Global Guidance For Cervical Cancer Prevention and Control...

transcript

GlobalGuidanceFor

CervicalCancerPreventionandControl

October2009

TableofContents

1. Overview:FIGOComprehensiveGuidance

2. CervicalCancerControl:RightsandEthics

JoannaCain,MD,WomenandInfantsHospital,BrownUniversity

CarlaChibwesha,MDMSc.UniversityofAlabamaatBirmingham,Center

forInfectiousDiseaseResearchofZambia(CIDRZ)

3. AComprehensiveApproachtoCervicalCancer:ImprovingImpactToday

SarahGoltzShelbaya,MPH,MIA

DebbieSaslow,PhD,AmericanCancerSociety

4. Overview:PrimaryPrevention

5. HPVVaccines:Characteristics,TargetPopulationandSafety

MarthaJacob,MBBS,FRCOG,MPH,PATH

6. Vaccine:PresentDeliveryStrategiesandResults

ScottWittet,MA,PATH

SuzanneGarland,MD,UniversityofMelbourne

7. Overview:EarlyScreeningandTreatment

8. TheSingleVisitApproach

NeerjaBhatla,MBBS,MD,FICOG,AllIndiaInstituteofMedicalSciences

9. VisualInspectionwithAceticAcid(VIA)

NeerjaBhatla,MBBS,MD,FICOG,AllIndiaInstituteofMedicalSciences

EnriquitoLu,MD,Jhpiego

10. EarlyDiagnosisofCervicalNeoplasia:PapTest(Cytology)

NahidaChakhtoura,MD,UniversityofMiamiMillerSchoolofMedicine

11. HPVTesting:anAdjuvanttoCytology‐basedScreeningandasaPrimary

ScreeningTest

JoseJeronimo,MD,PATH

12. Colposcopy

HextanY.S.Ngan,MBBS,MD,FRCOG,UniversityofHongKong

13. Cryotherapy

JohnSellors,MD,McMasterUniversity,Canada

14. LEEP/CervicalCone

KatinaRobison,MD,WomenandInfantsHospital,BrownUniversity

15. Overview:CervicalCancerTreatment

16. FIGOCancerCommitteeGuidelinesforEarlyInvasiveCervicalCancer

Management

HextanY.S.Ngan,MBBS,MD,FRCOG,UniversityofHongKong

Overview:FIGOComprehensiveGuidance

TheInternationalFederationofGynecologyandObstetrics(FIGO)offersthisguidanceasafocusedupdateoncervicalcancerprevention,screeningandtreatmentstrategies.ItisintendedtobecomplimentarytotheWorldHealthOrganization2006“ComprehensiveCervicalCancerControl:AGuidetoEssentialPractice”1andbridgethegapwithemergingdatanowavailableuntilthenextedition,expectedoutin2011.ItalsotakesdirectionfromtheAmericanCollegeofObstetricsandGynecology(ACOG)andSocietyofObstetriciansandGynecologistsofCanada(SOGC)intheseareas.

Theinformationprovidedisrelevanttoallsettings,withanemphasisonlow‐resourcesettingswherethediseasecontinuestobethelargestcauseofcancerdeathamongwomen.Itisintendedtoprovideguidancetocliniciansandpolicymakersandinformcurrentandfutureplanningtopreventandcontrolcervicalcancer.

Theauthorsofthisguidanceforcervicalcancercontrolseektobringtogetherthemostuptodateknowledgeaboutoptionsthatwillprovideapproachesfordiversesettings,thatwillalsoencourageculturalsensitivity,resultinginnotonlycontrolofcervicalcancerbutimprovementinassuringtherightsandhealthofwomenglobally.

Oursincerethankstothemanycontributors,writers,editors,reviewersandmostofall–theresearchers,cliniciansandwomen’shealthadvocateswhoaremakingthecontrolofthisdiseasepossible.

1 World Health Organization. Comprehensive cervical cancer control: A guide to essential practice. 2006. Available at: http://www.rho.org/files/WHO_CC_control_2006.pdf

Authors

NeerjaBhatla,MBBS,MD,FICOG

JoannaCain,MD

NahidaChakhtoura,MD

CarlaChibwesha,MD,MSc.

SuzanneGarland,MD

MarthaJacob,MBBS,FRCOG,MPH

JoseJeronimo,MD

EnriquitoLu,MD

HextanY.S.Ngan,MBBS,MD,FRCOG

KatinaRobison,MD

DebbieSaslow,PhD

JohnSellors,MD

ScottWittet,MA

Editors

JoannaCain,MD

Reviewers

PaulBlumenthal,MD

LynetteDenny,MD

EnriquitoLu,MD

SuzanneGarland,MD

CarlaChibwesha,MD,MSc.

AishaJumaan,PhD,MPH

DebbieSaslow,PhD

FIGOExecutiveBoardMembers

FIGOCervicalCancerWorkingGroup

JoannaCain,MD

LynetteDenny,MD

SuzanneGarland,MD

HenryKitchener,MD

ConnieTrimble,MD

ThomasWright,MD

Sponsorship

ThisguidancewasfundedbyFIGO.FIGOreceivesunrestrictededucationalgrantsfromPATH,QIAGEN,GlaxoSmithKlineBiologicalsandMerckandCo.Inc.tosupportthisandothercervicalcancereducationactivities.

ConflictofInterestStatementbyAuthors

NeerjaBhatla,MBBS,MD,FICOG–Noconflictofinterest

JoannaCain,MD–Noconflictofinterest

NahidaChakhtoura,MD–Noconflictofinterest

CarlaChibwesha,MD,MSc.–Noconflictofinterest

MarthaJacob,MBBS,FRCOG,MPH–Noconflictofinterest

JoseJeronimo,MD–Noconflictofinterest

EnriquitoLu,MD–Noconflictofinterest

KatinaRobison,MD–Noconflictofinterest

DebbieSaslow,PhD–Noconflictofinterest

JohnSellors,MD–Noconflictofinterest

ScottWittet,MA–Noconflictofinterest

SuzanneGarland,MD–Receivedadvisoryboardfeesandgrantsupportfrom

CommonwealthSerumLaboratoriesandGlaxoSmithKline,lecturefeesfromMerckand

GlaxoSmithKline.Institutionalresearchsupporthasbeenprovidedbybothvaccine

manufacturers.

SarahGoltzShelbaya,MPH,MIA‐ConsultantforGlaxoSmithKlineBiologicalsin2006

andQIAGENin20072008.Notpresentlyconsultingwithanycompanies.

HextanY.S.Ngan,MBBS,MD,FRCOG‐Nodirectconflictwithsectionswritten.

AdvisortoMerckandGlaxoSmithKlineforvaccines.Spokeatconferenceorganisedby

CervicalCancerControl:RightsandEthics

JoannaCain,MD,andCarlaChibwesha,MD

Inthisdecade,theexpandingknowledgeofhumanpapillomavirus(HPV)anditsrelationshiptocervicalcancerhasledtonewtoolsforprimarypreventionwithHPVvaccinesandnewscreeningstrategiesthatgivecliniciansoptionsforeveryresourcesetting.Theabilitytosubstantiallyreducethemorethanonehalfmillionwomenperyearthatarediagnosedwithcervicalcancer,andmoreimportantlytheabilitytoreducethequarterofamillionwomenperyearthatdieofthedisease‐particularlyinunderresourcedareasofdevelopinganddevelopedcountries‐isnowinthehandsofwomen’shealthprofessionalsandgovernments.ThereisnolongeranyjustificationforNOTaddressingthehumanrightsdeniedtowomenwithcervicalcancerdiagnoses‐therighttothehighestattainablestandardofhealthcareandtherighttoqualityoflife.Controllingcancernotonlypreventsdeathanddisabilitybutalsowillcreateimprovementinthehealthandwellbeingoffamiliesbypreservingtheeconomicandparentalsupportofwomen,children,families,andcommunities.

Stateofthescience:rightsandethics

FifteenyearsagokeystakeholdersinthehumanrightsanddevelopmentmovementsconvergedinCairoforthelandmarkInternationalConferenceonPopulationandDevelopment(ICPD).Sexualandreproductivehealthwasembracedasabasichumanright,aswellasbeingcriticaltoeconomicandsocialdevelopmentforallcountries.1,2Assuch,educators,politicians,andhumanrightsandlegaladvocacygroupsplayaroleaspivotalastheroleofhealthprofessionalsinthepreventionandtreatmentofcervicalcancer.Protectinghealthandensuringaccesstohealthcareistheresponsibilityofallsocieties.Ifwomenaredeniedaccesstohealtheducation,qualityevidence‐basedhealthcare,andautonomousdecisionmakingaboutthewayinwhichtheyaccessthatcare,theirrightsareviolated.

Contemporarymedicalethicsprovidesadditionalguidanceforhealthpractitioners.Theprinciplesofbeneficence,nonmaleficence,autonomy,andjusticeformthecornerstoneofthisethicalframework.Beneficencerelatestoaprovider’sobligationtoprotectpatients’interestsaboveallelse.Theprincipalofnonmaleficenceremindsustoavoidpracticesthatmaybeharmful.Furthermore,providersareobligatedtorespectthoseforwhomtheycareasautonomousindividuals.This,inturn,impliesthatpatientsbefullyeducatedabouthealthanddisease,andwhenill,thattheirtreatmentoptionsrepresentcurrentevidence‐basedstandards.Finally,theprincipalofjusticedictatesthatwomenaretreatedfairly;inparticularthattheybenefitequallyfromscientificadvancesregardlessoftheirsocioeconomicstandingortheirracial,ethnic,cultural,orreligiousbackground.3Table1highlightsexamplesoftheseprincipalsastheyrelatetocervicalcancerpreventionandtreatment.

Barrierstoapplicationandgapsinknowledge

Althoughdiscoursesurroundingwomen’shealthhasbeenre‐framedtoreflectacontemporaryhumanrightsparadigm,actionslagfarbehind.4Tragically,thecaseofcervicalcancerisnotunlikeotherpreventableillnessesforwhichthegreatestdiseaseburdenfallsonthepoorandthosewithlimitedaccesstohealthcare.

Thebarrierstopreventionandtreatmentincludeabroadlackofawarenessofcervicalcancerandtheconsequentburdensofbleeding,bowelandbladderdysfunction,fistulas,andpainandsufferingthatresultfromadvanceddisease.Thislackofawarenessisfurthercomplicatedbyculturalsensitivitiesthatpreventdiscussionofuniquelywomen’scancersandthesexualtransmissionofHPV.Theabsenceofcancerregistriesanddatainmanydevelopingcountriesperpetuatesthisgapandinhibitsthepositiveinfluencethat“demonstratingimprovementsinpublichealthcanhavetoenhancethesupportofanddemandforhealthservices.”5

Otherbarrierscomefromlimitedresources.Sometimesthebarrierisresistancetolowerlevelprovidersprovidingservicesandalackofacceptanceofpracticaltechnologiesforscreeningwheretechnologysuchascytologyisnotfeasible.Treatmentoptionsmustbetailoredtotheavailabilityofhealthcarefunding,trainedpersonnel,healthinfrastructureandportabilityoftechnology,aswellastotheaccessibilityofpopulationsinneed.Barrierstoprimarypreventionthroughvaccination,andsecondarypreventionthroughscreeningandtreatmentofprecancerouslesions,arenotdissimilar.Competinghealthcareneedsmayalsocontributetounder‐prioritizationofcervicalcancercontrol.Moreover,thefactthatwomenwithpre‐invasivediseasearetypicallysymptom‐freemayresultindelayedpresentationtocare,particularlyinregionsoftheworldwherecervicalcancerscreeninghasyettobeestablished.6

Finally,humanrightsviolationsincludingpooreducation,lackoffreedomofmovement,andgenderdiscriminationinaccesstohealthcareimpactthesuccessofinitiativestoaddressthisnowmostlypreventabledisease:“Acentralelementthatcharacterizesinequityisthattheconditionsinvolvedareavoidable.”7

Recommendations

Achievingsuccessfulcervicalcancercontrolrequiresthatallofthesebarriers,andthosethatareuniquetoeachculture,beaddressed.“Embracingculturalrealitiescanrevealthemosteffectivewaystochallengeharmfulculturalpracticesandstrengthenpositiveones.”8Onlybycombiningabundleofoptionstargetedtotheuniqueneedsofeachregionorcountryandtailoredtothelocalculturewilltherebeprogressincontrollingcervicalcancer.

Women’shealthprofessionalsmustplayanintegralroleinthisadvocacy.Indeed,theobstetrician‐gynaecologisthasanethicalandsocialresponsibilitytodevelopanddisseminatecost‐effective,evidence‐basedcervicalcancerpreventionand

treatmentmodalitiesthatremainlocallyrelevant.Additionally,wearechargedwiththetaskofengagingotherhealthprofessionals,healthadvocates,policymakers,andpoliticalleadersinthisglobalefforttocontrolcervicalcancer.

Table1.

EthicalPrincipal Example

Beneficence Ensure that interventions meet the goal of medicine ‐ toprevent cervical cancer, treat the disease, and alleviatesuffering–andareaccessibletoallwomen.

Nonmaleficence Discuss HPV and the sexual nature of the infectionsensitively. Incomplete information may result in undueanxiety for patients, or worse, put them in danger ofphysicalviolenceorretaliationfromanabusivepartner.

Autonomy Educate women about their health. Seek and respect thechoicesthatwomenwithpre‐invasiveandinvasivediseaseofthecervixmakeabouttheirtreatmentoptions.SeeFIGOethicsguidelines(http://www.figo.org/about/guidelines).

Justice Ensure equitable access to bothpreventive strategies andcancer therapies,aswellaspalliativecare.Guaranteethatscientificgainsareaccessibletoall.

References

1CookRJ,DickensBM,FathallaMF.Reproductivehealthandhumanrights:Integratingmedicine,ethicsandlaw.Oxford:OxfordUniversityPress;2003.p.8‐14.

2CainJM,NganH,GarlandS,WrightT.Controlofcervicalcancer:Women’soptionsandrights.IntJGynaecolObstet2009;106(2):141‐43.

3OgwuegbuCC,EzeOH.Ethicalandsocialissuesfacingobstetriciansinlow‐incomescountries.ClinObstetGynecol2009;52(2):237‐249.

4ObaidTA.FifteenyearsaftertheInternationalConferenceonPopulationandDevelopment:Whathaveweachievedandhowdowemoveforward?IntJGynaecolObstet2009;106(2):102‐105.

5GrahamWJ,HusseinJ.Ethicsinpublichealthresearch:Mindingthegaps:Areassessmentofthechallengestosafemotherhood.AmJPublicHealth2007June;97(6):978‐83.

6PollackAE,BalkinMS,DennyL.Cervicalcancer:Acallforpoliticalwill.IntJGynaecolObstet2006;94(3):333‐342.

7TsuVD,LevinCE.Makingthecaseforcervicalcancerprevention:Whataboutequity?ReprodHealthMatters2008Nov:16(32):104‐12.

8MayorS.Consideringcultureprovidesa“window”thatcanhelpmakehumanrightsprojectsasuccess.BMJ2008Nov;337:a2508.

AComprehensiveApproachtoCervicalCancer:ImprovingImpactTodaySarahGoltzShelbaya,MPH,MIA,andDebbieSaslow,PhD

Thisguidanceprovidesevidence‐basedrecommendationsforphysiciansandpolicymakerstodevelopacomprehensivecervicalcancerprogrammeforaclinic,acommunityoracountry.Asclinicians,policymakers,andadvocates,wemustlooktothecurrenttools,resourcesandknowledgetodevelopthespecificbundleofservicesthatisappropriateforeachsetting.

Whyacomprehensiveapproach?Decadesofexperience,refinedbyrecentresearchandenhancedbynewdiscoveries,provideanewpictureofthenecessaryelementstoimpactcervicalcancer.Evidenceshowsthatonlyacomprehensiveapproach,whicheffectivelyembracesdiversetoolsthatmeettheneedsofdistinctpopulationsandenvironmentsandexpandsaccesstocancerpreventionandcarewithinthehealthsystem,willhaveasignificantandsustainableimpactonthisdisease.Thisapproachembracesbothanexpandedandimproved“bundleofservices”andgreaterfocusontheelementsofthepublichealthsystemnecessarytoprevent,treatandmonitordisease.

Implementingcervicalcancerpreventionandcontrolprogrammesisfarfromsimple.Educationwithoutscreeningandtreatmentwillraisehopesamongwomenthatwesimplydonothavethemeanstosupport.Screeningwithouttreatmentwouldunethicallyfinddiseaseweareunabletotreat.Preventivevaccinationwithoutscreeningwillimpacttheyoungestgenerationwhilefailingtoprovideforwomenalreadyatriskforthedisease.Assuch,preciousresources—women’strust,providertime,clinicinfrastructure,andfinancialresources—shouldbeusedtowardmaximizingtheimpactonthelivesofindividualwomen,theirfamiliesandcommunities.

Evidenceshowsthatregardlessofresources,healthsystemorgeography,allcost‐effectivecomprehensivecervicalcancerprogrammesshouldincludesomeformulationofthefollowingelements:

• Educatedchoicebywomenandgirlsaboutdiseasepreventionandcare

• Ethicalandinformedengagementbyproviders

• Primaryprevention,throughsafe,affordableandaccessiblevaccination

• Secondaryprevention,earlydiagnosis,andearlytreatmentatthemostappropriatepointofcare

• Healthplanningandsystemsupportthataimsforthegreatestpublichealthimpactandstrengthensthenationalcervicalcancerpreventionsystem

includingactiveoutreachtoeligiblewomenforscreeningandgirlsforvaccination,effectivemonitoringsystemsthathavehighcoverageandpreventlosstofollowup,andstrongreferralandmonitoringsystemstoensurethatcancercasesarehandledanddocumentedappropriately.

• Diseasemanagement,palliativecare,andendoflifecare

• Afunctioningnationalcancerregistrytomonitorprogrammeprogressandmeasureimpactagainstnationalprogramcosts

Asevidencedinthisguidance,currentresearchhasconfirmedthatthereisgreatvariationintoolsandstrategiesthatareappropriateandcost‐effectiveindifferentsettings.Nooneapproachwillprovidethesolution.Thebundleofservicesthatdefineacomprehensiveapproachwilllikelyvarynotonlybetweencountries,butalsowithincountries.Yet,allelementsareessentialinordertoachievethegreatestpublichealthimpact.

