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Unauthorized reproduction of this article is prohibited. beenmade,magneticresonanceimagingcanprovideusefulinfor- mationfortreatmentplanningforthosecasesnotamenabletosur- gery.Magneticresonanceimagingcanprovideinformationon tumorbulk,depthofmyometrialinvasion,andcervicalinvolve- mentandextrauterinespread. 11 StagingprotocolsarebasedonT2- weightedsequences,butcontrast-enhancedT1-weightedsequences maybecomplementaryandoptimizetheaccuracyofinterpreta- tion.Magneticresonanceimaginghasitslimitations,including microscopicinvasionandintranodallymphnodemetastases;itis possiblethatsensitivityfordetectionofthelatterwillbeimproved bytheuseofultrasmallparticlesofironoxide(USP10)contrast agents.Evaluationofpositronemissiontomography,particularly forlymphnodestagingandearlydetectionofrecurrence,warrants evaluation. 12 TreatmentofEC RoleofSurgery Theroleofprimaryhysterectomyforthetreatmentofen- dometrialcarcinomaiswellaccepted.Morecontroversialisthe roleoflymphadenectomy.AssignmentofFIGOstageisbasedon presenceorabsenceofmetastaticdiseaseintheretroperitoneal lymphnodes.Asnotedbelow,somegynecologicsurgeonsperform staginglymphadenectomiesonallpatients,someonnopatients, andsometailorstagingtoincludelymphadenectomyforpatients thoughttobeatsuf“cientlyhighriskoflymphnodeinvolvement. Inaddition,theextentoflymphadenectomyremainsasubjectof debate. Furthermore,understandingpatternsoffailureiscriticalin understandinghowbesttomanageECinpostsurgicalcare.Of 612womenmanagedwithhysterectomyandadjuvantradiother- apy(RT)attheMayoClinic,141(23%)relapsedandsitesof recurrencewereknownfor132cases;60hematogenous,44lym- phatic,and37intraperitoneal. 13 Amongwomenwithmyometrial invasionoflessthan50%,5%developedhematogenousspread comparedwith23%inthosewithmorethan50%invasion. Lymphaticembolizationwasfoundonlyinhigh-riskcases.Pelvic sidewallrecurrenceoccurredatarateoflessthan1%inwomen withoutlymphovascularinvasion(LVI)orpositivenodesatpre- sentation,andpara-aorticrecurrencewasalsoasrareinwomenwho werenode-negativeandhadnoLVI.Inthepresenceofthese, however,sidewallandpara-aorticrecurrenceswere26%and33%, respectively.Intraperitonealspreadwaslargelyassociatedwithad- vanceddiseaseatpresentation.Vaginalfailurewasassociatedwith grade3histologicsubtypeandLVI. GOG-99isarandomizedtrialevaluatingpelvicradiationto nofurthertherapyamongwomenconsideredatintermediaterisk forrecurrenceafterhysterectomyandlymphadenectomy. 14 Among thosewomenwithnoevidenceofdiseaseintheretroperitoneal lymphnodes,age,grade,depthofmyometrialinvasion,andlym- phovascularspaceinvasionwereindependentpredictorsofrecur- rence.ThesesamefactorsalsopredictedrecurrenceinthePORTEC 1studythatinvolvedwomenwhounderwenthysterectomybut notlymphadenectomyasprimarytherapyforEC. 15 Therefore,bothhysterectomyandlymphadenectomy,ifper- formed,canhelpdetermineboththeriskofrecurrentdiseaseand thedominantpatternsoffailure,whetherperitonealornodal.Wedo notknowyethowtointegrateadjuvantradiationtherapyandche- motherapytominimizetheriskofrecurrence. RadicalHysterectomy Unlikeasimplehysterectomy,aradicalhysterectomywill removeparametrialtissue,uppermostvagina,andpelvic T para- aorticlymphnodes.Asnotedbelow,theoptimalextentoflym- phadenectomyisnotwellde“ned.Thiscombinedsurgical procedurecouldhavetheeffectofreducingcentralpelvicandvag- inalfailures,aswellasde“newomenatlowriskoflymphaticsite relapse.Thereis,however,noevidencetosupportradicalhyster- ectomyforstageIdisease.Radicalhysterectomyshouldbecon- “nedtowomenwithknownbulkyinvolvementofthecervix,that is,IIB. 16 RoleofLymphadenectomy Theroleoflymphadenectomyistostagediseaseandinso doingtode“neprognosisanddeterminetheneedforadjuvant therapy.Theextentoflymphadenectomyalsoremainscontrover- sial,includingtheoptimalnumberoflymphnodestoremove,the sitesforlymphadenectomy,andhowhighuptheaortathelym- phadenectomyshouldextend.Somegroupshaveadvocatedto abovetheaorticbifurcation,otherstotheleveloftheIMA,and otherstotherenalvessels.Whetherlymphadenectomyisthera- peuticinitselfbyremovinginvolvednodesisahighlycontro- versialissue.Nonrandomized,retrospectivecaseserieshavebeen