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Risk-basedguidelinesfor

managementofabnormalcervicalcancerscreeningtestresults:raisingthebaronprevention

RebeccaPerkinsMDMScHPV/CervicalCancerSummit

11/30/2018

Disclosureofcommercialinterest

•  Noconflictsofinteresttoreport

HPVinfectionandthedownstreamconsequences

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Cervical HPV infection

HPV-relatedcancersinwomenbyage

https://www.cdc.gov/cancer/hpv/statistics/age.htm

MostHPVinfectionsclear…thosethatpersistcauseCIN3+overtime

…knowingHPVhistorycanpredictcurrentandfuturerisks ScreeningdetectsCIN3(“pre-cancer”)

TreatingCIN3preventscancer

GoalofscreeningistodetectCIN3andpreventcervicalcancer

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UntreatedCIN3:30%(95%CI22.7-42.3)chanceofdevelopinginvasivecanceroverthenext30yearsTreatedCIN3:<1%(95%CI0.3-1.9)chanceofdevelopingcancerBasedondatafromtheNationalWomen'sHospital,Auckland,NewZealand,wheretreatmentofCIN3waswithheldfromasubstantialnumberofwomenbetween1965and1974

RiskofcervicalcancerwithuntreatedCIN3over30years

MRMcCredieetal,LancetOncol.2008May;9(5):425-34

CervicalcancerscreeningwithPaptestingandcervicalcancer

Calendar year

CIN3

Incidence cervical cancer

Invasive squamous

Invasive adenoCA

Chen, BJC, 2009. Taiwan

CIN3detectionincreases

SquamousCancerratesdecrease

Screeningstarts

AdenocarcinomaratesDONOTdecrease

Existingscreeningandmanagementguidelinestreatallwomenthesameway

Butpasthistorypredictsfuturerisk

UpcomingASCCPguidelinesforthemanagementofabnormalresultswillincorporatehistoryANDtestresult

todeterminethenextstepinawoman’scare

Schiffmanetal,JLGTD,2016

ExamplesofRiskModifiersthatpredictCIN3+risk

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Highereffectivenesswithvaccinationatyoungerages

Ageatvaccination

OddsoftestingHPV16/18+atfirstscreen(age20-21)

15-16 7.7%

17 12.5%

18 16.6%

19-21 30.3%(oddsratio5.31)

Cameronetal2016:linkagedata,Scotland,CastleBMJ2009,Kjaer,JNCI2010

NotethatwomenwhoremainpositiveforHPV16/18haveupto40%riskofhighgradeprecancerorcancerin3-10years!

HPVvaccinationreducesriskofCIN2+

Prevalen

ceofC

IN2+

per1

000wom

ensc

reen

ed

HPVtestingpredictsfutureriskbetterthancytology

•  331,818womenover2003-2009

•  Followedfor5yearsforCIN3+

•  BothHPVandcytologypredictedriskonthedateofscreening

•  HPVpredicted5-yearriskofCIN3andcancer

HPV+

cytology+

KatkietalJLowGenitTractDis.2013Apr;17(5Suppl1):S28-35.

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MultiplenegativeHPVtestspredictverylowcancerrisk

Cancerriskfellfrom9.2/100,000afterfirstnegativeHPVteststo1.5/100,000after3rdconsecutivenegativeHPVtest

Castleetal,AnnalsofInternalMedicine,2018

NewHPVinfectionconferslowerCIN3+risk

HPV+allcomers

HPV+afterHPV-

•  331,818womenover2003-2009

•  RiskofCIN3+at3years•  5%withunknownpriorHPVresult

•  3%withnegativepriorHPVresult

•  PriornegativeHPVtestreducedriskofCIN3withanewHPV+result

KatkietalJLowGenitTractDis.2013Apr;17(5Suppl1):S28-35.

PriorHPV+orunknownhistoryishigherrisk

•  26,799womenwithacurrentpositiveHPV+testandnopriorCIN2+

•  CumulativeCIN3+incidenceratesover4yearsamongwomenwithcurrentHPV+/Papnegscreen•  PriorHPVpositive:4.36•  PriorHPVnegative:1.32•  PriorHPVunknown:4.67

•  NotepriorHPV+havethesameriskaswomenwithanunknownscreeninghistory

Castle,P.ObstetGynecol2011:117:650-6;

Long-termpersistentHPVisespeciallyhighrisk

Kjaer, et al. J Natl Cancer Inst 2010 Oct 6; 102(19):1451-3

•  8656womenage20-29underwentco-testingyears1&3

•  Followedfor12yearsforCIN3+

•  RiskofCIN3+•  47%persistentHPV16+•  19%persistentHC2•  HPVneg2%

•  HPVhistoryisanimportantriskmodifier

HPV16+

HC2+

AllwomenwithpersistentHPVdevelopCIN2+195womenpapneg/HPV+atstart,40remainedHPV+for7yearsandall

developedCIN2+

Elfgren,AJOG,2017

TreatedCIN2+hasahighriskofrecurrencewithin5yearsoftreatment

•  8-16%riskaftertreatedCIN3/AIS

•  5-10%riskaftertreatedCIN2

•  0.08%riskafterneg/negco-test

•  ThushistoryofCIN2/3denotes100-foldCIN2+riskovernegativeco-testing,evenaftertreatment

Katkietal,JLowGenitTractDis.2013Apr;17(5Suppl1):S78-84andS28-35..

