Vienna, Austria. Abstract LBA26.2. van der Graaf W. Successful targeting of VEGFR insoft tissue sarcomas. Presented at: European Society forMedical Oncology 2012 Congress; September 30, 2012;Vienna, Austria.3. van der Graaf WTA, Judson I, Verweij J, et al. Resultsof a randomised phase III trial (EORTC 62012) of singleagent doxorubicin versus doxorubicin plus ifosfamide asfirst line chemotherapy for patients with advanced ormetastatic soft tissue sarcoma: a survival study by theEORTC Soft Tissue and Bone Sarcoma Group. Presentedat: European Society for Medical Oncology 2012Congress; October 1, 2012; Vienna, Austria. AbstractLBA7.4. Verma S, Miles D, Gianni L, et al. Updated overall

survival results from EMILIA, a phase 3 study oftrastuzumab emtansine (T-DM1) vs. capecitabine (X)and lapatinib (L) in HER2-positive locally advanced ormetastatic breast cancer (MBC). Presented at: EuropeanSociety for Medical Oncology Congress; October 1,2012; Vienna, Austria. Abstract LBA12.5. Borad M, Reddy S, Bahary N, et al. TH-302 + gemcitabine (G+T) vs gemcitabine (G) in patients with pre-viously untreated advanced pancreatic cancer (PAC).Presented at: European Society for Medical Oncology2012 Congress; September 29, 2012; Vienna, Austria.Abstract 6660.6. Foley K. A global policy approach to freedom fromcancer pain. Presented at: European Society for MedicalOncology 2012 Congress; September 29, 2012; Vienna,Austria.



The addition of an investigationalhypoxia-targeted agent, TH-302, togemcitabine improved overall survival(OS) versus gemcitabine alone inpatients with advanced pancreatic can-cer in an open-label phase 2b trial(Abstract 6660).5The lead author of this trial, Mitesh

Borad, MD, of the Mayo Clinic inScottsdale, Arizona, said that the dif-ference in OS was not significant, butthat the trend was toward improvedOS with the addition of TH-302. Thedrug will enter phase 3 trials shortly. Hypoxia is due to the disordered

vasculature that is a hallmark of pan-creatic cancers and other solidtumors. TH-302 selectively targetslevels of hypoxia common in tumorsbut rare in normal tissues. When thedrug enters cancer cells, it is convert-ed to an active form, dibromoisophoramide mustard, a potent DNA

alkylator. The active form of the drugdiffuses into the surrounding oxy-genated regions of the tumor, exertinga bystander effect and killing more of thetumor than can be accounted for by thehypoxic fraction alone. Theoretically,

this drug will produce less systemic tox-icity than that caused by most cytotox-ic agents.The study randomized 214 previous-

ly untreated patients with locallyadvanced, unresectable or metastatic

pancreatic cancer in a 1:1:1 ratio toreceive either TH-302 240 mg/m2 plusgemcitabine; TH-302 340 mg/m2 plusgemcitabine; or gemcitabine alone.Treatment was given on days 1, 8, and15 of a 28-day cycle.

Median OS was 9.2 months withTH-302 340 mg/m2 plus gemcitabine;8.7 months with TH-302 240 mg/m2

plus gemcitabine; and 6.9 months withgemcitabine alone.Borad said that these results were

consistent with an overall improve-ment in progression-free survivalreported earlier this year. The trial wasnot designed to detect a statisticallysignificant improvement in OS, andsurvival was confounded by crossoverallowing patients in the gemcitabine-alone arm to receive TH-302 plus gem-citabine at progression. The most common adverse events

related to TH-302 included skin andmucosal toxicity, and myelosuppression.At the higher dose of TH-302, the rate ofrash was 47% and stomatitis was 42%,but these events were mainly mild andmoderate. Hematologic toxicity on thehigher dose of TH-302 was much greaterthan that seen with gemcitabine alone:thrombocytopenia was 63% versus 11%,respectively, and neutropenia was 60%versus 30%, respectively.The dose of 340 mg/m2 will be taken

forward in the phase 3 trial.

Promising New Drug for Pancreatic Cancer

The most common adverse events related

to TH-302 included skin and mucosal

toxicity, and myelosuppression.

Initiative Improves Pain Control in Several Countries

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“The solution is to

identify champions at a

country level and work

with them.”—Kathleen Foley, MD

Identifying agents that can preventchemotherapy-induced peripheralneuropathy (CIPN) is a work in

progress. Studies of some interventions

suggest modestly encouraging findings,but research on prevention has beenhampered by a poor understanding ofthe different mechanisms of this toxic-

ity with the various chemotherapyagents that induce CIPN.1“We still have much work to do. We

are getting better at trial design, finding

the best outcome measures, and includ-ing homogeneous populations in clini-cal trials. We need better preclinicalmodels and better biomarkers,” statedDawn Hershman, MD, of the HerbertIrving Comprehensive Cancer Centerat Columbia University MedicalCenter in New York City.“One problem in studying CIPN is

that numerous anticancer drugs causethese symptoms, and the mechanismfor each drug may be different. Ourapproach to treating one symptom canbe problematic. We may miss signalsthat one drug works for one type ofCIPN but not another,” she explained.Hershman reviewed completed clin-

ical trials for the prevention of CIPN atthe 2012 Multinational Association ofSupportive Care in Cancer Intern a -tion al Symposium.1 She emphasizedthat a drug that works for preventionmay not be effective for treatment ofCIPN, and vice versa.

Vitamin E has been studied in neu-ropathic pain, based on positive pilotand phase 2 studies suggesting a neuro-protective effect when given with plat-inum or taxanes. However, a phase 3placebo-controlled study found noeffect of vitamin E 300 mg twice dailyon any CIPN parameters in patientstreated with adjuvant platinum or tax-ane therapy.2“Think twice about recommending

vitamin E to your patients for preven-tion of CIPN,” Hershman said.Calcium/magnesium has been stud-

ied in patients with colon cancerundergoing adjuvant infusional fluo-rouracil, leucovorin, and oxaliplatin(FOLFOX) therapy.3 The study of 104patients had a primary end point ofdevelopment of grade 2 or higher

Preventing Chemotherapy-Induced PeripheralNeuropathy Remains ElusiveBy Alice Goodman


Side Effect Management

“Quality care iseveryone’s business.”

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“One problem in studying

CIPN is that numerous

anticancer drugs

cause these symptoms,

and the mechanism

for each drug may

be different.”—Dawn Hershman, MD

CIPN. The intervention appeared tobe beneficial, but the study was closedprematurely because of concern thatcalcium/magnesium could decreasetreatment efficacy; further analysisshowed that this concern was false.“Even with a smaller sample size,

there is a likely benefit of calcium/magnesium in this setting, with a sug-gestion of significant im provement inobjective and patient-reported out-comes,” she stated.Acetyl-L-carnitine is a supplement

that improves neuropathy in patientswith diabetes and HIV infection and isalso reported to improve fatigue andcognition, with toxicity limited to mildnausea.1 Based on positive results of asmall phase 2 trial showing improve-ment in sensory and motor neuropathy, the Southwest Oncology Groupmounted a phase 3 trial in approxi-mately 400 patients with breast cancertreated with taxanes.4 No effect ofacetyl-L-carnitine was observed at 12weeks, but at 24 weeks worsening neu-ropathy was observed in the grouptreated with the supplement.“This is a big surprise. After control-

ling for age and regimen, the odds ratiofor worsening neuropathy was 1.57.This study shows that we have to becareful when we give agents topatients. Not everything we give isbenign, and this is a good reason tostudy these agents,” Hershman said.Glutamine has also been studied in

CIPN in a small trial of 86 patientswith colon cancer and oxaliplatin-induced peripheral neuropathy.5 Thestudy found a reduction in grades 1 and2 neuropathy as well as a significantlylower incidence of grades 3 and 4 neu-ropathy in the glutamine-treatedgroup, according to patient-reportedoutcomes, but no difference in electro-physiological abnormalities with gluta-mine. Hershman commented thatelectrophysiologic ex am may not bethe right end point to study.With these equivocal results in a

small trial, glutamine is not a strongrecommendation.Although 4 clinical trials of amifos-

tine conducted in patients treatedwith cisplatin found that pretreatmentwith amifostine reduced, prevented, orprovided some protection against cumu-lative neurotoxicity, in the AmericanSociety of Clinical Oncology 2008 clin-ical practice guideline update, amifos-tine is not recommended for preven-tion of cisplatin- or paclitaxel-inducedneuropathy due to insufficient data.6Ongoing clinical trials of prevention

of CIPN include phase 3, placebo-con-trolled trials of alpha lipoic acid and oferythropoietin.A separate 12-week, single-blind

study at Hershman’s institution islooking at electroacupuncture given

weekly with paclitaxel chemotherapyin 50 patients with stage I to III breastcancer.7Results of these studies are awaited, she

said, but prevention of CIPN remains theideal rather than the reality. l

References1. Hershman D. Cancer induced peripheral neuropathy:prevention. Presented at: 2012 Multinational Assoc i -ation of Supportive Care in Cancer InternationalSymposium; June 28-30, 2012; New York, NY.

2. Kottschade LA, Sloan JA, Mazurczak MA, et al. The

use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a random-ized phase III clinical trial. Support Cancer Care.2011;19:1769-1777.

3. Grothey A, Nikcevich DA, Sloan JA, et al.Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon can-cer: NCCTG N04C7. J Clin Oncol. 2011;29:421-427.

4. Hershman DL, Unger JM, Crew KD, et al. SWOGS0715: randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-inducedneuropathy during adjuvant breast cancer therapy.Presented at: 2012 American Society of ClinicalOncology Annual Meeting; June 1-5, 2012; Chicago,IL. Abstract 9018.

5. Wang WS, Lin JK, Lin TC, et al. Oral glutamine iseffective for preventing oxaliplatin-induced neurop-athy in colorectal cancer patients. Oncologist. 2007;12:312-319.

6. Hensley ML, Hagerty KL, Kewalramani T, et al.Amer ican Society of Clinical Oncology 2008 clinicalpractice guideline update: use of chemotherapy orradiation therapy protectants. J Clin Oncol. 2009;27:127-145.

7. Hershman DL. Acupuncture study for the preventionof taxane induced myalgias and neuropathy. Clin i calTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01163682?term=electroacupuncture&rank=31. Updated October 27, 2011. Accessed Sep -t ember 5, 2012.


Side Effect Management

*Other treatment options may also be considered.References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 2. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 3. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.

Janssen Biotech, Inc.© Janssen Biotech, Inc. 2012 10/12 K08Z12191BR1

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T

Healthcare professionals (HCPs)are often asked to provide someform of documentation to help

certify their patients’ medical condi-tions. To protect patient privacy,HIPAA (Health Insurance Portabilityand Accountability Act) significantlyrestricts both the type of informationthat can be disclosed and the categoriesof recipients that can receive it.However, there are numerous situa-tions—in the context of employmentrights or access to public benefits—inwhich disclosure of certain informationmay be necessary to help patients getaccess to protections and services tohelp them along the survivorship jour-ney. Employment-related and publicbenefits–related certifications have twovery different processes and potential

consequences, so it is important to keepboth in mind when trying to help yourpatient navigate the system.

Less Is More—When and How toProvide Medical Certification forEmployment MattersIn the context of certifying medical sta-tus for employees with cancer, there aretwo main occasions when an employermay request an employee’s medical infor-mation. However, even in those situa-tions in which the employer is allowed toaccess certain information, the certifica-tion that you as an HCP provide can andshould be limited. Under the Family andMedical Leave Act (FMLA) and theAmericans with Disabilities Act (ADA),employers are allowed to get limitedinformation about their employees’ med-

ical status when requesting leave or a rea-sonable accommodation, respectively.The FMLA gives certain employees

working for covered employers (usuallythose with 50 or more employees) theright to take time off to care for them-selves or family members with a serioushealth condition. Although the leaveperiod is unpaid, and the law has veryspecific eligibility criteria, it is oftenvery useful for people undergoing can-cer treatment, because it gives 12workweeks of job and health benefitprotection. Any time an employeerequests leave under the FMLA, anemployer is allowed to ask for medicalcertification. The ADA prohibits employers

(those with 15 or more employees)from discriminating against employees

on the basis of disability, includingcancer or a history of cancer in manycases. Under the ADA, employers arerequired to grant “reasonable accom-modations” to qualified employeeswith disabilities to allow the employeesto perform the essential functions oftheir job. Employers have to grant thataccommodation unless doing so wouldbe an undue hardship for the employer.When an employee makes a reasonableaccommodation request, employers areallowed to require some kind of med-ical certification when the disability orneed for accommodation is not knownor obvious.In either case, if a patient is not able

to provide this information to theemployer, the employer can deny theleave or accommodation. However,where em ployment-related medicalcertifications are concerned, less isoften more. Although many employerswould never discriminate against anemployee because of his or her medicalhistory or cancer diagnosis, unfortu-nately some would. To ensure that allpatients are protected against unneces-sary discrimination, best practices dic-tate that HCPs should give just enoughinformation to address the patients’goals with the employer, but not givethe employer too much informationthat may be used against the patient asan employee. The Table highlights thedifferences in how and whether toreport information about your patients’medical status.

