global guidance for cervical cancer prevention and control...
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GlobalGuidanceFor
CervicalCancerPreventionandControl
October2009
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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
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14. LEEP/CervicalCone
KatinaRobison,MD,WomenandInfantsHospital,BrownUniversity
15. Overview:CervicalCancerTreatment
16. FIGOCancerCommitteeGuidelinesforEarlyInvasiveCervicalCancer
Management
HextanY.S.Ngan,MBBS,MD,FRCOG,UniversityofHongKong
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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
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Authors
NeerjaBhatla,MBBS,MD,FICOG
JoannaCain,MD
NahidaChakhtoura,MD
CarlaChibwesha,MD,MSc.
SuzanneGarland,MD
SarahGoltzShelbaya,MPH,MIA
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
SarahGoltzShelbaya,MPH,MIA
Reviewers
PaulBlumenthal,MD
LynetteDenny,MD
HextanY.S.Ngan,MBBS,MD,FRCOG
EnriquitoLu,MD
SuzanneGarland,MD
CarlaChibwesha,MD,MSc.
AishaJumaan,PhD,MPH
DebbieSaslow,PhD
FIGOExecutiveBoardMembers
FIGOCervicalCancerWorkingGroup
FIGOCervicalCancerWorkingGroup
JoannaCain,MD
LynetteDenny,MD
SuzanneGarland,MD
SarahGoltzShelbaya,MPH,MIA
MarthaJacob,MBBS,FRCOG,MPH
HenryKitchener,MD
HextanY.S.Ngan,MBBS,MD,FRCOG
ConnieTrimble,MD
ThomasWright,MD
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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
GSK.
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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.
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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
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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.
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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.
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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
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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
Cost
• Initialandrecurringcostsassociatedwithmaterialsanddelivery• Providertime• Patienttime• Cost‐effectivenessofapproachspecifictotargetedpopulations
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Educational • Keyinformationthateverywomanshouldknowtomakeaninformedchoiceabouthercare
• Appropriatedecisionmakingaroundintegrationwithothertools
Policy
• Necessarysupportivenational,regionalandinternationalpoliciesfocusedontaskshiftingandequitableaccesstotreatmentandcare
• Publicfinancialcommitmentrequired• Nationalandregionalinvestmentintreatmentfacilities,cancerregistries
FIGObelievesthatweareataturningpointinthefightagainstcervicalcancer.Atnotimebeforehavewehadthetoolsandknowledgeorevencapacitytochangethecourseofthiscancer—especiallyamongthemostunderservedwomen.Aseffortsadvance,drivenbyourownvisionandthatofourpartners(otherclinicians,publichealthleadersandchampions,suchastheWorldHealthOrganization,InternationalPediatricAssociation,andothers),FIGOhopesthattheinformationhereinwillprovidetheevidence,guidanceandinspirationforagreater,moreeffectiveandfinalassaultoncervicalcancer.
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Overview:PrimaryPrevention
ThefocusinthissectionisontheunparalleledopportunitytopreventcervicalcancerthroughimmunitytoHPVinfection.HPVvaccineprogramsalsoprovideanimportantspringboardtoincreasesupportforcervicalcancerpreventionamongparents,educatorsandcommunityleadersandreachadolescentgirlswithimportanthealthinformation.Strategiestodelivervaccinestobroadpopulationsofgirlswillrequirenewcollaborationsbetweenchildhealth,schoolhealth,cancerandreproductivehealthprogrammesandclinicians.
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HPVVaccines:Characteristics,TargetPopulationandSafety
MarthaJacob,MBBS,FRCOG,MPH
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)
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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
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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
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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
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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.
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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
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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.
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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
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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.
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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
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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.
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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.
Gapsinknowledgeandfurtherareasofresearchneeded
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
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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.
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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.
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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.
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Overview:EarlyScreeningandTreatment
Evenwithastrongvaccinationprogramme,therewillbeasmallpercentofthepopulationwhoareatriskforcancerfromuncoveredsubtypesorthosewhoarealreadyexposedtothevirus.Inaddition,theunvaccinatedpopulationwillcontinuetoneedsignificantattentiontoscreeningandearlytreatmentfordecadestocome.Thiswillremainamajorfocusforeverycancercontrolprogramme.Thissectionreviewsscreeningandtreatmentstrategiesforeveryresourcesetting.
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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
32
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.
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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.
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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
35
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]
36
Policy • Nationalpoliciesthatrestrictscreeningandtreatmenttophysiciansonly
• NationalcervicalcancerpreventionpoliciesthatdonotrecognizeorsupporttheuseofVIA.
