Cervical Cancer Prevention Initiatives at PATH · 2016-04-14 · oping countries. And while most of...
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PATH cervical cancer prevention initiatives • HPV vaccination—operations research exploring a variety of strategies for effectively delivering vaccine to girls in the developing world, plus analysis and computer modeling of supply and demand scenarios necessary to build a comprehensive evidence-base for national and global decision-making (page 1). • Innovative approaches to screening in low-resource settings—low-cost solutions for situations where cytological (Pap smear) screening has not proven feasible, such as visual inspection and molecular HPV tests designed especially for developing world conditions (page 7). • Improved precancer treatment using cryotherapy— development and introduction of more reliable equipment for low-resource settings (page 9). • Advocacy for comprehensive cervical cancer prevention—global partnerships and dissemination of science-based information for policymakers, program planners, clinicians, and the public (page 10). PATH first began to focus on the problem of cervical cancer in 1991, supported by a small amount of seed funding from the World Bank. Over nearly two decades our portfolio has grown tremendously, with the most rapid expansion since 1998 and thanks in large part to grants from the Bill & Melinda Gates Foundation. Our four key areas of interest are summarized in the box at right, and are described in depth later in this report. Background: cervical cancer and HPV Human papillomavirus, or HPV, is the primary cause of cervical cancer. HPV is a common sexually transmitted infection (STI) that many women acquire at some point in their lives, although most will not develop cervical cancer as a result. Two new vaccines can prevent infection with HPV types 16 and 18, which account for 70 percent of cervical cancer cases worldwide. e vaccines have been proven at least 90 percent effective in safely preventing these two types when administered prior to onset of sexual activity. In industrialized countries, even before the vaccines were developed, screening programs (traditionally using Pap smears) helped detect and treat the precursors of cervical cancer, saving countless lives. Routine Pap screening (cytology) continues to be a powerful tool in those places where it can be used effec- tively. But low-resource countries do not have the laborato- ries and trained technicians necessary to implement effective cytology-based programs, with the result that the vast majority of women cannot access screening or treatment. Of the estimated 270,000 annual cervical cancer deaths worldwide, 85 percent occur in developing countries (see box on page 2). e loss of these productive adult women rends the fabric of their families, villages, and nations. Vaccinating young adolescent girls against HPV—while simul- taneously improving cancer screening for older women—could reduce developing country cancer deaths to the very low levels currently observed in many developed countries. Yet there are many challenges to ensuring that vaccines, screening, and treat- ment become available to those who need them most. Cervical cancer, while a serious problem, is not well-known or understood in many communities, making education and advocacy another top priority. Following are descriptions of PATH’s contributions to the field, with a focus on activities in recent years. For additional informa- tion about HPV and cervical cancer, consult the resource guide at the end of this report. PATH’s HPV Vaccines: Evidence for Impact project In 2006, shortly aſter new vaccines against HPV became available, PATH launched the HPV Vaccines: Evidence for Impact project. As mentioned previously, most cervical cancer deaths occur in devel- oping countries. And while most of those countries have achieved good vaccine coverage for infants and very young children, HPV vaccine is intended for an older population—girls aged 9 and above. It is rare for developing world immunization programs Cervical Cancer Prevention Initiatives at PATH Two decades of progress toward a world free of HPV-related cancers School girls in Piura, Peru. PATH/Amynah Janmohamed
Transcript of Cervical Cancer Prevention Initiatives at PATH · 2016-04-14 · oping countries. And while most of...
PATH cervical cancer prevention initiatives
• HPV vaccination—operationsresearchexploringavarietyofstrategiesforeffectivelydeliveringvaccinetogirlsinthedevelopingworld,plusanalysisandcomputermodelingofsupplyanddemandscenariosnecessarytobuildacomprehensiveevidence-basefornationalandglobaldecision-making(page1).
• Innovative approaches to screening in low-resource settings—low-costsolutionsforsituationswherecytological(Papsmear)screeninghasnotprovenfeasible,suchasvisualinspectionandmolecularHPVtestsdesignedespeciallyfordevelopingworldconditions(page7).
• Improved precancer treatment using cryotherapy—developmentandintroductionofmorereliableequipmentforlow-resourcesettings(page9).
• Advocacy for comprehensive cervical cancer prevention—globalpartnershipsanddisseminationofscience-basedinformationforpolicymakers,programplanners,clinicians,andthepublic(page10).
PATHfirstbegantofocusontheproblemofcervicalcancerin1991,supportedbyasmallamountofseedfundingfromtheWorldBank.Overnearlytwodecadesourportfoliohasgrowntremendously,withthemostrapidexpansionsince1998andthanksinlargeparttograntsfromtheBill&MelindaGatesFoundation.Ourfourkeyareasofinterestaresummarizedintheboxatright,andaredescribedindepthlaterinthisreport.
Background: cervical cancer and HPVHumanpapillomavirus,orHPV,istheprimarycauseofcervicalcancer.HPVisacommonsexuallytransmittedinfection(STI)thatmanywomenacquireatsomepointintheirlives,althoughmostwillnotdevelopcervicalcancerasaresult.TwonewvaccinescanpreventinfectionwithHPVtypes16and18,whichaccountfor70percentofcervicalcancercasesworldwide.Thevaccineshavebeenprovenatleast90percenteffectiveinsafelypreventingthesetwotypeswhenadministeredpriortoonsetofsexualactivity.
Inindustrializedcountries,evenbeforethevaccinesweredeveloped,screeningprograms(traditionallyusingPapsmears)helpeddetectandtreattheprecursorsofcervicalcancer,savingcountlesslives.RoutinePapscreening(cytology)continuestobeapowerfultoolinthoseplaceswhereitcanbeusedeffec-tively.Butlow-resourcecountriesdonothavethelaborato-riesandtrainedtechniciansnecessarytoimplementeffectivecytology-basedprograms,withtheresultthatthevastmajorityofwomencannotaccessscreeningortreatment.Oftheestimated270,000annualcervicalcancerdeathsworldwide,85percentoccurindevelopingcountries(seeboxonpage2).Thelossoftheseproductiveadultwomenrendsthefabricoftheirfamilies,villages,andnations.