Theopportunitiesfornewandmoreeffectivecombinationsofstrategiesforprevention,detectionandtreatmentaremany.HPVtestingfollowedbyvisualinspectionmethodsfortest‐positivewomencouldbeusedtocoveragreaternumberofwomenandfocushealthworkertimeonwomenatrisk.AsHPVvaccinesbecomeincreasinglyaffordableandavailable,vaccinatingyounggirlscanrelievepressureonscreeningsystems,sincevaccinatedwomenarelikelytoneedtobescreenedlaterandlessoftenthanunvaccinatedwomen.Therewillneedtobeintegrationof,andlinkstootherservices,includingadolescentvaccinationprogrammes,schoolclinics,familyplanningandreproductivehealthservicesforwomen.

Thisguidancereviewscurrenttoolsandapproachesforcervicalcancerpreventionandtreatmentinlightofseveralkeycharacteristicstoguidedecisionmaking.

Medical

• Relevanceorcontraindicationsforspecificpopulationsorages• Potentialtoengagemid‐levelserviceprovidersindelivery• Opportunitytomaximizepatientvisitandreducelosstofollowup

Physical

• Patientaccessissues• Clinicinfrastructurerequirements• Healthsystemdemands(referral,treatment,palliativecare)

Training

• Levelofprovidertrainingrequired• Qualityassurancemechanisms• Patienteducation/communitymobilizationneeded

• Initialandrecurringcostsassociatedwithmaterialsanddelivery• Providertime• Patienttime• Cost‐effectivenessofapproachspecifictotargetedpopulations

Educational • Keyinformationthateverywomanshouldknowtomakeaninformedchoiceabouthercare

• Appropriatedecisionmakingaroundintegrationwithothertools

Policy

• Necessarysupportivenational,regionalandinternationalpoliciesfocusedontaskshiftingandequitableaccesstotreatmentandcare

• Publicfinancialcommitmentrequired• Nationalandregionalinvestmentintreatmentfacilities,cancerregistries

FIGObelievesthatweareataturningpointinthefightagainstcervicalcancer.Atnotimebeforehavewehadthetoolsandknowledgeorevencapacitytochangethecourseofthiscancer—especiallyamongthemostunderservedwomen.Aseffortsadvance,drivenbyourownvisionandthatofourpartners(otherclinicians,publichealthleadersandchampions,suchastheWorldHealthOrganization,InternationalPediatricAssociation,andothers),FIGOhopesthattheinformationhereinwillprovidetheevidence,guidanceandinspirationforagreater,moreeffectiveandfinalassaultoncervicalcancer.

Overview:PrimaryPrevention

ThefocusinthissectionisontheunparalleledopportunitytopreventcervicalcancerthroughimmunitytoHPVinfection.HPVvaccineprogramsalsoprovideanimportantspringboardtoincreasesupportforcervicalcancerpreventionamongparents,educatorsandcommunityleadersandreachadolescentgirlswithimportanthealthinformation.Strategiestodelivervaccinestobroadpopulationsofgirlswillrequirenewcollaborationsbetweenchildhealth,schoolhealth,cancerandreproductivehealthprogrammesandclinicians.

HPVVaccines:Characteristics,TargetPopulationandSafety

Background

Cancerofthecervixcanbepreventedintwoways:(1)preventinginitialHPVinfectionthroughvaccinationand(2)screeningforprecancerouslesionsandprovidingearlytreatmenttopreventprogressiontocancer.Acomprehensivediseasecontrolinitiative—acombinationofimprovedscreeningandtreatmentwitheffectiveHPVvaccination—hasthebestpotentialtosignificantlyreducetheburdenofcancerofthecervixrelativelysoon.

TwovaccineshavebeendevelopedtopreventinfectionwithHPV‐16and‐18.BothvaccinesuserecombinanttechnologyandarepreparedfrompurifiedL1capsidproteinsthatreassembletoformHPVtype‐specificvirus‐likeparticles(VLP).Bothvaccinesarenon‐infectious,astheydonotcontainlivebiologicalproductsorviralDNA.Neithervaccinecontainsthimerosalorantibiotics.Bothvaccinesactbyinducinghumoralandcellularimmunity.TheyaredesignedforprophylacticuseonlyanddonotclearexistingHPVinfectionortreatHPV‐relateddiseases.

CharacteristicsofthetwoHPVvaccines

Quadrivalentvaccine Bivalentvaccine

Manufacturer(tradename)

Merck(Gardasil®alsomarketedasSilgard®)

GlaxoSmithKline(Cervarix™)

VLPsofHPVgenotypes

6,11,16,and18 16and18

Substrate Yeast(S.cerevisiae) Baculovirusexpressionsystem

Adjuvant Proprietaryaluminiumhydroxyphosphatesulphate,225µg(Merckaluminiumadjuvant)

Proprietaryaluminiumhydroxide,500µg,plus50µg3‐deacylatedmonophosphoryllipidA(GSKAS04adjuvant)

Scheduleusedintrials‐threedoseswithintervalsof:

Twomonthsbetweendoses1and2;sixmonthsbetweendoses1and3

(0,2,6schedule)

Onemonthbetweendoses1and2;sixmonthsbetweendoses1and3

(0,1,6schedule)

Storage&Transport

Requiresacoldchainsystem,storedandtransportedat20Cto80C

Shouldnotbefrozen

Requiresacoldchainsystem,storedandtransportedat20Cto80C

Shouldnotbefrozen

ApprovedlicensesasofFeb2009andWHOprequalification

Licensedin109countries

WHOprequalified

Licensedin92countries

WHOprequalified

Immunogenicity

Resultsfromseveralinternational,randomizedcontrolledstudieswithfollowupforoverfiveyearshaveshownthatnearlyalladolescentandyoungfemaleparticipantsinthestudieswhowerenaïvetovaccine‐relatedHPVtypes16and18developedtype‐specificantibodyresponsestotheseantigensafterthreedoses.Antibodyresponsepeaksafterthethirddose,declinesgradually,andlevelsoffby24months.Antibodylevelsweremorethantenfoldhigherthanfollowingnaturalinfection.BothvaccineshavebeenshowntoinduceimmunememoryresponsethroughhigherfrequencyofmemoryBcells.1,2Bothvaccinesinducehigherantibodylevelsinfemaleslessthan15yearsofage.3,4Theminimumnecessarylevelofantibodyresponsetoensureprotectionagainstinfection(correlateofprotection)isnotyetknown,asefficacyhasbeensohighthatnobreakthroughdiseasehasoccurredtodate.

VaccineefficacyagainstpersistentinfectionandprecancerouslesionssuchasCIN2/3oradenocarcinomainsituhasbeenwidelyacceptedasasurrogatemarkerforprotectionagainstcancer.Thisisnecessaryascervicalcancerdevelopsslowlyanditwouldrequireverylarge,long‐termtrials(30+years)todemonstrateimpactagainstinvasivedisease.Inaddition,itwouldbeunethicaltosimplyobservewomenwithprecancerouslesionswhensuchlesionscanbeeffectivelytreated.Bothvaccineshaveshownmorethan90%efficacytopreventprecancerouslesionsinfemalesnaïvetovaccine‐specificHPVtypesandwhohavecompletedallthreedoses.5Recentdataindicatesustainedefficacyandimmunogenicityofthebivalentvaccineupto6.4years.6

RecentlypublishedstudiesreportthatHPVvaccinesalsoinduceantibodyresponsetoandpartialefficacy(around50%)againstHPVtypes31and/or45.ThesetypesarephylogeneticallysimilartoHPV‐16and‐18.7,8

Ageatvaccination

EvidencefromclinicalstudiessupportstheadministrationofcurrentlyavailableprophylacticHPVvaccinestoyoungadolescentgirlsbetweentheagesof9or10and13yearspriortoinitiationofsexualactivity.Antibodyresponseishighinthisagegroupandvaccineefficacyishighestinthosewhoarenaïvetovaccine‐specificoncogenicHPVtypes.HencethegreatestimpactofHPVvaccinationoncervicalcancerwillbethroughbroadparticipationofyoungadolescentgirlsratherthanoldergirlsorwomen.HPVcatch‐upvaccinationinoldergirlsorwomencanpreventdiseaseduetoHPVvaccinetype‐specificinfectioninwomenwhoarenotalreadyinfectedwiththeseHPVtypes.However,modellingstudiessuggestdiminishingprotectionwhenageofvaccinationisincreased.

HPVVaccinationinmales

Studiesshowthatbothvaccinesareasimmunogenicandsafeinyoungadolescentmalesastheyareinadolescentfemales.Modellingstudiesindicatethatincludingboysinvaccinationprogrammes,evenifachievinghighlevelsofcoverage,conferredlittleaddedbenefitcomparedtovaccinatingonlygirlsandisnotcost‐effective.9,10,11TherearepresentlynostudiesindicatingthatHPVvaccinationofmaleswillresultinlesssexualtransmissionofvaccine‐specificHPVinfectionfrommalestofemalestherebyreducingcervicalcancer.

Safety

Extensiveclinicaltrials(prelicensuresafetydata)andpost‐marketingsurveillancecontinuetoshowthatbothHPVvaccineshavegoodsafetyprofiles,withsafetysimilartoothercommonlyadministeredvaccines.5,12,13,14

Themostcommonadverseeventreportedisinjectionsitepain,swellingandorerythema.Otherreportedsystemicadverseeventswerefever,nauseaanddizziness,andfatigue,headacheandmyalgia.SyncopeorfaintingwasreportedmorefollowingHPVvaccinationcomparedtoothervaccinesgiventoteenagersandyoungwomen.Faintingafterinjectionismorecommonamongteensthanamongyoungchildrenoradultsandseemstoberelatedmoretotheinjectionprocessratherthanasideeffectofthevaccine.Inordertopreventinjuriesduetofallsduringfaintingepisodesitisrecommendedthatallvaccinatedgirlsrestandbeobservedfor15minutesfollowingHPVvaccinationaswithothervaccines.

Reportedanaphylaxisrateswerelow(2.6/100,000doses)similartoothervaccines.5Seriousadverseeventsrequiringhospitalizationorcausingdisabilityorothermedicallyimportantconditionshavebeenreportedtobearoundthreeeventsper100,000individualsvaccinated.9Nocausallinkshavebeendemonstrated

betweenHPVvaccinationandreportsofGuillain‐Barresyndrome,autoimmunediseases,ortoanyofthedeathsthatfollowedtheadministrationoftheHPVvaccine.

Cost/efficacyanalysis

Modellingstudiesconsistentlyshowthatindevelopedcountriesvaccinatingadolescentgirlsiscosteffectiveandthemainbenefitisfrompreventingmortalityfromcervicalcancer.Durationofvaccineefficacyisshowntobethemostimportantfactorincosteffectiveness.12ModellingstudiesforGAVI‐eligiblecountriesshowthatvaccinesagainstHPV‐16and‐18canbecosteffectiveinreducingcervicalprecancersandcancersandthatHPVvaccinecanreducelifetimeriskofcancerby40‐50%.15Factorsaffectingabsolutereductionarecervicalcancerincidence,populationagestructureandvaccinationcoverage(70%).ForGAVI‐eligiblecountries,thesemodelssuggestthatHPVvaccinationwouldbeverycost‐effectiveat$2.00/doseor$10perfullyvaccinatedgirl,includingprogrammecosts.

Gapsinknowledgeandfurtherareasofresearchneeded

1. GiventheknownprogressionofdiseasefromCIN2/3toinvasivecancer,protectionfromCIN2/3bybothvaccineswillpreventcervicalcancer.Long‐termstudies(suchasthosecurrentlyunderwayinScandinaviancountries)willdemonstratethelong‐termimpactofthesevaccines.

2. Theneedforaboosterdosetoensurelong‐termprotectionisunknown,withnoindicationofreducedperformanceateightyears.

3. FurtherstudyofimmuneresponsetocurrentlyavailablevaccinesinHIV‐infectedandimmunocompromisedindividualswouldbehelpful.

4. ThereislackofdatademonstratingthatHPVvaccinationofmaleswillresultinlesssexualtransmissionofvaccine‐specificHPVinfectionfrommalestofemales,therebyreducingcervicalcancer.

5. Dataonco‐administrationwithrubellavaccineandothervaccinationsforadolescentsandolderchildrenisbeingassessedandhasthepotentialtoexpandcurrentdeliverystrategies.

6. Theefficacyofalternativedosingschedulesandreducednumberofdosesforbothvaccinesisneeded.

7. DataareawaitedonoptimalHPVvaccinedeliverystrategiesindifferentsettings.

8. Theimpactofvaccinationoncervicalcancerscreeningbehaviourrequiresfurtherstudy.

Integrationwith/orreplacementofotherpreventionapproaches

Cervicalcancerscreeningandtreatmentforprecancershouldcontinueaspernationalguidelinesatpresent,asthecurrentlyavailablevaccinepreventsinfection

causedprimarilybytwooftheoncogenicHPVtypes(HPV‐16andHPV‐18),potentiallymissingupto30%ofcancerscausedbyotheroncogenicserotypes.Furthermore,thecurrentlyavailableprophylacticvaccinesarenoteffectiveforwomenpreviouslyinfected.

Considerationforspecialpopulations:HIVpositive,pregnantwomen

HPVvaccinationisnotrecommendedinpregnancythoughadverseeventshavenotbeenreportedinthemotherorthefoetusforeitherofthetwovaccinesinwomenwhowereinadvertentlyadministeredthevaccine.IftheHPVvaccinehasbeeninadvertentlyadministeredduringpregnancy,furtherdosesshouldbedelayeduntilafterthepregnancy.

ThereiscurrentlyverylittledataontheantibodyresponseandefficacyofHPVvaccinesinHIV‐infectedandinimmunocompromisedindividuals.

Keypoints:

1. BothvaccinesareprophylacticvaccinespreventingHPV‐16and‐18primaryinfections.TheydonotclearexistingHPVinfectionortreatHPV‐relateddiseases.

2. CurrentevidencesupportsHPVvaccinationofyoungadolescentgirls(9or10through13yearsofage)priortoonsetofsexualdebuttopreventcervicalcancerinlaterlife.

3. BothvaccinesinducehighserumneutralizingantibodylevelsagainstHPV16and18inmorethan99%offemaleswhoarenaïvetospecificHPVtypes.Neutralizingantibodiescorrelatewithvaccineefficacy.

4. EfficacyagainstsurrogatemarkerssuchaspersistentHPVtype‐specificinfectionandprecancerlesionssuchasCIN2orhigherismorethan90%forbothvaccines.

5. Bothvaccinescontinuetoshowgoodsafetyprofilessimilartoothercommonlyadministeredvaccines.Mostcommonstatisticallysignificantadverseeventsreportedforbothvaccinesareinjectionsitepain,swellingorerythema.

6. Severalregulatorybodiesgloballyhavereviewedthesafetyandefficacydataforbothvaccinesandapprovedtheuseofthevaccinesinover100countries.

References1GianniniSL,HanonE,MorisP,VanMechelenM,MorelS,DessyF,etal.EnhancedhumoralandmemoryBcellularimmunityusingHPV16/18L1VLPvaccineformulatedwiththeMPL/aluminiumsaltcombination(ASO4)comparedtoaluminiumsaltonly.Vaccine2006Aug;24(33‐34):5937‐5949.

2OlssonSE,VillaLL,CostaRL,PettaCA,AndradeRP,MalmC,etal.Inductionofimmunememoryfollowingadministrationofaprophylacticquadrivalenthumanpapillomavirus(HPV)types6/11/16/18L1virus‐likeparticle(VLP)vaccine.Vaccine2007Jun21;25(26):4931‐9.

3PedersenC,PetajaT,StraussG,RumkeHC,PoderA,RichardusJH,etal.Immunizationofearlyadolescentfemaleswithhumanpapillomavirustype16and18L1virus‐likeparticlecontainingASO4adjuvant.JAdolescHealth2007Jun;40(6):564‐571.

4GiulianoAR,Lazcano‐PonceE,VillaL,NolanT,MarchantC,RadleyD,etal.Impactofbaselinecovariatesontheimmunogenicityofaquadrivalent(types6,11,16and18)humanpapillomavirusvirus‐like‐particlevaccine.JInfectDis2007Oct;196(8):1153‐62.

5 WorldHealthOrganization.WeeklyEpidemiologicalRecord(WER).2009Apr;84(15):117‐32.Availableat:http://www.who.int/wer/2009/wer8415/en/index.html 6 RomanowskiB,etal.SustainedefficacyandimmunogenicityoftheHPV‐16/18AS04‐adjuvantedvaccine:Analysisofarandomisedplacebo‐controlledtrialupto6.4years.Lancet2009(inpublication). 7BrownDR,KjaerSK,SigurdssonK,IversenOE,Hernandez‐AvilaM,WheelerCM,etal.Theimpactofquadrivalenthumanpapillomavirus(HPV;types6,11,16,and18)L1virus‐likeparticlevaccineoninfectionanddiseaseduetooncogenicnonvaccineHPVtypesingenerallyHPV‐naïvewomenaged16‐26years.JInfectDis2009Apr;199(7):926‐35.

8PaavonenJ,NaudP,SalmerónJ,WheelerCM,ChowSN,ApterD,etal.Efficacyofhumanpapillomavirus(HPV)‐16/18AS04‐adjuvantedvaccineagainstcervicalinfectionandprecancercausedbyoncogenicHPVtypes(PATRICIA):Finalanalysis

ofadouble‐blind,randomisedstudyinyoungwomen.Lancet2009Jul;374(9686):301‐14.

9KimJJ,Andres‐BeckB,GoldieSJ.ThevalueofincludingboysinanHPVvaccinationprogram:Acost–effectivenessanalysisinalow‐resourcesetting.BrJCancer2007Nov;97(9):1322‐8.

10KulasinghamS,ConnellyLB,ConwayE,HockingJ,MeyersE,ReganD,etal.Acost‐effectivenessanalysisofaddingahumanpapillomavirusvaccinetotheAustralianNationalCervicalCancerScreeningProgram.SexHealth2007Sept;4(3):165‐75.