More Is More—When and How toProvide Medical Certification forPublic Benefits MattersWhereas in the employment contextHCPs need to balance the potential fordiscrimination by an employer againstthe ultimate goal of leave or accommo-dation for the employee, in the publicbenefits context, the more medical infor-mation you can provide for a patient the better. For example, public bene-fits–related medical certification isrequired under an application for SocialSecurity Administration (SSA) bene-fits—including Social Security DisabilityInsurance (SSDI) and SupplementalSecurity Income (SSI)—or underMedicaid. For any of these programs, eli-gibility is determined using a govern-mental standard for “disability” thatrequires proof of some kind of medicallydeterminable impairment. With thatsaid, although more medical information


Medical Certifications

Medical Certification by Healthcare Professionals forPatients With a History of CancerBy Shawn Kravich, EsqCancer Legal Resource Center, Los Angeles, California

Table The Differences in How and Whether to Report Information About Your Patients’ Medical Status

FMLA ADA

What documentation may anemployer require a patient to getfrom HCPs?

• Name, address, phone and fax numbers of the HCP

• HCP’s type of practice/specialization • Approximate date the serious healthcondition began and how long it willprobably last

• Description of the serious healthcondition sufficient to support theneed for leave (may include informa-tion on symptoms, doctor visits,medications, and other regimens ofcontinuing treatment)

Employer may ask employee for documenta-tion to prove that he or she has a disabilityunder the ADA and needs the requestedaccommodation.

The documentation is sufficient if itdescribes: 1) the nature, severity, and duration of the

employee’s impairment; 2) the activities limited by the impairment; 3) the extent to which the employee’s ability

to perform these activities is limited; and 4) why a reasonable accommodation is

needed

Does the HCP have to disclose a specific diagnosis?

NO, as long as the documentation establishes a serious health conditionsufficient to support the need forFMLA leave

NO, as long as documentation establishesthat the employee has a “mental or physicalimpairment that substantially limits a majorlife activity” and needs a reasonable accommodation

Can an employer ask the HCP toprovide complete medical records?

NO NO

Is there a limitation on informationincluded in certification?

YES, information in the certificationmust relate only to the serious healthcondition related to the need for leave

YES, information must relate to the disabilityat issue and the need for accommodation

What type of HCP can provide certification?

Doctors, psychologists, dentists,optometrists, chiropractors, nurse practi-tioners, nurse-midwives, physician assis-tants, and clinical social workers

Doctors, psychologists, nurses, physical thera-pists, occupational therapists, speech thera-pists, vocational rehabilitation specialists, and licensed mental health professionals

Can the employer contact the HCP directly?

YES, but only to clarify handwriting,ensure that it is not a forgery, etc.Employers cannot ask for informationbeyond that on the certification form

MAYBE, but employers must have employeepermission

Abbreviations: ADA, Americans with Disabilities Act; FMLA, Family and Medical Leave Act; HCP, healthcare professional.

increases the chances of a benefits appli-cation going through, the governmentalprograms are concerned with facts, notopinion. Too often, HCPs see a patientpresenting with a serious health condi-tion and know that the patient has adisability. However, because the specif-ic agency overseeing each applicationultimately decides whether the patientis “disabled” by its own definition,HCPs should refrain from using con-

clusory language such as “the patient isdisabled” in the certification and stickto providing as much supportive med-ical information as possible. HCPs should familiarize themselves

with the language that the SSA uses inits listing of disabling conditions (see

http://www.ssa.gov/disability/professionals/bluebook/AdultListings.htm) and usethat language where appropriate. HCPsalso should consider whether the patienthas symptoms of more than one condi-tion listed, particularly where the cancerdiagnosis has had a negative effect on thepatient’s mental health. For example,someone’s cancer might not be quite asadvanced as the language requires forthat condition, but when combined with

symptoms of depression or a mobilityimpairment, the person cannot work.Although a patient must be eligibleunder the programs’ other criteria, SSDIand SSI also offer a CompassionateAllowances program that expedites theapplication process for severe condi-tions that fall on the list (see http://ssa.gov/compassionateallowances/conditions.htm). Overall, the process for medical cer-

tification is relatively straightforward—just remember that keeping the patients’best interests in mind means using dis-cretion with the amount of informationyou as an HCP disclose when certifyingthe documents your patients provide. l

For information about the Cancer Legal Resource Center, please visit www.cancerlegalresourcecenter.org.


Medical Certifications

HCPs should refrain from using conclusorylanguage such as

“the patient is disabled”in the certification andstick to providing as

much supportive medicalinformation as possible.

ReaderPoll

Have you ever had to certify a patient’s medical status?

r Yesr No

Go towww.TheOncologyNurse.com

to answer the question andadd your comments. Please let us know how the processworked when you provided

information about a patient’smedical status for mattersinvolving employment or

public benefits.

Learn more at inhibitandrogen.com/excess References: 1. Narimoto K, Mizokami A, Izumi K, et al. Adrenal androgen levels as predictors of outcome in castration-resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second-line anti-androgen. Int J Urol. 2010;17(4):337-345. 2. Luo S, Martel C, LeBlanc G, et al. Relative potencies of flutamide and Casodex: preclinical studies. Endocr Relat Cancer. 1996;3:229-241. 3. Labrie F, Dupont A, Belanger A, et al. Combined treatment with an LHRH agonist and the antiandrogen flutamide in prostate cancer. In: Moody TW, ed.Neural Endocrine Peptides and Receptors. New York, NY: Plenum Press; 1986:627-644.

Androgen levels may impact antiandrogen therapy.1-3

Janssen Biotech, Inc.© Janssen Biotech, Inc. 2012 8/12 08Z12235A


T


Breast Cancer

Expanded utility of the 21-generecurrence score (RS) (Onco typeDX) was shown in a retrospective

analysis reported at the AmericanSociety of Clinical Oncology 2012 BreastCancer Symposium by investigators fromthe National Surgical Adjuvant Breastand Bowel Project (NSABP).1

The RS can help identify estrogenreceptor (ER)-positive patients with anynumber of positive lymph nodes who willhave residual disease after adjuvantchemotherapy, who might benefit fromadditional treatment, reported EleftheriosP. Mamounas, MD, of the AultmanCancer Center in Canton, Ohio.

As such, the RS can help in makingtreatment decisions, Mamounasmaintained. “We can identify patientswith high residual risk in spite ofreceiving chemotherapy. We can tryto find a better treatment for them orenroll them in a clinical trial. On theother hand, patients with low residual

risk may do well with less treatment,”he said. Such patients might be sufficiently

treated with only 4 cycles of chemo -therapy, rather than a full course of 8cycles, including a taxane, he said. TheNSABP B-28 analysis indicates thatthe extent of chemotherapy might be

21-Gene Recurrence Score Predicts for ResidualDisease After ChemotherapyBy Audrey Andrews

Three commonly used radiologi-cal tests rarely detect metastasesin newly diagnosed breast cancer

patients and should not be routinelyperformed, according to a comprehen-sive literature review presented at theAmerican Society of Clinical On -cology (ASCO) 2012 Breast CancerSymposium, held in San Francisco,California.1Bone scan, liver ultrasound, and

chest x-ray are often used as first-linescreening for potential metastases.However, there is no established proto-col for this costly screening—which isoften accompanied now by advancedimaging such as CT, PET, and MRI—and there is no solid evidence to justifyits use, said Allison M. Staley, MPH, amedical student at the University ofNorth Carolina School of Medicine inChapel Hill. “Our literature analysis suggests that

these 3 tests are of little use in screen-ing women for metastases, and likelyresult in a lot of false negatives inearly-stage disease,” Staley said at apress briefing. “The relevant topic is cost contain-

ment. When you look at the cost ofthese 3 tests, they are significantly lessexpensive than other more advancedimaging options; however, when theyare used routinely in thousands of newbreast cancer patients annually, collec-

tively they become costly to the healthcare system,” she said. Staley noted that as a tertiary care

center, her institution receives manyreferrals from community oncologists.“Many patients do come in having hadstaging evaluations, and physicians areusing chest x-ray and liver ultrasound inmany cases,” she said.

Literature Review Examined Tests’ UtilityThe study asked whether bone scans,chest x-rays, and liver ultrasounds helpto determine the extent of metastaticdisease among newly diagnosed asymp-tomatic breast cancer patients. Theresearchers searched publications from1990 to the present for articles thatused detection rate—defined as thenumber of patients with an abnormaltest result divided by the total numberof patients tested—as their primaryoutcome of interest. Eight studies of

232 met the investigator’s criteria. The primary outcome measure,

pooled detection rates, ranged from<0.5% to approximately 4%. As ex -pected, they were highest for patientswith stage III disease. Per modality andby stage, the detection rates were asfollows: • Bone scan: stage I (1.29%), stage II(3.09%), stage III (12.5%), for anaverage of 4.18%

• Liver ultrasound: stage I (0.47%),stage II (1.0%), stage III (4.2%),for an average of 1.34%

• Chest x-ray: stage I (0%), stage II(0.42%), stage III (4.57%), for anaverage of 0.87%

“These very low detection rates, par-ticularly in stage I and II disease, makeus question the utility of these 3 modal-ities for an adequate staging evalua-tion,” she said. Rates of metastases were higher for

women with stage III disease than forthose with stage I or II breast cancer, par-ticularly as detected by bone scans(12.5%), suggesting this modality maystill have a role in this subgroup.However, the authors suggested thatthese 3 particular imaging tests may beunnecessary even in these women, whenthe patients are also assessed with moresensitive imaging.Andrew Seidman, MD, of Memorial

Sloan-Kettering Cancer Center, New

York, commented on the findings. “Itstrikes me that we are living in a timewhen we move quickly to embrace new,more sensitive technologies, but the ele-phant in the room are the false-positives.The ‘Choosing Wisely’ campaign, whichASCO participates in, recommends thatwe back off from examinations that arereally not evidence based and which, inmany cases, do more harm than good.” This study is consistent with other

findings suggesting that extensive test-ing is futile in patients with a very lowrisk of distant metastases, he said.“Doing extensive imaging, looking forsomething that has a very low yield andlittle impact on health, can lead tounnecessary procedures, biopsies, com-plications, and costs,” he noted. The higher yield in stage III

patients probably exempts this groupfrom such restrictions, he added.Seidman said for patients with stage Iand II cancer, he does not order theseimaging tests, nor does he order PETscans. “I reserve these for patients athigh risk, which includes stage IIIbreast cancer,” he said. l

Reference1. Moffat Staley A-S. Staging evaluation with bonescan, liver ultrasound, and chest radiograph in patientswith primary breast cancer: a systematic review.Presented at: American Society of Clinical Oncology2012 Breast Cancer Symposium; September 13-15,2012; San Francisco, CA. Abstract 4.

Some Staging Studies Offer No Benefit in Early Breast Cancer WorkupBy Caroline Helwick

Bone scan, liverultrasound, and chest x-ray are often used

as first-line screening forpotential metastases.

SECOND ANNUAL CONFERENCE

��

Clinical Approaches to Targeted Technologies�REGISTER TODAY AT www.globalbiomarkersconsortium.com

October 4-6, 2013The Seaport Boston Hotel

1 Seaport LaneBoston, MA 02210

tailored according to the estimation ofresidual risk, he said.Oncotype DX is currently approved

for use in patients with ER-positive,node-negative breast cancer to estimatewhether the addition of chemotherapyto endocrine therapy would be benefi-cial. The current study shows that theRS can also be applied to ER-positivepatients with any number of positivenodes, treated with chemotherapy aswell as endocrine therapy. In this popu-lation, the RS was prognostic across thespectrum of subgroups. NSABP B-28 included 1065 patients

treated with adjuvant endocrine therapyand anthracycline/cyclophosphamidewith or without paclitaxel in the ran-domized NSABP B-28 trial. Researcherscalculated RS using tissue specimensfrom past breast surgeries and then corre-lated the RS with outcomes. Median fol-low-up was 11.2 years.