VaccinatingyoungadolescentgirlsagainstHPV—whilesimul-taneouslyimprovingcancerscreeningforolderwomen—couldreducedevelopingcountrycancerdeathstotheverylowlevelscurrentlyobservedinmanydevelopedcountries.Yettherearemanychallengestoensuringthatvaccines,screening,andtreat-mentbecomeavailabletothosewhoneedthemmost.Cervicalcancer,whileaseriousproblem,isnotwell-knownorunderstoodinmanycommunities,makingeducationandadvocacyanothertoppriority.
FollowingaredescriptionsofPATH’scontributionstothefield,withafocusonactivitiesinrecentyears.Foradditionalinforma-tionaboutHPVandcervicalcancer,consulttheresourceguideattheendofthisreport.
PATH’s HPV Vaccines: Evidence for Impact projectIn2006,shortlyafternewvaccinesagainstHPVbecameavailable,PATHlaunchedtheHPV Vaccines: Evidence for Impactproject.Asmentionedpreviously,mostcervicalcancerdeathsoccurindevel-opingcountries.Andwhilemostofthosecountrieshaveachievedgoodvaccinecoverageforinfantsandveryyoungchildren,HPVvaccineisintendedforanolderpopulation—girlsaged9andabove.Itisrarefordevelopingworldimmunizationprograms
Cervical Cancer Prevention Initiatives at PATHTwo decades of progress toward a world free of HPV-related cancers
School girls in Piura, Peru.
PATH
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�—Cervical Cancer Prevention Initiatives at PATH
tohaverobustsystemsforreachingyoungadolescents,sothequestionbecomes“howandwherecanwebestreachyoungadolescentgirlswithHPVvaccine?”Furthermore,thefactthatthevaccinegenerallyisofferedonlytogirls,andthatHPVusuallyistransmittedthroughsexualcontact,raisespotentialsocialandculturalconcernswhichmustbeaddressedthroughcarefullydesignedcommunicationprograms.Understandingexistinghealthsystemsandoppor-tunitiesanddevelopingeducationalmessagesthatresonatewithgirls,theirparents,andothersarekeystosuccess.
ThePATHprojectseekstoaddressthesechallengesby:
• Generatinganevidencebasefordecision-makingaboutpublicsectorintroductionofHPVvaccines,withanemphasisonresearchingvaccineintroductioninfourdevelopingcountries—India,Peru,Uganda,andVietnam.
• Leveragingvaccineintroductionactivitiestoinformandsupportglobaladvocacyefforts,regionalHPVvaccinestrategies,andintroductioninothercountries.
• Developinganddisseminatingstrategicforecasts,invest-mentcases,anddecision-makingtoolstoinformandinfluenceindustryproductioncapacityandpricingdecisions,internationalagencyfinancinginitiatives,andcountrygovernmentintroductionplans.
Theprojectisnotaclinicaltrialofanewvaccine—thevaccinesusedintheprojectarealreadylicensedinover100countries.Instead,theprojectaimstoassessanddocumentthebestpossibleapproachestoHPVvaccinedelivery,andtoaddressglobalissuesofHPVvaccineavailability.Theprojectwillbecompletedin2011.
Shaping strategies for HPV vaccine introduction
PATHiscollaboratingwithmanypartners,includingminis-triesofhealthandothergovernmentagencies,industry,andcommunities,toexplorethemostacceptablestrategiesforvaccinatingyoungadolescentgirlsagainstHPVinIndia,Peru,Uganda,andVietnam.Theworkisbeingimplementedinthreephases:
• Formativeresearchtoexploretheknowledge,attitudes,andbeliefsofdiverseaudiences,andtobetterunderstandhealthsystemandpolicyfactors.
• Operationsresearch(demonstrationprojects),informedbyformativeresearchdata,toevaluatevariousstrategiesforreachinggirlswithHPVvaccine.
• Rapiddisseminationoflessonslearnedtoserveasanevidencebaseforgovernmentsthatwishtodeveloporscaleupcervicalcancerpreventionprograms.
Formative research
Duringthefirsttwoyearsoftheproject,PATHandourpartnersconductedformativeresearchineachcountrytobetterunderstandthemedical,policy,fiscal,andsocio-culturalenvironmentsinwhichthedemonstrationprojectswouldbeimplementedandtoguidetheirdesign.PATHstaffcollaboratedcloselywithlocalresearchers,usingavarietyofqualitativeandquantitativeresearchmethods.Theteamsmetwithnationalandregionalstakeholders,policymakers,healthcareproviders,parents,youngadolescents,andothercommunitymemberstounderstandwhichfactorsaremostlikelytoresultinachildreceivingtheHPVvaccineandwhichfactorsaremostlikelytofosterinstitutionaldeci-sionsthatresultinsuccessfulvaccinedelivery.Inadditiontoexploringtargetaudienceknowledgeandattitudesaboutcervicalcancer,theresearchteamsalsoinvestigatedclinicandschoolhealthprograms,assessedequipmentandtrainingneeds,andmappedthepolicyenvironmentrelatedtonewvaccineintroduction.
Summary of results:Overall,theresearchdemonstratedlowlevelsofknowledgeandawarenessregardingcervicalcancer,HPV,andtheHPVvaccineinallfourcountries.Whengivenmoreinformation,however,mostpeoplerespondedposi-tivelyabouttheHPVvaccine.Specificconcernsaboutthevaccineandimportanthealthsystemsorpolicyobstacleswerealsoidentifiedineachcountry,andlocallyappropriatestrategiesweredevelopedtoaddressthem(seeboxonpage3andcommunicationmaterialsonpage6).
Demonstration projects
Drawingontheresultsoftheformativeresearch,PATHisworkingwithnationalhealthofficialsandotherlocalpartnerstodesigneffectivevaccinedeliverystrategies,appropriatecommunicationapproaches,andtargetedadvocacyefforts.Thedeliverystrategieswillbeevaluatedthroughdemon-strationprojectsintermsofvaccinecoverageachievedandprogramfeasibility,acceptability,andcost.
Age-specific cervical cancer mortality rates per 100,000 women
Source: Globocan �00�
Manymorewomendieofcervicalcancerinthedevelopingworldthaninwealthiercountries.Intheindustrializedworld,effectivescreeningprogramshelptoidentifyprecancerouslesionsatastagewhentheycaneasilybetreated.Butlackofscreeningprogramsinpoorercountriesmeansthatthediseaseisnotidentifieduntilitistoolate,resultinginhighermortality.
