Ellen Lavoie Smith PhD, APRN, AOCN, FAAN Associate Professor

PhD Program Director University of Michigan School of Nursing

Chemotherapy-InducedPeripheralNeuropathy(CIPN)Measurement

Approaches

Faculty Disclosure

Company Name Honoraria/ Expenses

Consulting/ Advisory Board

Funded Research

Royalties/ Patent

Stock Options

Ownership/ Equity

Position Employee Other

(please specify)

Mundipharma x

ASCO x

Columbia University x

No, nothing to disclose x Yes, please specify:

CIPNhasbeenadifficultsideeffecttomeasure.

MeasurementChallenges

•  Don’ttell,don’task•  Lackskills•  Nostandardizedapproach•  Lackaccesstobestmeasures•  Hardwireduseofunreliablegradingscales

– Under-es?mateseverity– Measurementerrorinclinicaltrials

Hershman,etal.,2014;Gewandter,etal.,2017;Postma,etal.,1998;Griffith,etal.,

2010;CavaleP,etal.,2010;Smith,etal.,2013;Albers,etal.,2011

SymmetricalDistaltoProximalExtensionofSignsandSymptoms

Stubblefield,etal.,2009

NeurotoxicDrugs&OurNervousSystems

Injury

Descendingpathway

Peripheralnerve DRG

C-fiber

A-betafiberA-deltafiber

Ascendingpathways

Dorsalhorn

Brain

Spinalcord

AdaptedwithpermissionfromWebMDScien?ficAmericanMedicine.

MeasurementApproaches

•  Thereisno“goldstandard”approachforclinicalandresearchsePngs.

•  Acomprehensiveapproachimprovesvalidity.– Objec?vemeasurementoflargeandsmallfibers– Distaltoproximalextension– Pa?ent-reportedoutcomes(PRO)– Func?onassessment

•  Musthavestrongpsychometricproper?es

England,etal.,2005;EFNS/PNS,2010;Alber?,etal.,2014;Griffith,etal.,2010;CavaleP,etal.,2010

ObjecGveMeasuresClinicalneurologicexam,quan?ta?vesensorytes?ng(QST),nerveconduc?onstudies(NCS),electromyography(EMG),skinbiopsy

Advantages DisadvantagesQuan?fiesactualnervedamage Requirespecializedtraining&

equipmentAssessespre-clinicalsigns NCS&EMG-largefibersUsefulinmechanis?cstudies Skinbiopsy–smallfibersMaybeimportantfordiagnosisincomplexcases

QST,NCS,EMG&biopsyarecostly,inconvenient,painful,?me-consuming,&maynotbereimbursedQST–?reliabilityPoorcorrela?onwithpa?entreportEngland,etal.,2005,Ruppert,etal.,2003;EFNS/PNS,2010;Smith,etal.,2008;Alber?,etal.,2014

TotalNeuropathyScore(TNS)

•  Theonlycomprehensivecompositetooltobeextensivelytestedinpa?entsreceivingneurotoxicchemotherapy–  Reliable,valid,sensi?ve,&responsive

•  Mul?dimensional–  Symptoms-ProximalExtensionTingling,Numbness,Pain–  Signs–e.g.,Reflexes,Vibra?on&PinSensibility,Strength–  NCSandQST-Op?onal

•  Abbreviatedversionscanbeusedinclinicalprac?cetoassessadultsandchildren.

Griffith,etal.,2010;CavaleP,etal.,2007,2010,2013;Smith,etal.,2008,2010,2011,2013;Wampler,etal.,2006;Gilchristetal.,2009

5-itemTNSScoring

Smith,etal.,2013.

TNS-PVResponsiveness

0

1

2

3

4

5

6

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

MeanScores

TNSVersusGradingScaleScoresbyWeek

TNSTotal(A)

TNSTotal(B)

CTCMotor

CTCSensory

BalisMotor

BalisSensory

Smith,etal.,2013

N=65

•  Sample:Childrenages1-18receivingvincris?neforALL

Month

TesGngVibraGonSensibility

Useweighted128HzTuningFork

Feasibletoperforminindividuals>6yearsofage

Smith,etal.,2013,CancerNursing;Smithetal.,2013,ClinicalJournalofOncologyNursing

GradingScaleProblems•  OKforscreeningbut...•  Under-reportsseveritywhencomparedtopa?entreport

•  Poorsensi?vity&responsiveness•  Noopera?onaldefini?ons,poorreliability•  Impreciselycapturesprogression

– Preclinicalandclinicalsigns/sxinsamegrade– Distaltoproximalextension– Whataboutpain?