Recurrence Score a RobustIndependent Predictor ofOutcomesThe RS was low (<18) in 36% ofpatients, intermediate (18-30) in 34%,and high (≥31%) in 30% of patients. Inthe univariate analysis, the RS was a sig-nificant predictor of disease-free survival,distant recurrence-free interval, breastcancer–specific survival, and overall sur-vival. In multivariate analysis, the RSprovided independent prognostic infor-mation for all 4 end points beyond clini-cal and pathologic factors, includingtreatment, age, tumor size, tumor grade,number of positive nodes, and type ofsurgery (P <.001), Mamounas reported. For patients with a low RS, disease-

free survival was close to 76%, while itdropped to 48% for those with a highRS. Overall survival was 90% for thelow RS group, versus 63% for the highRS patients, he reported. The RS was strongly related to a 10-

year risk of recurrence, with eventsoccurring in 54% of patients in the highRS group versus 17% of those with lowRS. Breast cancer –specific deathsoccurred in 33% and 2%, respectively.By treatment assignment, outcomes

were very similar between treatmentarms in patients with low RS, with the

benefit of paclitaxel seen mainly in theintermediate and high RS groups.Andrew Seidman, MD, of Memorial

Sloan-Kettering Cancer Center, NewYork, said at a press briefing that thestudy “highlights the fact that despitehormone receptor positivity and HER2negativity, many patients will have a

high risk of recurrence despite receiv-ing chemotherapy and appropriateendocrine therapy. This gene assay rep-resents a biological tool that may beuseful in the future in stratifyingpatients for clinical trials and in iden-tifying candidates whose outcomes canbe improved.” l

Reference1. Mamounas EP, Tang G, Paik S, et al. Prognosticimpact of the 21-gene recurrence score (RS) on disease-free and overall survival of node-positive, ER-positivebreast cancer patients treated with adjuvant chemother-apy: results from NSABP B-28. Presented at: AmericanSociety of Clinical Oncology 2012 Breast CancerSymposium; September 13-15, 2012; San Francisco,CA. Abstract 1.


Breast Cancer

Janssen Biotech, Inc.© Janssen Biotech, Inc. 2012 10/12 K08Z12236AR1

Learn more at inhibitandrogen.com/sequence*Currently in the absence of published, randomized, clinical data on treatment sequencing in mCRPC posttreatment with docetaxel.mCRPC=metastatic castration-resistant prostate cancer.References: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2012. © National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed October 3, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2007 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25(12):1596-1605.


T

21-Gene Recurrence Score Predicts.... Continued

Researchers calculatedRS using tissue

specimens from pastbreast surgeries and thencorrelated the RS with

outcomes.

Cancer has long been a part of mylife. My grandmother was diag-nosed with late-stage breast can-

cer when I was 12. My mother livedwith the diagnosis, radical surgery, andpost-op radiation treatment for 10 years.She succumbed to the ravages of breastcancer at 69 when I was 37 years old.

Seven years later, my father died ofbladder cancer at 77.My wife of 38 years died of breast

cancer on Dec. 27, 2008. She was 59.Kathy, first diagnosed with a Stage 3lobular carcinoma in November 2001,experienced a recurrence in 2006. Herlong, arduous course of treatment

included two individual mastectomies(one prophylactic), localized radiation,several courses of chemo therapy, andfinally stereotactic brain radiation as aresult of further metastasis.All along I knew I’d married an

incredibly strong woman and wasblessed with wonderful daughters,

now 28 and 32. Throughout thecourse of Kathy’s illness we experi-enced an extraordinary closeness as acouple. Early on we realized that wecouldn’t fight cancer alone. So wefaced the disease together.In the beginning it was difficult for

us to become dependent on otherpeople, but cancer forced us to reachout to each other and those aroundus. We needed help with transporta-tion to and from treatment and rou-tine chores. We needed flexibility inwork scheduling. At the same timewe received our share of unsolicitedadvice from well-meaning people andsorted through their conflicting rec-ommendations for kernels of usableinformation. Some friends drifted away while

others acted like nothing had hap-pened or expected that everythingwould remain unchanged.

But Kathy’s breast cancer diagnosiswas a sea change in our lives. Itstopped the clock and underminedall our distant hopes and dreams.Kathy had just completed a master’sdegree in social work a year beforeher diagnosis. Her achievement ful-filled a lifelong dream to help othersovercome the effects of personaltrauma, especially childhood incestsurvivors like herself. Cancer treat-ment delayed her plans to begin a pri-vate counseling practice. Then the dis-ease cut it short after only four yearswhen it became impossible for her tocarry on.Two months before we found out

Kathy had cancer I had accepted anearly retirement buyout from atelecommunications firm. So I had toscramble to find a new job to help meetour escalating medical bills.All our plans were replaced by what


Caregiving

We Faced the Disease TogetherBy Rich Devlin

In the beginning it

was difficult for us to

become dependent on

other people, but

cancer forced us to

reach out to each

other and those

around us.

TARGET AUDIENCEThis initiative will target medical oncologists, hematologists, breast surgeons, radiationoncologists, oncology nurses, advanced practice nurses, nurse practitioners, physicianassistants, oncology pharmacists, managed care professionals, and others with clinicalresearch and management interest in treatment of ductal carcinoma in situ (DCIS) andearly-stage breast cancer.

STATEMENT OF NEEDAbility to detect DCIS has dramatically improved in recent decades, and the current inci-dence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increaseduse of mammography screening.1,2 However, attempts to identify subsets of DCIS womenwho may be spared radiotherapy and perhaps treated with surgery alone have heretoforebeen unsuccessful. This inability to predict which patients will develop recurrent DCIS orinvasive disease has complicated DCIS management. Many clinicians and other health-care professionals dealing with patients diagnosed with DCIS are unaware or incomplete-ly knowledgeable about the most recent results from a clinical trial examining the abilityof the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, andthe implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141.2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence,treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVESAfter completion of this activity, participants will be better able to:

• Identify approaches currently available or in development to predict recurrence riskin DCIS patients

• Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer

• Describe the design and findings of the ECOG 5194 validation study• Apply the 12-gene assay for DCIS into clinical decision-making• Explain relevant information about the 12-gene DCIS assay and DCIS score topatients

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches

www.coexm.com/ace09LOG ON TODAY TO PARTICIPATE

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

FACULTYChair:Lawrence J. Solin, MD, FACR,FASTROChairman Department of Radiation OncologyAlbert Einstein Medical CenterPhiladelphia, PA

E. Shelley Hwang, MD, MPHProfessor and Chief, Breast SurgeryDuke University Medical CenterDurham, NC

Kathy D. Miller, MDAssociate Professor Department of MedicineIU School of MedicineIndianapolis, IN

ACCREDITATIONPhysicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing MedicalEducation (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activityfor a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of theirparticipation in the activity.Nurses:CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC)Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status doesnot imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity.Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case ManagerCertification. Case Managers number 790005057.

This activity is supported by an educational grant from Genomic Health, Inc.

��

� � ��

was happening at the present moment— waiting nervously for biopsy andscan reports, holding back Kathy’s hairwhile she got sick from chemotherapy,cradling each other in bed onChristmas Eve and still counting ourblessings days before she died.One particular eerie moment

occurred on Sept. 11, 2001. Kathy wasscheduled for an MRI in the after-noon to confirm her diagnosis butwhen we arrived at the hospital wefound it under shutdown. All appoint-ments had been canceled in anticipa-tion of an influx of injured from theWorld Trade Center. The place was aghost town. We just sat on the curband cried. For a long time I was angry that

Kathy had to endure such things. Theemotion receded very slowly. Here wasa woman who did all the right thingsbecause she knew she was at high riskfor the disease. Her grandmother suc-cumbed to ovarian cancer in her early50s. Kathy’s mother, diagnosed withbreast cancer 20 years ago, had a mas-tectomy and is alive today at 84.So Kathy had had regular mammog -

raphies and annual checkups. She didself-exams religiously. But her cancerdefied early detection. Lobular breastcancer can be particularly difficult tocatch in its early stages of develop-ment. According to a recent study bythe National Cancer Institute, mam-mography — our first line of defenseagainst breast cancer — still missesabout 20 percent of breast cancers pres-ent at the time of screening.Sadly, Kathy was part of that 20 per-

cent. Her breast cancer turned out tobe elusive and particularly aggressive.Throughout the journey I learned

that Kathy’s love for me and ourdaughters knew no bounds because shefought so hard to stay alive for us. Oneparticular grueling procedure involvedscrewing a metal halo into her skull inpreparation for stereotactic brain radi-ation treatment. She was fully awake.She never whimpered. She nevercried. Everyone in the room was in aweof her courage. That spirit was her gift to her fami-

ly and friends. We were fortunate tohave been allowed time for intimacyand closure and for that I am verythankful. But there is never, ever,ever enough time.Make no mistake about it: people are

living longer with a cancer diagnosis.But the price of survivorship is heavyand unacceptable. In exchange formore time breast cancer survivors fre-quently endure a slash-and-burn treat-ment plan offered as a cure. Too oftenthey become case studies shuttled fromone specialist to another as they getlost in a sea of symptom managementand diagnostic testing. All the while

the actual disease consumes the personwithin the body that is being treated.Today I fear for my own daughters

and for any women, or men, faced withthis dreaded disease. Forty years haveelapsed since President Richard Nixon

signed the National Cancer Actdeclaring a war on cancer that, ineffect, harnessed the nation’s resourceswith the “… same kind of concentrat-ed effort that split the atom and tookman to the moon.”How far we have come. How very far

we have yet to go. l

Reprinted with permission from New JerseyPress Media.


Caregiving

Throughout the journey I learned that Kathy’s love

for me and our daughters knew no bounds

because she fought so hard to stay alive for us.

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CONFERENCE CO-CHAIRS

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida

Craig K. Deligdish, MDChief Medical OfficerOncology Resource Networks

Gary M. Owens, MDPresidentGary Owens Associates

Burt Zweigenhaft, BSPresident and CEOOncoMed

THURSDAY, MAY 2, 20138:00 am - 5:00 pm Registration

FRIDAY, MAY 3, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am Session 1: Welcome, Introductions, and Opening RemarksConference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am Keynote Address

10:15 am - 10:30 am Break

10:30 am - 11:45 am Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder CollaborationsRoy A. Beveridge, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm Session 3: Cost of Cure: When, How, and How Much?John Fox, MD; John Hennessy

2:00 pm - 2:45 pm Session 4: Where Is Oncology Care Headed in the Future?Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm Session 5: What Will the Cancer Delivery System Look Like in 2015?Linda Bosserman, MD, FACP; John D. Sprandio, MD

3:30 pm - 3:45 pm Break

3:45 pm - 4:30 pm Session 6: Employers and Oncology CareF. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm Session 7: The Role of Government in the Future of Oncology CareJayson Slotnick, JD, MPH

5:15 pm - 5:45 pm Summary/Wrap-Up of Day 1

6:00 pm - 8:00 pm Cocktail Reception in the Exhibit Hall

SATURDAY, MAY 4, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 8: Advanced Care Directives: Palliative Care, Hospice, EthicsJ. Russell Hoverman, MD, PhDThomas J. Smith, MD, FACP, FASCO

9:15 am - 10:00 am Session 9: Medicaid: A Healthcare Delivery System ReviewMatthew Brow

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality

11:00 am - 11:45 am Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence IssuesPat McKercher

12:00 pm - 1:00 pm Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling,Genome Sequencing—The Impact on Cost, Treatment, and the Value PropositionMark S. Boguski, MD, PhD

3:45 pm - 4:15 pm Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm Cocktail Reception in the Exhibit Hall

SUNDAY, MAY 5, 20137:00 am - 8:00 am Simultaneous Symposia/Product Theaters

8:15 am - 8:30 am Opening Remarks

8:30 am - 9:15 am Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship CareJulie Silver, MD

9:15 am - 10:00 am Session 15: Current and Future Considerations for the Oncology Practice ManagerDawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am Break

10:15 am - 11:00 am Session 16: Access to Drugs—Shortages, BiosimilarsDouglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am Session 17: Perspectives from Large Oncology Group Practices—Successes, Issues, and Challenges

11:45 am - 12:00 pm Summary and Conclusion of Conference

*Agenda is subject to change.

PROGRAM OVERVIEWFollowing on the success of our Second Annual Conference, AVBCC will be comingto Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise ofleaders in these fields providing at tendees with a thorough understanding of the evo-lution of the value equation as it relates to cancer therapies. Our goal is to be able toassist them in implementing, improving, and sustaining their organizations and institu-tions, while improving access for patients and ultimately quality patient care.