analyzedtodeterminewhetherremovalofagreaterorlessernum- berofnodesorindeedanynodesisassociatedwithimproved survival.AnumberofsuchstudiesfromtheUnitedStateshave suggestedasurvivalbene“tinwomenundergoingsurgicalstaging, butmostofthesestudieshavenotcontrolledforstandardofcare, comorbidity,andstagemigration,thatis,node-positivewomenare movedoutofstageIdisease,leavingnode-negativewomenbeing comparedwithwomenofunknownnodestatus.Arecentlypub- lishedstudybyChanetalreportedthatamongwomenwhohad beenstagedandfoundtohavepositivenodes,thoseinwhom11 to20nodeswereremovedandmorethan20nodeswereremoved hadarelativehazardrateof0.77and0.60,respectively,compared withthosewhohadupto10nodesremoved. 17 Thebene“tof lymphadenectomyamongwomenwhosehysterectomyspecimens putsthematlowriskforextrauterinediseaseseemstobesmall.As notedabove,thereisnoconsistentapproachtolymphadenectomy eveninNorthAmerica. Decisiveproofofwhetherlymphadenectomyistherapeutic requiresdatafromarandomizedtrialinwhichadjuvanttherapy doesnotconfoundthe“ndings.Therecentlyreported,butasyet unpublishedASTECtrial,performedintheUnitedKingdom,was designedtoaddresstheeffectoflymphadenectomyonsurvivaland theeffectofadjuvantRTonsurvivalofat-riskwomen.Thepub- lishedresultsofASTECareeagerlyawaited,althoughaprelimi- naryanalysispresentedattheAnnualMeetingoftheSocietyof GynecologicOncologists(PalmSprings,Calif,March2006)sug- gestednosurvivalbene“tassociatedwithlymphadenectomy. SentinelNodeBiopsy Therationaleofsentinelnodesurgeryrequireshighnegative predictivevalueasameansofavoidingtheneedforsystematic lymphadenectomyinallandusingapositivesentinelnodetode- terminetheneedforfulllymphadenectomyoradjuvanttherapy. Sentinelnodescanbeidenti“edlaparoscopically,whichcouldpre- cedede“nitivesurgery.Sentinelnodescanbeidenti“edusing eithertoluidineblueorradiolabeledtechnetium. 18 Usingbothhysteroscopicallypresentedmarkerandcervical orsubserosalcorpusinjectionhasachievednegativepredictivevalue approaching100%. 19 Sentinelnodedetectionratesaremorethan 90%,mostlypelvicwithpara-aorticnodesbeingthesentinelsiteon much

rareroccasions.Althoughsentinelnodesurgeryseemstobe feasibleinEC,itsusehasnotbecomewidespread.Inaddition,the utilityofsentinelnodesurgeryinECmanagementneedstobe establishedinclinicaltrials. KitchenerandTrimble InternationalJournalofGynecologicalCancer & Volume19,Number1,January2009 136 * 2009IGCSandESGO Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited. bydatathatdemonstratedahazardratioforECof89,when comparedwithbenignendometrialbiopsyduringaperiodof10 years. 2 Mutationof PTEN ,atumorsuppressorgene,isimplicated becausethemutationratesfornormalendometrium,endometrioid intraepithelialneoplasia(EIN),andendometrialcarcinomaare0%, 55%,and83%,respectively. PTEN knockoutmicedemonstratevery highratesofEIN,and20%developEC.Progestinscanachieve regressionofprecancerouslesions,whichcurrentlyofferthebest prospectforsecondarypreventioninpredisposedwomen. MolecularGeneticsofEndometrioidEC Type1andtype2tumors(non Y estrogen-related)havediffer- entgeneticpro“les. 3 Inadditionto PTEN ,type1featuresmutations inmismatchrepairgenesaswellasK- ras and A -catenin .Type2 featuresaneuploidyandp53mutations.Microarraytechnologyhas beenusedtodemonstrateupregulatedanddownregulatedgenes inECcomparedwithnormalendometrium.Avarietyofdifferen- tiallyexpressedgenescanalsobeidenti“edbetweenearlyandlate stagediseases.Someofthemostsigni“cantoverexpressedgenes areinvolvedinkeypathways:cellproliferation(eg, CCNE1 ),an- giogenesis(eg, MMPG ),andchromosomalinstability( BIRC5 ). Thesehavebeencon“rmedaspredictedtargetgenesbymeans ofmicroRNAs,mostdifferentiallyexpressedinECcomparedwith normalendometrium.Greaterunderstandingofkeygenesinvolved inendometrialcarcinogenesiswillhelpindevelopingbiomarkers ofprognosisandtherapeutictargets.Fundamentalstudiesofthese candidategeneswillbeimportantinelucidatingmechanismsof causation,progression,andmetastasis. SerousandClearCellCarcinoma Type2EC,whichcomprisesaround5%to10%ofECs, includesbothserouscarcinomaandclearcellcarcinoma. 