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0

2

4

6

8

10

12

14

3negativeco-tests

1negativeco-test

HPVvaccinated

HPV+afterHPV-

HPV+,unknownhistory

TreatedCIN3/AIS

Percen

trisk

ofC

IN3+

RiskofCIN3+at5yearsisaffectedbypriorhistory

Perkins,Schiffman,Guido,CurrentProblemsinCancer,inpress

WhyreviseASCCPmanagementguidelinestoincluderiskdata?

1.  Detectandtreatmoreprecancer2.  Decreasetestingandtreatmentthatwon’t

preventcancerandmaycausereproductiveharmRisk-basedtestingshouldallowbetter

precancerdetectioninhighriskwomen,andfewerproceduresinlow-riskwomen

THENEXTGENERATIONOFRISK-BASEDMANAGEMENT

ConsensusprocessledbyASCCPwith>26organizationsincludingprofessionalsocietiesforphysiciansandmid-levelproviders,researchandeducationgroups,and

patientorganizations

NewASCCPrisk-basedguidelines

RiskofCIN2/3

<0.01%

0.02%

0.05%

1-4%

5-60%

61-100%

•  Patient’scurrenttestresultsandpasthistory

•  RiskmatrixisusedtocalculateherriskofCIN2/3

•  Computerprogramgeneratesriskscore

•  Recommendsnextstepinmanagement

Clinicaltrials

Highqualityobservationalstudies

Medicalrecorddata

Riskstrata Risknow

1-yearrisk

2-yearrisk

3-yearrisk

4-yearrisk

5-yearrisk

HPVandcytology

Biomarkers

Screeninghistory

Vaccinationdata

Othervariables

Riskmatrix:CalculatingriskofCIN2+/CIN3+forall

meaningfulcombinations

Clinicalconsensus

Settingrisk-actionthresholds

Clinicalrecommendations

Consortium,includingASCCP,CISNET,DCCPS,others

Patient: Doe,JaneAge: 42HPV: PosGenotype:16Cytology:LSILVaccine:NoLastscreen:NegativePriorLEEP:No

Dataentry

COLPOSCOPYREFERRAL

Recommendation

Showdetails

A42yearoldwomanwithLSILcytologyandHPV16hasan%riskofCIN3+,whichisabove

thecolposcopyreferralthresholdof

m%.

RecommendationEnterriskdata

Showrecommendation

ReducingcomplexityforprovidersCurrenttestresultsandpriorhistory

RiskAlgorithm

Treatment

colposcopy

1yearreturn

3yearreturn

5yearreturn

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Canbeadjustedformethodsindevelopment

Cytology-based Molecular Visual

p16/Ki-67/Automation

Cytology/AutomationVIA/AutomationHPVgenotyping

Methylation

In-vivoimaging

Workinggroups

•  Treatment•  Colposcopy•  Surveillance•  RiskModification•  NewTechnologies•  Highvaluecare•  Communication

Projectedtimeline•  Workinggroupsreviewdataanddraftrecommendations – Fall/Winter/Spring2018

•  Releaseofdraftrecommendationsforpubliccomment– Summer2019

•  Votingandfinalratificationofguidelinesbyconsensusorganizations– Fall2019

•  Publicreleaseofguidelinesviaapp– Spring2020

AdaptedfromWebinargiven10/29withDebbieSaslow,PhD│SeniorDirector,HPV-relatedandWomen’sCancers,AmericanCancerSociety&ViceChair,NationalHPVVaccinationRoundtable

Fundingforthiswebinarwasmadepossible(inpart)bytheCentersforDiseaseControlandPreventionCooperativeAgreementgrantnumberNH23IP922551-03,CFDA#93.733.Thecontentintheguide(or)doesnotnecessarilyreflecttheofficepoliciesoftheDepartmentofHealthandHumanServices,nordoesthementionoftradenames,commercialpractices,ororganizationsimplyendorsementbytheU.S.Government.

ChangingGears:

ApprovedExpansionofHPVVaccinationtoAge45:WhatDoesItMean?

HPVvaccinationOFKIDSeliminatesHPVacquisition,whicheliminatesdownstreamconsequencesofpre-cancerandcancer

Schiffman M et al. CEBP 2013.