TARGET AUDIENCEThis conference is intended for medical oncologists, practice managers/administrators,and managed care professionals. Stakeholders in a position to impact cancer patientcare, such as advanced practice nurses, pharmacists, and medical directors, are alsoinvited to join this exciting forum.

SPONSORSThis activity is jointly sponsored by Medical Learning Institute Inc, the Association forValue-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core PrincipleSolutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENTGrant requests are currently being reviewed by numerous supporters. Support will beacknowledged prior to the start of the educational activities.

REGISTERED NURSE DESIGNATIONMedical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

REGISTERED PHARMACY DESIGNATIONThe Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Comple-tion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs)

of continuing pharmacy education credit. The Universal Activity Number for this activityis (To be determined).

PHYSICIAN CREDIT DESIGNATIONThe Medical Learning Institute Inc designates this live activity for a maximum of 17.25AMA PRA Category 1 Credits™. Physicians should claim only the credit commensuratewith the extent of their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of the AccreditationCouncil for Continuing Medical Education through the joint sponsorship of the MedicalLearning Institute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for Continuing Medical Educa-tion to provide continuing medical education for physicians.

DESIGNATION OF CREDIT STATEMENTS

LEARNING OBJECTIVESUpon completion of this activity, the participant will be able to:• Discuss the current trends and challenges facing all stakeholders in optimizing valuein cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to health-care reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.• Analyze the patient issues around cost, quality, and access to care.

CONFERENCE REGISTRATIONDiscounted Pricing Available!

$375.00 until January 15, 2013$475.00 until March 15, 2013$675.00 after March 15, 2013

Influencing the Patient-Impact Factor

THIRD ANNUALAssociation for Value-Based Cancer Care Conference

www.regonline.com/avbcc2013REGISTER TODAY AT

AGENDA*

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CONTINUING EDUCATION

CONSIDERATIONS inMultiple Myeloma™5th Annual

ASK THE EXPERTS: Retreatment Settings

Jeffrey Wolf, MDClinical ProfessorDepartment of Medicine, UCSFDirector, Myeloma Program UCSF Helen DillerFamily Comprehensive Cancer CenterSan Francisco, CA

Jennifer Knoche, RN, BSNLead Practice NurseUCSF Hematology/BMT AmbulatoryCare CenterSan Francisco, CA

Helen T. Wu, PharmD, BCOPClinical PharmacistAdult Hematology/Oncology and Health SciencesAssociate Clinical Professor School of Pharmacy, UCSFSan Francisco, CA

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

PUBLISHING STAFF

President & CEOBrian F. Tyburski

Chief Operating OfficerPam Rattananont Ferris

Editorial DirectorSusan Berry

[email protected]

CopyeditorDana Delibovi

Director, Production and ManufacturingAlaina Pede

Director, Creative and DesignRobyn Jacobs

Quality Control DirectorBarbara Marino

Director, Digital and MediaAnthony Romano

Web CoordinatorJose Valentin

Digital Content SpecialistDavid Maldonado

Business ManagerBlanche Marchitto

BookkeeperTeresa Torgersen

Executive AdministratorJackie Luma

Circulation [email protected]

Center of Excellence Media, LLC1249 South River Road

Suite 202BCranbury, NJ 08512

LETTER FROM THE EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). Thisis due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinicalinvestigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria fordiagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management ofcomorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regardingthe application and interpretation of recent clinical advances.

In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently askedquestions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questionsare answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowl-edge, and professional experience regarding evidence-based care. In this fourth issue, experts from the University ofCalifornia, San Francisco answer questions pertaining to the management of patients in the retreatment setting.

Sincerely,

Sagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

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

FACULTY

NOVEMBER 2012 • VOLUME 5 • NUMBER 4

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CONSIDERATIONS IN MULTIPLE MYELOMA

IntroductionNovel agents and regimens have greatly improved the manage-

ment of multiple myeloma (MM). However, the retreatment setting

remains complex, since many patients have already received nu -

merous therapies at the time of disease progression. The result can

be resistance to specific agents and/or cumulative toxicities, which

may influence the choice of therapy. In this article, Jeffrey Wolf, MD,

discusses therapeutic decision-making in relapsed and refractory MM

and the latest evidence on investigational drugs that may expand

treatment options for the disease.

When a patient experiences a first relapse, what factors do youconsider in choosing retreatment with previously used therapyversus treatment with different agents?

Because first-line therapy for MM often involves several different combi-nations,1 choosing second-line therapy can be a challenge. In the setting ofinitial treatment, we are using doublet and triplet combinations that mayinclude bortezomib, lenalidomide, cyclophosphamide, or dexamethasone.

Eligible patients advance to autologous stem cell transplantation (ASCT)following this therapy. More and more patients receive maintenance thera-py, either with lenalidomide or bortez omib. Therefore, when patients re -lapse, they have already re ceived quite a bit of therapy. The choice of treat-ment for relapsed MM must take into account the resultant toxicities andefficacy of prior drugs.

For example, if a patient has progressed on lenalidomide maintenance, wewould not choose lenalidomide as part of second-line therapy. However, ifthat same patient achieved a very good partial response (VGPR) or a com-plete response during induction with a bortezomib-based regimen, we mightutilize bortezomib at relapse, provided that the patient did not have signifi-cant peripheral neuropathy (PN) or other adverse events (AEs) associatedwith treatment. Bortezomib-related AEs might suggest the use of an alkylatoralone at the time of relapse in such a patient. Another example is a patient who relapses after initial therapy with a com-

bination of lenalidomide, bortezomib, and dexamethasone (RVD)2 but whohas not undergone transplant or maintenance therapy. We could go back toRVD, which has been shown to be effective (Figure),3 or we may switch thepatient to a regimen of cyclophosphamide, bortezomib, and dexametha-

Making Treatment Decisions in Relapsed andRefractory Multiple Myeloma

Jeffrey Wolf, MDClinical Professor, Department of Medicine, UCSFDirector, Myeloma ProgramUCSF Helen Diller Family Comprehensive Cancer CenterSan Francisco, CA

SponsorsThis activity is jointly sponsored by Medical Learning Institute Inc andCenter of Excellence Media, LLC.

Commercial Support AcknowledgmentThis activity is supported by educational grants from Celgene Corporationand Millennium: The Takeda Oncology Company.

Target AudienceThe activity was developed for physicians, nurses, and pharmacists in -volved in the treatment of patients with multiple myeloma (MM).

Purpose StatementThe purpose of this activity is to enhance competence of physicians, nurs-es, and pharmacists concerning the treatment of MM.

Physician Credit DesignationThe Medical Learning Institute Inc designates this enduring material for a max-imum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim onlythe credit commensurate with the extent of their participation in the activity.This activity has been planned and implemented in accordance with theEssential Areas and policies of the Accreditation Council for ContinuingMedical Education through the joint sponsorship of the Medical LearningInstitute Inc and the Center of Excellence Media, LLC. The Medical LearningInstitute Inc is accredited by the Accreditation Council for ContinuingMedical Education to provide continuing medical education for physicians.

Registered Nurse DesignationMedical Learning Institute IncProvider approved by the California Board of Registered Nursing, Pro viderNumber 15106, for 1.25 contact hours.

Registered Pharmacy DesignationThe Medical Learning Institute Inc is accredited by the Accredi -tation Council for Pharmacy Education as a provider of continu-

ing pharmacy education. Completion of this knowledge-based activityprovides for 1.25 contact hours (0.125 CEUs) of continuing pharmacyeducation credit. The Universal Activity Number for this activity is0468-9999-12-030-H01-P.

Learning ObjectivesUpon completion of this activity, the participant will be able to:• Review data from recent clinical trials evaluating novel agents for MM

in the relapsed/refractory setting • Apply evidence-based retreatment strategies for MM, taking into con-

sideration patient- and disease-related factors • Describe appropriate prophylactic measures for managing adverse

events to optimize treatment efficacy

DisclosuresBefore the activity, all faculty and anyone who is in a position to have con-trol over the content of this activity and their spouse/life partner will dis-close the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses,grants, consulting roles, speakers’ bureau membership, stock ownership, orother special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vettedby Medical Learning Institute Inc for fair balance, scientific objectivity ofstudies mentioned in the materials or used as the basis for content, andappropriateness of patient care recommendations.

Planners’ and Managers’ DisclosuresDana Delibovi,Medical Writer, has nothing to disclose.William J. Wong, MD, MLI Reviewer, has nothing to disclose.Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has disclosedthat her spouse is investigator on a study for Agenix, ImClone, and Lilly;on the data monitoring committee for Infinity; on the Advisory Com -mittee for Boehringer Ingelheim; and on the data monitoring committeeand principal investigator on a study for Pfizer.

Faculty Disclosures*Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, CelgeneCorporation, Merck, Millennium: The Takeda Oncology Company,Novartis, and Onyx.*Jeffrey Wolf, MD, is on the speakers’ bureau for Celgene Corporation,Millennium: The Takeda Oncology Company, and OnyxPharmaceuticals, Inc.Helen T. Wu, PharmD, BCOP, has nothing to disclose.Jennifer Knoche, RN, BSN, is on the speakers’ bureau for CelgeneCorporation.

*Content will include non–FDA-approved uses.The associates of Medical Learning Institute Inc, the accredited providerfor this activity, and Center of Excellence Media, LLC, do not have any

financial relationships or relationships to products or devices with anycommercial interest related to the content of this CME/CPE/CE activityfor any amount during the past 12 months.

Disclaimer The information provided in this CME/CPE/CE activity is for continuingeducation purposes only and is not meant to substitute for the indepen -dent medical judgment of a healthcare provider relative to diagnostic andtreatment options of a specific patient’s medical condition. Recommenda -tions for the use of particular therapeutic agents are based on the best availablescientific evidence and current clinical guidelines. No bias towards or promotionfor any agent discussed in this program should be inferred.

Instructions for Credit

There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest,posttest, and evaluation. The pretest, posttest, and evaluation can be com-pleted online at www.mlicme.org/P12028.html. Upon completion of theevaluation and scoring 70% or better on the posttest, you will immediatelyreceive your certificate online. If you do not achieve a score of 70% or bet-ter on the posttest, you will be asked to take it again. Please retain a copyof the Certificate for your records.

For questions regarding the accreditation of this activity, please contactMedical Learning Institute Inc at 609-333-1693 or [email protected].

Estimated time to complete activity: 1.25 hoursDate of initial release: November 13, 2012Valid for CME/CPE/CE credit through: November 13, 2013

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Web browser, and select “Download”• Visit the app store for your smartphone

The choice of treatment for relapsed MM must take into account the resultant toxicities and efficacy of prior drugs.

� ��



sone.4,5 Both of these regimens yield a response rate of about 75% in therelapsed setting.3-5 We could consider ASCT as part of second-line therapy,usually with some initial therapy to get better control pretransplant. If themyeloma is particularly aggressive at relapse, we may use a combination suchas bortezomib and dexamethasone with cisplatin, doxorubicin, cyclophos-phamide, and etoposide (VD-PACE) and then go to transplant.6 If thepatient has renal insufficiency, we will use modified HyperCVAD(cyclophosphamide, bortezomib, doxorubicin, and dexamethasone; withbortezomib in place of vincristine) instead of VD-PACE.7

How would you choose therapy for a patient who is resistant toinitial treatment?

Drug resistance is a topic of ongoing investigation, and therapeutic choicesin this setting require careful consideration. Recently, we had a patient whowas treated with a 2-drug regimen of bortezomib and dexamethasone andattained only a partial response. We added lenalidomide, and his responseimproved to a VGPR. At the time of relapse, we might be disinclined to usebortezomib for such a patient, because of the modest initial response. Thereis a caveat here, however. Evidence suggests that, if you wait long enough,you can often go back to a drug such as bortezomib despite initial resistance(Table 1).8,9 We now believe that myeloma is made up of various clones withmultiple sensitivity and resistance patterns to different drugs. Sometimes, if apatient has not received a drug for a period of time, the clone that may berelapsing most recently may be one that is sensitive to bortezomib. Therefore,it may be worth retrying this agent. Often we do see a response in patients

who exhibited resistance earlier in the clinical course of the disease. In otherwords, “once resistant, always resistant” may not be true.Of course, one could argue that the best option for a patient resistant to

bortezomib would be treatment with carfilzomib. That is an argument thatwill play out now that both agents are available. My point is that going backto a proteasome inhibitor makes sense, even if a patient had only a modestprior response to bortezomib.

Has the approval of carfilzomib impacted treatment approachesin the retreatment setting?