Cervical Cancer Prevention Initiatives at PATH—�
Forexample,formativeresearchparticipantsinallfourcountriessupportedschool-baseddeliveryoftheHPVvaccine,alongwithadditionaleffortstoreachgirlswhodonotattendschool.SomerespondentsinUgandaandVietnamexpressedstrongsupportforalsoassessingHPVvaccinedeliveryinthecommunityorathealthclinics.Inthesetwocountries,aschool-basedvaccinedeliverystrategywillbecomparedwithastrategyusingexisting,non-schooloutreachsystems.InUganda,asemi-annualeventcalledChildDaysPlusdeliversanintegratedpackageofpreventativeservices(e.g.,catch-upimmunizations,vitaminAsupplementation,anddewormingmedicine)toolderchildrenthroughhealthcenters,churches,communitycenters,andschools.TheUgandaprojectthereforewillmeasuretheeffectivenessofschool-baseddeliverycomparedwithdeliverythroughChildDaysPlus.AndinVietnam,wherethereisastrongfacility-basedvaccinationsystemalreadyinplace,thedemonstrationprojectwillcomparedeliveryoftheHPVvaccinethroughschoolswithdeliverythroughcommunehealthcenters.
Demonstrationprojecttimelinesareabitdifferentinallfourcountries,inpartduetotheneedtowaitfortherelevant
vaccinetobelicensed.ThePerudemonstrationprojectbeganfirst(June2007),followedbyUganda(June2008).Attimeofwriting,IndiaandVietnamhadnotyetbeguntheirdemon-strationprojects,thoughitisanticipatedthatthevaccineswillbelicensedbynationalauthoritiesbytheendof2008orearly2009.
ThePeruviandemonstrationprojectdiffersslightlyfromtheothercountriesbecauseitisbeingimplementedintwophases:asmallstudycomparingtwoapproachestovacci-nation,followedbyascaled-upstudythatapplieslessonslearnedfromthefirstphase(seeboxonpage5).
Project update:OnMay9,2008,thesecondphaseofPeru’sdemonstrationprojectbeganwithMinisterofHealthHernánGarrido-Leccainattendance.Inthefollowingmonths,morethan8,900girlswerevaccinatedinover700schools.Atthetimeofthiswriting,earlydemonstrationprojectresultsinbothPeruandUgandashowreasonablyhighlevelsofaccep-tanceofthevaccineandveryhighcontinuationratesonceagirlandherfamilyconsentedtothefirstdose.
PATH’sformativeresearchfoundthatawarenessofcervicalcancervariesbothwithinandamongthefourcountriesstudied.Forexample,inUganda,veryfewpeoplerecognizedtheterm“cervicalcancer,”althoughmanywereabletoaccuratelydescribethecondition’ssymptoms.InVietnam,bycontrast,75percentofparentsinthestudyhadheardofcervicalcancer.NotmanypeoplehadheardofHPVinanycountry,withtheexceptionofsomehealthworkersinUgandaandVietnam.Inallfourcountries,onceageneralunderstandingwasestablished,cervicalcancerwasperceivedbymosttobeanimportantandveryseriousdisease.AsoneteacherinIndiaputit,“Themotheristheheartofthefamily.Ifshegotsick,thewholefamilywouldgointoadepression.”
Overall,participantsinallfourcountriesexpressedthatvaccinationisimportantforpreventingillnessandhassignificanthealthbenefits.OnefatherintheGuludistrictofUgandareportedthat,“Thesedaysourchildrendonotsufferfromcertaindiseaseslikemeasles…Ithinkitisbecausetheystartedvaccinatingchildrenearlyinhospitals.Thatisthereasonthediseaseisdisap-pearing.”Inallfourcountries,whenprovidedwithobjectiveinformationabouttheHPVvaccinebyresearchers,mostparticipantsrespondedpositively.AsoneyoungadolescentgirlinPerustated,“Weallhavearighttoreceivethatvaccine.”
Participantsinallcountriesdidexpressconcernsaboutsideeffectsorpossiblelong-termeffectsoftheHPVvaccine.ConcernsregardingfertilitywereexpressedinPeru,Uganda,andVietnam,duetothefactthatthetargetgroupforthisvaccineisyoungadolescentgirls.However,itwaswidelynotedinallcountriesthatvisiblesupportfrompoliticalandcommunityleaderswouldgofarinallayingpeople’sdoubtsandfears.OneparticipantinVietnamexplained,“Themostimportantthingistohavesupportandleadershipofpeople’scommitteesandgovernmentagencies.”
Cervical cancer, HPV, and vaccination: knowledge and perceptions from India, Peru, Uganda, and Vietnam
A girl receives HPV vaccine in Ibanda, Uganda.
PATH
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�—Cervical Cancer Prevention Initiatives at PATH
Answering new questions about HPV vaccination: A small grants program
TosupplementthedatafromthefourHPVvaccinedemonstrationprojects,PATHalsohasestablishedasmallgrantsprogramtoanswertargetedques-tionsaroundHPVvaccinationinotherdevelopingcountriesandnon-projectstatesinIndia.Todate,theCSIHoldsworthMemorialHospitalinKarnakata,India,andtheInstitutoNacionaldeCancerologiainBogota,Colombia,havebeenfundedtoconductstudiesonknowledgeandacceptabilityoftheHPVvaccineamonghealthworkersandparentsofadolescents.Pendingapprovalbyanethicalreviewboard,CentrodeEstudiosdeEstadoySociedad(CEDES)inArgentinawillreceivesupporttoevaluatetheactualuptakeofthevaccineamongfamilieswhoreceivemotivationalmessagesaboutHPVimmuniza-tionemphasizingacancerpreventionperspective,comparedwiththosewhoreceiveanSTIpreventionperspective.Inthecomingmonthsandyears,PATHwillcontinuetosolicitapplicationsforitssmallgrantsprogram.Formoreinformation,visittheRHOCervicalCancerwebsiteatwww.rho.org.Making the case for investment in HPV vaccination
IdentifyingandmobilizingresourcesforvaccinepurchaseanddeliveryisoneofthemostsignificantchallengestomakingtheHPVvaccinewidelyavail-ableinthedevelopingworld.Therefore,anotherimportantelementoftheHPV Vaccines: Evidence for Impactprojectistoacceleratekeysupply,demand,andfinancingdecisionsrelatedtoHPVvaccines.Aspartofourcountry-levelformativeresearch,forexample,PATHconductedbaselineimmuniza-tionfinancingassessmentsineachofthefourcountries.Also,aspartofthedemonstrationprojects,weareexploringaffordabilitythroughestimatingtheprogramcostsassociatedwithintroducingtheHPVvaccinethroughdifferentdeliverystrategiesineachsetting.