Postma,etal.,1998;Griffith,etal.,2010;CavaleP,etal.,2007,2010,2013;Smith,etal.,2010,2011;Baschetal.,2006,2009,2010;Atkinson,etal.,2016

NaGonalCancerInsGtute(NCI)CTCAEV.4.0MandatedinallNCI-SponsoredTrials

Grade0 Grade1 Grade2 Grade3 Grade4 Grade5

Nosignsorsymptoms

Asymptoma?c:lossofdeep

tendonreflexesorparesthesia

Moderatesymptoms:limi?ng

instrumentalADL

Severesymptoms:limi?ngselfcareADL

Life-threatening

consequences:urgent

interven?onindicated

Death

SensoryNeuropathy

Published:May28,2009(v4.02:Sept.15,2009)Na?onalIns?tutesofHealth;Na?onalCancerIns?tute

PROMeasuresSevenMeasures:ThemostextensivelytestedaretheFACT-GOG/NTX&EORTCQLQ-CIPN20. Advantages DisadvantagesCapturesthepa?ent’sexperiencebererthanprovider-ratedscales

Doesn’tcapturepre-clinicalsigns

Canbecollectedelectronically Pa?entburden,?Workflow

Extensivelytested,mul?pletransla?ons

Lackofsystemstointegrate&visualizescoreswithinEMRsystems

Doesn’trequirespecialtrainingandeaseofuseinmul?sitetrials

Noreimbursementincen?vefrompayersdespitesurvivalbenefit

SomeassessspecificCIPNtypes(i.e.,taxane,oxalipla?n)

Sufficientlytested?Areallitemsgoodandnecessary?

Curcioetal.,2017;Griffith,etal.,2010;CavaleP,etal.,2010;Haryani,etal.,2017;Basch,etal.,2016,2017;Atkinson,etal.,2016

Nostandardforuseinprac?ceorclinicaltrials

FACTGOG-NTX

QLQCIPN20

QLQCIPN20(cont.)

ComparisonofFACTGOG/NTXwithCIPN20FACTGOG/NTX/NTX12 QLQ-CIPN20

NumberofStudies 10 9

Popula?ons NRange20–395US,European,Asian,African

VariousCancers

NRange25–1155US,European,AsianVariousCancers

Proper?esTested ICR,Contras?ngGroup,Content,Structural,Contras?ngGroups,&ConvergentValidity,Sensi?vity&

Specificity,Responsiveness

ICR&Test-RetestReliability;Content,Structural,Contras?ngGroup,&ConvergentValidity,Sensi?vity,

Responsiveness,ModeEquivalence,ItemResponse

Languages Numerous Numerous

NeuropathyTypes Taxanes,Pla?nums,Vinblas?ne,Bortezomib

Taxanes,Pla?nums,Vincas,Bortezomib

Strengths Feasibleformul?sitetrialsBrief(11/12-items,4-items)

Feasibleformul?sitetrialsBrief(20-items)butlongerthanFACT.

Weaknesses Someitemsmaynotbeneuropathy-specific

LackofConsensusAboutAutonomic&Drivingitems;Disorderedresponse

thresholds

RaschAnalysis-ResponseOrdering

SmallObjects FootDrop

Pedals Erec?on

PRO-CTCAE-NeuropathyWhatwastheSEVERITYofyourNUMBNESSORTINGLINGINYOURHANDSORFEETatitsWORSTinthepast7days?HowmuchdidNUMBNESSORTINGLINGINYOURHANDSORFEETINTERFEREwithyourusualordailyac?vi?esinthepast7days?

1NotAtAll

2 34

VeryMuch

ConcurrentvaliditywhencomparedtoQLQCIPN20

Knoerletal.,2017

FuncGonMeasuresExamples:TimedUp-and-Go(TUG),9-HolePegTest,BumpsTest

Advantages DisadvantagesAssessesfunc?onaloutcomessuchaswalkingandbalance,handdexterityandsensoryfunc?on.

Requiresspecialtrainingandequipment

UsefulforresearchsePngs Time-consumingLimitedpsychometrictes?nginCIPN

Kennedy,etal.,2011;Stubblefield,etal.,2009;Manniletal.,2014;Gilchrist,etal.,2016;Caronni,etal.,2016

Summary

NoConsensusAboutMeasurementApproachesButManyGoodOp?ons

Assess:AtBaseline,DuringRx,&InSurvivors

Prac?ceSePngs:CTCAE

PRO-CTCAE5-itemTNS

ResearchSePngs:Objec?veMeasuresFACTGOG/NTXor

QLQ-CIPN20Func?onalMeasures

PRO-CTCAE

Thankyou!