Cost/efficacyanalysis
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
37
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.
38
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.
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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%
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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
Canbeusedinasinglevisitapproach/seeandtreat
Sankaranarayananetal.IntJObstetGynaecol,2005
41
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.
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11AllianceforCervicalCancerPrevention(ACCP).NewevidenceontheimpactofcervicalcancerscreeningandtreatmentusingHPVDNAtests,visualinspection,orcytology.Factsheet.Availableat: http://www.rho.org/files/ACCP_screening_factsheet_July09.pdf
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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
44
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.
45
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.
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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.
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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.
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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
49
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.
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• 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.
Cost/efficacyanalysis
HPVtestingiscosteffectiveforscreeningwomenatage30orolder,especiallywhenonlyafewscreeningopportunitieswillbeavailabletoawomaninherlifetime.14Thetestislesscosteffectiveinyoungerwomenduetotheincreasedprevalenceof
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transientHPVinfectionsandmildcervicalabnormalities.Forthisagegroup,HPVtestingmaybemostcosteffectiveasatriagetoolforwomenwithsuspectedcytologicalabnormalities,pendingfurthertargetedresearchandcostanalysis.
RecentreportssuggestthatperformanceofVIAorcytologyaremorecosteffectivewhenusedforevaluationofHPVinfectedwomen.14
Gapsinknowledgeandfurtherareasofresearchneeded
HPV‐DNAtestingpermitsdetectionofprevalentinfectioninagivenpopulation,butitisstillimpossibletodetermineusingasingle‐timetestwhichwomenwillclearthevirusandwhichwillbecomechronicallyinfectedandprogresstocancer.Additionalevaluationisneededtodeterminepatienteligibilityfortreatment.Guidelinesforpatientmanagementareneeded,especiallyforareaswithlimitedresources.
Recommendationsforoptimaluse
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.
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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.
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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.
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Colposcopy
HextanY.S.Ngan,MBBS,MD,FRCOG
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.
Barrierstoapplication
Themainbarriertocolposcopyislackofresourcesinacquiringtheequipment,whichisquiteexpensive,andthetrainingandretentionofskilledmedicalpersonnel.Areliablesupplyofelectricityisneededtooperateacolposcope.Accreditationandre‐accreditationhelpinmaintainingqualityofcarestandards.Otherissuesincludetheaccesstopathologysupportinprocessingandinterpretingthebiopsiedsamplesandthequalityassuranceofthelaboratory.Thecostofallofthesecomponentsmaybeprohibitiveinsomesettings.
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Cost/efficacyanalysis
Thecostofcolposcopyexaminationcontributestothecost/efficacyanalysisofacytology‐basedcervicalcancerscreeningprogramme.Thus,usingcytologyscreeningcouldcostmorebecauseoftheneedforcolposcopyforanabnormalcytology.However,thecostforcolposcopyexaminationnotonlyincludestheconsultationfee,butforthepatient,thetimeandcostforasecondorthirdvisitaswellasanxietywhilewaitingfortheresult.Thoughseeandtreatmaybeanoption,overtreatmentwithitsrelatedmorbidity1maynotjustifythereductionofcostforasecondvisit.Nevertheless,ifanexperiencedcolposcopistidentifiesahigh‐gradelesion,seeandtreatinonevisitisacceptable.
Gapsinknowledgeandfurtherareasofresearchneeded
Recently,theuseofcolposcopy/biopsyasthegoldstandardindetectionofcervicallesionsfollowinganabnormalcervicalcytologywaschallenged.2Fourquadrantcervicalbiopsiesfromthesquamocolumnarjunctionandendocervicalsamplingpickedupmorecervicallesionsthancolposcopicdirectedbiopsy.Morestudyisneededtoconfirmthisfinding.
TheroleofcolposcopyinprimaryscreeningwithhighriskHPVtestingneedsfurtherstudytodeterminetheappropriatefollowup.
Recommendationforoptimaluse
Inscreeningprogrammes,colposcopyremainsthegoldstandardformakingthedefinitivediagnosis.Theindicationforcolposcopyvariesdependingonthescreeningmethodsused.Ifcervicalcytologyisusedastheprimaryscreeningtool,guidelinesshouldbefollowedonwhencolposcopyshouldbeperformed.Basically,allhigh‐gradecytologyhastobeassessedbycolposcopyandbiopsieswithinareasonablelengthoftimesuchaswithinfourweeks.IfhighriskHPVtestingisusedastheprimaryscreeningtool,thealgorithmisyettobedecided.However,therecentrecommendationfromASCCPistoperformcolposcopyinwomentestedtohaveHPV16evenintheabsenceofabnormalcytology.IfVIAorVILAisusedastheprimaryscreeningtool,theroleofcolposcopyislesscertain.