11SladeBA,LeidelL,VellozziC,WooEJ,HuaW,SutherlandA,etal.Postlicensuresafetysurveillanceforquadrivalenthumanpapillomavirusrecombinantvaccine.JAMA2009Aug;302(7):750‐57.

12BrissonM,VandeVeldeN,BoilyMC,Economicevaluationofhumanpapillomavirusvaccinationindevelopedcountries.PublicHealthGenomics2009;12(5‐6):343‐351.

13 PaavonenJ,NaudP,SalmerónJ,WheelerCM,ChowSN,ApterD,etal.Efficacyofhumanpapillomavirus(HPV)‐16/18AS04‐adjuvantedvaccineagainstcervicalinfectionandprecancercausedbyoncogenicHPVtypes(PATRICIA):Finalanalysisofadouble‐blind,randomisedstudyinyoungwomen.Lancet.2009Jul;374(9686):301‐14. 14KahnJ.HPVvaccinationforthepreventionofcervicalintraepithelialneoplasia.NEnglJMed2009Jul;361(3):271‐8.

15GoldieSJ,O’SheaM,CamposNG,DiazM,SweetS,KimSY.HealthandeconomicoutcomesofHPV16,18vaccinationin72GAVI‐eligiblecountries.Vaccine2008Jul;26(32):4080‐93.

Vaccine:PresentDeliveryStrategiesandResults

ScottWittet,MA,andSuzanneGarland,MD

StateofthescienceCurrently,therearetwoprophylacticHPVvaccines,oneofwhichisbivalentandtheotherquadrivalent.Bothhavebeenrecentlylicensedinover100countries.Registrationofthesevaccineshasbeenbasedonimmunogenicity,safetyandefficacy,asreportedinphase3trials.1,2,3Bothvaccinesarehighlyefficaciousinpreventinginfectionaswellasprecursorlesionstocervicalcancer(high‐gradedysplasia—cervicalintraepithelialneoplasias[CIN2/3+]—asurrogateforcervicalcancer),causedbygenotypes16and18.Worldwidethesemakeup70%ofcancers,and50%ofCIN2/3.

AccessLicensurehoweverdoesnotnecessarilytranslateintoHPVvaccineprovisionthroughpublicsectorprogrammes,especiallyinthedevelopingworldwhereHPVvaccineswillhavethegreatestimpact.TheWorldHealthOrganization(WHO)recommendsthatroutineHPVvaccinationbeincludedinnationalimmunizationprogrammeswhenpreventionofcervicalcancerorotherHPV‐relateddiseases,orboth,constitutesapublichealthpriority(inthatcountry);vaccineintroductionisprogrammaticallyfeasible;sustainablefinancingcanbesecured;andthecosteffectivenessofvaccinationstrategiesinthecountryorregionisconsidered.4

WealthiergovernmentsbyandlargehavealreadybegunprovidingHPVvaccinethroughpublichealthprogrammes.Forthelowest‐resourcecountries,procurementofvaccinewillbepossibleonlywithsubstantialfinancialsupport.TheGAVIAlliance,whichsubsidizesvaccinesforthe72poorestcountries,isconsideringincludingHPVvaccinesintheportfolioofvaccinesreceivingitssupport.5IfGAVIsupportbecomespossible,eligiblegovernmentswillbeabletoaccessHPVvaccinesatradicallylowerprices.Middle‐incomecountrygovernmentsalsoaregrapplingwiththechallengeofpayingforHPVvaccine.LatinAmericancountriesmaybenefitfromgrouppurchasingplanssuchasthePanAmericanHealthOrganization’s“RevolvingFund”forvaccines.Othercountrieswillneedtonegotiatelowerpricesbasedonthebulkpurchasingpoweroftheircountryalone.Overthepastyear,HPVvaccinepriceshavedroppedsignificantlyformiddle‐incomecountrygovernments—insomecasestheyarelessthanone‐thirdofthemarketpriceintheUnitedStatesandEurope.Inthecomingyears,thesepricesareexpectedtocontinuetodecline.Itishopedthat

HPVvaccinewillexperiencethesortofpricereductionsseenwithothernewvaccines.Iftheyenterapricerangeoflessthan$10adose,low‐andmiddle‐incomecountriesmaybeabletoaffordtovaccinatemost,ifnotall,vaccine‐agegirls.Age

Thetargetagefortheseprophylacticvaccinesisbeforesexualdebut.WHOstatesthat:

“HPVvaccinesaremostefficaciousinfemaleswhoarenaivetovaccine‐relatedHPVtypes;therefore,theprimarytargetpopulationshouldbeselectedbasedondataontheageofinitiationofsexualactivityandthefeasibilityofreachingyoungadolescentgirlsthroughschools,health‐carefacilitiesorcommunity‐basedsettings.Theprimarytargetpopulationislikelytobegirlswithintheagerangeof9or10yearsthrough13years.”4

Inaddition,theWHOpositionpaperonHPVvaccinationnotesthatextendingtheagetargettoolderadolescentoryoungwomenisrecommendedonly“ifitdoesnotdivertresourcesfromthisprimaryeffortorfromeffectivecervicalcancerscreening.”BecauseHPVvaccinesarenottherapeutic,theydonotbenefitwomenwhoareorhavebeeninfectedwiththevaccine‐relatedgenotypes.WhileanyindividualwomanmaybenefitfromHPVvaccination(sinceshemaynotalreadyhavebeeninfectedwithHPV16and/or18),duetothehighprevalenceofinfectioninmostcommunitiesandthecriticalneedtoconsidercost‐effectiveness,mostpublichealthprogrammesprioritizevaccinatinggirlsatyoungerages,wherethevaccineislikelytohavethegreatestimpact.Vaccinationofboysormengenerallyisconsideredtobelesscosteffectivebecausetheburdenofdiseaseismuchlessinmales(onlyabout7%ofcancerscausedbyHPV16/18occurinmen).6Furthermore,computermodellingsuggeststhatvaccinatingmentoreduceinfectioninwomenmaynotbeascosteffectiveasmaximizingimmunizationcoverageamonggirls.7

StrategiesforHPVvaccinedelivery

EventhepoorestcountriesintheworldhaveExpandedProgrammesonImmunization(EPIs),withwell‐developeddeliverysystemstargetinginfantsandyoungchildren.Hence,shouldHPVvaccinesonedaybelicensedforusewiththosegroups,itislikelythatthevaccinewouldbeintegratedintoexistingEPIprogrammes,ashasbeendoneoverthepastdecadewithhepatitisBvaccine.However,mostEPIprogrammesinthedevelopingworlddonotfocusheavilyonservicesforyoungadolescentsandyoungwomen,soEPImustbeexpandedtoreachthosepopulations(ortheadolescentsmustbevaccinatedusingothersystems).HepatitisBvaccinewasquicklyabsorbedintonationalEPIprogramsonceitspricedroppedto$0.25perdoseanditbecameavailableasaninfantvaccine.

ResearchconductedamongprogrammeplannersinPeru,India,UgandaandVietnamfoundthatmostrespondentsendorsedusingEPItodeliverHPVvaccineratherthancreatingparallelsystems8andexpandingbeyondinfantimmunizationisakeyobjectiveinWHO/UNICEF’s“GlobalImmunizationVisionandStrategy”(GIVS).9

SchoolsseemtobepromisingvenuesforHPVimmunizationbothinhigher‐andlower‐resourcecountries.Whilesomegirlsdonotremaininschooltotheageofvaccination,attendancerateshaveincreaseddramaticallyinthepasttwodecades.SeveralHPVvaccinedemonstrationprojectsinthedevelopingworldareassessingschoolsasvaccinationvenues,whileconcurrentlydevelopingsystemstoreachout‐of‐schoolyouth.Dataarebeinggatheredontherelativecostsandcoverageachievedthroughschooloutreach,comparedtoaskingparentstobringtheirdaughterstoclinics.10ScreeningprogramstargetingmothersofadolescentgirlsarealsobeingstudiedasamechanismtocreatedemandforHPVvaccination.

Insituationswhereresourcesdonotpermitvaccinationoftheentirecohortofyoungadolescentgirls,plannersmaylookforaspecifichigh‐risksubpopulation.However,thehighincidenceofHPVacrosspopulationsdoesnotfacilitatesuchastrategy—asmighthavebeenusedforothersexuallytransmittedinfections.Instead,theselectionofalimitedgeographicareainwhichtovaccinateallgirlsandthentoexpandtheprogrammeinsucceedingyearsmaybeanappropriatestrategytoconsider.

EarlyexperiencewithpublicorNGObasedHPVvaccinationprogrammes

PublicHPVvaccinationinhighincomecountries:Australia

Australiaprovidesanexampleofasuccessfulvaccinationprogrammeinahighresourcesetting.ThequadrivalentvaccinewasregisteredthereinJune2007forbothfemalesnineto26yearsofageandboysnineto15yearsofage.FromApril2008,agovernment‐funded,school‐basedvaccinationprogrammewasinitiatedforfemaleadolescentsaged11‐12yearswithcatch‐upvaccinationupto26yearsofageforfemalesforthesubsequenttwoyears.Forcost‐efficacyreasons,boysarenotbeingvaccinatedthroughthepublicprogramme.AlltheseprogrammeshaveresultedinrelativelyhighratesofHPVvaccinationcoverage.Forexample,HPVvaccinecoverageamongschoolagedfemaleadolescentsinAustraliahasbeenestimatedupto80%.11Inthesecondyear’sschool‐basedcohortof2008,thefigureremainsinthehigh70percentiles.Thishighcoveragehasalreadytranslatedintoareductioningenitalwartsinyoungwomen<27yearsoldandyoungheterosexualmen.Thelowerratesofwartsinheterosexualmensuggestthepotentialforherdimmunity.12

Similarschool‐basedprogrammesforallage‐eligiblefemaleadolescentsalsohavebeenmountedintheUKandCanada,largelyresourcedthroughpublicfunds.13IntheUnitedStates,whereHPVvaccinesarenotactivelyprovidedbythegovernmentinschools,butprovidedbycliniciansattheexpenseofindividualfamiliesorreimbursedbyinsurancecompanies,thecurrentvaccinecoveragerateismuchlower.PublicHPVvaccinationinmiddleandlowresourcecountriesHPVvaccinationprogrammesinmiddle‐andlow‐resourcecountriesarefewandtendtobelimitedinscope.WiththeexceptionofPanama,nootherdevelopingworldgovernmenthasintroducedtheHPVvaccineatnationalscale.Mexicohasasignificantdemonstrationprojectdesignedtodeliverthevaccinetogirlsinthe125mostdisadvantagedmunicipalitiesinthecountry.ThemajorityofHPVvaccineprojectsindevelopingcountriesarebeingrunbynationalandinternationalNGOs.Manyofthesearedemonstrationprojects,whichaimtodevelopmodelsforfuturepublicsectoradoptionofthevaccine.PreliminaryfindingsfromdemonstrationprojectsinIndia,Peru,Uganda,MexicoandVietnamsuggestthataschool‐basedapproachcanachievecoverageratessimilartothosefoundinAustralia.Projectexperiencetodatealsosuggeststhatwheneffortsaremadetoeducatehealthcareprovidersandcommunitiesaboutcervicalcancer,andwhenHPVvaccineisintroducedasa“vaccineagainstcervicalcancer”(asopposedtousingtheunfamiliarterm“HPVvaccine”),coveragelevelsof80‐90%arenotuncommon,indicatinghighacceptability.10SelectionofvaccineThekeydifferencebetweenthetwovaccinesisthatthequadrivalentvaccinealsoprotectsagainsttwonon‐oncogenicHPVtypesthatcausethemajorityofgenitalwarts(types‐6and‐11).14Programmeplannerswillneedtocomparethecostsofthetwovaccinesanddeterminewhichrepresentsthebettervaluebasedonavailableresourcesandcurrenthealthpriorities.Emergingevidencesuggestssomelevelofadditionalprotectionwiththebivalentvaccine15andpotentialforatwo‐doseregimenthatmayberelevanttochoiceasdatamatures.

PublicdebaterelatedtoHPVvaccinesOverthepastseveralyears,publicacceptanceofHPVvaccinationremainsstronginhigh,middle‐andlow‐incomecountries,thoughsomeissueshaveinspireddebate.IntheUnitedStates,forexample,muchofthediscussionhasfocusedoneffortstomandateHPVvaccinationformiddle‐schoolentry.IntheUK,thebulkofcontroversyhasfocusedonthecriteriausedtoselectaspecificbrandofHPVvaccine.Somealsoworrythatlimitedcervicalcancerscreeningresourcescouldbere‐allocatedtoHPVvaccineprogrammes.

Inbothhigh‐resourceandlow‐resourcesettings,understandingofcervicalcancerandHPVvaccineshasprovenvulnerabletomisinformationdisseminatedbygroupswhodonotunderstandtheevidence,orwhoaresuspiciousofallopathicmedicineingeneralandvaccinationinparticular.Unfortunatelythesecampaignshaveproveneffectiveingainingmediaattentionandraisinginappropriateconcernsamongparentsandpolicymakers.

Regardlessofthepublicdebate,currentHPVintroductionprojectsarefindingveryhighdemandandacceptabilityforthevaccineamongparents,girlsandclinicians.Aslongasthesafetyrecordofthevaccineremainspositive,itislikelythatpublicsupportforHPVvaccinationwillcontinuetogrowasaresultofincreasededucation,asvaccinepricesdrop,andaspilotintroductionprogrammeresultsbecomeavailable.Furthermore,publicacceptancemayincreaseifotherhealthinterventionsappropriateforolderchildrenalsoareprovidedalongwithHPVimmunization,suchastetanus,rubella,hepatitisB,measles,andpotentiallyHIVimmunization;nutritionalsupplementation;malariaintermittentpreventivetreatment;treatmentofschistosomiasis,filariasis,andtrachoma;deworming;ironand/oriodinesupplementation;provisionofbednetsandeducationabouthandwashing,tobacco,drugs,bodyawareness,andlife‐choicedecision‐making.

Moreevidenceisneededon:

• ThemosteffectivemodelsforreachinggirlswithHPVvaccine,especiallyinlow‐resourcesettings;

• Therelativecostsofvariousvaccinationstrategies;• Whetheralternativestomanufacturer‐recommendedthree‐dosevaccination

schedulesmaybemoreconvenientforhealthsystemsandmayprovidesimilarprotectionasthestandardschedules.

Considerationsforspecialpopulations–HIV+,pregnantwomenWhileHPVvaccinescontainnoDNAandconsequentlyarenotinfectious,theyareclassifiedasapregnancycategoryBmedication.Hence,vaccinationisnotrecommendedduringpregnancy,astherearestilllimiteddataonvaccinationandpregnancytodate.Howeverdespitetherequirementforadequatecontraceptionduringphase3clinicaltrials,17%ofvaccinatedwomenbecamepregnant.1,2Follow‐upofthesepregnanciesshowedthatvaccinationdidnotappeartonegativelyimpactpregnancyoutcomes,withnosignificantdifferencesnotedoverallfortheproportionsofpregnanciesresultinginlivebirth,foetalloss,orspontaneousabortion.16

DataalsoarelimitedrelatingtouseofHPVvaccinesinimmunocompromisedindividuals.AstheHPVvaccineisnotalivevirus,thevaccineissafeforHIVpositiveindividuals.Whatisnotwellknownistheamountofprotectionconferredwhenanindividualwithacompromisedimmunesystemisvaccinated.TheoneresearchstudyavailableshowsthatimmuneresponseandtheefficacyofHPVvaccinesmaybelower—butnotinsignificant—inHIVpositiveindividuals.17SinceHIVpositiveindividualsareknowntobeespeciallyvulnerabletoHPV‐relateddiseases,especiallycervicalcancer,WHOsuggeststhatthebenefittothisgroupremainshigh.Duetothesafetyofthevaccineforimmunocompromisedindividuals,WHOdoesnotconsiderHIVtestingtobeapre‐requisiteofHPVvaccination.4Integrationwith/orreplacementofotherpreventionapproachesCervicalcancerscreeningandtreatmentforprecancershouldcontinueaspernationalguidelinesasthecurrentlyavailablevaccinepreventsinfectioncausedbyHPV16andHPV18only.RoleofObstetricians/Gynaecologists,Paediatricians,NursesandotherprovidersinHPVvaccineeducation

Aswithothernewhealthtechnologies,inmanycountriesaccesstoHPVvaccinethroughprivatephysiciansandclinicsisfaroutpacingpublicsectorprogrammes.Asaresult,HPVvaccinesarequicklybecomingavailabletogirlswhoseparentshavethefinancialresourcestocoverthecost.

Asgirls,parents,teachers,andpolicymakersseekinformationonthevaccine,theywillturntoobstetrician/gynaecologists,paediatricians,nurses,midwivesandcommunityhealtheducatorsforinformation.Professionalassociationsandprovidernetworksshouldfindwaystoassurethatfamiliesaregettingconsistentandaccurateinformationaboutthevaccine,andtoquicklyandeffectivelydispelanymisconceptionsaboutitsuses,safetyandefficacy.ProvidersalsomustworkwithpolicymakerstoensurethatHPVvaccinesaredirectedtocommunitieswheretheywillhavethelargestimpact,especiallyunderservedcommunitieswherescreeningsystemscontinuetobeweak.