PATHisalsoworkingtomaptheprocessofdecision-makinginordertoidentifypotentialobstaclesanddevelopcreativeandproactivewaystoaddressthem—forexample,havingdatareadyforgovernmentsandglobal
WhilethemainfocusoftheHPV Vaccines: Evidence for Impactprojectisoperationsresearch,notclinicalstudies,oneimportantclinicalques-tionwillbeaddressedinVietnam:doalternativedosingschedulesforHPVvaccines—schedulesthatmaymeshmoreeffectivelywithcountrysystems—offerthesamelevelsofprotectionastheidealdosingsched-ulessuggestedbythemanufacturers?
BothHPVvaccinescurrentlyintheglobalmarketrequirethreedosesforfullcoverage.Theyalsohavesimilarvaccinationschedules:theseconddoseisgiveneitheroneortwomonthsafterthefirstdose,andthethirddoseisgivensixmonthsafterthefirstdose.However,itmaybethatmorechildrencouldbereachedmoreefficientlyifthedoseswereofferedquarterly,semi-annually,orannually.Forexample,thesemi-annualChildDaysPlusactivitiesinUgandacreateopportunitiesforprovidingthefirstandthirdvaccinedosesonly—specialvaccinationsessionswillhavetobeorganizedtoprovidetheseconddose.Butifthevaccineprovestobeaseffectivewhenthedosesaregivensixmonthsapart—i.e.,theseconddosesixmonthsafterthefirstandthethirdsixmonthsafterthat—itwouldbemucheasierforthegirlsandforthevaccinators,andmaybelessexpensiveforthegovernment.
ThePATHprojectinVietnamwillmeasureimmuneresponsegeneratedbyseveralalternativedosingschedulestodeterminewhetherthereisanyimmu-nogenicdisadvantagewhenusingthevaccinesinthisway.ThestudybeganinOctober2007andwillgenerateinitialresultsin2009.
Vietnam alternative dosing schedule study
A vaccinator in Vietnam meets with school girls to explain HPV vaccine.
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Cervical Cancer Prevention Initiatives at PATH—�
actorsbeforetheyareneeded.A2008InternationalAIDSVaccineInitiativeandPATHreport,HPV Vaccine Adoption in Developing Countries: Cost and Financing Issues,providesanoverviewofsomeoftheseissuesandisavailableatwww.rho.org.
TheGAVIAlliance,animmunizationcoalitionoftheworld’stopglobalhealthagencies,governments,andprivatepartners,offerssubsidizedvaccinestoover70countriesofthedevelopingworld.Manylow-incomecountrieswillrelyonsupportfromtheGAVIAlliancetoprocuresubsi-dizedHPVvaccine.Generally,GAVImakesdecisionsaboutwhethertoallocatefundstosupportintroductionofcertainvaccinesbasedonaninvestmentcasethatanalyzesthevalueofthevaccine.Inthefirstyearoftheproject,PATHconvenedameetingofrepresentativesfromtheWorldHealthOrgani-zation(WHO),GAVI,vaccinemanufacturers,andtheBill&MelindaGatesFoundation,amongothers,todevelopthecomponentsofaninvestmentcasedemonstratingthevalueofintroducingtheHPVvaccineinGAVI-eligiblecountries.
Cervical cancer…affects 500,000
women each year and leads to more
than 250,000 deaths, the vast majority
in poor countries…[GAVI’s] strategy will
attack some of the world’s major killers
and gives us a new challenge in our
efforts to provide good health to the
world’s most vulnerable people.
Julian Lob-Levyt
Executive Secretary, GAVI Alliance
Two phases of Peru’s demonstration project
. ThefirstphaseofPeru’sdemonstrationproject,completedinJanuary2008,assessedthebenefitsandcostsof“activefollow-up”ofschool-basedimmunization,comparedwithsimpleprovisionofvaccinewithoutactivefollow-up.Activefollow-upincludedhomevisitsforgirlswhomissedfirst,second,orthirddosesofvaccine.Thestudyteamfoundthatabout60percentofgirlsacceptedvaccination,regardlessofwhethertheywereactivelyfollowed-upornot.*Becausefollow-updidnotreallyincreasefirst-dosecoverage,andhadthepotentialtoincreasecosts,follow-upafteramissedfirstdosewaswasjudgednottobeaworthwhileapproach.
Anadditionalfinding,however,wasthatdrop-outrateswereverylowbetweendosesofthevaccine.Inotherwords,veryfewgirlswouldrequireactivefollow-upafterthesecondorthirddoses.Additionally,follow-upwasconsideredimportantintermsofensuringthatthosewhoinitiatedvaccinationwerefullyprotected(basedonthecurrentscien-tificevidence,whichrecommendsthreedosesforfullcoverage).Therefore,inthesecond,scaled-upphaseofthedemonstra-tionproject,onlythosegirlswhoreceivedthefirstdose,butmissedthesecondorthirddose,arecandidatesforactivefollow-up.Thisisexactlythekindofevidence-based,programmaticdecision-makingthattheprojectwasmeanttostimulate.
*GiventhatHPVvaccineisnewandthatstudyrespondentswereaskedtosignconsentformsforHPVvaccination(whichdoesnothappenforinfantvaccinesorotherroutineinjections)theteamconsiders60percentcoverageinthefirstphaseofPeru’sdemonstrationprojecttobeasuccess.Thelengthandcomplexityoftheconsentformsseemtohaveincreasedparentalconcernsandtohavebeenasignificantbarriertovaccineacceptance.PreliminarydatashowthatoverallcoverageinthesecondphaseofPeru’sproject,whenasimplerauthorizationformwasused,reachedabout85percent. Girls in Piura, Peru display their vaccination cards after receiving
HPV vaccine.
PATH
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�—Cervical Cancer Prevention Initiatives at PATH
Community education and mobilization is crucial to successful cervical cancer prevention.
InordertobuildanHPVvaccineinvestmentcaseforGAVIandotherstakeholders,PATHhasgatheredandsynthesizedinformationonseveralcomponentsrelatedto:
• Theproblemofcervicalcancer,includingthediseaseburdenandchallengesinpreventingandmanagingthedisease.