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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.
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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.
Barrierstoapplication
• Medicalcontraindications:
o Relative:generallynotrecommendedforpregnantwomen;largelesionsmorethanthreecervicalquadrants;presenceofmenstrualbleeding.
o Absolute:suspicionofinvasivecancer;lesioninvolvingtheendocervicalcanalorextendingtothevagina;morethan2mmoflesionmarginsnotcoveredbythecryoprobe;presenceofuntreatedPIDorcervicitis;bleedingdiathesis;vaginalwallprolapsecausingeitherinadequatevisualizationofthecervixorcontactofthefrozen
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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.
Cost/efficacyanalysis
Basedonareviewofpublishedevidenceinbothdevelopedanddevelopingcountries,cureratesatoneyearare90%overall,83‐100%forCIN1,65‐95%forCIN2,and55‐92%forCIN3.2Modellinghasshownthat,inlow‐resourcesettingswherescreeningislimitedtoonceortwiceinalifetime,cryotherapyisverycost‐effectiverelativetoothertreatmentmethods.
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Gapsinknowledgeandfurtherareasofresearchneeded
Experiencehasshownthatinsomelow‐resourcesettings,blockage(orcloggingofthegasflowwithinthepassagesofthecryounit)mayoccurduringtheprocedure.Aninteragencycollaborationisaddressingtechnicalissuessuchashowtopreventblockageandequipmentfailurebydevelopingspecificationsforprocedures,equipment,refrigerantgas,andaccessories.ThedegreeofriskofSTIorHIVtransmissionoracquisitionduringthehealingphaseaftercryotherapyneedsfurtherresearch.6,7TheeffectivenessofcryotherapyinwomenwithHIVinrelationtotheirCD4countshouldalsobeexplored.
Recommendationsforoptimaluse
Cryotherapymaybeusedinawidevarietyofsettings,includinglow‐resourcesettings,wherethereareadequatequalityassurancemechanismsinplacesuchasclinicalmonitoringandsupervision.Useofcryotherapyinasinglevisitapproachoptimizesprogrammeeffectiveness.Theequipmentisportableandthetreatmentmethodissimpleenoughthatitcanbeusedinamobileoutreachcervicalcancerpreventionprogramme.
Integrationwithorreplacementofotherpreventionapproaches
Inlow‐resourcesettingscryotherapyisrecommendedasthemaintreatmentmethodinsuitablepatients.InthosewithcontraindicationstocryotherapyothertreatmentsshouldbeconsideredsuchasLEEPorconization.
Considerationsforspecialpopulations(HIV+,pregnancy,etc.)
PreviouslymentionedinsubheaddealingwithBarriersandGapsinknowledge.
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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.
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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.
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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
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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.
Cost/efficacyanalysis
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
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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.
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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.
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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.
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12KyrgiouM,KoliopoulosG,Martin‐HirschP,ArbynM,PrendivilleW,ParaskevaidisE.Obstetricoutcomesafterconservativetreatmentforintraepithelialorearlyinvasivecervicallesions:Systematicreviewandmeta‐analysis.Lancet2006Feb;367(9509):489‐98. 13HimesKP,SimhanH.Timefromcervicalconizationtopregnancyandpretermbirth.ObstetGynecol2007Feb;109(2Pt1):314‐19.
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Overview:CervicalCancerTreatment
Thebeststrategyforcervicalcancercontrolisprimaryprevention,screeningandtreatmentofpre‐invasivedisease.Ofnecessity,cervicalcancertreatmentrequiresfocusedexpertiseandavailabilityofoperatingtheatres,chemotherapyandradiotherapy,allofwhichcarryhighpricetags.Inresourcepoorcountries,concentrationoftheseexpensiveresourcesinonecentralfacilityhelpstolimitcostsbutrequiresadequatetransportationandsupportmechanismsforwomenandfamiliestousewhensuchcareisneeded.Regardlessoftheefficacyofprevention,screeningandearlytreatmentofpreinvasivedisease,therewillstillbecasesofinvasivecancer.Thisrequireseachprogrammetohaveaplaninplaceforwomenwithcervicaldisease.Inaddition,astrategyforendoflifetreatmentincludingadequatepaincontrolisacriticalpartofthecreationoftheuniquebundleofservicesforcervicalcancercontrolineachsetting.