References

1FUTUREIIStudyGroup.Quadrivalentvaccineagainsthumanpapillomavirustopreventhigh‐gradecervicallesions.NEnglJMed2007May;356(19):1915‐27.2GarlandSM,Hernandez‐AvilaM,WheelerCM,PerezG,HarperDM,LeodolterS,etal.Quadrivalentvaccineagainsthumanpapillomavirustopreventanogenitaldiseases.NEnglJMed2007May;356(19):1928‐43.3PaavonenJ,NaudP,SalmerónJ,WheelerCM,ChowSN,ApterD,etal.Efficacyofhumanpapillomavirus(HPV)‐16/18AS04‐adjuvantedvaccineagainstcervicalinfectionandprecancercausedbyoncogenicHPVtypes(PATRICIA):Finalanalysisofadouble‐blind,randomisedstudyinyoungwomen.Lancet.2009Jul;374(9686):301‐14.4 World Health Organization. Human papillomavirus vaccines: World Health Organization position paper. Weekly Epidemiological Record (WER). 2009 Apr; 84(15):117-32. Available at: www.who.int/wer/2009/wer8415.pdf 5GAVIAlliance.Whichvaccinestoinvestinandwhen:GAVI'sstrategicapproach[Online].2009[accessed2009Jun2].Availableat:www.gavialliance.org/vision/strategy/vaccine_investment/index.php 6 SchillerJT,CastellsagueX,VillaLL,HildesheimA.AnupdateofprophylactichumanpapillomavirusL1virus‐likeparticlevaccineclinicaltrialresults.Vaccine2008Aug;26S:K53‐K61. 7 Goldie S. A public health approach to cervical cancer control: Considerations of screening and vaccination strategies. Int J Gynaecol Obstet 2006 Nov;94S:S95-105. 8 PATH.ShapingstrategiestointroduceHPVvaccines:FormativeresearchresultsfromIndia,Peru,Uganda,andVietnam[Online].2008.Availableat:www.rho.org/formative-res-reports.htm 9WorldHealthOrganization.Globalimmunizationvisionandstrategy[Online].2007[accessed2007Nov12].Availablefrom:www.who.int/immunization/givs/en10 Unpublished data from PATH 11GarlandSM,BrothertonJM,SkinnerSR,PittsM,SavilleM,MolaG,etal.HumanpapillomavirusandcervicalcancerinAustralasiaandOceania:Risk‐factors,epidemiologyandprevention.Vaccine2008Aug;26(Suppl12):M80‐M88.

12FairleyG,HockingJ,ChenM,Donovan,BradshawC.RapiddeclineinwartsafternationalquadrivalentHPVvaccineprogram.The25thInternationalPapillomavirusConference;2009May8‐14;Malmö,Sweden.13 SheferA,MarkowitzL,DeeksS,TamT,IrwinK,GarlandSM,etal.EarlyexperiencewithhumanpapillomavirusvaccineintroductionintheUnitedStates,CanadaandAustralia.Vaccine2008Aug;26(Suppl10):K68‐K75.14 Garland SM, Steben M, Sings HL, James M, Lu S, Railkar R, et al. Natural history of genital warts: Analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis 2009 Mar;199(6):805-14. 15Discussedinpreviouschapter, “HPV Vaccines: Characteristics, Target Population and Safety”. page 16.

16 Garland SM, Ault K, et al. Pregnancy and infant outcomes in the clinical trials of human papillomavirus type 6/11/16/18 vaccine. Obstet Gynecol 2009. In press. 17 Weinberg A, et al. Safety and immunogenicity of a quadrivalent vaccine to prevent human papillomavirus (HPV) in HIV-infected children: IMPAACT P1047. Poster 619a presented at the 15th Conference on Retroviral and Opportunistic Infections; February 3-6, 2008; Boston, USA.

Overview:EarlyScreeningandTreatment

Evenwithastrongvaccinationprogramme,therewillbeasmallpercentofthepopulationwhoareatriskforcancerfromuncoveredsubtypesorthosewhoarealreadyexposedtothevirus.Inaddition,theunvaccinatedpopulationwillcontinuetoneedsignificantattentiontoscreeningandearlytreatmentfordecadestocome.Thiswillremainamajorfocusforeverycancercontrolprogramme.Thissectionreviewsscreeningandtreatmentstrategiesforeveryresourcesetting.

TheSingleVisitApproach

NeerjaBhatla,MBBS,MD,FICOG

Traditionalcervicalcancerscreeningandpreventionprogrammesrequirethewomantomakeatleasttwovisitsifthetestisnegativeandmanymoreifpositive.Thecervicalsmearistakenatthefirstvisitandthewomanmustwaitforaproviderresponseviamailorreturntotheclinicafterafewdays.Ifanabnormalityisfound,furtherevaluationmaybescheduleddependingonavailabilityofpersonnelandavailableresources.Atthatpoint,diagnosticworkup/treatmentwillbescheduledasrequired.Inhigh‐resourcesettings,inordertopreventlosstofollowup,screeningprogrammeshaveincorporatedauditstomonitortheefficacyoftheprogrammeanddevisedmeanstoencouragepatientcompliance.Somecountrieshaveintroducedincentivesforhealthcareworkerstoencouragescreeningcoveragerates,call‐recallsystemsasareminderfornon‐compliantpatients,andpubliceducationtoencourageregularscreening.Theseapproachesrequireresources,patienttime,andsophisticatedhealthinformationsystems.ResearchbytheAllianceforCervicalCancerPreventionandothersindicatesthatdespitedecadesofeffort,thereplicationofmultiplevisit‐basedscreeningprogramshasnotbeensuccessfulinreducingcancerratesinlow‐resourcesettings.Therequirementofmultiplevisitsresultsinpoorpatientcomplianceandlosstofollowup.Thiscoupledwithalackofaccesstotreatmentatthepointofcarehaveallcontributedtopooroutcomesinlow‐resourcesettings.Inordertoimproveoutcomes,whileworkingwithinthetechnologicalandlogisticallimitationsoflowresourcesettings,thesinglevisitapproachhasbeendeveloped.SinglevisitapproachInthesinglevisitapproach,theintentistohavescreeningandtreatmentperformedatthesamevisittominimizethechanceofabnormalresultsgoingunmanaged.Thisapproachisoftenreferredtosynonymouslyasthe“ScreenandTreat”or“SeeandTreat”approach.Thisuniqueapproachrequiresthatthescreeningtestproviderapidandaccurateresultsandanappropriate,effective,adequatemethodoftreatmentisavailabletowomenwithabnormaltestsinthesamesitting.Bothscreeningandtreatmentareperformedatthescreeningsite,withnoneedfortransport,delayorrelianceoncomplexinfrastructureorspecializedcare.Sometimesthesinglevisitapproachisnotfeasiblebecauseofunexpectedfindings,orafterarapidscreen,apatientdecidestothinkmoreaboutoptionsfortreatment.However,thegoalistoprovidebothatthesamevisit.Overthepastseveralyears,anumberofscreeningandtreatmentoptionshavebeenconsideredforusewithinthesinglevisitapproach.Cytology1wasconsideredasan

optionbyplacinglabsinclinicsinordertocollapsethetimeneededtoreceivetestresults.Theseattemptsfocusedonresolvingtheproblemoflosstofollow‐up,aslongastreatmentwasprovidedduringthesamevisit.However,thisapproachdidnotprovideasolutiontotheassociateddemandsofinfrastructure,costandphysicianandcytologisttime.HPVtestinghasalsobeentriedinascreenandtreatapproach.2TheuseofHPVtestingwithinthesinglevisitapproachcurrentlyfacestwolimitations—timeandinfrastructurerequiredforcurrentHPVtestsandalackofconsensusaboutappropriatefollowupfortestpositives.ItisnotyetdeterminedifproceedingdirectlytotreatmentwithcryotherapyafterapositiveHPVtestistheappropriatealgorithmforcare.IfevidencebecomessufficienttorecommendtreatmentdirectlyafterapositiveHPVtest,afast,simpleandaffordableHPVtestmaymakeHPVtestingwiththesinglevisitapproachfeasiblewithinthecomingyears.3Atpresent,themostaccessiblemodalityforthesinglevisitapproachisvisualinspectionwithaceticacid(VIA)followedbycryotherapyofpositivecasesatthesamesitting.4ArandomizedtrialinSouthIndiafounda25%reductionincervical‐cancerincidenceanda35%reductioninmortalitycomparedtocontrolswithVIAfollowedbycryotherapy.5InSouthAfrica,asingle‐visitapproachtocervicalcancerpreventioncombiningVIAandcryotherapywasfoundtobesafe,acceptable,andfeasible.ItwasfoundthatthisscreenandtreatmethodeffectivelycuredCINin88%ofwomen,including70%ofwomenwithabaselinediagnosisofCIN3.6EvidenceshowsthatprovidingasingleroundofVIAfollowedbycryotherapyfortestpositivecasescanreducethelifetimeriskofcervicalcancerby30%,ifdeliveredtowomenbetweentheagesof35‐45years.7Theuseofthiscombinedapproachhasproventobeaneffectiveandviablecombinationinlow‐resourcesettings.VIA,cytology,HPVandcryotherapyareallreviewedindetaillaterinthisguidance.

References

1 Megevand E, Van Wyk W, Knight B, Bloch B. Can cervical cancer be prevented by a see, screen, and treat program? A pilot study. Am J Obstet Gynecol 1996 Mar;174(3):923-8. 2 Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright TC. Screen-and-treat approaches for cervical cancer prevention in low-resource settings. A randomized controlled trial. JAMA 2005;294:2173-81.

3 Qiao YL, Sellors JW, Eder PS, Bao YP, Lim JM, Zhao FH, et al. A new HPV-DNA test for cervical-cancer screening in developing regions: A cross-sectional study of clinical accuracy in rural China. Lancet Oncol 2008 Oct;9(10):929-36. 4 Soler ME, Gaffikin L, Blumenthal PD. Cervical cancer screening in developing countries. Prim Care Update Ob Gyns 2000 May-Jun;7(3):118-23. 5 Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R, Shanthakumari S, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: A cluster-randomised trial. Lancet 2007 Aug;370(9585):398-406. 6 Luciani S, Gonzales M, Munoz S, Jeronimo J, Robles S. Effectiveness of cryotherapy treatment for cervical intraepithelial neoplasia. Int J Gynaecol Obstet 2008 May;101(2):172-7. 7 Goldie SJ, Gaffikin L, Goldhaber-Fiebert JD, Gordillo-Tobar A, Levin C, Mahé C, et al. Cost-effectiveness of cervical-cancer screening in five developing countries. Alliance for Cervical Cancer Prevention Cost Working Group. N Engl J Med. 2005 Nov;353(20):2158-68.

VisualInspectionwithAceticAcid(VIA)

NeerjaBhatla,MBBS,MD,FICOG,andEnriquitoLu,MD

Stateofthescience

Indevelopingcountries,cytologybasedscreeninghasbeenabletomakelittleimpactoncervicalcancer.Cytologyscreeninghasarelativelyhighfalsenegativeratebutcytology‐basedscreeningprogrammesforcervicalcancercompensateforthisthroughfrequent,regularscreening.Theseprogrammeshavebeensuccessfulindevelopedcountriesastheyareabletoensurecompliance,coverageandquality.However,developingcountriessufferfrommajorobstacles:

• Lackofinfrastructure(laboratories,cytotechnicians),lackofqualitycontrolforlaboratoriesandcytologyreporting,andpoortreatmentfacilities.

• Poorcomplianceandlackoffollowup.Asaresult,womenwithabnormaltestsdonotreceivetreatmentandcostsareincurredwithoutbenefits,therebydecreasingcost‐effectiveness.

Theseproblemsmaybeaddressedincertainsettingsbyvisualinspectionwithaceticacid(VIA)followedbycryotherapyofpositivecasesatthesamesitting(asinglevisitstrategy).Althoughnotnew,thisapproachhasbeenvalidatedandrevitalizedbyanumberofstudiesbetween1996and2004,whichestablishthatVIAisanalternativeoptiontoscreeningcervicalprecancer.ThesestudiesdemonstratedinTable1,showtherelativelyhighsensitivityofVIAbutaspecificitythatisslightlylowerthancytology.1,2,3,4,5,6

VIAusesinstrumentsetsandequipmentusuallyavailableathealthcarecentres.Itdoesnotrequirealaboratoryandprovidesanimmediateresult,allowingtheuseof"screenandtreat"methodology.Nursesandmidwivescanbetrained,andhavedemonstratedthattheycanperformaswellasanysimilarlytrainedphysicians.7Theabilitytoutilizemid‐levelprovidersisimportantasitextendsaccessibilitytocervicalcancerscreeninginregionswherephysiciantimeandresourcesarescarce.

Theprocedureinvolvesapplying3‐5%freshlypreparedaceticacidtothecervixandobservingafteroneminute.Aceticaciddehydratescellsandreversiblycoagulatesthenuclearproteins.Thus,areasofincreasednuclearactivityandDNAcontentexhibitthemostdramaticcolourchangetowhite.AcetowhitestainingisnotspecificforCINandmayalsooccurtosomeextentinareasofsquamousmetaplasiaandinflammation.TheVIAresultsaregenerallycategorizedintothreesubsets:suspiciousforcancer,VIAnegativeandVIApositive.AVIAtestpositiveorpositive

cervixisdefinedbytheInternationalAgencyforResearchonCancer(IARC)asaraised,thickened,whiteplaqueoracetowhiteepitheliumatorclosetothesquamocolumnarjunction(SCJ).AdditionalinformationonIARCcriteriaforreportingtheresultsofVIAareavailableat:http://screening.iarc.fr/viavilichap2.php?lang=1

Adversereactionstodilutedaceticacidaremildandrangefromaslightwarmfeelingtoanuncomfortablestingingsensation.Therearenoreportsoflong‐termsequelaeorcomplications.

BarrierstoApplication

Barrier Lowandmiddleresourcesettings

Medical • Resistancefromprofessionalmedical/specialiststodepartfromtraditionalcytologicapproach

• Lackofreferralcentresforlesionssuspiciousforcancerandlargerlesionsneedingadditionalcare

• VIAnotsuitableforpost‐menopausalwomenwheresquamocolumnarhasrecededintoendocervicalcanal

• Combinedwithcryotherapy,notsuitableforwomenwithlargelesions,endocervicalextension,orsuspicionforcancer

Physical • Absorptivecapacityofhealthcentrestomeetincreaseddemandfororganizedscreening

• [Opportunity:Materialsareinexpensiveandportable]

Training • Conductinghighquality,competencybased,hands‐onclinicaltraining

Cost • Accesstocryotherapyequipmentandthesupplyofcryogen• Initialqualityassurancesupervisionforcliniciansof3‐6months.Translatinglearningintoeffectivescreenandtreatservicesrequiresposttrainingfollow‐uptosupportthenewprovider.Confidenceindecision‐making,particularlyincallingawhitelesionsignificant,andthesubsequentapplicationofcryotherapyisstrengthenedthroughorganized,structuredtransferoflearningvisitsinthefirst1‐3monthsposttraining.Subsequentvisitsusingsupportivesupervisionapproachesprovidethemechanismtoensurethatqualityofcareismaintained.Implementingthisapproachrequirestime,investmentinhumanresourcesandmoney.

• [Opportunity:Lowcoststerilizationtechniquessuchasboilingareacceptableforinstrumentsused]

Policy • Nationalpoliciesthatrestrictscreeningandtreatmenttophysiciansonly

• NationalcervicalcancerpreventionpoliciesthatdonotrecognizeorsupporttheuseofVIA.

Goldieetal.comparedthecostofdifferentscreeningapproachesinfivecountries.In2000,thecostofprovidingVIArangedbetween<US$5inIndiatoashighas$30inSouthAfrica.Ineachcountry,VIAprovedtobethemostcosteffectivescreeningtest.8

Gapsinknowledge/furtherresearchneeded

• VIAasaperiodicscreentest:VIAhasmostlybeenevaluatedasaonce‐in‐a‐lifetimescreeningtest.ThereisacontinuedneedformoreinformationonitsperformanceinperiodicscreeningorconsensusonthefrequencywithwhichVIAnegativewomenmustbere‐examined.Thereisalsoaneedforconsensusastowhatagetostartandstopscreening.

• VIAperformancedetectingrecurrentorpersistentdisease:Itisexpectedthatthesensitivityandspecificityofvisualscreeningcouldchangewheninuseinpreviouslyscreenedandtreatedpopulations.Largepublishedscreeningtrialshavemainlyfocusedonpreviouslyunscreenedanduntreatedpopulationswithahighprevalenceoflesions.However,theThailandSafeStudyfoundthatamongwomenwhowereVIApositiveandreceivedtreatmentatthetimeofscreening,about94.3%wereVIAnegativeoneyearlater.7ThesepositiveresultshavebeenreplicatedinGhana,acountrywithfewerresources.9

• Variedresultsfromrecenttrialscreatedconfusionaboutimpact:Arecent

articleonHPVscreeninginruralOsmanabad,India,10reportedthatasingleHPVtestingresultedina50%reductioninincidenceandmortalitywhileVIAandcytologyhadnoeffect.SankaranarayananinanAllianceforCervicalCancerPrevention(ACCP)guidancepaper11noted“thechallengesofinterpretingthevaryingresultsfromthetwoIndianstudiesinOsmanabadandDindigul,andobservedthatthetreatmentrateamongVIA‐positivewomenwasmuchhigherintheSouthIndiantrialofDindigulthantheOsmanabadtrial,whichmaybeafactorinthedifferentstudyresults.”Despite,thesecontradictoryoutcomes,VIAhasbeenvalidatedasaneffectivescreeningapproachandtheACCPandotherinternationalbodiescontinuetosupportitsexpansion.

• Theadventofapotentiallysimpler,affordableandsensitiveHPVDNAtest

providesanopportunitytofurtherstrengthensinglevisitprogrammesbased

onvisualinspectionandcryotherapy.StudiesexploringhowtodeploythistechnologyincombinationwithVIAunderfieldconditionswillhelpinthecontinueddevelopmentofappropriate,costeffectivecervicalcancerscreeningservice.OptionsforcombiningthesetestsincludeusingVIAtotriageHPVpositivewomenforfollow‐uptreatmentorreferral.AnotheroptionunderstudyistouseVIAonlytoruleoutlargelesionsandcancersuspectsamongHPVpositivewomenandtooffertreatmentregardlessofVIAstatustoallHPV+women.

• ThebestscreeningintervalforVIAinpopulationswithhighHIVprevalence

isnotpresentlywelldefined.

Recommendationsforoptimaluse

MostVIAscreeningprogrammesfocusonwomenbetween30‐45yearsold.Thisistheperiodwhencervicalpre‐cancerlesionsstarttomanifest.Itisalsothesametimeperiodwhenpre‐cancerlesionsarestilltreatableandrespondfavourablytocryotherapy.

• AthreetofiveyearscreeningintervalshouldbeconsideredforVIAnegativewomenbetweentheagesof25‐49.