4,5 The termserouscarcinomaispreferredtothecommonlyusedaspa- pillaryserouscarcinomabecauseaglandularvariantexistswithout papillaryformation.Unliketype1tumors,type2neoplasmsare associatedneitherwithestrogenexcessnorwithendometrialhy- perplasia,althoughaproportionmayevolvefromatype1tumor viaprogressionandmutation.Serouscarcinomasarethoughtto ariseinatrophicendometriafromaprecursorlesionknownas serousendometrialintraepithelialcarcinoma(serousEIC).They are,byde“nition,highgradeandhaveamuchpoorerprognosis thantype1tumors.TheprecursorlesionserousEIChasapropen- sitytoariseinendometrialpolypsandmaygiverisetoextrauterine disease,evenintheabsenceofendometrialstromalormyometrial invasion.Immunohistochemicalstudieshaveshownthatp53is diffuselypositiveinapproximately90%ofserouscarcinomas.Other markerssuchasHER-2 neu andER/PRareinconsistentlyexpressed (manycasesarehormonereceptor Y negative).Mostserouscarcino- masareassociatedwithmutationsinthe p53 tumorsuppressorgene. Thesemutationsoccurearlyintheevolutionofuterineserous carcinomaandaredemonstrableintheprecursorlesionserousEIC. Inclearcellcarcinomas,whicharealsoaggressiveneoplasmsand whicharerarerthanserouscarcinomas,moleculareventshavebeen lesswellstudied. p53 andER/PRarebothinconsistentlyexpressed. Mixedtype1andtype2carcinomasarenotuncommonandmay evolvefromatype1neoplasmsecondaryto p53 mutation. LynchSyndrome ThetermLynchsyndromeisnowusedtoencompassHNPCC andLynchsyndromeI/II.Endometrialcancerasaresultofthe Lynchsyndromeaccountsfor2%to3%ofallcases. 6 Inwomenwith ECbelowtheageof50years,9%haveLynchmutations.Individ- ualswhoexhibittheLynchsyndromehavearounda50-foldlifetime riskofdevelopingECcomparedwithunaffectedwomen,with studiessuggestingarangeof40%to60%lifetimeriskforthosewith amutation.Thesyndromecanbede“nedclinicallyusingthe Amsterdamcriteriaorgeneticallybygermlinemutationin MLH1 , MSH-2 ,or MSH-6 defectiveDNArepair. Thesemutationscanbetestedforonatumorspecimento demonstrateamutationcarrierusingimmunohistochemistryand,if bothnormalandtumortissueareavailable,microsatelliteinstability canbetestedfor,which,inhereditarycancer,isassociatedwitha germlinemutationinthemismatchrepairgene.Insporadictumors, itisassociatedwithhypermethylationofthe MLH1 promoter. ThirtypercentofindividualswithLynchsyndromewillde- velopasecondcancerwithin10yearsofthe“rstcancer(compared witharound3% Y 4%ofunaffected),andforwomendiagnosedwith EC,themediantimeforasecondcanceris11years.Theonly provenmeansofpreventionofECishysterectomy;however,en- docrinechemoprophylaxisiscurrentlybeingexploredintrialsboth intheUnitedStatesandintheUnitedKingdom. ER/PRExpressions TwoisoformsofbothER(ER � andER A )andPR(PRAand PRB)havebeendescribed. 7 Progesteronetreatmentiscapableof inhibitinginvasionofendometrialcellsbydown-regulatinganum- berofgenes,forexample, integrins and K-cadherin .PRAisnu- clear,whereasPRBshuttlesbetweenthenucleusandcytoplasm. WhereasERandPRtendtobeabundantinwell-differentiated EC,theyaresparseinpoorlydifferentiateddisease. G-proteincoupledwithreceptorforestrogen(GRP30),whose functionisunknown,ishighlyexpressedinsomehigh-gradeECs, anditsunderexpressionissigni“cantlycorrelatedwithimproved survival. InGOG-119,tamoxifenincombinationwithmedroxypro- gesteroneacetatewasusedinwomenwithmetastaticcancer;tu- morswithabundantERhadimprovedsurvivalupto5years. 8 This hormonalregimenshouldbeconsideredtobecombinedwithtem- sirolimus,anM-TORinhibitor,inarandomizedstudyinwomen withadvanced/metastaticdisease. SelectiveEstrogenReceptorModulatorsand theEndometrium Tamoxifenwasthe“rstselectiveestrogenreceptormodu- lator. 9 Ithasastimulatingeffectonuterinestromaandonepithelial cells,whichmayrangefromcysticchangetoproliferative,hyper- plasic,toinvasivecancer.Thesetissue-speci“cdifferentialchanges aredependentondifferentialERconformationuponligandbind- ing,differentialexpression,andbindingofcoregulatoryproteinsto theER. Tamoxifenmayalsoexertacarcinogeniceffectviaageno- toxicpathwaythroughtamoxifenDNAadducts.Comparedwith non Y tamoxifen-relatedtumors,ahigherproportionoftamoxifen- relatedtumorsexhibit p53 mutations.Itisnotknownwhethersome womenaremoresusceptibletocarcinogenesisbytamoxifenthan otherwomen,andifso,w