The next-generation proteasome inhibitor carfilzomib is now availablefor use in the relapsed/refractory setting for MM, but it is approved by theUS Food and Drug Administration only for patients who have re ceived atleast 2 prior therapies including bortezomib and an immuno modulatoryagent.10 Clinical trials have shown the efficacy of carfilzomib in this set-ting and have also indicated that carfilzomib is less likely than bortezomibto cause PN.11,12

Because we see many patients who have run through all of the other treat-ment options and have progressed on bortezomib-based therapies, our teamhas used carfilzomib frequently since its approval. However, in patients whoreceived bortezomib with good response a long time ago, or in patients whoprogressed on bortezomib 2 to 5 years ago, retreatment with bortezomib couldbe considered at relapse. In such cases, the decision of which drug to use maybe influenced by possible prior toxicities.

For instance, in a patient who still has PN that developed during priortreatment with bortezomib, I would probably lean toward using carfilzomib.Even though you can give bortezomib subcutaneously (SC) and possiblyavoid making neuropathy worse,13 it may not be worth taking that chance. Incontrast, if there is no neuropathy and the patient did not progress on bor -tezomib initially, I would lean toward bortezomib retreatment. Convenienceis a consideration here. At the present time, carfilzomib is cumbersome toadminister. It is given intravenously over 2 to 10 minutes 2 days in a row,weekly for 3 weeks followed by a 12-day rest period.10 Bortezomib, which cannow be given SC twice a week,13 is more convenient.

For the patient with relapsed or refractory MM, what investigationaltherapies show the most promise?

The immunomodulator pomalidomide is the first agent that comes tomind, as it may be approved in the next 6 months. Clinical data support theefficacy of this agent when combined with weekly dexamethasone in therelapsed/refractory setting for MM, and it is fairly well tolerated. In 2 phase 2trials of pomalidomide plus dexamethasone in patients refractory to bortez -omib and lenalidomide, overall response rates were 43% to 49%.14 In an ear-lier report, this combination showed a 63% response rate in patients receiv-ing 1 to 3 prior therapies; however, the incidence of grade �2 toxicities washigh, including neutropenia, fatigue, leukopenia, and anemia (Table 2).15

Elotuzumab is an antibody that does not have a lot of activity on its own,but looks good when combined with lenalidomide and dexamethasone.16

Figure. Response rates with RVD in a phase 2 trial ofrelapsed/refractory MM (N=64).3

Pati

ents

(%

)

100

90

80

70

60

50

40

30

20

10

0

CR indicates complete response; MR, minimal response; NR, no response; ORR, overall responserate; PR, partial response; RVD, lenalidomide, bortezomib, and dexamethasone.

CR/near CR PR NR ORR (��MR)

25%

64%

22%

78%

Table 1. Response to Bortezomib-Based Retreatment FollowingResponse to Initial Bortezomib-Based Therapy (N=22)8

Response to Initial Therapy, n (%) Response to Retreatment, n (%)

Complete orpartial response

No response

15 (68%)

7 (32%)

Complete or partial response

No response

Complete or partial response

No response

9 (60%)

6 (40%)

2 (29%)

5 (71%)

Drug resistance is a topic of ongoing investigation,and therapeutic choices in this setting require careful consideration.

� ��



There are also CD38 antibodies—daratumumab and SAR650984—inphase 1/2 trials that look promising.17,18

Additional drugs that are progressing through clinical trials include theBruton’s tyrosine kinase inhibitor ibrutinib (PCI-32765)19 and the mam-malian target of rapamycin inhibitor MLN0128.20 The histone deacetylaseinhibitor vorinostat and the pan-deacetylase inhibitor panobinostat do notseem to have very good antimyeloma activity on their own. Vorinostat hasprovided a slight advantage in combination with bortezomib, but it appearsto add quite a bit of toxicity.21 Panobinostat is in trials in combination witha proteasome inhibitor,22-24 but it is not yet clear if this drug will perform bet-ter than vorinostat.

ConclusionOver the past decade, we have witnessed spectacular progress in the area

of treating myeloma. Today, a majority of patients are alive and doing wellat 5 years following initial treatment. It is becoming apparent that manypatients can hope for very extended survival because of novel drugs and ourability to treat relapsed and refractory disease. �

References1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in

Oncology™: Multiple Myeloma.Version 1.2013. http://www.nccn.org. Accessed October 12, 2012.2. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone com-

bination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686.3. Richardson PG, Jagannath S, Jakubowiak AJ, et al. Phase II trial of lenalidomide, bortezomib,

and dexamethasone in patients (pts) with relapsed and relapsed/refractory multiple myeloma(MM): updated efficacy and safety data after >2 years of follow-up. Blood (ASH Annual MeetingAbstracts). 2010;116:Abstract 3049.

4. Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of cyclophos-phamide, Velcade and dexamethasone (CVD) induces high response rates with comparabletoxicity to Velcade alone (V) and Velcade plus dexamethasone (VD). Haematologica. 2007;92:1149-1150.

5. Fu W, Delasalle K, Wang J, et al. Bortezomib-cyclophosphamide-dexamethasone for relapsingmultiple myeloma [published online ahead of print June 18, 2011]. Am J Clin Oncol.doi:10.1097/COC.0b013e31822043f6.

6. Barlogie B, Anaissie E, van Rhee F, et al. Incorporating bortezomib into upfront treatment formultiple myeloma: early results of total therapy 3. Br J Haematol. 2007;138:176-185.

7. Pegylated liposomal doxorubicin hydrochloride, bortezomib, cyclophosphamide, and dexa -methasone in treating patients with multiple myeloma (NCT00849251). http://www.clinicaltrials.gov. Accessed October 22, 2012.

8. Wolf J, Richardson PG, Schuster M, LeBlanc A, Walters IB, Battleman DS. Utility of bor -tezomib retreatment in relapsed or refractory multiple myeloma patients: a multicenter caseseries. Clin Adv Hematol Oncol. 2008;6:755-760.

9. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination forpatients with multiple myeloma following an initial response to bortezomib. Am J Hematol.2009;84:657-660.

10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.11. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-

A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.12. Vij R, Siegel DS, Jagannath S, et al. An open-label, single-arm, phase 2 study of single-agent

carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previ-ously treated with bortezomib. Br J Haematol. 2012;158:739-748.

13. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

14. Lacy MQ, Allred JB, Gertz MA, et al. Pomalidomide plus low-dose dexamethasone in myelomarefractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011;118:2970-2975.

15. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexametha-sone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008-5014.

16. Lonial S, Vij R, Harousseau JL, et al. Elotuzumab in combination with lenalidomide andlow-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012;30:1953-1959.

17. Gimsing P, Plesner T, Nahi H, et al. A phase I/II, dose-escalation study of daratumumab, aCD38 Mab in patients with multiple myeloma—preliminary safety data. Blood (ASH AnnualMeeting Abstracts). 2011;118:Abstract 1873.

18. Dose escalation study of anti-CD38 monoclonal antibody in patients with selected CD38+hematological malignancies (NCT01084252). http://www.clinicaltrials.gov. Accessed October22, 2012.

19. Study of the Bruton’s tyrosine kinase inhibitor in subjects with relapsed or relapsed and refractorymultiple myeloma (NCT01478581). http://www.clinicaltrials.gov. Accessed October 22, 2012.

20. Dose escalation study of MLN0128 in relapsed or refractory multiple myeloma or Waldenstrommacroglobulinemia (NCT01118689). http://www.clinicaltrials.gov. Accessed October 28, 2012.

21. Dimopoulos MA, Jagannath S, Yoon S-S, et al. Vantage 088: vorinostat in combination withbortezomib in patients with relapsed/refractory multiple myeloma: results of a global, random-ized phase 3 trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 811.

22. San Miguel JF, Hungria VTM, Yoon S-S, et al. Update on a phase III study of panobinostatwith bortezomib and dexamethasone in patients with relapsed multiple myeloma: PANORA-MA 1. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 3976.

23. Richardson PG, Alsina M, Weber DM, et al. Phase II study if the pan-deacetylase inhibitorpanobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (PANORAMA 2). Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 814.

24. Carfilzomib plus panobinostat in relapsed/refractory multiple myeloma (MM) (NCT01301807).http://www.clinicaltrials.gov. Accessed October 22, 2012.

Table 2. Toxicities Grade ��2 with Pomalidomide PlusDexamethasonea in a Phase 2 Trial (N=60)15

Toxicity Patients, n (%)

Anemia 20 (33%)

Lymphopenia 4 (7%)

Neutropenia 30 (50%)

Thrombocytopenia 6 (10%)

Leukopenia 24 (40%)

Fatigue 27 (45%)

Nausea 1 (2%)

Diarrhea 5 (8%)

Constipation 11 (18%)

Pneumonia 6 (10%)

Hyperglycemia 10 (17%)

Confusion 5 (8%)

Insomnia 7 (12%)

Agitation 7 (12%)

Peripheral neuropathy 6 (10%)

Thrombosis 1 (2%)

aPatients also received aspirin 325 mg once daily for thromboprophylaxis. Patients wereallowed to substitute full-dose anticoagulation with either low-molecular-weight heparinor warfarin at physician discretion.

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Nursing Interventions in the Relapsed andRefractory Settings for Myeloma

IntroductionFor patients with multiple myeloma (MM), prompt and effective

nursing interventions can make a significant difference in care—from

minimizing adverse events (AEs) to protecting bone health and alle-

viating pain. In this article, Jennifer Knoche, RN, BSN, examines key

strategies for improving outcomes in the relapsed/refractory setting

for myeloma, and discusses best practices for whole-patient care.

When patients are retreated with agents such as bortezomib orthalidomide, what strategies are effective for minimizing the risk ofperipheral neuropathy (PN)?

The main strategy for minimizing this risk remains dose adjustment ortreatment interruption. With thalidomide, which is administered orally, PNcan be an especially challenging toxicity to manage. We often use thalido-mide at a low dose in the relapsed/refractory setting; therefore, to reduce theamount even further may require patients to cut their pills in half or taketheir medication every other day—neither of which are ideal options. Withintravenous (IV) bortezomib, reducing or holding the dose is easier. Rec -ommended dose reductions for thalidomide- and bortezomib-based PN areshown in Tables 1 and 2.1,2

Of course, we cannot make an informed decision regarding dose adjust-ment without an accurate assessment of a patient’s condition. In therelapsed/refractory setting, we must look at current symptoms as well as treat-ment history. What drugs have been administered previously? Did thepatient experience neuropathy with prior treatment, and if so, did dosereduction or discontinuation provide relief? Did supportive therapies help toreduce symptoms? Are there comorbid conditions associated with the exist-ing PN? Is the patient taking any medications for comorbidities that maycontribute to neuropathy? Answers to these questions help us to plan theschedule and dose of agents at the time of relapse.Complementary therapies, such as alpha lipoic acid, L-carnitine, and vita-

min B6 may be helpful.3 At our institution, we begin patients on these ther-apies prior to antimyeloma treatment to prevent or minimize PN. In thosewho already exhibit symptoms, we may add these therapies as supplements,to keep neuropathy from progressing. Some patients need a more robust med-ical intervention, in which case we may prescribe gabapentin, pregabalin, tri-cyclic antidepressants, or even nonopioid analgesics.3 Our goal is to do what-ever works to manage pain, tingling, burning, and functional impairment tokeep the patient on therapy.PN may cause the nerves that control intestinal muscle contractions to

malfunction, leading to gastrointestinal problems, including constipation.4 Ifthis occurs, a good bowel regimen, proper diet, hydration, and exercise, and

laxation become important components of therapy, in addition to dosereduction. Fortunately, we now have the option of administering bortezomibsubcutaneously (SC), which has been shown to help reduce the incidenceand severity of PN.5

How has the recent approval of carfilzomib affected yourapproach to treating relapsed and/or refractory disease?