• Womenunder25yearsofageshouldbescreenedonlyiftheyareathighriskfordisease.Womenathighriskforcervicalabnormalitiesarethosewhohavehadearlysexualexposure,multiplepartners,previousabnormalscreeningresultsorCIN,orareHIVpositive.

• VIAisnotappropriateforwomenover50years.Thesewomenshouldbescreenedatfive‐yearintervalsusingcytologyorHPVtesting.

• ForHIVpositivewomen,annualscreeningisrecommended.• Annualscreeningisnotrecommendedatanyageforthegeneralpopulation.• Inthesinglevisitapproach,VIA‐positivesareofferedcryotherapyatthetime

ofscreeningtomaximizetheeffectivenessofthecervicalcancerpreventionprogramme.Post‐cryotherapy,thesewomenareseenin12monthsforarepeatscreening.

Integrationwith,orreplacementofotherapproaches

Thailand,amiddle‐incomecountry,hasdemonstratedthatthesingle‐visitapproachwithVIAandcryotherapyisprogrammaticallyfeasibleandsustainableandshouldbeconsideredinnationalinvestmentstocontrolcervicalcancer.7Mid‐levelproviderssuchasmidwivesandnursesmaybetrainedforVIAandcryotherapy,andthecervicalcancerscreeningprogrammecanbeintegratedwithexistingreproductivehealthprogrammes.Areferralsystemmaybesetupforpatientswhoarehighrisk,ineligibleforcryotherapyorifinvasivecancerissuspected.Thismaybeaccomplishedbyprovidingappropriatetrainingandequipmentatthefirstreferralcentre.

Considerationsforspecialpopulations

HIV/AIDSandimmunesystemsuppressionareassociatedwithmorerapidCINprogressionandHIV‐positivewomengenerallyhavehighrecurrenceratesofCINaftertreatment.Womenmayalsotransmitthevirusmorereadilyaftercryotherapyand,therefore,requirecounsellingregardingabstinenceandcondomuse.

IngeneralVIAisacceptableasascreenforpregnantwomenifthatisthemostcosteffectivemethodfortheregionbuttreatmentisgenerallydiscouragedduringpregnancy.Keypoints:

1. AsinglevisitapproachtocervicalcancerpreventioncombiningVIAandcryotherapyissafe,acceptable,feasibleandcosteffectiveforthepreventionofcervicalcancerinlow‐resourcesettings,whichminimizeslosstofollowup.OnceinalifetimescreeningwithVIA(andappropriatetreatment)hasthepotentialtoreducecancerriskbyonethird.

2. MoststudieshaveevaluatedtheimpactofasingleroundofscreeningwithVIAinunscreenedpopulations.HealthpolicymodellingstudiessuggestthatitwouldbebestifVIAcouldbedoneseriallyatfive‐yearintervals.

3. Mid‐levelprovidersmaybetrainedforVIAandcryotherapy,andthecervicalcancerscreeningprogrammecanbeintegratedwithinexistinghealthprogrammes.Womenineligibleforcryotherapyneedtobereferredforcolposcopy,LEEP,ormanagementofinvasivecancer,asrequired.

4. EffectivetrainingandqualityassuranceprogrammesareessentialtoensuringtheeffectivenessofVIA.ThisisespeciallytrueasVIAisknowntohavealowerspecificitythanothermethods,thuscreatingthepotentialforovertreatmentifinspectionisnotcarefullyandconsistentlysupervised.

5. CytologyorHPVtestingaremoresuitableforscreeningofpost‐menopausalwomenandshouldbeconsideredinthefollow‐upoftreatedwomen.

Table1–VIAtestqualities

DetectionofHGSILandcancerStudy Country Numberofcases

Sensitivity Specificity

Megevandetal(1996) SouthAfrica 2,426 65% 98%

Sankaranarayananetal(1998)

India 2,935 90% 92%

UniversityofZimbabwe/Jhpiego(1999)

Zimbabwe 2,148 77% 64%

Belinson(2001) China 1,997 71% 74%

Dennyetal(2000) SouthAfrica 2,944 67% 84%

Sankaranarayananetal(2004)

India 56,939 76.8% 85.5%

Table2–Testcharacteristicsandimplicationonascreenandtreatservicedeliverymodel

Testcharacteristics

Conventionalcytology

HPVDNAtests*

VIA VILI

Sensitivity 4762% 66100% 6779% 7898%

SpecificityforHSILandInvasiveCancer

6095% 6296% 4986% 7391%

Comments Assessedoverthelastfiftyyearsinawiderangeofsettingsindevelopedanddevelopingcountries

Assessedoverthelastdecadeinmanysettingsindevelopedcountriesandrelativelyfewindevelopingcountries

Assessedinthelasttenyearsinresourcepoorcountries

Numberofvisitsforscreeningandtreatment

Twoormore Twoormorevisits

Canbeusedinasinglevisitapproach/seeandtreat

Sankaranarayananetal.IntJObstetGynaecol,2005

References

1 MegevandE,DennyL,DehaeckK,SoetersR,BlochB.Aceticacidvisualizationofthecervix:Analternativetocytologicscreening.ObstetGynecol1996Sep;88(3):383‐6. 2SankaranarayananR,WesleyR,SomanathanT,DhakadN,ShyamalakumaryB,SreedeviAN,etal.Visualinspectionoftheuterinecervixaftertheapplicationofaceticacidinthedetectionofcervicalcarcinomaanditsprecursors.Cancer1998;83(10):2150–6. 3UniversityofZimbabwe/JHPIEGOCervicalCancerProject.Visualinspectionwithaceticacidforcervical‐cancerscreening:Testqualitiesinaprimary‐caresetting.Lancet1999Mar;353(9156):869‐73 4DennyL,KuhnL,PollackA,WainwrightH,WrightTCJr.Evaluationofalternativemethodsofcervicalcancerscreeningforresource‐poorsettings.Cancer2000Aug;89(4):826–33. 5BelinsonJ,PretoriusR,ZhangW,WuL,QiaoY,ElsonP.Cervicalcancerscreeningbysimplevisualinspectionafteraceticacid.ObstetGynecol2001;98:441‐4. 6SankaranarayananR,RajkumarR,TheresaR,EsmyPO,MaheC,BagyalakshmiKR,etal.InitialresultsfromarandomizedtrialofcervicalvisualscreeninginruralsouthIndia.IntJCancer2004Apr;109(3):461–7. 7GaffikinL,BlumenthalPD,EmersonM,LimpaphayomK;RoyalThaiCollegeofObstetriciansandGynaecologists(RTCOG)/JHPIEGOCorporationCervicalCancerPreventionGroup.Safety,acceptability,andfeasibilityofasingle‐visitapproachtocervicalcancerpreventioninruralThailand:Ademonstrationproject.Lancet2003Jun;361(9360):814–20. 8GoldieSJ,GaffikinL,Goldhaber‐FiebertJD,Gordillo‐TobarA,LevinC,MahéC,etal.Cost‐effectivenessofcervical‐cancerscreeninginfivedevelopingcountries.AllianceforCervicalCancerPreventionCostWorkingGroup.NEnglJMed.2005Nov;353(20):2158‐68.

9BlumenthalPD,GaffikinL,DeganusS,LewisR,EmersonM,etal.Cervicalcancerprevention:safety,acceptability,andfeasibilityofasingle‐visitapproachinAccra,Ghana.AmJObstetGynecol.2007Apr;196(4):407.e1‐407.e9. 10SankaranarayananR,NeneBM,ShastriSS,JayantK,MuwongeR,BudukhA,etal.HPVscreeningforcervicalcancerinruralIndia.NEnglJMed2009Apr;360(14):1385‐94.

11AllianceforCervicalCancerPrevention(ACCP).NewevidenceontheimpactofcervicalcancerscreeningandtreatmentusingHPVDNAtests,visualinspection,orcytology.Factsheet.Availableat: http://www.rho.org/files/ACCP_screening_factsheet_July09.pdf

EarlyDiagnosisofCervicalNeoplasia:PapTest(Cytology)

NahidaChakhtoura,MD

StateofthescienceWidespreadcervicalcancerscreeninginthedevelopedareasoftheworldhascontributedtoadecreaseintheincidenceofcervicalcancer,primarilyduetocytologyscreeningandtreatmentofprecancerouslesions.1,2,3Lackofinfrastructureinlowresourceareashaspreventedsimilarprogrammesfrombeingsuccessfullyimplemented.4Manycomponentsareneededtoestablishaneffectivecytologyprogrammeonawidescale.Governmental/nationalsupportandrecognitionoftheneedforscreeningandtreatmentandtheburdenofdiseaseperspecificareaarerequiredtogarnerappropriatefunding.5Culturallyappropriateeducationofwomenandhealthcareprovidersmayhelpensurecompliancewithscreeningrecommendationsthatrequiremorethanonecytologyexamtoincreaseefficacy.Trainingpersonnelsuchascytologytechniciansisnecessarytoprovidefollowupforcytologyfindings.Allscreeningefforts,includingcytology,canonlybeeffectiveifdiagnosticandtreatmentmodalitiesareavailableandaccessible.Inlowresourcesettings,particularlydevelopingcountries,evidenceindicatesinvestmentsincytologyhavenotyieldedadequateresults.Forthisreason,otherscreeningmodalitiescoveredinthisguidanceshouldbeexploredtoimproveandexpandcurrentefforts.

BarrierstoapplicationMedicalbarriers:Inallenvironmentsandresourceareas,therearenomedicalconditionsthatshouldexcludepatientsfromreceivingappropriatescreening,includingpregnancy.Culturalbarriers:Acceptabilityofcytologyscreeningandpelvicexamsvaries.Insomecultureswomendonotattendscreeningprogrammesaftercompletionofchildbearingorcessationofsexualactivity.Thisisparticularlyimportantinlow‐ormiddle‐incomeareaswherescreeningsareonlysetinreproductivehealthclinics.Culturallysensitiveeducationisimportanttoaddressthisbarrier.

Physicalbarriers:Infrastructureneedsforhigh‐qualitycytologyscreening—relianceonlaboratories,trainedcytologistsandinformationnetworkshaverenderedthisapproachdifficult,ifnotunviable,inmanydevelopingcountrysettings.Twoapproachestocytologyhaveslightlydifferentphysicaldemands.Theequipmentusedforconventionalcytologyscreeningisresilienttotemperature

changes,reagentsarerelativelylowcost,usuallyportableandgenerallylowmaintenance.Whileliquidbasedcytologyistemperatureresilient,theequipmentislarge,andthereforerequiresarelativelylargespace,reliableelectricalsource,dailymaintenanceandiscostly.Theadvantageoftheliquidbasedcytologyistheabilitytouseacomputerizedscreeningsystem.Thisallowsthecytotechnologist/pathologisttoconcentrateontheslidesmostlikelytocontainabnormalities;thereforemorecytologicalspecimenscanbescreenedatafasterrate.6ReflextestingforHPVisalsofacilitatedwithliquidcytology.However,inadevelopingcountrysetting,thedistancefromclinicstoacentralscreeningsitecanbeprohibitive.

Trainingbarriers:Acytologyspecimencaneitherbeself‐collected,promisingespeciallyforHPVtesting,7orcollectedbymedicalpersonnelincludingtrainedmid‐levelpersonnel.Readingthecytologicalspecimenandperformingdiagnostictestingwithcolposcopyismorechallengingandrequireshighlyskilledcytologistsandhealthprofessionals.Costbarriers:Inlowresourceareas,thecostofestablishingthenecessaryinfrastructure,developingandsupervisingtherequiredpersonnelforacytology‐basedscreeningprogrammehasbeenprohibitive.Eveninmediumresourceareaswherescreeningmayexist,theremaybelimitedsupportforsubsequentneededdiagnostictestingandtreatmentorgeographicbarriers.Itisimportanttonotethateveninhighresourceareas,therearepocketsofunderservedpopulationswithlimitedaccesstomedicalcare8andconsequentfailureofacytologyscreeningstructure.Policybarriers:Inloweconomicresourceareas,policymakershavetoevaluatetheoptionstoaddresstheneedforasustainableandsupportedscreeningprogramme.Inmediumorhigheconomicresourceareas,ensuringaccessforallwomen,particularlybeyondthereproductiveage,isthechallenge.Manyofthehigheconomicresourceareasalsohavedisparitiesbetweeninsuredanduninsuredindividualsorruralandurbanareas.

CostbenefitanalysisWhenpartofanestablishedprogrammeinhighresourcesettings,withrepeatedscreeningatfive‐yearintervalsandcombinedwithappropriatediagnosisandtreatment,cytologycanbecosteffective.Themajorityofthelosstobenefitofcytologyistheneedtohaveatwoorthreestepprocesswherethepatientisscreened,needstofollowupfordiagnostictesting,andthenfinallytreatment.Multiplevisitsinpoorresourceareasleadnotonlytoincreasedcostsbutalsotohigherlosstofollowup.

Author Region Cytologyscreenintervals

ReductioninCA(%)

Costperyearoflifesaved($)

Kimetal9 HongKong 3,4,5years

86‐90 800‐12300

Mandelblatt10 Thailand 5years 13.5 1459Goldieetal11 S.Africa Onetime 19 81

GapsinknowledgeandfurtherareasofresearchneededIdealscreeningmodelshavetobeidentifiedperregion.Applyingtheguidelinesfromdevelopedcountriestolowresourceareasisnotcost‐effectiveandcouldnotbesustained.ImprovementsincytologicaltestingsuchasmolecularmarkersforHPVwouldimprovethesensitivity.Idealscreeningmethodologiesarecosteffective,relylessonlaboratoryinfrastructurethancurrentcytologymethods,andrequireaone‐timevisitwithhighsensitivityandspecificitythatwillyieldimmediateresults,allowingforsamedayevaluationandtreatment.RecommendationsforoptimaluseThereisnoglobalconsensusonagetobeginorintervalofscreening.Indevelopedcountries,suchastheUnitedStates,screeningisinitiatedatage21orwithinthreeyearsofsexualactivityandcontinuesuntiltheageof65or70.12Inothercountries,suchasEngland,screeningisinitiatedatage25.Itisperformedeverythreeyearsuptotheageof49,andtheneveryfiveyearsuntilage65(NationalHealthScreeningProgramme).Inlowtomiddleresourcecountries,screeningisinconsistent,maybeinitiatedinthemid‐30sandthenconductedeveryfiveyears.Ifonlyone‐timescreeningisavailable,thenitisusuallyperformedbetween35and40yearsofageusuallybyvisitinggroupssincenointernalsystemsexist.13Aswithotherformsofscreening,cytologyscreeningshouldbeprovidedtobothvaccinatedandunvaccinatedwomen.Keypoints:

1. Well‐establishedscreeningandtreatmentprogrammeshavebeenproventodecreasetheincidenceofcervicalcancerinhighresourceenvironments.

2. Componentsofacomprehensivescreeningprogrammeshouldincludeeducation,training,screening,diagnostictesting,andtreatment.

3. Initiationofcytologicalscreening,whereresourcesareavailable,shouldoccurbetweenages21and25.Inlowtomediumresourceareas,initiationshouldbeatage35.

4. Intervalofscreeningshouldfollowacceptedregionalstandardsbutshouldnotbelongerthanfiveyearsinwomenundertheageof60.

5. Cytology‐basedprogrammescanbecosteffectiveifscreeningtargetsthepopulationathighestriskfordisease,andtheinfrastructureisinplace.

References

1KitchenerHC,SymondsP.Detectionofcervicalintraepithelialneoplasiaindevelopingcountries.Lancet1999Mar;353(9156):856‐7.2 Gustafsson L, Pontén J, Zack M, Adami HO. International incidence rates of invasive cervical cancer after introduction of cytological screening. Cancer Causes Control. 1997 Sep;8(5):755-63. 3 Safaeian M, Solomon D, Castle PE. Cervical cancer prevention-cervical screening: Science in evolution. Obstet Gynecol Clin North Am. 2007 Dec;34(4):739-60. 4 Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002: Cancer incidence, mortality and prevalence worldwide. IARC CancerBase No. 5, version 2.0. Lyon, France: IARC Press, 2004. 5 Goldie SJ, Gaffikin L, Goldhaber-Fiebert JD, Gordillo-Tobar A, Levin C, Mahé C,et al. Cost-effectiveness of cervical-cancer screening in five developing countries. Alliance for Cervical Cancer Prevention Cost Working Group. N Engl J Med. 2005 Nov;353(20):2158-68. 6 Lozano R. Comparison of computer-assisted and manual screening of cervical cytology. Gynecol Oncol. 2007 Jan;104(1):134-8. 7 Soisson AP, Reed E, Brown P, Ducatman B, Armistead J, Kennedy S, et al. Self-test device for cytology and HPV testing in rural Appalachian women: An evaluation. J Reprod Med. 2008 Jun;53(6):441-8. 8 Downs LS, Smith JS, Scarinci I, Flowers L, Groesbeck P. The disparity of cervical cancer in diverse populations. Gynecol Oncol 2008 May;109(2, Supplement 1);S22-S30. 9 Kim JJ, Leung GM, Woo PP, Goldie SJ. Cost-effectiveness of organized versus opportunistic cervical cytology screening in Hong Kong. J Public Health (Oxf) 2004 Jun;26(2):130-7. 10 Mandelblatt JS, Lawrence WF, Gaffikin L, Limpahayom KK, Lumbiganon P, Warakamin S,et al. Costs and benefits of different strategies to screen for cervical cancer in less-developed countries. J Natl Cancer Inst 2002 Oct;94(19):1469-83.

11 Goldie SJ, Kuhn L, Denny L, Pollack A, Wright TC. Policy analysis of cervical cancer screening strategies in low-resource settings: Clinical benefits and cost-effectiveness. JAMA 2001 Jun;285(24):3107-15. 12 Smith RA, Cokkinides V, von Eschenbach AC, Levin B, Cohen C, Runowicz CD, et al. American Cancer Society guideline for the early detection of cervical neoplasia and cancer. CA Cancer J Clin 2002 Jan-Feb;52(1):8-22. 13GoldieSJ,KimJJ,WrightTC.Cost‐effectivenessofhumanpapillomavirusDNAtestingforcervicalcancerscreeninginwomenaged30yearsormore.ObstetGynecol2004Apr;103(4):619‐31.