hatmaybethebiomarkersforthis. CurrentStateofImaging ThemostcommoneventbeforethediagnosisofECispost- menopausalbleeding,forwhichultrasoundexaminationoftheuter- ushasconsiderableutility. 10 Thenegativepredictivevalueofan endometrialecholessthan5mmis99%,whichprovidesavery reliablemeansofexcludingcancer.Anultrasoundimagethat showsanabnormallythickenedendometriumisnotspeci“cfor benignormalignantlesions,whichrequirefurtherinvestigations, includinghysteroscopyandbiopsy.WhenadiagnosisofEChas InternationalJournalofGynecologicalCancer & Volume19,Number1,January2009 ECStateoftheScienceMeeting * 2009IGCSandESGO 135 Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited. EndometrialCancerStateoftheScienceMeeting HenryC.Kitchener,*EdwardL.Trimble, Þ andfortheEndometrialCancerWorkingGroupoftheGynecologicCancerIntergroup Abstract: Thereisapressingneedtoimproveourunderstandingofendometrialcancer(EC)anduterine carcinosarcomaandtodevelopnewtreatmentstrategiestoimproveoutcomes.Inrecognitionofthis,aStateofthe SciencemeetingonECwasheldlastNovember28and29,2006,inManchester,UnitedKingdom.Themeeting wascosponsoredbytheNationalCancerResearchInstitute(UK),theNationalCancerInstitute(US),andthe GynecologicalCancerIntergroup. Theobjectivesofthemeetingwereasfollows: 1.ToreviewcurrentknowledgeandunderstandingofECanditstreatments. 2.Toidentifykeyissuesfortranslationalresearchandclinicaltrials. 3.Toidentifythemostimportanttrialsforwomenwithendometrialcarcinomaanduterinecarcinosarcoma,both thosealreadyunderwayortobedone,forwhichtheGynecologicalCancerIntergroupmightfacilitate internationalcooperation. KeyWords: Endometrialcancer,Clinicaltrials,Translationalresearch ( IntJGynecolCancer 2009;19:134 Y 140) E ndometrialcancer(EC),thesecondmostcommongynecologic cancerworldwide,hasnowbecomethemostcommongynecol- ogiccancerindevelopedcountries.Itsrisingincidenceisrelated toincreasinglifeexpectancy,tamoxifenuse,andtheepidemicof obesity.Thelastisalsoresponsibleforcomorbidity,notablyadult- onsetdiabetesandhypertension.Together,comorbidityandobesity presentchallengesindeliveringoptimaltherapyformanywomen withEC.TherisingincidenceofEChasbeenassociatedwitha risingdeathrate.Althoughtheprognosisofearlydiseaseisgood withasurvivalrateof80%,thosewithveryhigh-riskdiseaseand advanceddiseaseatpresentationhaveasurvivalratebelow50% withverylittlegainintherapeuticef“cacyduringthepast30years. Thislackofprogressintreatmentis,inpart,relatedtoourlimited understandingofthemolecularpathologyofEC.Thereisapressing needtoimproveourunderstandingofECandtodevelopnewtreat- mentstrategiestoimproveoutcomes.Inaddition,comparedwith ovarianandcervicalcancer,ECanduterinecarcinosarcoma(CS) havebeenstudiedmuchlessextensively.Fewertrialshavebeen openedforwomenwiththesecancers,andaccrualtothosetrialshas beenslow. Inrecognitionofthis,aStateoftheSciencemeetingon ECwasheldlastNovember28and29,2006inManchester,United Kingdom.ThemeetingwascosponsoredbytheNationalCan- cerResearchInstitute(NCRI,UK),theNationalCancerInstitute (US),andtheGynecologicalCancerIntergroup(GCIG).Amulti- disciplinarygroupof75,drawingonsurgeons,gynecologiconcol- ogists,radiation(clinical)oncologists,medicaloncologists, pathologists,translationalscientists,andpatientadvocatesfrom 18countriesandrepresenting14trialgroupsattended. Theobjectivesofthemeetingwereasfollows: 1.ToreviewcurrentknowledgeandunderstandingofECandits treatments. 2.Toidentifykeyissuesfortranslationalresearchandclinical trials. 3.Toidentifythemostimportanttrialsforwomenwithendo- metrialcarcinomaanduterineCS,boththosealreadyunderway ortobedone,forwhichtheGCIGmightfacilitateinternational cooperation. The“rsthalfoftheproceedingswasdedicatedtoaseriesof presentations,whichoutlinedourcurrentknowledge.Thesecond halfofthemeetingbeganwithparallelsessionsofearlydiseaseand advanced/recurrentdiseasetode“nestaging,treatment,andtrans- lationalresearchissuestoleadtocandidateclinicaltrialsquestions. Thiswasfollowedbyplenarydiscussionofthequestionstobe addressedinthesecandidatetrialsandanattempttodevelopan internationalconsensusofthemostfavoredconceptsforfuture developmentandinternationalcollaboration. Thispaperreportsthecontentandconclusionsarisingfrom thismeeting. CURRENTKNOWLEDGE MolecularPathologyofEC EndometrialHyperplasia Thereisbroadagreementthattype1(estrogen-related)EC progressesviaaprecursorlesion,atypicalhyperplasiaorendome- trialintraepithelialneoplasia. 