With the approval of carfilzomib, we now have another treatment optionat our disposal, which is extremely important. Given the challenges pa -tients face in the relapsed/refractory setting, including the fact that theyhave already been treated with so many therapies, it matters greatly to haveone more way to attack the disease. In addition to demonstrating good effi-cacy, carfilzomib has been associated with low rates of PN (Figure).6

Anecdotally, we are not seeing this toxicity among patients receiving carfil-zomib. How ever, since these individuals are on so many drugs, sequencedover time, it can be hard to determine whether AEs are related to past orcurrent regimens. For instance, an agent may cause some degree of neu-

Jennifer Knoche, RN, BSNLead Practice NurseUCSF Hematology/BMT Ambulatory Care CenterSan Francisco, CA

Table 1. Thalidomide Dose Modifications Based on Severity ofPeripheral Neuropathy1

Severity of Peripheral Neuropathy Modification of Dose and Regimen

Grade 1 (mild)

Grade 1 with pain or grade 2

Grade 3

Grade 4 (permanent sensory loss that interferes with function)

No action

Intermittent symptoms:Continue therapy

Continuous symptoms:Withhold thalidomide until toxicity resolves, then reduce dose

Withhold thalidomide until toxicity resolves, then restart at reduced dose

Discontinue thalidomide

Table 2. Bortezomib Dose Modifications Based on Severity ofPeripheral Neuropathy2

Severity of Peripheral Neuropathy Modification of Dose and Regimen

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

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

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

Grade 4 (permanent sensory loss that interferes with function)

No action

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

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

Discontinue bortezomib

��



ropathy, but symptoms do not appear until later, after another therapy isgiven.Administration of carfilzomib—2 days in a row intravenously, weekly for 3

weeks7—is not as simple as administration of bortezomib, especially borte-zomib SC. Some patients, depending on how far they live from the cancercenter, may have to spend the night once a week to receive carfilzomib. Theinfusion time for this drug is longer than it is for IV bortezomib. Additionally,if you compare IV carfilzomib administration to the use of bortezomib SC,

there is a big difference in convenience favoring bortezomib. Dose adjustment schedules for carfilzomib-related PN are available, along

with those for hematologic, cardiac, pulmonary, and hepatic toxicities. Insome patients, we have noticed a decline in red blood cells with carfilzomibuse, typically during the first cycle. As with any agent, careful monitoring ofblood counts and vital organ functions are an essential part of nursing care.

How do you support bone health and manage skeletal-relatedevents over the course of care in the relapsed/refractory setting?

Supporting bone health in this setting is essential but can be complex.Many myeloma patients are older, with comorbidities such as osteoarthritis

and osteoporosis. When treating a patient for osteoporosis, we need to assesshis or her current bisphosphonate regimen and see how it dovetails with theneed for myeloma bone support.In a patient who has experienced a long clinical course and relapsed, prior

bisphosphonate treatment is a given. Currently, the American Society of Clin -ical Oncology recommends 2 years of bisphosphonate therapy for myeloma-related bone disease. After that, treatment is at the discretion of the physician.8

Unfortunately, there is no road map to guide us in restarting or continuing bis-phosphonates in a relapsed or refractory patient who has already had 2 years oftherapy. Our biggest concern is the risk for osteonecrosis of the jaw, whichincreases with prolonged time on bisphosphonate therapy.9

As the myeloma disease process continues, and as patients age, they mayneed supportive devices, surgical care, and pain management strategies.Functional limitations and pain can be improved with antimyeloma thera-py and bisphosphonates, but for some individuals, canes, walkers, wheel-chairs, or braces may be necessary. We may also refer patients with spineinvolvement for vertebroplasty or kyphoplasty, which can be very effec-tive.10 Local irradiation is occasionally used for supportive care, especiallyif there is a plastocytoma. Bone pain often requires opioid analgesics, andwe encourage our patients to accept such medications when necessary.11

Pain can delay healing and diminish quality of life and must therefore beminimized whenever possible.

ConclusionNurses need to carefully monitor relapsed and refractory MM patients, and

be ready to intervene to ensure the continuation of treatment and the abilityto perform activities of daily living. The detection and effective managementof AEs, skeletal-related complications, and pain are essential components ofevidence-based care, which will lead to better clinical outcomes. �

References1. Thalomid [package insert]. Summit, NJ: Celgene Corporation; 2012.2. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; June 2012.3. Tariman JD, Love G, McCullagh E, et al. Peripheral neuropathy associated with novel therapies

in patients with multiple myeloma: Consensus statement of the IMF Nurse Leadership Board.Clin J Oncol Nurs. 2008;12:29-36.

4. National Institute of Neurological Disorders and Stroke. Peripheral neuropathy fact sheet.http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm.Accessed October 27, 2012.

5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

6. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

7. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals Inc.; July 2012.8. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical

practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol.2007;25:2464-2472.

9. Badros A, Weikel D, Salama A, et al. Osteonecrosis of the jaw in multiple myeloma patients:clinical features and risk factors. J Clin Oncol. 2006;24:945-952.

10. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture man-agement for treatment of painful vertebral body compression fractures in patients with cancer:a multicentre, randomised controlled trial. Lancet Oncol. 2011;13:225-235.

11. Definitions related to the use of opioids for the treatment of pain: Consensus statement of theAmerican Academy of Pain Medicine, the American Pain Society, and the American Society ofAddiction Medicine. www.asam.org. Accessed October 30, 2012.

Figure. Carfilzomib-related, nonhematologic adverse eventswith an incidence ��5% in a single-agent study ofrelapsed/refractory MM patients (N=266).6

Patients (%)

40

35

30

25

20

15

10

5

0Fat

igue

Nausea

Diarrh

ea

Dyspne

a

Headac

he

Increa

sed serum

creatin

ine Vomitin

gPyr

exia

Periph

eral ne

uropat

hy

Hypoph

osphat

emia

Unfortunately, there is no road map to guide us in restarting or continuing bisphosphonates in a relapsed or refractory patient who has already had 2 years of therapy.

� ��



Pharmacologic Considerations in theRetreatment Setting for Multiple Myeloma

IntroductionIn patients with relapsed/refractory multiple myeloma (MM), re -

treatment can contribute to longer survival and better quality of life,

but can also pose a number of clinical challenges. When choosing

therapies for this indication, it is necessary to consider numerous fac-

tors, including preexisting toxicities, patient preferences and perfor -

mance status, and agents used during initial therapy. In this article,

Helen T. Wu, PharmD, BCOP, shares her perspective on these issues in

both the transplant and nontransplant settings and discusses recent

advances that may promote better patient outcomes.

How do comorbidities and other patient factors affect selectionand administration of therapy in the retreatment setting?

An important issue to consider is how well a patient has tolerated a specif-ic agent or regimen in the frontline setting, as this may affect administrationand dosing at the time of retreatment. For example, if a patient did not expe-rience serious adverse events (AEs) with frontline therapy, we can typicallystart retreatment at the standard, recommended dose of the same agent.Conversely, if a patient did suffer significant toxicities, we may choose toretreat with an agent from a different class. However, studies have shown atherapeutic benefit when patients are retreated with agents they have re -ceived previously.1-5 Therefore, if a patient has achieved a good response to aspecific agent as induction, we may try using dose modifications to reduce theincidence of AEs.For example, we can consider a patient with preexisting peripheral neu-

ropathy (PN) who relapses after being treated with lenalidomide, bortez -omib, and dexamethasone (RVD) and autologous stem cell transplantation(ASCT). According to the most recent National Comprehensive CancerNetwork (NCCN) guidelines for the treatment of MM, RVD is a recom-mended primary therapy (category 2A) for transplant candidates.6 If relapseoccurs at >6 months, the same primary regimen may be repeated. However,in a patient who has residual PN, clinicians may consider avoiding bortez -omib and instead select a regimen that has less potential for neurotoxicity. Inaddition, because of previous ASCT and lenalidomide treatment, a regimenthat has the least hematologic toxicity would be preferred. It would be nec-essary to look at which agents are available for salvage therapy, based onthese factors.In a different type of scenario, you may be treating a relapsing patient who

is not eligible for transplant and who has renal impairment. Such a patientmay have been treated initially with bortezomib, melphalan, and prednisoneor lenalidomide plus low-dose dexamethasone—regimens that are recom-

mended in the NCCN guidelines for this indication.6 In the salvage setting,choosing therapies that are least likely to be toxic to the kidneys is a must. Itis also important to remember that myeloma patients with renal dysfunctionoften have other comorbidities and poor performance status.7 Therefore,therapeutic benefit must be balanced with drug-related toxicities.Although lenalidomide can be effective in the retreatment setting, this

agent needs to be dose-adjusted for patients with varying degrees of renal dys-function.8 Bortezomib and carfilzomib, which have also demonstrated effi -cacy as second-line therapies, do not require dosing adjustments in renallyimpaired patients.9,10

How has the approval of subcutaneous (SC) bortezomib impactedyour approach to retreatment?

In January 2012, the US Food and Drug Administration (FDA) approvedSC administration of bortezomib for the treatment of MM. This mode ofdelivery has several advantages, as shown in a recent multicenter trial byMoreau and colleagues.11 These investigators compared the efficacy and safe-ty of SC versus intravenous (IV) bortezomib in patients with relapsed MMwho had received �3 previous lines of therapy. The end point was to shownoninferiority of SC versus IV bortezomib in terms of overall response rate(ORR) following 4 treatment cycles. After these cycles, ORR was 42% inboth groups, showing noninferiority (P=.002). After a median follow-up of11.8 months in the SC group and 12.0 months in the IV group, there wereno significant between-group differences in time to progression and 1-yearoverall survival. PN of any grade was significantly reduced with SC versus IVbortezomib (Figure). Grade 3 or higher AEs were reported in 57% of patientsin the SC group versus 70% in the IV group; the most common were throm-bocytopenia (13% vs 19%), neutropenia (18% vs 18%), and anemia (12%vs 8%), respectively.11

It is important for pharmacists to be aware of how to prepare SC bortez -omib for administration. The concentration for IV infusion of bortezomib is1 mg/mL, which is significantly different from the concentration for SCinjection, which is 2.5 mg/mL.9 Pharmacists should be cautious when recon-stituting this medication and calculating the volume to be administered.However, the amount of work involved in preparing bortezomib for SC ver-sus IV administration is really no different, and SC bortezomib appears to bea much-preferred route of administration for several reasons. For nurses, itsimplifies care, since there is no need to obtain IV access, and the potentialrisks and complications of inserting IV lines are eliminated. In addition, itreduces chair time, allowing for a much quicker turnaround time forappointments. For patients, it is easier and generally less stressful to receivean SC injection compared with IV administration. Since there is no need

Helen T. Wu, PharmD, BCOPClinical PharmacistAdult Hematology/Oncology and Health SciencesAssociate Clinical Professor, School of Pharmacy, UCSFSan Francisco, CA

if a patient has achieved a good response to a specific agent as induction, we may try using dosemodifications to reduce the incidence of AEs.

� ��



to insert an IV line, wait time is much shorter, which can potentially im -prove quality of life.

How is the recently approved agent carfilzomib being used at yourcenter in the retreatment setting?

On July 20, 2012, the FDA approved carfilzomib, a next-generation pro-teasome inhibitor, for the treatment of patients with MM who havereceived at least 2 prior therapies, including bortezomib and an immuno -modulatory agent, and who have demonstrated disease progression on orwithin 60 days of therapy completion. Many patients who have re -lapsed/refractory MM are being treated with carfilzomib at our institution,given its proven efficacy and good safety profile. In a phase 2 study conduct-ed by Siegel and colleagues, patients received single-agent IV carfilzomib forrelapsed/refractory MM; all of these individuals were heavily pretreated.12

Of the evaluable patients in this study, 95% were refractory to their lasttherapy, and 80% were refractory to both bortezomib and lenalidomide. Thetreatment regimen was designed as IV carfilzomib 20 mg/m2 (cycle 1) fol-lowed by 27 mg/m2 (cycle �2), on days 1, 2, 8, 9, 15, and 16 of each 28-daycycle. The ORR was 23.7%, median duration of response was 7.8 months,and median overall survival was 15.6 months. Reported AEs included

fatigue (49%), anemia (46%), nausea (45%), and thrombocytopenia (39%).The rate of treatment-related PN was 12.4%.Our institution was one of the participating centers for clinical trials of

carfilzomib prior to its FDA approval. Now, we are able to offer this agentto patients off study, and we make sure to follow the recommended dosing,reconstitution, and administration guidelines to ensure maximum benefitand safety. Although we rarely use carfilzomib in the inpatient setting, wedo utilize it in patients who come in for emergent plasmapheresis after fail-ing transplant, administering concomitant IV hydration to prevent tumorlysis syndrome. I think this agent is becoming an important retreatmentoption in MM.

ConclusionAlthough MM remains an incurable disease, retreatment with novel

agents is leading to higher response rates, prolonged survival, and better qual-ity of life. An important goal in this setting is the prevention and manage-ment of AEs, which allows the cancer care team to maximize dose intensityand provide continuation of therapy. This requires careful consideration ofcomorbidities and other patient factors, as well as a thorough understandingof the doses, schedules, and modes of administration recommended for avail-able agents. �

References1. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for

patients with multiple myeloma following an initial response to bortezomib. Am J Hematol.2009;84:657-660.

2. Berenson JR, Jagannath S, Barlogie B, et al. Safety of prolonged therapy with bortezomib inrelapsed or refractory multiple myeloma. Cancer. 2005;104:2141-2148.