HPVTesting:anAdjuvanttoCytologybasedScreeningandasaPrimary

ScreeningTest

JoseA.Jeronimo,MDStateofthescience

Thereareseveraldiagnostictestsfordetectionofoncogenicgenotypesofhumanpapillomavirus(HPV);somedetectHPV‐DNAandotherstargetHPV‐RNA.RecentresearchindicatesthatHPVtestingisthemostsensitivescreeningtoolavailableatthistimeforthedetectionofCIN3andcervicalcancer.In2009,arandomizedcontrolledtrialofover130,000womeninIndiashowedthatasingleroundofHPVtestingsignificantlyreducedcervicalcancerdeathswithinthesevenyearsoffollow‐up.1

Howtomosteffectivelyintegratethisnewapproachintoascreeningandearlytreatmentregimedependsuponthesuccessofcurrentprogrammes,healthinfrastructureandresources.CurrentguidanceontheuseofHPVtestingvarieswithregardstoitsuseasastand‐aloneprimaryscreeningtestorincombinationwithcytologyorevenforfollow‐upofpatientswithCINaftercompletingtreatment.

HPVDNAasprimaryscreeningtest

TheHPVtestishighlysensitive,althoughlessspecific,inprimaryscreeningofprecancerouslesionsofthecervix(CIN2andCIN3).Globalestimatessuggestthattheoverallage‐adjustedprevalenceofHPVis10.5%.Thereissomegeographicvariation,includingadisproportionateprevalenceinresourcepoorregions.Thisprevalencedeclinesinolderwomen,asmosthaveclearedHPVinfectionbytheirearly30s.2

Therefore,focusingHPVtestingonwomenovertheageof30islikelytoyieldthebestresults,aspositivetestsaremorelikelytopickuppersistentinfectionthanamongyoungerwomen.Meta‐analysesofstudieshaveshownthatthemeansensitivityofHPV‐DNAtestingfordetectionofCIN2/3isover90%3althoughreportsfromstudiesperformedindevelopingcountriesobtainedlowersensitivities.4

SpecificityofHPV‐DNAtestingforcross‐sectionalCIN2/3rangedfrom85‐90%.5Thissub‐optimalspecificityisoneofthelimitationsofthetestsinceaconsiderablenumberofwomenwithpositiveresultsmaybeunnecessarilyreferredforadditionalevaluation,usuallycolposcopyanddirectedbiopsy.Thisisanespeciallyimportantconsiderationinareaswheretreatmentresourcesarelimitedandunnecessaryfollowuptreatmentpresentsaworrisomeburdentothehealthsystem.

OneoftheadvantagesofHPV‐DNAtestingisthehighnegativepredictivevalue.RecentstudiesinEuropeandtheUnitedStatesdemonstratedthattheriskof

developingCIN3afteranegativeHPV‐DNAtestisalmostzerowithin6and10yearsrespectively.6,7ThischaracteristicofHPV‐DNAtestingcouldpermitlongerinter‐screeningperiodsandfeweroverallscreeningsduringawoman’slifetime.

SeveralstudieshaveshownthatHPVtestingofself‐collectedvaginalsamplesprovidehighsensitivityandthismaybeusefulincertaincultures.8,9,10Iffuturestudiesindicatethatself‐samplingisaviableoptionforlowresourcesettings,currentpressureoncliniciantimemayberelieved.Self‐samplingalsoprovidesanoptionforwomentoaccesscervicalcancerscreening,eveniftheyareresistanttoapelvicexamination.

HPVDNAasanancillaryscreeningtest:

• Triageofpatientswithcytologicalabnormalities

HPVtestingdoesnothavearolefortriagingwomenwithclearcytologicalabnormalities(LSIL)sinceaconsiderablepercentageofthesewomenareHPVinfected;addingHPVtestingwouldonlyaddadditionalcostanddelayoftreatment.11ButthereissignificantbenefitinusingHPVtestinginwomenwithundeterminedcytologicalchanges;mostofthesewomenwillbenegativeforHPVinfectionanddonotneedcolposcopyorbiopsy.HPVtestingwomenwithASCUSfindingsreducesthenumberofreferralstocolposcopy,whichisespeciallyimportantinareaswherethereisalackofcolposcopyandpathologyunits,wherethoseservicesareverycostlyortransportationtosuchavisitisimpractical.

• Combinedscreening:CytologyandHPVtesting

ThecombinationofHPVtestingandcytologyhasdemonstratedaslightincreaseinsensitivityfordetectionofCIN2/3comparedtoHPVtestingalone,butthisbenefitwillvanishinareaswherecervicalcytologyperformanceissub‐optimal.AnotherlimitationofcombiningHPV‐DNAtestingandcytologyistheincreasedcost,whichcanbeprohibitiveinlow‐resourcesettings.

• HPVDNAforprimaryscreeningfollowedbyVIA

Sinceaccesstocolposcopyisverylimitedinlowresourceareas,especiallyinruralareasofdevelopingcountries,VIAhasbeenproposedasatriagetoolforwomenwithapositiveHPVresult.AstudyfromSouthAfricashowedVIAimmediatelyfollowedbycryotherapyresultedinasignificantreductionintheincidenceofCIN3atone‐yearfollow‐upcomparedtowomentriagedwithcytologyoracontrolgroup.12Itisimportanttohighlightthat,inthisstrategy,VIAisusedtoidentifywomenwhoarenoteligibleforcryotherapybecauseofalargepre‐cancerouslesionorsuspicionofinvasivecancer;allotherwomenareimmediatelytreatedevenifnolesionisobserved.Inhighresourcecountries,HPVtestingwithtriagetocytologyhasbeenproposed.

• ArapidlowresourceHPVtest

Arapid,low‐cost,portableHPVtestdesignedforruraldevelopingcountrysettingsisexpectedin2011.Thistest,theproductofadonorfundedpublic‐privatepartnership,isdesignedtoallowforHPVtestingwithinthescreenandtreatapproachastestresultsareavailablewithinhours.A2008studyconductedamong2,400womeninChinafoundthisnewtesttobe90%accurateatdetectingprecancerouscellswhenconductedbyamid‐levelprovider;84.2%ofwomenwithoutprecancerouscellswereidentifiedasnegative.13Theseencouragingresultsarenowbeingvalidatedthroughanexpandeddemonstrationprojectinseveralcountries.ItishopedthatthistestcanbesuccessfullyemployedtobringaffordableHPVtestingtopreviouslyunscreenedpopulations.

Barrierstoapplication

• Medicalbarriers:Contraindications‐endocervicalsamplingisnotrecommendedduringpregnancy.

• Physicalbarriers:HPVtestingrequiressophisticatedinstrumentsandequipmentthatareavailableindevelopedcountriesandsomeurbanareasofdevelopingcountries.Theseinstrumentsaredifficulttotransportandareusuallylocatedonlyinwell‐implementedlaboratories.Thisbarriermaybesignificantlyreducedifaviable,rapidlow‐resourcetestbecomesavailableandaccessible.

• Training:MostHPVtestsrequirewell‐trainedlabtechnicians.

• Costbarriers:MostproductsforHPVtestingrequiresignificantinvestmentinlaboratoriesinadditiontothecostofeachtest.Currentmethodsarebecomingavailablethroughprivateprovidersinurbanareasindevelopingcountries.MexicoispilotingtheuseofHPVtestinunderservedareasofthecountry.Formostcountriesandunderservedcommunities,thesetestsaretooexpensive.Incomingyears,alow‐resourcerapidtestmaybeprovidedatacostthatiswithinreachofgovernmentsandlow‐incomeserviceproviders.

• Policybarriers:AlgorithmsformanagementofpatientsafteranHPVtestresultarenotclearlydefinedorunderstoodbymanyprofessionals.Thereisaneedformedicaleducationonthistopic.Also,discountedaccesstoHPVteststogovernments,agenciesandNGOswillneedtobesupportedbyinternationalpurchasingmechanismsanddonors.

HPVtestingiscosteffectiveforscreeningwomenatage30orolder,especiallywhenonlyafewscreeningopportunitieswillbeavailabletoawomaninherlifetime.14Thetestislesscosteffectiveinyoungerwomenduetotheincreasedprevalenceof

transientHPVinfectionsandmildcervicalabnormalities.Forthisagegroup,HPVtestingmaybemostcosteffectiveasatriagetoolforwomenwithsuspectedcytologicalabnormalities,pendingfurthertargetedresearchandcostanalysis.

RecentreportssuggestthatperformanceofVIAorcytologyaremorecosteffectivewhenusedforevaluationofHPVinfectedwomen.14

HPV‐DNAtestingpermitsdetectionofprevalentinfectioninagivenpopulation,butitisstillimpossibletodetermineusingasingle‐timetestwhichwomenwillclearthevirusandwhichwillbecomechronicallyinfectedandprogresstocancer.Additionalevaluationisneededtodeterminepatienteligibilityfortreatment.Guidelinesforpatientmanagementareneeded,especiallyforareaswithlimitedresources.

HPVtestingiswidelyrecommendedforwomenabovetheageof30upto55‐65yearsofage.Inlowresourcesettings,aonceortwiceinalifetimescreeningatage35and45,withtriageofHPVpositivewomentocytologyorVIA,maybeoptimal.Inhighresourcesettings,HPVco‐testingisrecommended(althoughprimarytestingwithtriagetocytologyisbeingstudied).Thescreeningintervaliscurrentlyrecommendedat3‐5yearsbutlongerintervalsarebeinginvestigatedandearlyevidencehasshownthemtobesafeandeffective.

Integrationwithorreplacementofotherpreventionapproaches

Atthistime,HPVtestingisrecommendedwithexistingscreeningmethodsorasatriagetest.ThereplacementofcurrentscreeningapproacheswithasoleHPVtesthasnotbeenrecommended.Thisapproachmayberecommendedinthefutureforcertainsettingsoncesufficientevidenceisavailable.

Considerationsforspecialpopulations(HIV+,pregnancy,etc.)

HPVinfectionismoreprevalentinconditionsassociatedwithimmune‐suppression.HPVprevalenceinHIV‐infectedwomenisdoubleortriplethatofthegeneralpopulation;therefore,asignificantpercentageofHIVpositivewomenwillbereferredforadditionalevaluationafterHPVtesting.Similarly,naturaltransientimmunesuppressionoccursduringpregnancywhenHPVinfectionismoreprevalent,especiallyduringthesecondandthirdtrimester.

Keypoints–HPVtesting:1. HPVtestingisthemostsensitivescreeningtestfordetectionofCIN2/3and

cervicalcancer.2. Sub‐optimalspecificityofHPVtestingresultsinanincreasednumberof

womenreferredforfurtherevaluation.Itcouldbealimitationinsettingswherecolposcopyisnotavailable.

3. HPVtestingiscost‐effectiveforprimaryscreeninginwomen30yearsandover,andfortriageofabnormalcytologyinyoungerwomen.

4. ThehighnegativepredictivevalueofHPVtestingpermitslongerinter‐screeningperiodsandareductioninthenumberofscreeningvisitsneededoveralifetime.

5. Introductionofafaster,simplerandmoreaffordableHPVtestcurrentlyusedindemonstrationprojectswillbenefitareaswithlimitedresources.

References

1 Sankaranarayanan R, Nene BM, Shastri SS, Jayant K, Muwonge R, Budukh A, et al. HPV screening for cervical cancer in rural India. N Engl J Med 2009 Apr;360(14):1385-94. 2 Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose S, Bruni L, et al. Epidemiology and natural history of human papillomavirus infections and type-specific implications in cervical neoplasia. Vaccine 2008 Aug;26(Suppl 10):K1-16. 3 Mayrand MH, Duarte-Franco E, Rodrigues I, Walter SD, Hanley J, Ferenczy A, et al. Canadian Cervical Cancer Screening Trial Study Group. Human papillomavirus DNA versus Papanicolaou screening tests for cervical cancer. N Engl J Med 2007 Oct;357(16):1579-88. 4 Shastri SS, Dinshaw K, Amin G, Goswami S, Patil S, Chinoy R, et al. Concurrent evaluation of visual, cytological and HPV testing as screening methods for the early detection of cervical neoplasia in Mumbai, India. Bull World Health Organ 2005 Mar;83(3):186-94. 5 Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Chapter 9: Clinical applications of HPV testing: A summary of meta-analyses. Vaccine 2006 Aug;24(Suppl 3):S3/78-89. 6 Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: Joint European cohort study. BMJ 2008 Oct;337:a1754. 7 Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005 Jul;97(14):1072-9. 8 Longatto-Filho A, Roteli-Martins C, Hammes L, Etlinger D, Miranda Pereira SM, Erz˘en M, et al. Self-sampling for human papillomavirus (HPV) testing as cervical cancer screening option. Experience from the LAMS Study. Eur J Gynaecol Oncol 2008; 29(4):327-32.

9 Stewart DE, Gagliardi A, Johnston M, Howlett R, Barata P, Lewis N et al. Self-collected samples for testing of oncogenic human papillomavirus: A systematic review. J Obstet Gynaecol Can 2007 Oct;29(10):817-28. 10 Petignat P, Faltin DL, Bruchim I, Tramèr MR, Franco EL, Coutlée F. Are self-collected samples comparable to physician-collected cervical specimens for human papillomavirus DNA testing? A systematic review and meta-analysis. Gynecol Oncol 2007 May;105(2):530-5. 11 Arbyn M, Martin-Hirsch P, Buntinx F, Van Ranst M, Paraskevaidis E, Dillner J. Triage of women with equivocal or low-grade cervical cytology results: A meta-analysis of the HPV test positivity rate. J Cell Mol Med 2009 Apr;13(4):648-59. 12 Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright TC Jr. Screen-and-treat approaches for cervical cancer prevention in low-resource settings: A randomized controlled trial. JAMA 2005 Nov;294(17):2173-81. 13 Qiao YL, Sellors JW, Eder PS, Bao YP, Lim JM, Zhao FH, et al. A new HPV-DNA test for cervical-cancer screening in developing regions: A cross-sectional study of clinical accuracy in rural China. Lancet Oncol 2008 Oct;9(10):929-36,. 14 Goldie SJ, Kim JJ, Myers E. Chapter 19: Cost-effectiveness of cervical cancer screening. Vaccine 2006 Aug;24(Suppl 3):S3/164-70.

Colposcopy

Stateofthescience

ColposcopywasfirstintroducedbyHansHinselmannin1925inGermany.Acolposcopeallowsbothmagnificationandilluminationofthecervix,thusfacilitatingbiopsyoftheworstareaafterapplicationofaceticacidandLugol’siodine.Colposcopyisnotasufficienttoolforscreening,asaloneithaslowsensitivityandlowpositivepredictivevalue.However,itisessentialinacervicalcytologyscreeningprogrammeforassessmentofabnormalcytologyfindingstomakeadiagnosisofpre‐invasiveorinvasivecervicalneoplasia.Withanabnormalcervicalcytologyresultinascreeningprogramme,guidelinesonwhentoperformcolposcopyonminimalabnormalitiessuchasatypicalsquamouscellsofundeterminedsignificancevaryamongcountries.However,forhighgradeabnormality,colposcopyisindicated.

After3‐5%aceticacidsolutionisappliedtothecervix,thecervixisdirectlyvisualizedusinglow‐andhigh‐powermagnificationfollowedbyagreenfilterinspection.Aceticacidhasatemporarydehydratingeffectonsquamouscellsandaccentuatestheirhighnuclear‐cytoplasmicratios.Tothehumaneye,thehigherthegradeofthecervicallesion,themoreopaqueitappears,asthenucleiimpedeslighttransmission.Theselesionsaredescribedas“acetowhite.”Apartfromcolourchanges,acharacteristicmicrovasculaturepatternthatincludespunctuationandmosaicismmaybeseen.Anexperiencedcolposcopistdeterminestheseverityofcervicalneoplasiabasedonsuchchanges.Althoughbenignconditionsmaycauseacetowhitechangesonthesquamousepithelium,dysplasticlesionsaresharplydemarcatedfromadjacentnormalepithelium,andaremostoftenlocatedatthesquamocolumnarjunction.Histologicalassessmentbybiopsiestakenfromtheacetowhitelesionsisneededtomakeadefinitivediagnosisoflesionscausingtheabnormalcytology.Colposcopicadequacyisdefinedbyvisualizationoftheentiresquamocolumnarjunctionaswellasanyacetowhitelesions.Colposcopyiscarriedoutinanout‐patientsetting.Itrequirestrainingandassuranceofqualityandhenceaccreditationsystemsarecommoninmanycountries.

Themainbarriertocolposcopyislackofresourcesinacquiringtheequipment,whichisquiteexpensive,andthetrainingandretentionofskilledmedicalpersonnel.Areliablesupplyofelectricityisneededtooperateacolposcope.Accreditationandre‐accreditationhelpinmaintainingqualityofcarestandards.Otherissuesincludetheaccesstopathologysupportinprocessingandinterpretingthebiopsiedsamplesandthequalityassuranceofthelaboratory.Thecostofallofthesecomponentsmaybeprohibitiveinsomesettings.

Thecostofcolposcopyexaminationcontributestothecost/efficacyanalysisofacytology‐basedcervicalcancerscreeningprogramme.Thus,usingcytologyscreeningcouldcostmorebecauseoftheneedforcolposcopyforanabnormalcytology.However,thecostforcolposcopyexaminationnotonlyincludestheconsultationfee,butforthepatient,thetimeandcostforasecondorthirdvisitaswellasanxietywhilewaitingfortheresult.Thoughseeandtreatmaybeanoption,overtreatmentwithitsrelatedmorbidity1maynotjustifythereductionofcostforasecondvisit.Nevertheless,ifanexperiencedcolposcopistidentifiesahigh‐gradelesion,seeandtreatinonevisitisacceptable.

Recently,theuseofcolposcopy/biopsyasthegoldstandardindetectionofcervicallesionsfollowinganabnormalcervicalcytologywaschallenged.2Fourquadrantcervicalbiopsiesfromthesquamocolumnarjunctionandendocervicalsamplingpickedupmorecervicallesionsthancolposcopicdirectedbiopsy.Morestudyisneededtoconfirmthisfinding.

TheroleofcolposcopyinprimaryscreeningwithhighriskHPVtestingneedsfurtherstudytodeterminetheappropriatefollowup.