1 Thishasbeenclearlydemonstrated *UKNationalCancerResearchInstituteandUniversityofManchester, Manchester,UnitedKingdom;and  NationalCancerInstitute,Bethesda,MD. AddresscorrespondenceandreprintrequeststoEdwardL.Trimble, CIB,CTEP,DCTD,NationalCancerInstitute,NationalInstitutesof Health610ExecutiveBlvd,Suite7025,Bethesda,MD20892.E-mail: tt6m@nih.gov. Copyright * 2009byIGCSandESGO ISSN:1048-891X DOI:10.1111/IGC.0b013e3181995f90 O RIGINAL A RTICLE 134 InternationalJournalofGynecologicalCancer & Volume19,Number1,January2009 Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited. CancerCenter(GOG);WilliamSmall,NorthwesternUniversity (RTOG);GavinStuart,UniversityofVancouver(NCICCTG);Ann- MarieSwart,UKMedicalResearchCouncil(NCRI),PaulSymonds, UniversityofLeicester(NCRI);SunKuieTay,SingaporeGeneral Hospital;J.TateThigpen,UniversityofMississippi(GOG);Gillian Thomas,UniversityofToronto(GOG,ACRIN);IanTominson,Barts andtheLondonNHSTrust(NCRI);HemantTongaonkar,Tata MemorialHospital,Mumbai,India(GOG);EdwardTrimble,NCI; JoanWalker,UniversityofOklahoma(GOG);Y.F.Wong,Chinese UniversityofHongKong. REFERENCES 1.HechtJL,MutterGL.Molecularandpathologicaspectsof endometrialcarcinogenesis. JClinOncol .2006;24:4783 Y 4791. 2.BaakJP,MutterGL,RobboyW,etal.Themoleculargeneticsand morphometry-basedendometrialneoplasiaclassificationsystem predictsdiseaseprogressioninendometrialhyperplasiamore accuratelythanthe1994WorldHealthOrganizationclassification system. Cancer .2005;103:2304 Y 2312. 3.YongWF,CheungTH,LoKW,etal.Identificationofmolecular markersandsignallingpathwayinendometrialcancerinHongKong Chinesewomenbygenome-widegeneexpressionprofiling. Oncogene . 2007;26:1971 Y 1978. 4.GehrigPA.Uterinepapillaryserouscarcinoma:arev

iew. ExpertOpin Pharmacother .2007;8:809 Y 816. 5.LaxSF.Moleculargeneticchangesinepithelial,stromal,andmixed neoplasmsoftheendometrium. Pathology .2007;39:46 Y 54. 6.LuKH.Hereditarygynecologiccancers:differentialdiagnosis, surveillance,managementandsurgicalprophylaxis. FamCancer . (inpress). 7.LeslieKK,SteinMP,KumarNS,etal.Progesteronereceptorisoform identificationandsubcellularlocalizationinendometrialcancer. GynecolOncol .2005;96:32 Y 41. 8.WhitneyCW,BrunettoVL,ZainoRJ,etal.PhaseIIstudyof medroxyprogesteroneacetateplustamoxifeninadvancedendometrial carcinoma:aGynecologicOncologyGroupstudy. GynecolOncol . 2004;92:4 Y 9. 9.MoralesL,TimmermanD,NevenP,etal.Endometrialsafetyofthird generationaromataseinhibitorsversustamoxifeninbreastcancer patients. IntJGynecolCancer .2006;16:Suppl2:515 Y 517. 10.AkinO,MironovS,Pandi-TaskarN,etal.Imagingofuterinecancer. RadiolClinNorthAm .2007;45:167 Y 182. 11.OrtashiO,JainS,EmannuelO,etal.Evaluationofthesensitivity, specificity,positiveandnegativepredictivevaluesofpreoperative magneticresonanceimagingforstagingendometrialcancer: aprospectivestudyof100casesattheDorsetCancerCentre. EurU ObstetGynecolReprodBiol .(inpress). 12.ChaoA,ChangTC,NgKK,etal. 18 F-FDGPETinthemanagement ofendometrialcancer. EurJNuclMedMolImaging .2006;33:36 Y 44. 13.MarianiA,DowdySC,KeeneyGL,etal.High-riskendometrial cancersubgroups:candidatesfortarget-basedadjuvanttherapy. GynecolOncol .2004;95:120 Y 126. 14.KeysHM,RobertsJA,BrunettoVL,etal.AphaseIIItrialofsurgery withorwithoutadjunctiveexternalpelvicradiationtherapyin intermediateriskendometrialadenocarcinoma:aGynecologic OncologyGroupstudy. GynecolOncol .2004;92:744 Y 751. 15.CreutzbergCL,vanPuttenWL,KoperPC,etal.Surgeryand postoperativeradiotherapyversussurgeryaloneforpatientswith stage-1endometrialcarcinoma:multicentrerandomisedtrial. PORTECstudygroup. Lancet .2000;355:1404 Y 1411. 16.MarianiA,WebbM,KeeneyG,etal.Roleofwide/radicalhysterectomy andpelvicnodedissectioninendometrialcancerwithcervical involvement. GynaecolOncol .2001;83:72 Y 80. 