• TherelevanceofHPVvaccineandcervicalcancerpreven-tiontoGAVIobjectivesandotherinternationalhealthpriorities(e.g.,theMillenniumDevelopmentGoalsandtheWHO/UNICEFGlobalImmunizationVisionandStrategy,orGIVS).
• TheconstraintsonHPVvaccinedelivery,andstrategiesforovercomingthem.
• Cost-effectivenessincomparisonorcombinationwithotherinterventions.
• Supplyanddemandfactorsthatwillaffectavailabilityandaccesstothevaccine.
• Expectedimpactofvaccinationatvariouslevelsofinvest-ment.
InJune2008,GAVIannouncedthatitwillincludeHPVvaccineamongthoseitconsidersforfuturesupport.
Accuratevaccinedemandestimatesarealsoneedednationally,regionally,andgloballytoensureasufficientsupplyofvaccinesandtosupportpricenegotiations.WorkingwiththeBostonConsultingGroup,PATHdevel-opedamodelforlong-termdemand,supply,andfinancingforecasting.Aswemoveforward,datafromthedemonstra-tionprojectswillbeincorporatedandusedtorefineglobalandcountry-leveldemandforecasts.PATHalsoworkedwithAppliedStrategiesConsultingtoanalyzethelikelihoodofadditionalHPVvaccineproductsenteringthemarket,criticalfactorsaffectingHPVvaccineproductioncosts,andthemedium-andlong-termevolutionoftheHPVvaccinesupplylandscape.
Cervical Cancer Prevention Initiatives at PATH—�
Innovative approaches to screening in low-resource settings
Working together to find alternatives
Asmentionedearlier,HPVvaccina-tionandcervicalcancerscreeningprogramsarebothneededtoreducerelatedmortality,yetmostdevelopingcountrieslacktheinfrastructureandtrainedpersonnelneededtoreplicatethecytology-based,multi-visitapproachusedinwealthiercountriestodetectpre-cancer(Papsmearsfollowedbycolposcopyandbiopsy).Inanefforttofindalternativestrategiessuitabletolow-resourcesettings,PATHjoinedfourotherinternationalagenciesin1999toformtheAllianceforCervicalCancerPrevention,orACCP.*OverthefollowingnineyearsACCPpartnersconductedstudiescomparinganumberofscreeningtechniques,includingcytology,visualinspectionmethodsusingaceticacid(VIA)orLugol’siodine(VILI),andastate-of-the-artHPV-DNAtest.Thetestswereevaluatedinover20low-resourcesettingsaroundtheworld.
VIAhasproventobeofspecialinterest.ACCPfoundthatVIAcompareswelltocytologyintermsofsensitivityfordiseasedetection,yetpresentsadvantagesbecauseitrequiresfewerspecializedpersonnelandlessinfrastructure,training,andequip-ment.CervicalcancerscreeningusingVIAcanbeofferedinremote,lessequippedclinics,therebyreachingmorewomen.AnotherimportantadvantageisthatVIAprovidesimmediateresults,makingitpossibletoscreenandeithertreatorreferwomenduringthesamevisit.Immediatetreatment,whereavailable,meansthatwomendonothavetomakeanextravisittothehealthcenter,thusreducingthenumberofwomenwhoarelosttotreat-mentbecausetheycannotreturnforonereasonoranother.IntheACCPstudies,VIAhassuccessfullybeenpairedwithcryotherapy,arelativelysimple,inexpen-sive,andsafemethodoffreezingaffected
*TheACCPpartnersareEngenderHealth,InternationalAgencyforResearchonCancer(IARC),Jhpiego,PanAmericanHealthOrganization(PAHO),andPATH.TheACCPwebsitecanbefoundatwww.alliance-cxca.org.
In2007,ACCPpartnersdevelopedthefollowingfindingsandrecom-mendationsforglobalpolicyandpracticebasedonpreviouskeystudiesinIndia,SouthAfrica,Peru,andThailand:
Everywomanhastherighttocervicalscreeningatleastonceinherlifetime.Inlow-resourcesettings,theoptimalageforscreeningtoachievethegreatestpublichealthimpactisbetween30and40yearsold.
Althoughcytology-basedscreeningprogramsusingPapsmearshavebeenshowntobeeffectiveintheUnitedStatesandotherdevelopedcountries,itisdifficulttosustainhigh-qualitycytologyprograms.Therefore,insituationswherehealthcareresourcesarescarce,resourcesshouldbedirectedtowardcost-effectivestrategiesthataremoreaffordableandtowhichaccesscanbeassured.
Studieshaveshownthatthemostefficientandeffectivestrategyforsecondarypreventionofcervicalcancerinlow-resourcesettingsistoscreenusingeitherHPV-DNAtestingorVIA(visualinspec-tionofthecervixafterswabbingitwithaceticacid),andthentreatprecancerouslesionsusingcryotherapy(freezing).Thisisopti-mallyachievedinasinglevisit(currentlypossiblewithVIApluscryotherapy)andcanbecarriedoutbyphysiciansandnon-physi-cians,includingnursesandmidwives.
TheuseofHPV-DNAtestingfollowedbycryotherapyresultsingreaterreductionofcervicalcancerprecursorsthantheuseofotherscreeningandtreatmentapproaches.
Cryotherapy,whenconductedbycompetentproviders,issafeandresultsincureratesof85percentorgreater.
StudiessuggestthatcryotherapyisprotectiveagainstthefuturedevelopmentofcervicaldiseaseamongwomenwithcurrentHPVinfection.Becauseofthis,andduetothelowmorbidityofcryotherapy,theoccasionaltreatmentofscreen-positivewomenwithoutconfirmedcervicaldiseaseisacceptable.
Unlessthereisasuspicionofinvasivecervicalcancer,theroutineuseofanintermediatediagnosticstep(suchascolposcopy)betweenscreeningandtreatmentisgenerallynotefficientandmayresultinreducedprogrammaticsuccessandincreasedcost.
Women,theirpartners,communities,andcivicorganizationsmustbeengagedinplanningandimplementingservices,inpartnershipwiththehealthsector.
Formaximumimpact,programsrequireeffectivetraining,supervi-sion,andcontinuousqualityimprovementmechanisms.
Additionalworkisneededtodeveloprapid,user-friendly,low-costHPVtestsandtoimprovecryotherapyequipment.