Cervical HPV infection

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DecreaseinHPVinfectionsintheU.S.Pre-VaccineEra,EarlyVaccineEraandLaterVaccineEra

02468101214161820

14-19 20-24

Pre-vaccine era 2003-2006

Early vaccine era 2007-2010

Later vaccine era 2011-2014 71% decline

61% decline

StudyalsofoundvaccinetypeHPVdecreased89%forvaccinatedgirls,and34%forunvaccinatedgirls:

indicatesherdimmunityOliver,etal.JID2017https://academic.oup.com/jid/article/216/5/594/3892427

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Highereffectivenesswithvaccinationatyoungerages

Ageatvaccination

OddsoftestingHPV16/18+atfirstscreen(age20-21)

15-16 7.7%

17 12.5%

18 16.6%

19-21 30.3%(oddsratio5.31)

Cameronetal2016:linkagedata,Scotland,CastleBMJ2009,Kjaer,JNCI2010

NotethatwomenwhoremainpositiveforHPV16/18haveupto40%riskofhighgradeprecancerorcancerin3-10years!

Malignancy HPVVaccinatedwomen(65,565person-years)

Non-vaccinatedwomen(124,245person-years)

N Rate(95%CI) N Rate(95%CI)Cervix 0 - 8 6.4(3.1,13)Vulva 0 - 1 0.8(0.1,5.7)Oropharyngeal 0 - 1 0.8(0.1,5.7)AllHPVassociatedcancers

0 - 10 8.0(4.3,15)

Luostarinem,T.VaccinationprotectsagainstHPV-associatedcancers.Int.J.Cancer2018https://www.ncbi.nlm.nih.gov/pubmed/29280138

ZeroCasesofHPV-RelatedCancersinVaccinatedWomen

Sowhataboutvaccinationofadultwomen?

Timelineq October5th,2018:FDAapprovedGardasil9formenandwomenages27-45yearsq Basedonsafetyandefficacyinaclinicaltrial

q February27-28,2018:ACIPpresentationsonadditionalevidenceandeconomicanalysis,potentialvoteconsideringq Diseaseburdenq Effectiveness(inarealworldsetting)q Cost-effectiveness

Effectivenessandcost-effectivenessq 11studiesfrom6countriesq 2/3ofstudiesdidnotshoweffectivenessorcost-effectivenessforwomenoverage20

BurdenofDiseaseq Vaccinatingthroughat26q Estimatedtoprevent25,000HPV-relatedcancersannually

q Vaccinatingthroughage45q Estimatedtopreventonly193morecancers

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Peoplewanttoknow

•  Isitsafe?• Doesitwork?• Willmyinsurancepayforit?

HPVvaccinationissafeforallages

CastellagueetalBrJCancer,2011

•  Commonsideeffectsareasorearm,andoccasionallyshort-termfeverorheadache,similartoothervaccines

•  Noserioussideeffectshavebeenreportedcausedbythevaccineforkidsoradults

Doesitwork?

• Willitworkforme?

• Willitworkformychild?

HPVvaccinationworksREALLYWELLforkids….....Butlesswellafterage18

0

1

2

3

4

5

6

7

8

unvaccinated vaccinated<18 vaccinated18-20 vaccinated21-24

CIN3+risk

Castle,PrevMed,2018

Extremelylowriskofpre-cancerforkidsvaccinatedon

time

Notmuchcervicalpre-cancerwaspreventedbyvaccinationin27-45yearoldwomen

0

5

10

15

20

25

30

Perprotocol Intentiontotreat

Vaccine

PlaceboLowerriskinwomenwithoutanyinfection

Nochangeforwomenwithinfectionbeforevaccination(mostpeople)

CastellagueetalBrJCancer,2011

Whoismostlikelytobenefit?

1)  Kids2)  Adultswhose

HPVriskapproximatesthoseof11-12yearolds

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Shouldyouvaccinatethewholefamily?KidsshouldallbeVaccinated.Clearevidenceofbenefit.Vaccineissafe.

Momanddadcanbevaccinated.PossiblebenefitbypreventingHPVtypestheydon’thavenowbutmaybeexposedtointhefuture.Vaccineissafe.

Willinsurancecovervaccinationforages27-45?

q ItisprobablyNOTcoveredrightnowq CoveragewilldependonACIPvoteq IfCategoryBrecommendation(individualdecision-making),ACAmandatesinsurancecoverage,thoughsomeissuescanpersist

Insummary•  VaccinationofkidsisMOSTIMPORTANTandwillpreventmanycancers– Clearevidenceofpreventionofpre-cancersandcancers

•  VaccinationofadultsisanINDIVIDUALDECISION– Limitedevidenceofbenefit,butminimalrisk

– Alladultwomenshouldcontinuecervicalcancerscreening

Otherquestions?