3. Hrusovsky I, Emmerich B, von Rohr A, et al. Bortezomib retreatment in relapsed multiple myelo-ma—results from a retrospective multicentre survey in Germany and Switzerland. Oncology.2010;79:247-254.

4. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial oflenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J ClinOncol. 2009;27:5713-5719.

5. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory drugs(IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma.Blood. 2011;118:1763-1765.

6. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines inOncology™: Multiple Myeloma. Version 1.2013. http://www.nccn.org. Accessed October 24, 2012.

7. Glade J, Fernandez-Llama P, Bosch F, et al. Renal failure in multiple myeloma presenting featuresand predictors of outcome in a series of 94 patients from a single institution. Arch Intern Med.1998;158:1889-1893.

8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; 2012.9. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; June 2012.10. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals; July 2012.11. 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-inferioritystudy. Lancet Oncol. 2011;12:431-440.

12. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

Figure. Incidence of peripheral neuropathy in a phase 3 trialcomparing SC versus IV bortezomib dosing in relapsedmyeloma (N=222).11

Patients (%)

60

50

40

30

20

10

0

IV indicates intravenous; SC, subcutaneous.

Any grade �Grade 2 �Grade 3

SC bortezomib

IV bortezomib

38%

53%

24%

41%

6%

16%

P=.044

P=.012

P=.026

��


Interest in pancreatic neuroen-docrine tumors (pNETs) has grownsince the recent approval of targeted

agents for advanced disease, as was evi-dent by the attendance at several ses-sions during the European Society forMedical Oncology (ESMO) 2012Congress in Vienna, Austria.1Kjell Öberg, MD, of Uppsala

University in Sweden, noted, “Thesetumors are steadily increasing, comparedwith other malignant neoplasms. It’s nota rare disease any longer, and we don’tknow why. Partly, it’s better awarenessamong physicians. This room at ESMOis filled. And also, better diagnosticmethods and treatment opportunities.” “Still, there is usually a delay of 4 to 5

years from first symptom to diagnosis,and 50% of patients present withmetastatic disease. They have an indo-lent course, but median overall survival[OS] is only 33 months, and that is notvery impressive,” he said. The good news, added Tim Meyer,

MD, of University College London inthe United Kingdom, “is that withpNETs we are now in the luxurious posi-tion of having lots of treatments. Thequestion now is, which is best?”

Treatment Options Prior to May 2011, options were limit-ed. For patient with hormonal symp-toms, octreotide LAR could be benefi-cial, and for oncologic controlstreptozocin-based chemotherapy wasindicated. Upon disease progression,patients went on to investigationalagents or regional therapy; no approvedtherapies were available.

But identification of somatic muta-tions in the mTOR pathway in pNETformed the scientific rationale for test-ing mTOR inhibitors in this disease.The 410-patient RADIANT-3 trialdemonstrated that everolimus couldeffectively prolong remission, from amedian progression-free survival (PFS)of 4.6 months with best supportive care

alone to 11.0 months with everolimus,representing a 65% reduction in risk (P <.0001).An understanding of the role of the

angiogenesis pathway in pNETs also ledto the development of sunitinib for thismalignancy. The phase 3 trial showedmedian PFS increased from 5.5 monthswith placebo to 11.4 months with suni-tinib, which was a 58% reduction in

risk; this did not reach statistical signifi-cance due to early termination of thestudy and truncated enrollment.“We have clear and convincing evi-

dence that everolimus and sunitinib areeffective in improving PFS,” Meyer toldattendees.James C. Yao, MD, of the University

of Texas MD Anderson Cancer Center,

Houston, added, “Both everolimus andsunitinib result in about 6 months of PFSbenefit, but neither study was designed toevaluate overall survival.” He explainedthat because these tumors are rare, andpatients live for years, clinical trials withan OS end point are not feasible, and anOS might not be formally demonstrated.“Nonetheless, we actually do have

improved survival,” he suggested.“When we only had streptozocin, medi-an OS was 16 to 24 months. With thenewer drugs, we are pushing OS to 3years and beyond.”He added that while the drugs have

almost equivalent PFS benefit,everolimus has activity in controllinghormonal output from pNETs. “It is themost active agent I have seen for con-trolling hypoglycemia in patients withinsulinoma,” he noted, “and it mayreduce gastrin and glucagon as well.”

Algorithm for Managing Patients Yao said he approaches the initial man-agement of pNETs by considering thedisease burden (ie, the percentage ofliver involvement), the aggressiveness ofthe tumor (ie, Ki67 levels, tumor grade),and the primary site of the tumor.“If I have a patient with low-volume,

very low-grade disease, I think that sur-veillance or a somatostatin analogue isreasonable. For the opposite, a patientwith 50% liver involvement and a highKi67, chemotherapy may be the beststarting point. For the intermediatepatient, targeted therapy is a goodchoice,” he maintained.To decide whether to treat with

everolimus or sunitinib, Yao said,“There has been no head-to-head com-parison. Practically speaking, mostpNET patients will receive both agentsat some time, but there are some factorsto help you decide.”He believes that everolimus is the

preferred choice for the patient with afunctional tumor or a high risk of bleed-ing, such as patients with a primarytumor at the tail of the pancreas andthose with gastric varices. Everolimusalso is preferred for patients with coro-nary artery disease, congestive heartfailure, or uncontrolled hypertension.Sunitinib would be favored for patientswith severe lung disease and uncon-trolled diabetes, he said. l

Reference1. Öberg K, Meyer T. NETs and endocrine tumors.Presented at: European Society for Medical Oncology2012 Congress; September 29, 2012; Vienna, Austria.Proffered paper session.


Neuroendocrine Tumors

Advances in the Treatment of PancreaticNeuroendocrine TumorsBy Caroline Helwick

New Data Presented at ESMO Neuroendocrine tumors are highly vascular, expressing

vascular endothelial growth factor (VEGF) and demon-strating angiogenesis. Since the mTOR inhibitoreverolimus has antiangiogenic activity, RADIANT-3investigators evaluated several VEGF pathway tumormarkers for their prognostic and predictive potential. Theresults were presented by James C. Yao, MD, in an abstractpresentation at ESMO.1Yao and colleagues evaluated pretreatment plasma samples

for levels of the angiogenic cytokines VEGF-A, solubleVEGF receptors (sVEGFR1 and sVEGFR2), and placentalgrowth factor (PlGF). The multivariate analysis showed thatsVEGFR1 and PlGF were significant prognostic markers,with lower baseline levels associated with longer progression-free survival (PFS). This means that patients with highsVEGFR1 and high PlGF are likely to have a worse progno-sis. None of the markers, however, proved predictive of abenefit with everolimus, he reported.“PFS was significantly improved to a similar extent in

patients receiving everolimus, compared with patients whoreceived placebo, regardless of baseline levels of these mark-ers,” he said, “suggesting that none of these markers are asso-ciated with the efficacy of everolimus in patients withpNET. The markers are prognostic but not predictive.”An updated overall survival (OS) analysis of the phase 3

sunitinib trial was also reported at ESMO by SandrineFaivre, MD, of Clichy, France.2“At trial closure, there was an advantage for sunitinib

over placebo in OS, a secondary end point. At that time69% of patients on placebo crossed over to sunitinib upondisease progression or trial closure, potentially confound-ing the OS analysis. We now present OS data 2 years afterstudy closure and after adjusting for crossover,” she said.The intent-to-treat analysis without adjustment for

crossover showed OS to be 33 months with sunitinib and26.7 months with placebo (hazard ratio [HR], 0.71). Theinvestigators then adjusted for crossover using 4 differentstatistical methods, which showed median OS with suni-tinib to range from 16.4 months (HR, 0.43) to 26.7 months(HR, 0.49), depending on the model employed. This yield-ed an OS benefit that ranges from 6.3 to 16.7 months.“Four methods of adjusting for crossover suggested that

the effect of sunitinib on OS may have been more pro-nounced had no crossover occurred,” she said. “Theseanalyses demonstrate a survival advantage and further sup-port the clinical benefit of sunitinib for patients withadvanced, progressive pNET.”

References1. Yao JC, Shah M, Panneerselvam A, et al. The VEGF pathway in patients withpancreatic neuroendocrine tumors: efficacy of everolimus by baseline marker level,and prognostic and predictive effect analyses from RADIANT-3. Presented at:European Society for Medical Oncology 2012 Congress; September 29, 2012;Vienna, Austria. Abstract 11540.2. Niccoli P, Faivre S, Raoul J, et al. Updated overall survival (OS) analysis froma phase III study of sunitinib vs. placebo in patients (Pts) with advanced, unre-sectable pancreatic neuroendocrine tumor (NET). Presented at: European Societyfor Medical Oncology 2012 Congress; September 29, 2012; Vienna, Austria.Abstract 11550.

“These tumors are steadily increasing, compared

with other malignant neoplasms. It’s not a rare

disease any longer, and we don’t know why.”

—Kjell Öberg, MD

The majority of caregiversare female (82%), and 71%are married. Almost half(47%) are over 50 years old.2

Six of 10 caregivers (61%)have been providing support for less than 6 months.2

In 54% of cases, caregiverslive with the patient forwhom they are caring.2

Health concerns resultingfrom providing care are anissue for 62% of caregivers.In fact, 70% of caregiversreport taking between 1 and10 medications per day.2

Often, caregivers miss asmany workdays as thosepatients for whom theycare, and almost half (46%)of caregivers report insuffi-cient financial resources.The weekly time requiredis greater than 40 hours perweek for 36% of caregivers.2

A feeling of resentment forhaving to provide care isfelt by 85% of caregivers,and 70% claim their fami-lies do not work welltogether.2

Although 97% of caregiverssay their roles are impor-tant, 35% are overwhelmedby their caregiving respon-sibilities.2

However, 81% want to pro-vide care and insist on

accepting the caregivingduties themselves.2


Noteworthy Numbers

�� Editor in ChiefSagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of Medicine

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

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

Newsletter Series

�� ™

��

Topics include:• Mantle Cell Lymphoma• Follicular Lymphoma

�� ™

��

AccreditationThese activities will be accredited for physicians, nurses, and pharmacists.

For complete accreditation information, please refer to each activity.

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

ALL NEW CONTENT FOR 2012

YOUR QUESTIONS ANSWERED

COEAsize71912AskExperts

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Spectrum Pharmaceuticals.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Celgene Corporation.

� ��

In 2012, approximately 1.6 million new cases of cancer will be diagnosed in the United States.1 A family caregiver, or informal

caregiver, will become a necessity for many of the newly diagnosed patients. A family caregiver provides emotional, physical,

psychological, and spiritual support to the patient. This, in turn, can take a toll on a caregiver’s own physical, emotional, and even

financial health as well. The following statistics provide a glimpse into the characteristics of these unique care providers.

Sources1. www.cancer.org/cancer/news/news/annualreport.

2. http://www.strengthforcaring.com/manual/about-you-you-are-not-alone/cancer-caregivers/.

According to a study from the USOncology Network, breast can-cer patients treated with adju-

vant chemotherapy have no increasedrisk for acute myeloid leukemia (AML)or myelodysplastic syndrome (MDS), atleast within the first 3 years of treat-ment. The study was presented at theAmerican Society of Clinical Oncology2012 Breast Cancer Symposium byNeelima Denduluri, MD, of VirginiaCancer Specialists.1“The rates of AML/MDS were

found to be low after adjuvantchemotherapy, and similar to thosenoted in non–chemotherapy-treatedpatients,” Denduluri reported.

Previous estimates have placed therisk of developing AML/MDS afterbreast cancer therapy at around 1%,with the greatest risk seen among olderpatients and those who receive anthra-cyclines, higher cumulative doses ofcyclophosphamide, and radiotherapy. Ithas not been established whether gran-ulocyte colony-stimulating factors arecorrelated with increased risk, nor areincidence rates with taxane combina-tions well characterized.Denduluri and colleagues explored

the oncology-specific electronic healthrecord, iKnowMed, which containsnearly 1.3 million patient records. The

base population included 20,900 breastcancer patients, of whom 11,295received chemotherapy.