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Alliance for Cervical Cancer Prevention 10 Key Findings and Recommendations for Effective
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cervicaltissue.Cryotherapycanbedoneinasinglevisit,orlaterataconvenientreferralsite.Studieshaveshownthatcryotherapycanbeeffectivelyandsafelyperformedbytrainednursesormidwives,inadditiontophysiciansandgynecologists—though,aswithallscreeningapproaches,attentiontoconsistentqualitystandardsiskey.
Asthebodyofevidenceonthesafetyandimpactofsingle-visitapproacheshasaccumulatedoverthepasttenyears,manycountrieshaveexpressedinterestinsuchstrate-gies,andrequestsforassistancehaveexceededtheabilityoftechnicalagenciestorespond.CountrieslikeThailandandthePhilippineshaveimplementedsuccessful,large-scale,VIA-basedprograms,butmoreeducationandtrainingarenecessaryifsuchprogramsaretoexpandregionally.Asmoreglobalhealthleadersandinternationalorganizationsurgehealthcareproviderstoexaminetheevidenceonalternativestocytology,andasmoreprovidershearaboutthesealterna-tives,PATHexpectsthatthenewparadigmswillbeadopted,andadapted,forlocalsituations.
Developing rapid screening tests
WorldhealthexpertsrecommenduseofHPV-DNAtestingforprimarycervicalcancerscreening,notingthatitisatleastaseffectiveascytology.BasedinpartonlessonslearnedbytheACCP,in2003PATHlaunchedtheScreeningTechnolo-giestoAdvanceRapidTesting(START)project.TheprojectsoughttodeveloptwodifferentHPVscreeningmethodsappropriateforuseinthedevelopingworld.Itwasimportantthatthetestsbeacceptabletowomenandtheirproviders,relativelysimpletouse,accurate,affordable,andrapid,toallowforsingle-visitefficiencies.
Bythetimetheprojectendedin2008,STARThaddevelopedatestbasedonthemorecomplexHybridCaptureII(HCII)test,producedbyQIAGEN.TheHCIItestisnotseenassuit-ableforlow-resourcesettingsbecauseitrequireslabora-toryequipment,refrig-eration,andotherresourcesoftennotavailableinthedevelopingworld.Buttheequipmentusedtoanalyzesamplesforthenewtestisportableandcanbepoweredwithrechargeablebatteries,thereagentsdonotrequirerefrigeration,andresultsareavailableintwotothreehours.Testresultsareeasy
toreadand,unlikecytologyandVIA,arenotvulnerabletomisinterpretation.
ClinicalperformanceofthenewtestwasevaluatedinChinaandIndia.InShanxi,where2,500ruralwomenwerescreenedusingvaginalandcervicalsamples,studyresultsshowedthatthesensitivityofthetestwasmuchbetterthanVIAandapproachedthatofHybridCaptureII.ResultsfromIndiaarestillbeinganalyzed.ThetestwillbeproducedinChinaandcommercializedin2009.
TheothertestdevelopedundertheSTARTprojectdetectstheE6protein,levelsofwhichmayindicatetheriskthatHPVinfectionwillprogresstocervicalcancer.Thetech-nologyisstillindevelopmentandcurrenteffortsarefocusedonimprovingthesamplemedium,simplifyingsamplepreparation,andaddingtheabilitytodetectE6proteinsofthesevenmostprevalenthigh-risktypes.
PATHrecognizesthatcreationofnewtestsalonewillnotsuffice.Indevelopingcountries,challengesexisttowide-spreadadoptionofnewtechnologies.Beforeincorporatingtestsintonationalcervicalcancerpreventionstrategiesandplans,ministriesofhealthneedevidencethatthetestsarefeasibleandappropriatefortheirhealthsysteminfrastructureandtheirgeographic,cultural,andeconomiccircumstances.Inaddition,privateindustryneedsguidancenavigatingthecomplexitiesofproductintroductioninthepublicsectorofdevelopingcountries,whicharegenerallyperceivedas“high-riskandlow-return”markets.
The careHPVTM test, an updated version of the Hybrid Capture II test, produced by QIAGEN.
QIA
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Cervical Cancer Prevention Initiatives at PATH—�
Toaddressthesechallengesofnewtechnologyintroduc-tion,inNovember2007,PATHinauguratedafollow-upprojecttoSTART,calledSTART-UP.START-UPfocusesonfoursetsofactivities:
Support and assist early-introduction projects to demonstrate the feasibility, effectiveness, and accept-ability of the new, quicker HPV-DNA screening test within the context of developing-country public-sector health care systems.Workingcollaborativelywithministriesofhealthandotherkeystakeholders,START-UPwillcomparethenewtestagainstotherscreeningstrategiesinIndia,Nicaragua,andUganda.Concurrently,andasresourcesallow,PATHwillassistotherlow-andmedium-resourcecountriesinterestedinthenewscreeningteststodesignprojectsandsecureseparatefunding.
Strengthen industry knowledge and understanding of developing-country public health care systems, policy and guideline decision-making, and supply and demand factors to be addressed in their public-sector commercialization plans for new rapid tests. Inordertoaccelerateaccesstothenewtest,PATHwillassistourindustrypartnertomaptheregulatoryapprovalprocessinthethreeprojectcountries,mapthehealthcommodityprocurementanddistributionsystemsinthepublicsectors,andforecastpotentialdemandforthetestinthepublicandprivatesectors.
Use lessons learned from the START-UP demonstra-tion projects to inform other developing countries about the feasibility, effectiveness, and acceptability of the new test.PATHwillaggregateandanalyzeclinicalandotherdatafromthethreedemonstrationprojects,makepresentationsatregionalandglobalconfer-ences,andgarnersupportforthenewtestsfromWHO,InternationalFederationofGynecologyandObstetrics(FIGO),andotherkeyagenciesforuseinadvocatingforandguidingdeveloping-countrycervicalcancerpreven-tionprograms.
Assess the clinical performance of E6 rapid-strip test prototypes in a low-resource setting.START-UPalsowillassesstheclinicalutilityoftheE6rapid-striptest,andE6ingeneral,asameansofdetectingpre-cancerouslesionswhenusedasaprimaryscreeningtool,andsecondlyasameansofpredictingriskofprogressionfromlesionstocancer.Evaluationresultswillguidefuturedecisionsaboutuseofthetechnology.