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FIGOCancerCommitteeGuidelinesforEarlyInvasiveCervicalCancerManagement
HextanY.S.Ngan,MBBS,MD,FRCOG
Stateofthescience
Stage
Standardtreatment Specialconsideration
StageIA1 Simplehysterectomy Conservative–conewithclearmargin
StageIA2 Simpleorradicalhysterectomyandbilateralpelviclymphadenectomydependingonlocalorregionalguidelines
Conservative–largeconeortrachelectomyandbilateralpelviclymphadenectomydependingonlocalorregionalguidelines
StageIB1 Radicalhysterectomyandbilateralpelviclymphadenectomyorradiotherapy
Conservativeforsmalllesion‐trachelectomyandbilateralpelviclymphadenectomy
StageIB2 Chemoradiationorradicalhysterectomyandbilateralpelviclymphadenectomy+/‐adjuvantradiotherapyorchemoradiation
Neoadjuvantchemotherapythensurgeryinselectedpatients
StageIIA1or2 Chemoradiationorradicalhysterectomyandbilateralpelviclymphadenectomyinselectedpatients+/‐adjuvantradiotherapyorchemoradiation
Neoadjuvantchemotherapythensurgeryinselectedpatients
StageIIB Chemoradiationorradicalhysterectomyandbilateralpelviclymphadenectomyinselectedpatients+/‐
Neoadjuvantchemotherapythensurgeryinselectedpatients
70
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.
Cost/efficacyanalysis
Inordertoreducethecostandincreaseefficacy,earlydetectionandprompttreatmentcanincreasechancesofsurvivalandreducecostofpalliativecare.Thecostofradiotherapytreatmentversussurgicaltreatmentvariesbetweencountries.Thus,thechoiceoftreatmentmayalsovarydependingonexpertiseandfacilitiesavailableon‐site.
Gapsinknowledgeandfurtherareasofresearchneeded
Theoptimaltypesandnumberofcoursesofchemotherapyconcurrentwithradiationneedtobebetterdefined.Theroleofadjuvantchemotherapyafterchemoradiationforadvanceddiseaseandtheroleandchoiceofchemotherapyregimeninneoadjuvantchemotherapybeforesurgeryinadvanceddiseaseare
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undergoingstudy.Theroleofnewradiotherapytechnologysuchasintensity‐modulatedradiotherapyindecreasingside‐effectsofradiotherapyneedfurtherstudy.
Recommendationsforoptimaluse
Womenwithcervicalcancershouldpreferablybetreatedbygynaecologicaloncologistsorradiotherapistsinacentrewithadequatefacilities.Thesecentresshouldbeestablishedwitheasyaccessandaffordabilitysoasnottodeprivewomenwithcervicalcancerthechanceofacure.Thechoiceofoptimaltreatmentofcervicalcancerdependsnotonlyonthestageofthediseasebutalsoontheavailabilityofexpertise,facilities,patient’swishesandaccessibility.Agoodpre‐treatmentassessment,appropriatetreatment,post‐treatmentmonitoringandpsychosocialsupportareimportant.Palliativecare,includingthelegaluseofmorphine,shouldbemadeavailableforthosewithnohopeofbeingcured.Inordertohaveabetterunderstandingoftheburdenandoutcomeofwomenwithcervicalcancer,acancerregistryshouldbeestablishedineachlocality.
TheWorldHealthOrganization’s“Comprehensivecervicalcancercontrol:aguidetoessentialpractice”hasausefulchapteronpalliativecare.
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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
Referralsystemtoappropriatecentraltreatment
ModeratelyLimitedResources
Prevention
Screening
Treatment
Dysplasia
Cancer
HPVVaccine
VIA*or
HPVTesting
• If+,VIAorColposcopySingleVisitApproach
• CryotherapyorLEEP
Referralsystemtoappropriatecentraltreatment
HPVVaccine
Cytologyand/orHPVTesting
• If+,VIAorColposcopy
+/‐biopsies
CryotherapyorLEEP
Referralsystemtoappropriatecentraltreatment
ResourceRich
Prevention
Screening
HPVVaccine
CytologyandHPVTesting
• Colposcopyasneeded
HPVVaccine
CytologyandHPVTesting
73
Treatment
Dysplasia
Cancer
CryotherapyorLEEP
ReferraltoGynaecologicOncologist
CryotherapyorLEEP
ReferraltoGynaecologicOncologist
*RapidHPVtestavailabilitymaychangerecommendations
**Preferabledotolimitationstounlimitedfollow‐upinhighlylimitedresourceareas
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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
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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.
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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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