17.ChanJK,UrbanR,CheungMK,etal.Lymphadenectomyin endometrioiduterinecancerstaging:howmanylymphnodesare enough?Astudyof11,443patients. Cancer .2007;109:2454 Y 2460. 18.Holub,JaborA,KlimentL.Comparisonoftwoproceduresof sentinellymphnodedetectioninpatientswithendometrialcancer: apilotstudy. EJGyneOncol .2002;23(1):L53 Y L57. 19.AltgassenC,PagenstecherJ,HornungD,etal.Anewapproachto labelsentinelnodesinendometrialcancer. GynaecolOncol . 2007;105:457 Y 461. 20.AaldersJ,AbelerV,KolstadP,etal.Postoperativeexternalirradiation andprognosticparametersinstageIendometrialcarcinoma:clinical andhistopathologicstudyof540patients. ObstetGynecol .1980; 56:419 Y 427. 21.MaggiR,LissoniA,SpinaF,etal.Adjuvantchemotherapyvs. radiotherapyinhigh-riskendometrialcarcinoma:resultsofa randomisedtrial. BrJCancer .2006;95:266 Y 271. 22.GrevenK,WinterK,UnderhillK,etal.FinalanalysisofRTOG 9708:adjuvantpostoperativeirradiationcombinedwithcisplatin/ paclitaxelchemotherapyfollowingsurgeryforpatientswithhigh-risk endometrialcancer. GynecolOncol .2006;103:155 Y 159. 23.MartinezAA,WeinerS,PodratzK,etal.Improvedoutcomeat tenyearsforserous-papillary/clearcellorhigh-riskendometrialcancer patientstreatedbyadjuvanthigh-dosewholeabdomino-pelvic irradiation. GynOncol .2003;90:537 Y 546. 24.RandallME,FiliaciVL,MussH,etal.RandomizedphaseIIItrial ofwhole-abdominalirradiationversusdoxorubicinandcisplatin chemotherapyinadvancedendometrialcarcinoma:aGynecologic OncologyGroupstudy. JClinOncol .2006;24:36 Y 44. 25.SmallW,EricksonB,KwakwaF.AmericanBrachytherapySociety surveyregardingpracticepatternsofpostoperativeirradiationfor endometrialcancer:currentstatusofvaginalbrachytherapy. IntJ RadiatOncolBiolPhys .2005:63:1502 Y 1507. 26.FlemingGF.Systematicchemotherapyforuterinecarcinoma: metastaticandadjuvant. JClinOncol .2007;25:2983 Y 2990. 27.ThigpenJT,BradyMF,AlvarezRD,etal.Oralmedroxyprogesterone acetateinthetreatmentofadvancedorrecurrentendometrialcarcinoma: adose-responsestudybytheGynecologicOncologyGroup. JClin Oncol .1999;17:1736 Y 1744. 28.FioricaJV,BrunettoVL,HanjaniP,etal.PhaseIItrialofalternating coursesofmegestrolacetateandtamoxifeninadvancedendometrial carcinoma:aGynecologicOncologyGroupstudy. GynecolOncol . 2004;92:10 Y 14. 29.RosePG,BrunettoVL,VanLeL,etal.AphaseIItrialofanastrozole inadvancedrecurrentorpersistentendometrialcarcinoma:a GynecologicOncologyGroupstudy. GynecolOncol .2000; 78:212 Y 216. 30.MaBB,OzaA,EisenhauerE,etal.Theactivityofletrozoleinpatients withadvancedorrecurrentendometrialcancerandcorrelationwith biologicalmarkers V astudyoftheNationalCancerInstituteofCanada ClinicalTrialsGroup. IntJGynecolCancer .2004;14:650 Y 658. 31.Martin-HirschPL,JarvisG,KitchenerH,etal.Progestagensfor endometrialcancer. CochraneDatabaseSystRev .2000;(2):CD001040. 32.ChenML,XuPZ,PengXD,etal.ThedeficiencyofAkt1is sufficienttosuppresstumordevelopmentin Pten T mice. GenesDev . 2006;20(12):1569 Y 1574. 33.PodsypaninaK,LeeRT,PolitisC,etal.AninhibitorofmTOR reducesneoplasiaandnormalizesp70/S6kinaseactivityin Pten T mice. ProcNatlAcadSciUSA .2001;98(18): 10320 Y 10325. KitchenerandTrimble InternationalJournalofGynecologicalCancer & Volume19,Number1,January2009 140 * 2009IGCSandESGO Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited. surgicalexcision,pelvicradiation,and,morerecently,chemothe- rapy.Theproposedtrial(GOG-0238)wouldrandomizewomen experiencingpelvicrecurrenceoftheirECstoradiationalonever- susplatinum-basedchemoradiation.Surgicalexcision/debulking, butnotexenteration,potentiallycurativesurgerywouldbeper- mittedbeforeentryintothetrial. TreatmentofStageIVorRecurrentEC Theproposedtrialsseektooptimizechemotherapyregi- mensordecreasethetoxicityofstandardchemotherapy.Inthe UnitedStates,onthebasisofGOG-177,paclitaxelseemstohave beenacceptedaspartofthestandardtreatmentregimenforad- vancedEC.OutsidetheUnitedStates,paclitaxelisnotwidely used.Inmanycountries,paclitaxelhasnotbeenapprovedforrou- tineuseamongwomenwithEC.IntheUnitedStates,therefore, theGOGplanstocompleteaccrualtoGOG-0209,whichcompares a3-drugcombinationofpaclitaxel,doxorubicin,andplatinumtoa 2-drugregimenofcarboplatinand