Improved treatment using cryotherapyPATHrecognizesthatitisimportanttodevelopprogramsofferingcomprehensivescreening,diagnosis(wherefeasible),andtreatment,notscreeningalone.Inadditiontoidenti-fyingpre-cancerouslesions,visualinspectionwithaceticacid(VIA)—discussedinaprevioussection—alsoallowsclinicianstoassesstreatmentoptionsforpatientswithHPVinfection,determiningwhicharecandidatesforcryotherapy
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inthelocalclinicandwhichmustbereferredtohigherlevelcareformorespecializedtreatment,suchastheloopelectro-surgicalexcisionprocedure(LEEP).WhenscreeningusingHPVtestingbecomesmorecommon,VIAfortriageandcryotherapyfortreatmentwillbeneededtomanagewomenwithpositiveHPVtestresults.CurrentworktostimulatedevelopmentofVIAandcryotherapyskillsindevelopingcountriescanestablishaservicedeliveryplatformpriortoHPVtestavailability.
Developing better equipment for low-resource settings
AsnotedintheACCPrecommendationsonpage7,cryotherapy(freezingcervicaltissuethatislikelytodevelopintocancer)isanappropriatetreatmentmethodforlow-resourcesettings.Itiseffective,haslimitedsideeffects,doesnotrequireelectricity,isinexpensivecomparedtoothertreatmentoptionsforprecancerouslesions,istechnicallysimplerthanothermethods,andcanbeperformedbylocalhealthworkers.
Cryotherapyunitsachievefreezingtemperaturesthroughuseofcompressedgas.Unfortunately,thecheapestandmostcommonlyavailablecompressedgas,carbondioxide,leadstoblockageofsomecryotherapydevicesasmuchas50percentofthetime.*Thisblockagemaypreventcompletionoftheprocedureormayresultinwarmertemperaturesinthefreeze
*Nitrousoxide,themostcommongasusedforcryotherapyinindustrializedcountries,isdifficulttoobtaininsomeareasofthedevelopingworld,andcostsseveraltimesmorethancarbondioxide.
PATH’s cryotherapy gas conditioner has been developed to prevent blockage of cryotherapy devices.
10—Cervical Cancer Prevention Initiatives at PATH
probe.Onemethodforpreventingblockageistointermit-tently“clear”thegaslinesduringthefreezingprocess.Thisisknownasthe“cough”techniqueandisroutinelytaughtduringcryotherapytraining—butPATHhasidentifiedlimi-tationswiththistechnique.Theblockageproblem,coupledwithdoubtsaboutthecoughtechniqueasasolution,hasraisedquestionsaboutwhethercryotherapyinitscurrentformisaneffectivetreatmentforcervicalprecancer.
Inresponse,PATHhasdevelopedanin-line“gascondi-tioner”whichisplacedbetweenthegastankandthelowtemperaturecryotherapyprobe.Todate,producttestinghasshownpromisingresults—thecryotherapyconditionerhaseliminatedtheproblemoftipblockageanddidnotnegativelyaffectthetemperatureachievedbythedevice—acriticalmeasureoftreatmenteffectiveness.PATHcurrentlyiscollaboratingwithWHOandotherpartnerstodeterminenextsteps,whichmayincludeamarketsurveyofexistingequipment,benchtestingofthatequipment,creationofcomprehensiverepairmanualsdesignedfordevelopingworldtechnicians,andimprovementandfieldtestingofthegasconditionerthrougharandomizedclinicaltrial.
Advocacy for comprehensive cervical cancer preventionAsdocumentedthroughPATH’sformativeresearchandotherstudies,accurate,in-depthknowledgeaboutcervicalcancertendstobelowworldwide.EducationandadvocacyinitiativesimplementedbyPATHandourpartnersseektoraiseawarenessandhelpdecision-makers,clinicians,andfamiliesmakeevidence-baseddecisionsthatcouldsavelives.
Mobilizing communities globally
Theissueofcervicalcancerpreventionhasthepotentialtogalvanizeadvocatesfromdiversefields,includingcancer,reproductivehealth,genderequity,adolescenthealth,STIs,andimmunization,tonameafew.PATHknowsfromexperiencethattheimpactofmanyadvocatescouldbefargreaterthanthatofoneindividualorganizationworkingindependently.PATHwasthereforeinstrumentalinthecreationofanewglobaladvocacycoalitioncalledCervicalCancerAction(CCA)(www.cervicalcanceraction.org).OtherkeyCCApartnersincludethePanAmericanHealthOrganization(PAHO),InternationalUnionAgainstCancer(UICC),CancerResearchUK(CRUK),AmericanCancerSociety(ACS),InternationalFederationofGynecologyandObstetrics(FIGO),theInternationalAIDSVaccineInitiative(IAVI),AIDSVaccineAdvocacyCoalition(AVAC),andtheInternationalPlannedParenthoodFederation(IPPF).
CollaborationwithCCApartnershasgeneratedmanyopportunities.Forexample,PATHandourCCApartnerslearnedearlyonthatWHO’sStrategicAdvisoryGroupofExperts(SAGE)hadrequestedfeedbackfromcountriesrelevanttointroductionofHPVvaccine,intimefortheirNovember2008meeting.Inpreparationforthemeeting,PATH,incollaborationwithCCA,producedoneofthemostinnovativeelementsofitsportfoliooncervicalcancerprevention.“EvidenceofDevelopingCountrySupportforImprovedCervicalCancerPrevention”isadossiercompilingpersonallettersofsupportfromministriesofhealth,nongov-ernmentalorganizations,andindividualsinAfrica,Asia,andLatinAmerica.Thedossieralsoincludeseditorials,op-eds,resolutions,anddeclarationscallingforimprovedcancercontrol,alongwiththenamesofthe1,200peoplewhoendorsedCCA’sonlineGlobalCalltoSTOPCervicalCancer.Ingatheringandsharingthesedocuments,PATHandCCAseektoraiseawarenessaboutthewidespreadsupportforbetterscreeningandvaccinationprograms.Thedossierisadynamicdocument,withnewlettersarrivingeachweek.LookforthedossierontheRHOCervicalCancerwebsite(www.rho.org),whereithasbeenpostedforusebyanyinter-estedadvocacygroup.
Disseminating the evidence base
Giventheclearneedforbetteraccesstoscientificallyaccu-rateinformationoncervicalcancer,oneofthefirstcommu-nicationandadvocacytoolsPATHdevelopedundertheHPVvaccineprojectwastheRHOCervicalCancerwebsite(www.rho.org),acomprehensivelibraryofcervicalcancerinfor-
PATH’s RHO Cervical Cancer website (www.rho.org) and PATH and Cervical Cancer Action’s “Evidence of Developing Country Support for Improved Cervical Cancer Prevention” serve as key tools for communication and advocacy.