Recommendationforoptimaluse

Inscreeningprogrammes,colposcopyremainsthegoldstandardformakingthedefinitivediagnosis.Theindicationforcolposcopyvariesdependingonthescreeningmethodsused.Ifcervicalcytologyisusedastheprimaryscreeningtool,guidelinesshouldbefollowedonwhencolposcopyshouldbeperformed.Basically,allhigh‐gradecytologyhastobeassessedbycolposcopyandbiopsieswithinareasonablelengthoftimesuchaswithinfourweeks.IfhighriskHPVtestingisusedastheprimaryscreeningtool,thealgorithmisyettobedecided.However,therecentrecommendationfromASCCPistoperformcolposcopyinwomentestedtohaveHPV16evenintheabsenceofabnormalcytology.IfVIAorVILAisusedastheprimaryscreeningtool,theroleofcolposcopyislesscertain.

References

1 CraneJM.Pregnancyoutcomeafterloopelectrosurgicalexcisionprocedure:Asystematicreview.ObstetGynecol2003Nov;102(5Pt1):1058‐62. 2 PretoriusRG,ZhangWH,BelinsonJL,HuangMN,WuLY,ZhangX,etal.Colposcopicallydirectedbiopsy,randomcervicalbiopsy,andendocervicalcurettageinthediagnosisofcervicalintraepithelialneoplasiaIIorworse.Am J Obstet Gynecol. 2004 Aug;191(2):430-4.

Cryotherapy

JohnW.Sellors,M.D.

Stateofthescience

Cryotherapyhasbeeninuseforover40yearsasasafeandeffectivewayofdestroying(ablating)CINlesionsontheectocervixbyfreezingthecervicalepithelialtissue.Cellsrapidlyreducedto‐20degreesCforoneormoreminuteswillundergocryonecrosis.

Aftervisualizationofthecervixusingavaginalspeculum,acryotherapyprobewithacircularmetaltipofapproximately2cmdiameterisappliedtotheectocervixandarefrigerantgas(nitrousoxideorcarbondioxide)isallowedtoflowthroughtheinstrumentcoolingthemetaltip.Guidedbyatimerorwatch,theaffectedtissueisfrozenforthreeminutes,allowedtothawforfiveminutesandthenre‐frozenforthreeminutes.1

Cryotherapyiswell‐suitedforlow‐resourcesettings.Itrequiresnoanaestheticorelectricity,theequipmentisportable,thecostofconsumablesandequipmentislessthanelectrosurgicalmethods,andwithadequatetrainingandsupervision,primaryhealthcareprofessionalsotherthanphysiciansareabletoperformthetechnique.Areviewoftheliteratureshowsacurerateof90%atone‐yearandover85%ofwomenfoundtheproceduretobesafeandhighlyacceptable.Mildsideeffectssuchasfaintingduringtheprocedure,vaginaldischarge,cramping,andspottingduringthefirstmontharecommon,butdonotimpacttheacceptabilityorsafetyoftheprocedure.2Recentstudiesindevelopingcountrysettings,withactivefollowup,showthatcomplicationssuchascervicitis(1%)andPelvicInflammatoryDisease(PID)(<1%)areunusual.3,4Longtermsequelaesuchascervicalstenosisorinfertilityarerare.2Womenareadvisedtoabstainfromsexualintercourseforatleastonemonthaftertreatmentortousecondoms.Adequatecounsellingisveryimportantforbetteracceptanceofsideeffectsandrecognitionofsignsofcomplication.

• Medicalcontraindications:

o Relative:generallynotrecommendedforpregnantwomen;largelesionsmorethanthreecervicalquadrants;presenceofmenstrualbleeding.

o Absolute:suspicionofinvasivecancer;lesioninvolvingtheendocervicalcanalorextendingtothevagina;morethan2mmoflesionmarginsnotcoveredbythecryoprobe;presenceofuntreatedPIDorcervicitis;bleedingdiathesis;vaginalwallprolapsecausingeitherinadequatevisualizationofthecervixorcontactofthefrozen

probewithvagina;inabilitytophysicallyoremotionallytoleratetheprocedure;awomanwithalesionthathasnotresolvedaftertwocryotherapysessionsshouldhaveexcisionaltreatment.

• Physicalbarriers:Afterusethemetaltipofthecryoprobeneedstobeadequatelydecontaminatedasrecommendedbythemanufacturer(10%bleachsolutionor70%ethylalcohol),scrubbedwithdetergentandwaterbypersonnelwearingrubberglovesandprocessedbyeithersterilizationorhighleveldisinfectivebeforereusetopreventspreadofinfectionfromonepatienttoanother.Theequipmentissimpletostore(preferablycovered)andeaseofrepairvarieswiththetypeofequipmentandavailabilityofserviceandspareparts.

• Training:Cryotherapyistechnicallysimplerthanothertreatmentmethodsandtrainingrequiresafewdaysformostprimaryhealthcareproviderswiththerequisiteskillsandknowledge.Ongoingmonitoringandsupervisionisnecessarytomaintainproviderskills.5

• Costbarriers:Inadditiontodirectcostsforthefacility,personnelfortreatmentandtwofollowupvisits(at1‐2monthsandtestofcureatoneyear),treatmentcostdependsontherefrigerantusedandsizeoftank(largertanksgenerallycostlesspertreatment).Industrialgradecarbondioxideisapproximately3‐5timescheaperthannitrousoxide.Thecostofacryotherapyunitvariesfromabout$400forreliableunitsmadeinlessdevelopedcountriestoover$1200forNorthAmericanorEuropeanunits.Duetothehighratesofcervicitisinmanydevelopingcountrysettings,presumptivetreatmentwithashortcourseofantibioticsmaybeprescribedimmediatelyaftercryotherapy(e.g.,combinationofmetronidazole400mgTIDanddoxycycline100mgBIDx5days).

• Policybarriers:Cryotherapyisrecommendedascost‐effective,safeandacceptableandcurrentlyispermittedinmostdevelopedanddevelopingcountries.Itwascommonintheindustrializedworlduntilothertechniques,suchasLEEP,wereadoptedinitsplace.Sincemanycountriesallowtrainedandsupervisednursesandparamedicalstafftoperformcryotherapy,thisaddressesthebarrieroflimitingtheproceduretophysicians.

Basedonareviewofpublishedevidenceinbothdevelopedanddevelopingcountries,cureratesatoneyearare90%overall,83‐100%forCIN1,65‐95%forCIN2,and55‐92%forCIN3.2Modellinghasshownthat,inlow‐resourcesettingswherescreeningislimitedtoonceortwiceinalifetime,cryotherapyisverycost‐effectiverelativetoothertreatmentmethods.

Experiencehasshownthatinsomelow‐resourcesettings,blockage(orcloggingofthegasflowwithinthepassagesofthecryounit)mayoccurduringtheprocedure.Aninteragencycollaborationisaddressingtechnicalissuessuchashowtopreventblockageandequipmentfailurebydevelopingspecificationsforprocedures,equipment,refrigerantgas,andaccessories.ThedegreeofriskofSTIorHIVtransmissionoracquisitionduringthehealingphaseaftercryotherapyneedsfurtherresearch.6,7TheeffectivenessofcryotherapyinwomenwithHIVinrelationtotheirCD4countshouldalsobeexplored.

Cryotherapymaybeusedinawidevarietyofsettings,includinglow‐resourcesettings,wherethereareadequatequalityassurancemechanismsinplacesuchasclinicalmonitoringandsupervision.Useofcryotherapyinasinglevisitapproachoptimizesprogrammeeffectiveness.Theequipmentisportableandthetreatmentmethodissimpleenoughthatitcanbeusedinamobileoutreachcervicalcancerpreventionprogramme.

Integrationwithorreplacementofotherpreventionapproaches

Inlow‐resourcesettingscryotherapyisrecommendedasthemaintreatmentmethodinsuitablepatients.InthosewithcontraindicationstocryotherapyothertreatmentsshouldbeconsideredsuchasLEEPorconization.

Considerationsforspecialpopulations(HIV+,pregnancy,etc.)

PreviouslymentionedinsubheaddealingwithBarriersandGapsinknowledge.

Keypoints–Cryotherapy:1. Cryotherapyisanacceptable,affordable,safeandeffectivetreatmentof

ectocervicalCINinbothlow‐andhigh‐resourcesettings.2. ComparedtotheequipmentandsuppliesrequiredforLEEP,cryotherapy

costsmuchlessanddoesnotrequireelectricity.3. Accessibilitytotreatmentisincreasedsinceprimaryhealthcarepersonnel

otherthanphysicianscanbetrainedtoperformcryotherapyundermonitoringandsupervision.

4. Insuitablepatientscryotherapycures90%ofCINoverallbutisnotrecommendedforlesionsinvolvingtheendocervixorvagina.

5. PendinganswerstoquestionsontheriskoftransmissionandacquisitionofSTI’sandHIVduringthepost‐cryotherapyhealingperiod,patientsareadvisedtoavoidintercourseortousecondomsforatleastonemonth.

References

1 Sellors JW, Sankaranarayanan R, editors. Colposcopy and treatment of cervical intraepithelial neoplasia: A beginner’s manual. Lyon, France: IARC Press; 2003/4. 2CastroW,GageJ,GaffikinL,FerreccioC,SellorsJ,SherrisJ,etal.Effectiveness,safety,andacceptabilityofcryotherapy:Asystematicliteraturereview.CervicalCancerPrevention:IssuesinDepth#1.AllianceforCervicalCancerPrevention.2003.Availableat:http://www.path.org/files/RH_cryo_white_paper.pdf3 Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R, Shanthakumari S, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: A cluster-randomized trial. Lancet 2007 Aug;370(9585):398-406. 4 Nene BM, Hiremath PS, Kane S, Fayette JM, Shastri SS, Sankaranarayanan R. Effectiveness, safety, and acceptability of cryotherapy by midwives for cervical intraepithelial neoplasia in Maharashtra, India. Int J Gynaecol Obstet 2008 Dec;103(3):232-6. 5 Blumenthal PD, Lauterbach M, Sellors JW, Sankaranarayanan R. Training for cervical cancer prevention programs in low-resource settings: Focus on visual inspection with acetic acid and cryotherapy. Int J Gynaecol Obstet 2005(May);89(Suppl 2):S30-7.

6 Wright TC Jr, Subbarao S, Ellerbrock TV, Lennox JL, Evans-Strickfaden T, Smith DG, et al. Human immunodeficiency virus 1 expression in the female genital tract in association with cervical inflammation and ulceration. Am J Obstet Gynecol 2001 Feb;184(3):279-85. 7 Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright TC Jr. Screen-and-treat approaches for cervical cancer prevention in low-resource settings: A randomized controlled trial. JAMA 2005 Nov;294(17):2173-81.

LEEP/CervicalCone

KatinaRobison,MD

Stateofthescience

Cervicalcancerandcervicaldysplasiaremainsubstantialhealthburdensworldwide.Cervicalconizationiswidelyacceptedasthepreferredmanagementofcervicalintraepithelialneoplasia(CIN).1,2,3,4Cervicalconetechniquescurrentlyusedincludecoldknifecone(CKC),loopelectrosurgicalexcisionprocedures(LEEPandLLETZ),andlaserconization.AllthreetechniquesareeffectiveinthetreatmentofCINandstudieshavefoundnodifferenceinthesampleadequacybetweenthetechniques.1,2,5,6Cervicalconeprocedureshavebeenshowntobesafeinmostsettings.Bleeding,infectionandanaesthesiareactionsarethemostcommoncomplications,buttheratesofcomplicationsremainlow.4,5

Thecervicalconizationtechniquechosenisbasedonmultiplefactors,includinghistologicdiagnosis,locationofthelesion,andavailableanaestheticandproceduralresources.Forexample,inlowresourcesettingsaloopexcisionispreferredbecauseitismorecosteffectiveandsaferthanaCKC.Inaddition,theavailabilityofresourcesmayinfluencethemanagementdecision.Conventionally,acervicalconeprocedureisperformedaftercolposcopyandbiopsies.However,acervicalconeproceduremayalsobedoneinasingle‐visit“see‐and‐treat”approachinwhichevaluationandtreatmentareperformedatthesametime.1Theapproachtocervicaldysplasiacanbetailoredbasedonresourceavailabilityanddiseasestatus.7,8,9,10

Barrierstocervicalconeprocedure

Barriers Lowresourcesettings Highresourcesettings

Medical • Anatomical:cervixflushwithvagina

• Infection

• Anatomical:cervixflushwithvagina

• InfectionPhysical • Voltagemismatch/irregularities

• Inadequatehaemostaticequipment

• Lackofcleanwater• Hazardouswastedisposal• Equipment• Operatingroom/clinicspace• PathologyServices• Traveltocentraltreatmentfacility

• Availabilityofanaesthesia

• Traveltocentraltreatmentfacility

Training • Requirestrainedmedicalpractitioner

• On‐sitetraining(atleastfourweeks)andretraining

• Requirestrainedmedicalpractitioner

• Trainingduringresidency/fellowship

Cost • Equipment• Laboratory• Pathologyservices• Deliveryofsupplies

• Insurancescheme/coveragedependent

Policy • Follow‐uplimited• Requiressupportoflocalproviders

• Insurancescheme/coveragedependent

AdaptedfromHolschneiderCH,GhoshK,MontzFJ.

Therearemultiplemanagementoptionsforcervicaldysplasia.Cold‐knifeconeandloopexcisionhavebeenshowntobeequallyeffectiveforthetreatmentofcervicaldysplasia.However,thereissomeevidencethatCKCisbetteratevaluatingendocervicalextension.Inaddition,whenCKCisimmediatelyavailableitmaybepreferredforlargerlesionsasithasbeenshowntoremovemoretissuethanloopexcision.1,2,4,6

Conventionalmanagementofcervicaldysplasiainhighresourcesettingsconsistsofcolposcopywithdirectedbiopsies.Ifnecessary,acervicalconizationisperformedbaseduponhistologicfindings.Inlowresourcesettings,the“see‐and‐treat”strategyhasbeenshowntobeacost‐effectivealternative.Holschniederetal.founda41%costreductioncomparedtoconventionalmanagement.8

Recommendationsforuse

Lowresourcesettings

Coldknifecone:Useislimitedbecauseitrequiresgeneralanaesthesiaandanoperatingroom.Itmaybeperformedasatreatmentoptioninearlystagecervicalcancerwhenfuturefertilityisdesired.

LEEP/LLETZ:Trainedmedicalpractitionersmayusetheseproceduresinsinglevisit/“see‐and‐treat”approach.Visualinspectionwithaceticacidmaybeperformedatthesamevisitasloopexcisionorpriorwithatrainednurseandreferredfortreatmentwhenappropriate.Womenwithhigh‐gradesquamousintraepitheliallesion(HGSIL)cytology,largelesions(>3quadrants)and/orhighgradeappearinglesionsonvisualizationshouldreceiveaLEEP.10

Highresource/highaccesssettings

Coldknifecone:Agynaecologistorgynaecologiconcologistshouldperforminanoperatingroom.Aftercolposcopy,womenwithbiopsyprovenadenocarcinoma‐in‐situ,microscopicinvasivesquamouscellcarcinomaormicroscopicadenocarcinomashouldhaveaCKC.CKCisalsorecommendedwithhigh‐gradedysplasiaonendocervicalcurettage(ECC).

LEEP/LLETZ:Trainedmedicalpractitionersshouldusetheseproceduresintheofficeoroperatingroomaftercolposcopyandcervicalbiopsieshavebeenperformed.Loopexcisionsarepreferredwheninvasivecancercannotberuledoutandtheriskishigh.Thisincludeswomenwithunsatisfactorycolposcopicexaminations,positiveendocervicalcurettage,largelesionswithhigh‐gradecolposcopicimpressionandpost‐treatmentrecurrenceofCIN2and3.Loopexcisionmayalsobeconsideredaspartofa“see‐and‐treat”approachforwomenreferredforahigh‐gradesquamousintraepitheliallesiononcytology,regardlessofcolposcopicfindings.1

Gapsinknowledge

Thereisstrongevidencesupportingtheuseofthe“see‐and‐treat”approachinlowresourcesettings.However,thedefinitionoflowresourceisbroadandcanincluderuralareasindevelopedcountries,uninsuredindividualswithlimitedaccessandwomenthatdonotroutinelyparticipateinscreening.Itislessclearifthisapproachshouldbeofferedinthesesettingswherenationalguidelinesmayalreadyexistandthisapproachdeviatesfromtheseguidelines.Insomeofthesesettings,theremayonlybetheopportunityforonevisitandthe“see‐and‐treat”approachmaybethemosteffective.However,therearelimitedstudiescomparingthisapproachtotheconventionalapproachinsuchsettings.Integrationwith/orreplacementofotherapproachesLoopexcisionshouldbeusedinconjunctionwitheithercytologyfollowedbycolposcopyorVIAbasedontheresourcesettingwhereitisperformed.LoopexcisionhaswidelyreplacedCKCinlowresourcesettingsandmaybeusedinplaceofCKCinhighresourcesettingsasdiscussedinthe“recommendationsforuse”section.AlternativestoloopexcisionincludeCKCandcryotherapy.ConsiderationsforspecialpopulationsPregnancyTreatmentofCINshouldbeavoidedduringpregnancy,asitisassociatedwithahighrateofcomplications,includingseverehaemorrhage.11Additionally,whenexcisionisperformedduringpregnancythereisahighrateofincompleteexcisionandrecurrence.Theonlyindicationforexcisionisdiagnosisofinvasivecancer.

However,early‐stagecervicalcancermaybefollowedduringpregnancyandtreatmentdelayeduntildelivery.

Adolescents

Theriskofinvasivecancerislowinadolescentsandthereisahighrateofspontaneousregressionofsquamousintraepitheliallesionsamongthisgroup.Cervicalconeprocedureshavebeenassociatedwithincreasedriskofpretermdelivery.Kyrgiouetal,performedameta‐analysisandfoundCKCandLLETZareassociatedwithpretermdelivery(<37weeks).12Arecentcase‐controlstudyreportedashortconization‐to‐pregnancyperiod(conceptionwithin2to3months)wasassociatedwithanincreasedriskofpretermdelivery,butnotcervicalconizationalone.12,13Performingcervicalconeproceduresonadolescentswouldincreasetheriskoffuturepregnancycomplicationsandpotentiallybeunnecessary.