At a median follow-up time of about3 years, 12 cases were identified amongchemotherapy recipients (0.106%),

including 1 case among 2466 patientsreceiving pegfilgrastim and 11 casesamong 8829 patients not receiving peg-


Breast Cancer

BRIEF SUMMARY OF PRESCRIBING INFORMATIONThe following is a brief summary: please see the package insert for full prescribing information.------------------------------ INDICATIONS AND USAGE -----------------------------XTANDI is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.--------------------------------- CONTRAINDICATIONS -------------------------------PregnancyXTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss . -------------------------- WARNINGS AND PRECAUTIONS -------------------------SeizureIn the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing seizure were permanently discontinued from therapy and all seizures resolved. There is no clinical trial experience re-administering XTANDI to patients who experienced seizures. The safety of XTANDI in patients with predisposing factors for seizure is not known because these patients were excluded from the trial. These exclusion criteria included a history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medications that may lower the seizure threshold. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. --------------------------------- ADVERSE REACTIONS -------------------------------Clinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared

in practice.In the randomized clinical trial in patients with metastatic castration-resistant prostate cancer who had previously received docetaxel, patients received XTANDI 160 mg orally once daily (N = 800) or placebo (N = 399). The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. All patients continued androgen deprivation therapy. Patients were allowed, but not required, to take glucocorticoids. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids. All adverse events and laboratory abnormalities were graded using NCI CTCAE version 4.

XTANDI in the randomized clinical trial were asthenia/fatigue, back pain,

upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3 and higher adverse

placebo-treated patients. Discontinuations due to adverse events were reported for 16% of XTANDI-treated patients and 18% of placebo-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients. Table 1 shows adverse reactions reported in the

the XTANDI arm compared to the placebo arm.Table 1. Adverse Reactions in the Randomized Trial

XTANDIN = 800

PlaceboN = 399

Grade 1-4 (%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)

General DisordersAsthenic Conditionsa 9.0 44.4 9.3Peripheral Edema 1.0 13.3 0.8

Musculoskeletal And Connective Tissue DisordersBack Pain 26.4 24.3 4.0Arthralgia 17.3 1.8Musculoskeletal Pain 1.3 0.3Muscular Weakness 9.8 6.8 1.8Musculoskeletal Stiffness

2.6 0.3 0.3 0.0

XTANDIN = 800

PlaceboN = 399

Grade 1-4 (%)

Grade 3-4(%)

Grade 1-4(%)

Grade 3-4(%)

Gastrointestinal DisordersDiarrhea 21.8 1.1 0.3

Vascular DisordersHot Flush 20.3 0.0 10.3 0.0Hypertension 6.4 2.1 2.8 1.3

Nervous System DisordersHeadache 12.1 0.9 0.0Dizzinessb

Spinal Cord Compression and Cauda Equina Syndrome

7.4 6.6 3.8

Paresthesia 6.6 0.0 0.0Mental Impairment Disordersc

4.3 0.3 1.8 0.0

Hypoesthesia 4.0 0.3 1.8 0.0Infections And Infestations

Upper Respiratory Tract Infectiond

10.9 0.0 0.3

Lower Respiratory Tract And Lung Infectione

2.4 4.8 1.3

Psychiatric DisordersInsomnia 8.8 0.0 6.0Anxiety 0.3 4.0 0.0

Renal And Urinary DisordersHematuria 6.9 1.8 1.0Pollakiuria 4.8 0.0 0.0

Injury, Poisoning And Procedural ComplicationsFall 4.6 0.3 1.3 0.0Non-pathologic Fractures

4.0 1.4 0.8 0.3

Skin And Subcutaneous Tissue DisordersPruritus 3.8 0.0 1.3 0.0Dry Skin 0.0 1.3 0.0

Respiratory DisordersEpistaxis 3.3 0.1 1.3 0.3

a Includes asthenia and fatigue.b Includes dizziness and vertigo.c Includes amnesia, memory impairment, cognitive disorder, and disturbance

in attention.d Includes nasopharyngitis, upper respiratory tract infection, sinusitis, rhinitis,

pharyngitis, and laryngitis.e Includes pneumonia, lower respiratory tract infection, bronchitis, and lung

infection.

Laboratory Abnormalities

patients on XTANDI (1% Grade 3-4) and in 6% of patients on placebo (no Grade 3-4). The incidence of Grade 1-4 thrombocytopenia was similar in both

thrombocytopenia. Grade 1-4 elevations in ALT occurred in 10% of patients on

Grade 1-4 elevations in bilirubin occurred in 3% of patients on XTANDI and 2% of patients on placebo. InfectionsIn the randomized clinical trial, 1.0% of patients treated with XTANDI compared to 0.3% of patients on placebo died from infections or sepsis. Infection-related serious adverse events were reported in approximately 6% of the patients on both treatment arms. Falls and Fall-related InjuriesIn the randomized clinical trial, falls or injuries related to falls occurred in 4.6% of patients treated with XTANDI compared to 1.3% of patients on placebo. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in patients treated with XTANDI and included non-pathologic fractures, joint injuries, and hematomas.HallucinationsIn the randomized clinical trial, 1.6% of patients treated with XTANDI were reported to have Grade 1 or 2 hallucinations compared to 0.3% of patients on placebo. Of the patients with hallucinations, the majority were on opioid-containing medications at the time of the event. Hallucinations were visual,

XTANDI® (enzalutamide) capsules for oral useInitial U.S. Approval: 2012

(continued) Table 1. Adverse Reactions in the Randomized Trial

No Increase in Leukemia or Myelodysplastic SyndromeWith Adjuvant Chemotherapy for Breast CancerBy Audrey Andrews

“This study can reassure

patients who receive

adjuvant chemotherapy

that their risk of a

secondary AML/MDS

is very low within the first

3 years.”

—Neelima Denduluri, MD

Photo by © ASCO/Tod

d Buchanan 2012.


Breast Cancer

----------------------------------DRUG INTERACTIONS -------------------------------Drugs that Inhibit or Induce CYP2C8

the composite area under the plasma concentration-time curve (AUC) of enzalutamide plus N-desmethyl enzalutamide in healthy volunteers. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dose of XTANDI

The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated . Co-administration of XTANDI with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP2C8 induction potential is recommended

Drugs that Inhibit or Induce CYP3A4Co-administration of a strong CYP3A4 inhibitor (itraconazole) increased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold in healthy volunteers The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated . Co-administration of XTANDI with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) may decrease the plasma exposure of XTANDI and should be avoided if possible. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Moderate CYP3A4 inducers (e.g.,

reduce the plasma exposure of XTANDI and should be avoided if possible .

Effect of XTANDI on Drug Metabolizing EnzymesEnzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. At steady state, XTANDI reduced the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Concomitant use of XTANDI with narrow therapeutic index drugs that are metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), CYP2C9 (e.g., phenytoin, warfarin) and CYP2C19 (e.g., S-mephenytoin) should be avoided, as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring . -------------------------- USE IN SPECIFIC POPULATIONS ------------------------Pregnancy- Pregnancy Category X XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. While there are no human or animal data on the use of XTANDI in pregnancy and XTANDI is not indicated for use in women, it is important to know that maternal use of an androgen receptor inhibitor could affect development of the fetus. XTANDI is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with XTANDI.Nursing MothersXTANDI is not indicated for use in women. It is not known if enzalutamide 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 XTANDI, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric UseSafety and effectiveness of XTANDI in pediatric patients have not been established.Geriatric Use Of 800 patients who received XTANDI in the randomized clinical trial, 71 percent

in safety or effectiveness were observed between these patients and younger

responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Patients with Renal ImpairmentA dedicated renal impairment trial for XTANDI has not been conducted. Based on the population pharmacokinetic analysis using data from clinical trials in patients with metastatic castration-resistant prostate cancer and healthy

adjustment is necessary for patients with mild to moderate renal impairment. Severe renal impairment (CrCL < 30 mL/min) and end-stage renal disease have not been assessed . Patients with Hepatic ImpairmentA dedicated hepatic impairment trial compared the composite systemic exposure of enzalutamide plus N-desmethyl enzalutamide in volunteers with baseline mild or moderate hepatic impairment (Child-Pugh Class A and B, respectively) versus healthy controls with normal hepatic function. The composite AUC of enzalutamide plus N-desmethyl enzalutamide was similar in volunteers with mild or moderate baseline hepatic impairment compared to volunteers with normal hepatic function. No initial dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. Baseline severe hepatic impairment (Child-Pugh Class C) has not been assessed

-------------------------------------- OVERDOSAGE --------------------------------------In the event of an overdose, stop treatment with XTANDI and initiate general

escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizures following an overdose. Carcinogenesis, Mutagenesis, Impairment of FertilityLong-term animal studies have not been conducted to evaluate the carcinogenic potential of enzalutamide. Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the mouse lymphoma thymidine kinase (Tk) gene mutation assay or the mouse micronucleus assay.

consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy

to the human exposure based on AUC). In 4- and 13-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed

PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling (PATIENT INFORMATION).

XTANDI can be taken with or without food. Each capsule should be swallowed whole. Do not chew, dissolve, or open the capsules.

treatment during the course of treatment with XTANDI.

risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

paresthesia, hypoesthesia, and falls.

if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day.

edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.

Patients should also be informed that they should use a condom if having sex with a pregnant woman. A condom and another effective method of birth control should be used if the patient is having sex with a woman of child-bearing potential. These measures are required during and for three months after treatment with XTANDI.

Manufactured by: Catalent Pharma Solutions, LLC, St. Petersburg, FL 33716Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062Marketed by:Astellas Pharma US, Inc., Northbrook, IL 60062

Issued: August 2012

Rx Only© 2012 Astellas Pharma US, Inc. XTANDI® is a registered trademark of Astellas Pharma Inc.

ONCOLOGY

filgrastim. Among breast cancer patientsnot receiving chemotherapy, there were16 cases (0.167%). The median time toonset of AML/MDS was 22 months.Risk was increased 7-fold among

patients aged ≥70 years and nearly 4-foldamong those who received anthracy-clines. These were statistically significanteffects, whereas the almost 3-foldincrease with pegfilgrastim use was

numerically higher but not statisticallysignificant, she said.“With the recent news that Robin

Roberts with Good Morning America

developed MDS after beating breast can-cer, many of my patients were concernedabout the risk,” Denduluri said. “Thisstudy can reassure patients who receive

adjuvant chemotherapy that their risk ofa secondary AML/MDS is very low with-in the first 3 years.” l

Reference1. Denduluri N, Espirito JL, Turnwald B, et al. Risk ofacute myeloid leukemia (AML) and myelodysplasticsyndrome (MDS) after adjuvant chemotherapy (CT)for early breast cancer (BC) in the community setting.Presented at: American Society of Clinical Oncology2012 Breast Cancer Symposium; September 13-15,2012; San Francisco, CA. Abstract 62.

Risk was increased 7-fold among patients aged ≥70 years and nearly 4-fold among those who

received anthracyclines.

AFFIRM: A phase 3, global, placebo-controlled, randomized study of patients with mCRPC who previously received docetaxel1

Reference: 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012.© 2012 Astellas Pharma US, Inc. All rights reserved. Printed in USA. 012I-076-6330 9/12XTANDI is a registered trademark of Astellas Pharma Inc.Astellas and the fl ying star logo are trademarks of Astellas Pharma US, Inc.

XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel.

Important Safety InformationContraindications XTANDI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. XTANDI is not indicated for use in women. XTANDI is contraindicated in women who are or may become pregnant.

Warnings and Precautions In the randomized clinical trial, seizure occurred in 0.9% of patients on XTANDI. No patients on the placebo arm experienced seizure. Patients experiencing a seizure were permanently discontinued from therapy. All seizures resolved. Patients with a history of seizure, taking medications known to decrease the seizure threshold, or with other risk factors for seizure were excluded from the clinical trial. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Adverse Reactions The most common adverse drug reactions (≥ 5%) reported in patients receiving XTANDI in the randomized clinical trial

were asthenia/fatigue, back pain, diarrhea, arthralgia, hot fl ush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

Drug Interactions XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Co-administration of XTANDI with strong or moderate CYP3A4 and CYP2C8 inducers can alter the plasma exposure of XTANDI and should be avoided if possible. Avoid CYP3A4, CYP2C9 and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Please see adjacent pages for Brief Summary of Full Prescribing Information.

NOW APPROVED for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) who have previously received docetaxel

Learn more at XtandiHCP.com

• 37% reduction in risk of death vs placebo (P < 0.0001; HR = 0.63 [95% CI, 0.53, 0.75])1

• XTANDI can be taken with or without food1

• Patients were allowed, but not required, to take glucocorticoids1

— In the clinical trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids1

• Oral, once-daily dosing1

• The rate of grade 3 and higher adverse reactions with XTANDI was 47% vs placebo at 53%1

• Seven patients (0.9%) out of 800 treated with XTANDI 160 mg once daily experienced a seizure. No seizures occurred in patients treated with placebo1

AND...

18.4 MONTHS MEDIAN OVERALL SURVIVAL VS 13.6 MONTHS WITH PLACEBO

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november 2012, vol 5, no 10 the oncology nurse

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