Evidence of Developing Country Support for Improved Cervical Cancer Prevention
This electronic dossier gathers messages from leaders in the countries most affected by cervical cancer. More letters arrive each week.
Cervical cancer is a huge problem worldwide, with about 270,000 deaths every year. Most of those deaths occur in Africa, Asia, and Latin America. The letters, video messages, editorials, and declarations in this dossier express support for improved cervical cancer prevention—screening and vaccination—for women throughout the developing world.
In addition to the documents, the dossier includes the names of over 1,200 individuals, representing nearly 700 organizations, who signed an online “Global Call to Stop Cervical Cancer” in 2007 and 2008.
Dossier contents
Evidence from Africa
Evidence from Asia
Evidence from the Americas
Global evidence
Signatories to the onlineGlobal Call to Stop Cervical Cancer
About this dossier
Dossier contents as of June 23, 2008 For further information, contact [email protected].
Cervical Cancer Prevention Initiatives at PATH—11
mation.Thewebsiteoffersbackgroundpapers,trainingmaterials,films,PowerPointpresenta-tions,andahostofotherdocumentsandtoolspublishedbytheworld’sleadingHPVexpertsandorganizations,includingWHO,theUSCentersforDiseaseControlandPrevention,USNationalCancerInstitute,UICC,PATH,andmanyothers.
Sometimesnewsmustbedisseminatedquickly,andwaitingforuserstovisitawebsiteisnotadequate.PATHcreatedHPVflashemailupdatestosharetimely,cervicalcancer-relatedinforma-tionaroundtheglobe.RecentalertsincludednewsoftheMay2008declarationfromtheAmericassupportingcervicalcancerpreventionandGAVI’sJune2008decisiontoconsiderpriori-tizationofHPVvaccine.UserscansubscribetoHPVFlashthroughRHOCervicalCancer.
Additionally,sincethebeginningoftheproject,PATHstaffhavecontributedtoorpublishedmorethan30articlesorreportsdocumentingevidenceoncervicalcancerprevention.OnepaperdesignedforbroaddistributionistheHPVissueofPATH’sflagshipreproductivehealthresource,Outlook.The12-pagedocumentprovidesaneasy-to-under-standoverviewofthesubject,andisavailableinEnglish,Chinese,French,Spanish,Russian,andVietnamese.PATHhasalsoproduceda“keypoints”documentincollaborationwithWHOandUnitedNationsPopulationFund(seelistofresourcesonpage12).
ConclusionPATHisexcitedtohavesomanyactivitiesaimedatexploringthemosteffectivestrategiesforimprovingcervicalcancerpreventionworldwide.Wealsoarepleasedtonotethatsupportforacomprehensiveapproachtocervicalcancerpreventioncontinuestogrowatnational,regional,andgloballevels:
• AtaMay2008meetingtodiscussplansforLatin America,healthofficialsandresearchersfrom21coun-triesformallydeclaredtheirintentionto“…strengthenpreventionandcomprehensivecontrol[ofcervicalcancer]throughimprovingcoverageandqualityofscreening,diagnostics,andtreatmentservices.”
• FromIndia,MemberofParliamentShabanaAzmirecentlywrote,“Althoughourcountryhasbeencommittedtoendthisdiseaseforsometime,wehavenothadtheappropriatetools,untilnow.Today,vaccinesforgirls,andnewandimprovedscreeningforallwomen,providetheopportunitytorealizeourcommitment.”
• Andinavideomessagetoamajorcervicalcancermeetinginthefallof2007,PresidentofLiberiaEllenJohnson-Sirleafstated,“TodayIwouldliketoaddmyvoicetothosedemandingthatcervicalcancerpreventiongetstheinternationalpoliticalrecognitionitdeserves…Letusnowmakethisrhetoricintoreality.”
Politicalwillisgrowingandthetechnicaldataareclear—itispossibletodosomethingaboutcervicalcancerinthedevelopingworld.WeknowhowtotrainhealthworkerstoperformappropriateandeffectiveprocedureslikeVIAandtotreatwomenusingcryotherapy.Andonedaysoon,whenlow-costHPV-DNAtestsbecomecommonplace,thesametrainedstaffcanusethenewtestsaswell.Weknowthatasingle-visitapproachcanbeincorporatedintoprimary-careservicesandthatitbringstheservicesclosertowherewomenreside,reducesthenumberofclinicvisitsrequired,andreducesbarrierstoscreeningandfollow-upcare.Theselifesavinginterventionsareavailableandproven.
Anothernewtechnology,themuch-heraldedHPVvaccine,alsohasanimportantroletoplayinacomprehensivecervicalcancercontrolprogram.WhilescreeningisneededforwomenwhomayalreadyhavebeeninfectedwithHPV,vaccinescanprotectyoungadolescentgirlsagainstinfectioninthefirstplace.Thistwo-prongedstrategy—screeningplusvaccination—hasthepotentialtosavemillionsoflivesoverthenextdecades.
PATHwillcontinueworkingtoensurethateverywomancanrealizeherrighttoscreening,andeverygirlherrighttoHPVvaccination.
Women participate in a mapping exercise during the PATH cervical cancer vaccine project formative research in Gujarat, India.
PATH
1��� NW Leary Way Seattle, WA ��10� USAPhone: �0�.���.��00 Fax: �0�.���.��1� www.path.org
Key cervical cancer resourcesRHO Cervical Cancer—an online collection of reliable information from the world’s leading institutions www.rho.org
Outlook. Preventing Cervical Cancer: Unprecedented Opportunities for Improving Women’s Health www.path.org/publications/details.php?i=1�0�
Cervical cancer, human papillomavirus (HPV), and HPV vaccines: Key points for policy-makers and health professionals (WHO, PATH, UNFPA) www.rho.org/files/WHO_PATH_UNFPA_cxca_key_points.pdf
Alliance for Cervical Cancer Prevention www.alliance-cxca.org
Evidence of Developing Country Support for Improved Cervical Cancer Prevention www.rho.org/CCAdossier
PATH Cervical Cancer Programs www.path.org/cervicalcancer
World Health Organization cervical cancer resource page www.who.int/reproductive-health/publications/cancers.html
Cervical Cancer Action www.cervicalcanceraction.org
International Agency for Research on Cancer www.iarc.fr
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August 2008