HIV‐infectedwomen

HPVismoreprevalentamongHIVinfectedwomenandHIV‐infectedwomenhavemorerapidprogressionratesofCINtocervicalcancer.10Therefore,routinescreeningispreferredinallresourcesettings.However,indicationsforcervicalconizationarethesameforHIV‐infectedwomenandnon‐HIV‐infectedwomen.The“see‐and‐treat”approachhasbeenimplementedinlowresourcesettingsforHIV‐infectedwomenandappearstobefeasible.

Keypoints:LEEP/CervicalCone

1. CervicalconizationissafeandeffectiveinthemanagementofCIN2/32. Coldknifeconeandloopelectrosurgicalexcisionproceduresappeartobe

equallyeffectiveinthetreatmentofcervicaldysplasia.3. Followupaftercervicalconizationshouldbebasedonpathologyresultsand

theresourcesetting.4. The“see‐and‐treat”approachiscost‐effectiveinlowresourcesettings.5. Cervicalconizationshouldbeavoidedinpregnancyunlessthereisinvasive

cancer.

References

1WrightTCJr,MassadLS,DuntonCJ,SpitzerM,WilkinsonEJ,SolomonD,etal.2006consensusguidelinesforthemanagementofwomenwithcervicalintraepithelialneoplasiaoradenocarcicnomainsitu.JLowGenitTractDis2007Oct;11(4):223‐39. 2CoxJT.Managementofcervicalintraepithelialneoplasia.Lancet1999Mar;353(9156):857‐9. 3WardBG,BroeSJ.Outpatientmanagementofabnormalsmears.AustNZJObstetGynaecol2003Feb;43(1):50‐3. 4PrendivilleW.ThetreatmentofCIN:Whataretherisks?Cytopathology2009Jun;20(3):145‐53. 5MitchelMF,Tortolero‐LunaG,CookE,WhittakerL,Rhodes‐MorrisH,SilvaE.Arandomizedclinicaltrialofcryotherapy,laservaporization,andloopelectrosurgicalexcisionfortreatmentofsquamousintraepitheliallesionsofthecervix.ObstetGynecol1998Nov;92(5):737‐744. 6GiacalonePL,LaffargueF,AligierN,RogerP.CombecalJ,DauresJP.Randomizedstudycomparingtwotechniquesofconization:Coldknifeversusloopexcision.GynecolOncol1999Dec;75(3):356‐60. 7SellorsJ,LewisK,KidulaN,MuhombeK,TsuV,HerdmanC.Screeningandmanagementofprecancerouslesionstopreventcervicalcancerinlow‐resourcesettings.AsianPacJCancerPrev2003Jul‐Sep;4(3):277‐80. 8HolschneiderCH,GhoshK,MontzFJ.See‐and‐treatinthemanagementofhigh‐gradesquamousintraepitheliallesionsofthecervix:Aresourceutilizationanalysis.ObstetGynecol1999Sep;94(3):377‐85. 9FungHY,CheungLP,RogersMS,ToKF.Thetreatmentofcervicalintra‐epithelialneoplasia:Whencouldwe‘seeandloop.’EurJObstetGynecol1997Apr;72(2):199‐204. 10PfaendlerKS,MwanahamuntuMH,SahasrabuddheVV,MudendaV,StringerJS,ParhamGP.Managementofcryotherapy‐ineligiblewomenina“screen‐and‐treat”cervicalcancerpreventionprogramtargetingHIV‐infectedwomeninZambia:Lessonsfromthefield.GynecolOncol2008Sep;110(3):402‐7. 11GinsbergGM,Tan‐TorresEdejerT,LauerJA,SepulvedaC.Screening,preventionandtreatmentofcervicalcancer —Aglobalandregionalgeneralizedcost‐effectivenessanalysis.Vaccine2009.Inpress.

12KyrgiouM,KoliopoulosG,Martin‐HirschP,ArbynM,PrendivilleW,ParaskevaidisE.Obstetricoutcomesafterconservativetreatmentforintraepithelialorearlyinvasivecervicallesions:Systematicreviewandmeta‐analysis.Lancet2006Feb;367(9509):489‐98. 13HimesKP,SimhanH.Timefromcervicalconizationtopregnancyandpretermbirth.ObstetGynecol2007Feb;109(2Pt1):314‐19.

Overview:CervicalCancerTreatment

Thebeststrategyforcervicalcancercontrolisprimaryprevention,screeningandtreatmentofpre‐invasivedisease.Ofnecessity,cervicalcancertreatmentrequiresfocusedexpertiseandavailabilityofoperatingtheatres,chemotherapyandradiotherapy,allofwhichcarryhighpricetags.Inresourcepoorcountries,concentrationoftheseexpensiveresourcesinonecentralfacilityhelpstolimitcostsbutrequiresadequatetransportationandsupportmechanismsforwomenandfamiliestousewhensuchcareisneeded.Regardlessoftheefficacyofprevention,screeningandearlytreatmentofpreinvasivedisease,therewillstillbecasesofinvasivecancer.Thisrequireseachprogrammetohaveaplaninplaceforwomenwithcervicaldisease.Inaddition,astrategyforendoflifetreatmentincludingadequatepaincontrolisacriticalpartofthecreationoftheuniquebundleofservicesforcervicalcancercontrolineachsetting.

FIGOCancerCommitteeGuidelinesforEarlyInvasiveCervicalCancerManagement

Stateofthescience

Standardtreatment Specialconsideration

StageIA1 Simplehysterectomy Conservative–conewithclearmargin

StageIA2 Simpleorradicalhysterectomyandbilateralpelviclymphadenectomydependingonlocalorregionalguidelines

Conservative–largeconeortrachelectomyandbilateralpelviclymphadenectomydependingonlocalorregionalguidelines

StageIB1 Radicalhysterectomyandbilateralpelviclymphadenectomyorradiotherapy

Conservativeforsmalllesion‐trachelectomyandbilateralpelviclymphadenectomy

StageIB2 Chemoradiationorradicalhysterectomyandbilateralpelviclymphadenectomy+/‐adjuvantradiotherapyorchemoradiation

Neoadjuvantchemotherapythensurgeryinselectedpatients

StageIIA1or2 Chemoradiationorradicalhysterectomyandbilateralpelviclymphadenectomyinselectedpatients+/‐adjuvantradiotherapyorchemoradiation

StageIIB Chemoradiationorradicalhysterectomyandbilateralpelviclymphadenectomyinselectedpatients+/‐

adjuvantradiotherapyorchemoradiation

StageIIIA Chemoradiationorradiotherapy

StageIIIB Chemoradiationorradiotherapy

StageIVA Chemoradiationorradiotherapy

Pelvicexenteration

StageIVB Palliativeradiotherapyorchemotherapy

Endoflifecareespeciallyadequatepaincontrolanduseofmorphine

Barrierstotreatment

Treatmentofinvasivecervicalcancerrequiresmultidisciplinarycontributionsfromgynaecologicaloncologists,radiationoncologists,radiationoncologyspecialists,medicaloncologists,radiologistsandnursespecialists.Establishmentofaregionaltreatmentcentrewithappropriatelytrainedspecialistscouldbeaprobleminlowresourcesettings.Inthecaseofradiationtherapy,thereisaneedforbothanexternalradiotherapymachinesaswellasabrachytherapysystem.Apartfromthefacilities,appropriatelytrainedsupportstaffandradiotherapistsmaynotbeavailableinlowresourcesettings.Otherbarriersincludelackofknowledgeofdetectionandcureofcervicalcancerandculturalbarriersofwhatisperceivedasforeign.Physicalaccesstoacancertreatmentcentre(transportationandabilitytolivenearbywhilereceivingtreatment)couldbeabarrierinsomecountries.

Inordertoreducethecostandincreaseefficacy,earlydetectionandprompttreatmentcanincreasechancesofsurvivalandreducecostofpalliativecare.Thecostofradiotherapytreatmentversussurgicaltreatmentvariesbetweencountries.Thus,thechoiceoftreatmentmayalsovarydependingonexpertiseandfacilitiesavailableon‐site.

Theoptimaltypesandnumberofcoursesofchemotherapyconcurrentwithradiationneedtobebetterdefined.Theroleofadjuvantchemotherapyafterchemoradiationforadvanceddiseaseandtheroleandchoiceofchemotherapyregimeninneoadjuvantchemotherapybeforesurgeryinadvanceddiseaseare

undergoingstudy.Theroleofnewradiotherapytechnologysuchasintensity‐modulatedradiotherapyindecreasingside‐effectsofradiotherapyneedfurtherstudy.

Womenwithcervicalcancershouldpreferablybetreatedbygynaecologicaloncologistsorradiotherapistsinacentrewithadequatefacilities.Thesecentresshouldbeestablishedwitheasyaccessandaffordabilitysoasnottodeprivewomenwithcervicalcancerthechanceofacure.Thechoiceofoptimaltreatmentofcervicalcancerdependsnotonlyonthestageofthediseasebutalsoontheavailabilityofexpertise,facilities,patient’swishesandaccessibility.Agoodpre‐treatmentassessment,appropriatetreatment,post‐treatmentmonitoringandpsychosocialsupportareimportant.Palliativecare,includingthelegaluseofmorphine,shouldbemadeavailableforthosewithnohopeofbeingcured.Inordertohaveabetterunderstandingoftheburdenandoutcomeofwomenwithcervicalcancer,acancerregistryshouldbeestablishedineachlocality.

TheWorldHealthOrganization’s“Comprehensivecervicalcancercontrol:aguidetoessentialpractice”hasausefulchapteronpalliativecare.

Resource–basedApproachestoCervicalCancerControl

Potential“BundlesofServices”

CancerregistryforALL Limitedvisits

(Onetofew)

Unlimited

followup

HighlyLimitedResources

Prevention

Screening/Treatment

Dysplasia

Cancer

HPVVaccine

SingleVisitApproach

• VIA*or• SinglelifetimeHPV

screen‐and‐treat• CryotherapyorLEEP

Referralsystemtoappropriatecentraltreatment

HPVVaccine

SingleVisitApproach**

• VIA*or• SinglelifetimeHPV

screen‐and‐treat• CryotherapyorLEEP

ModeratelyLimitedResources

Prevention

Screening

Treatment

Dysplasia

Cancer

HPVVaccine

VIA*or

HPVTesting

• If+,VIAorColposcopySingleVisitApproach

• CryotherapyorLEEP

HPVVaccine

Cytologyand/orHPVTesting

• If+,VIAorColposcopy

+/‐biopsies

CryotherapyorLEEP

ResourceRich

Prevention

Screening

HPVVaccine

CytologyandHPVTesting

• Colposcopyasneeded

HPVVaccine

CytologyandHPVTesting

Treatment

Dysplasia

Cancer

CryotherapyorLEEP

ReferraltoGynaecologicOncologist

CryotherapyorLEEP

ReferraltoGynaecologicOncologist

*RapidHPVtestavailabilitymaychangerecommendations

**Preferabledotolimitationstounlimitedfollow‐upinhighlylimitedresourceareas

UsefulWebsiteandResources*WebsitesRHOCervicalCancerwww.rho.orgPATHcervicalcancerpreventionwww.path.org/cervical‐cancer.phpAllianceforCervicalCancerPrevention(ACCP)www.alliance‐cxca.orgInternationalAgencyforResearchonCancer(IARC)ScreeningGroupwww.iarc.fr/cervicalindex.phpWorldHealthOrganization—cancersofthereproductivesystemwww.who.int/reproductive‐health/publications/cancers.htmlTwowebsitesonHPVvaccinesafety:MedicinesandHealthcareProductsRegulatoryAgency(MHRA)—currentlymonitoringthesafetyofGlaxoSmithKline’sCervarix®HPVvaccine.Cervarix®iscurrentlybeingintroducedthroughtheUKNationalHealthSystem(NHS)http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Product‐specificinformationandadvice/HumanpapillomavirusHPVvaccine/CON023340TheU.S.FoodandDrugAssociation(FDA)andtheCentersforDiseaseControlandPrevention(CDC)—currentlymonitoringtheintroductionandsafetyofMerck’sGardasil®,theonlyvaccineregisteredatpresentintheUnitedStateshttp://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/ucm179549.htmReferenceMaterialsandTrainingManuals:WorldHealthOrganization.Comprehensivecervicalcancercontrol:Aguidetoessentialpractice(2006)Theguideaimstocompilewhatisknownaboutcervicalcancerandrelatedmorbidityandmortality.Itisdesignedasacomprehensiveandeasy‐to‐useresourceforhealthcareprovidersattheprimaryandsecondarylevels(primarilyinlimited‐resourcesettings)onhowtoprevent,detectandtreatcervicalcancer.Evidence‐basedrecommendationscoverthefullcontinuumofcare.Accessibleat:http://www.rho.org/files/WHO_CC_control_2006.pdf

EngenderHealth.COPE®forcervicalcancerpreventionservices:AtoolbooktoaccompanytheCOPE®handbook(2004) COPE(client‐oriented,provider‐efficientservices)isaprocessthatinvolvesfacilitystaffandsupervisorstojointlyassessservicesinordertoimprovequality.Thistoolbookincludesguides,checklistsandformstohelpthoseinsettingswhereresourcesarehighlyrestrictedtointegratethevariouselementsofserviceprovisionintoacomprehensiveandqualitywhole.Accessibleat:http://www.rho.org/files/EngenderHealth_COPE_toolbook_2004.pdfACCP.10keyfindingsandrecommendationsforeffectivecervicalcancerscreeningandtreatmentprograms(2007Apr)ACCPpartnersmetinearly2007toassesstheresultsofkeystudiesinfourcountriesfromacrossregions:India,SouthAfrica,Peru,andThailand.Thesetenkeyfindingsandrecommendationsaretheresultofthisfreshdataandareintendedtoshapepolicyandpracticerelatedtocervicalcancerscreeningandtreatmentinlow‐resourcesettings.Accessibleat:http://www.guttmacher.org/archive/IFPP.jspWorldHealthOrganization.WER2009index.WHOPositionPaperonHPVVaccines10Apr2009;84(15):117‐32.ThispaperonHPVvaccines,providedinbothEnglishandFrench,ispartofaseriesthatpredominantlyfocusedonlarge‐scaleimmunizationprogrammes.IthasbeenreviewedbyWHOandoutsideexpertsandhasbeenendorsedbyWHO’sStrategicAdvisoryGroupofExpertsonvaccinesandimmunization.Itismainlyintendedforusebynationalpublichealthofficialsandimmunizationprogrammemanagers,butmayalsoberelevanttointernationalfundingagencies,vaccinemanufacturersandthemedicalcommunityatlarge.Accessibleat:http://www.rho.org/files/WHO_WER_HPV_vaccine_position_paper_2009.pdf

WorldHealthOrganization(WHO),PATH,UnitedNationsPopulationFund(UNFPA).Cervicalcancer,humanpapillomavirus(HPV),andHPVvaccines:Keypointsforpolicymakersandhealthprofessionals.WHOpublications2007.ThisbookletsummarizesandupdatespreviousWHOandWHO/UNFPApublications(WHO’s,“HumanpapillomavirusandHPVvaccine:Technicalinformationforpolicy‐makersandhealthprofessionals”andtheWHO/UNFPAguidancenote,“PreparingfortheintroductionofHPVvaccine:Policyandprogrammeguidanceforcountries”).ThisdocumentprovidesinformationonHPV,thelinkbetweenHPVandcervicalcancer,aswellassafety,efficacyanddeliverystrategiesfortheHPVvaccine(includingcost‐effectiveness,financingandcommunicationsstrategies).Accessibleat:http://www.rho.org/files/WHO_PATH_UNFPA_cxca_key_points.pdfPreventionofcervicalcancer:ProgressandchallengesonHPVvaccinationandscreening.BoschFX,WrightTC,FerrerE,MunozN,FrancoEL,RHerreroR,BruniL,GarlandSM,CuzickJ,LouieKS,StanleyM,eds.Vaccine19Aug2008;26(Supplement10):K1‐94.

AnextensivecompilationcoveringHPVepidemiology,screeningtechnologies,andvaccines(developedanddevelopingcountryintroduction).Accessibleat:http://www.sciencedirect.com/science?_ob=PublicationURL&_tockey=%23TOC%235188%232008%23999739999.8989%23697474%23FLA%23&_cdi=5188&_pubType=J&_auth=y&_version=1&_urlVersion=0&_userid=10&md5=3cc9a1872973aadf4dff06fdb14c5b29RHOCervicalCancer.ShapingstrategiestointroduceHPVvaccines:formativeresearchresultsfromIndia,Peru,Uganda,andVietnam(2009)TheseoverviewspresentresultsfromPATH'sformativeresearchonHPVandtheHPVvaccineinIndia,Peru,Uganda,andVietnam.Theresearchexamineshealthsystemsandthepolicycontextthatwillaffectvaccineintroduction,aswellasbeliefs,values,attitudes,knowledge,andbehaviorsrelatedtoHPV,cervicalcancer,andvaccination.Includesvaccinedelivery,communicationsandadvocacystrategies.Accessibleat:http://www.rho.org/formative‐res‐reports.htmEngenderHealth,PATH.Palliativecareforwomenwithcervicalcancer:Afieldmanual(2003)Amanualdesignedtobeusedasaresourceforhealthcareproviderssuchascommunitynursesandmedicaldoctorswhocareforwomenwhoaredyingofadvancedcervicalcancerinmostlow‐resourcesettings.Includeschaptersonsymptomsmanagement,painrelief,nutrition,socialandspiritualissues.AKenyanfieldmanualisavailablefromPATH,designedforvisitingnursesorhealthfacility‐basednursesandphysicians.Accessibleat:http://www.path.org/files/RH_palliative_care_guide.pdfPlanningandImplementingCervicalCancerPreventionandControlPrograms:AManualforManagers(2004)PATHandACCPThispublicationprovidesthoroughbackgroundinformationoncervicalcancerandextensivedetailonscreening.http://www.rho.org/files/ACCP_mfm.pdf*CourtesyofPATH

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