paclitaxel.OneproposedEuro- peantrialwouldcomparedoxorubicinpluscisplatinwithcarbop- latinplusliposomaldoxorubicin.Anovelagent,temsirolimus,an M-TORinhibitorasdescribedabove,seemstohaveactivityinEC. Twoproposedstudieswouldevaluatetheadditionoftemsirolimus tochemotherapyorhormonaltherapyinthetreatmentofwomen withstageIVorrecurrentEC. TreatmentofUterineCS UterineCSisarelativelyrarehistologicsubtypecompared withendometrialadenocarcinoma.Onlyintergroupandinterna- tionalcollaborationswillmakepossibletimelycompletionofde- “nitivetrialsforwomenwiththisdisease. WomenwithuterineCSareathighriskforbothlocaland distantrecurrencesafterprimaryhysterectomy.Theproposedstud- iesseektode“nethebene“tofpelvicRT,aswellastheoptimal chemotherapyregimen. AdjuvantTreatmentofFIGOStageItoII UterineCS OneproposedstudywouldrandomizewomenwithCSafter primaryhysterectomytopelvicRTorobservation.Asecondpro- posedtrialwoulduseabifactorialdesigntoaddressbothchemo- therapyandradiationtherapyquestions.WomenwithCSafter primaryhysterectomywouldberandomizedtopelvicRTornot RT,aswellastopaclitaxelpluscisplatinorpaclitaxelpluscis- platinplusdoxorubicinorepirubicin. ConsolidationTreatmentforFIGOStageIItoIV UterineCS Theproposedstudywouldalsouseabifactorialdesignto comparechemotherapywithorwithoutatargetedagentandto comparepelvicradiationtonoradiation. CONCLUSIONS TheEndometrialCancerConsensusprocessallowedasuc- cessfulpresentationofthecurrentstateofknowledgeandresulted inaneffectiveconsensustoemergeregardingtheprogressthat needstobeachievedtoimpactpatientcare. Asnotedabove,comparedwithovarianandcervicalcancer, ECanduterineCShavebeenstudiedmuchlessextensively.Rel- ativelyfewtrialshavebeenopenedforwomenwiththesecancers, andaccrualtothosetrialshasbeenslow.Throughintergroupand internationalcollaborations,wehopetoensurethatthebestscience informstrialsforwomenwithECanduterineCSandthatthese trialsarecompletedasrapidlyaspossible.Weplantoworkthrough theGCIGtopromoteaccrualtothosetrialsalreadyopenaswellas thetimelydevelopmentofthosetrialsproposedabove.Wewillalso needtoeducateoursponsorsandpartnersinresearch,including nationalgovernments,charities,andthepharmaceuticalindustry abouttheimportanceofidentifyingmoreeffectivetreatmentof womenwithECanduterineCS. ACKNOWLEDGMENTS Theauthorsthankthehelpofthefollowingindividualsin preparingthispaper:ChrisAltgassen,CarienCreutzberg,Gini Fleming,HaniGabra,GeoffHall,JaneHawnaur,AnujaJhingran, KimLeslie,KarenLu,WGlenMcCluggage,ScottMcMeekin,Karl Podratz,WilliamSmall,andGillianThomas. EndometrialCancerWorkingGroupparticipants:Chris Altgassen,UniversityofSchleswig-Holstein(AGO);Carol Aghajanian,MemorialSloan-KetteringCancerCenter(GOG), USA;FrederickAmant,CatholicUniversityofLeuven(EORTC); MichaelBirrer,USNationalCancerInstitute(GOG);PeterBlake, RoyalMarsdenHospital(NCRI);JeffBoyd,CurtisandElizabeth AndersonCancerInstitute(GOG);MarkBrady,RoswellPark CancerInstitute(GOG);DavidCantu,MexicanNationalCancer Institute;MichaelCibull,UniversityofKentucky(GOG);Larry Copeland,OhioStateUniversity(GOG);WilliamCreasman, MedicalUniversityofSouthCarolina(GOG);CarienCreutzberg, DanieldenHoedCancerCenter,ErasmusMedicalCenter(EORTC, PORTEC);KathleenDarcy,RoswellParkCancerInstitute(GOG); SusanDavidson(NCRI);PhilipDiSaia,UniversityofCalifornia- Irvine(GOG);GinnyFiliaci,RoswellParkCancerInstitute(GOG); GiniFleming,UniversityofChicago(GOG);HaniGabra,Imperial CollegeLondon(SGCTG);DavidGaffney,UniversityofUtah (RTOG);PatricaGoldman(patientadvocate);PaulGoodfellow, WashingtonUniversity(GOG);JohnGreen,LiverpoolUniversity (EORTC,NCRI);GeoffHall,UniversityofLeeds(NCRI);Jane Hawnaur,UniversityofManchester;ThomasHogberg,University ofLinkoping(NSGO);CathHolland,UniversityofManchester (NCRI);WilliamHoskins,CurtisandElizabethAndersonCancer Institute(GOG);JamesLinsey;AnjuaJhingran,TheUniversityof TexasMDAndersonCancerCenter(RTOG);SokbomKang,Seoul NationalUniversity(KGOG);SeanKehoe,BirminghamWomens Hospital(NCRI);JaeWeonKim,SeoulNationalUniversity (KGOG);HenryKitchener,UniversityofManchester(NCRI); IkuoKonishi,ShinshuUniversity(JGOG);GunnarKristensen, NorwegianRadiumHospital(NSGO);JonathanLedermann,Kings CollegeHospital(NCRI);KimLeslie,UniversityofNewMexico (GOG);TraceyLively,NCI;JacLivsey;KarenLu,TheUniversityof TexasMDAndersonCancerCenter(GOG);ChristianMarth, InnsbruckMedicalUniversity(AGO-Austria);LuizMathias, BrazilianNationalCancerInstitute;GlennMcCluggage,Royal GroupofHospitalsTrust,Belfast(NCRI);DynesMcConnell, WellingtonHospital,NZ(ANZGOG);ScottMcMeekin,Universityof Oklahoma(GOG);LarryMaxwell,WalterReedArmyMedical Center(GOG);DavidMiller,UniversityofTexas-Dallas(GOG); ArnoMundt,UniversityofChicago(RTOG);GeorgeMutter, BrighamandWomensHospital(GOG);JaneOrton,Leeds TeachingHospitalNHSTrust(NCRI);AmitOza,PrincessMargaret Hospital(NCICCTG);TimPerren,StJamessUniversityHospital, Leeds(NCRI);RayPetryshun,NCI;SandroPignata,National CancerInstitute,Naples,Italy(MITO);KarlPodratz,MayoClinic (GOG);MelaniePowell(NCRI);MarcusRandall,Universityof Kentucky(GOG);NickReed,UniversityofGlasgow(EORTC); SatoruSagae,SapporoMedicalUniversity,Japan(JGOG);Helga Salvesen,HaukelandUniversityHospital,Bergen,Sweden(NSGO); JalidSehouli,ChariteCampus,VirchowKlinikum,Berlin,Germany (AGO);EamonnSheridan,StJamessUniversityHospital,Leeds (NCRI);BrianSlomovitz,TheUniversityofTexasMDAnderson InternationalJournalofGynecologicalCancer & Volume19,Number1,January2009 ECStateoftheScienceMeeting * 2009IGCSandESGO 139 Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited. and2.7months,andoverallsurvivalof13and14months,res- pectively. 8,28 Thearomataseinhibitors,anastrozoleandletrozole, havebeenassessedbutdemonstratedlimitedclinicalactivity. 29,30 Progestogenhasbeenshowntoberelativelyineffectiveasanad- juvantinprimarytherapy. 31 Furthertrialsarerequiredtoidentifytheoptimalroleofhor- monetherapy,beforeorafterchemotherapy,andwhatbiomarkers maybeinformativeinpredictingresponse. Biotherapies Thehallmarksofendometrioid(type1)uterinecancerare beginningtobeunderstood,with PTEN inactivation,activating mutationswithinthePI3Kpathway,K- ras Y activatingmutations, MLH1/6 epigeneticinactivation,and A -catenin activationbeing

welldescribed.Incontrast,type2(nonendometrioid)uterinecar- cinomasarecharacterizedbyaneuploidy, p53 mutation,anddefects in p53 pathwaygenes(suchas p21/waf1 and MDM2 ).Targetsfor type1tumorsincludecomponentsofthePI3Kpathway,the A - catenin pathway,theepidermalgrowthfactorreceptorfamily,en- docrinetherapy(PgRandER),andantiangiogenictargets.Recently describedmousemodelsthatareheterozygouslydeletedfor PTEN developendometrialhyperplasiaandendometrioidendometrial carcinomaatahighrate.Theincidenceoftheseendometrialcarci- nomasisdrasticallyreducedbycrossingwithanAKT1-de“cient mouse. 32 Thissuggestsacaseforexploringendocrineorbiothera- pymanipulationofendometrioiduterinecancer. PhosphoM-TORandphosphoS6kinaseareexpressedin type1endometrialcarcinoma.Rapamycinanalogswereshownto inhibitendometrialcarcinomacelllinesgrowthinvitroandinhibit thedevelopmentofendometrialcarcinomain PTEN heterozygote knockoutmice. 33 Trialsoftemsirolimus(CCI-779)andRAD001 havebeenundertaken,whichhaveshownactivityinuterinecancer, althoughsurrogatemolecularmarkersofresponsehaveremained elusive.Forexample,temsirolimushasshowna26%responserate withasubstantialadditionalstablediseasefraction.Responseswere notcorrelatedwithexpressionofreceptors.Currently,thereisa drivetointegrateM-TORinhibitorsintochemotherapyschedules forEC. EpidermalgrowthfactorreceptorandHer-2areover- expressedin50%and60%ofECs,respectively.TKIsprevent multipleintracellularsignalingpathwaysfrombeingactivated.In- cludingmitogen-activatedproteinkinasepathway,proteinkinase B(Akt),trastuzumab,cetuximab,andlapatinibhavebeguntobe evaluatedinphase2studies. DEVELOPINGAPORTFOLIOOFKEYTRIALS Thisbodyofcurrentknowledgeprovidesaplatformforde- terminingthekeyquestions,whichneedtobeansweredinanat- tempttoimprovethestandardofcareandimprovesurvival.This requiresasetofclinicaltrialscombinedwithtranslationalresearch todemonstratetheoptimalroleofsurgery,RT,andchemotherapy andtobegintoevaluatebiologicaltargeteddrugsanddiscover biomarkersforlikelyresponse/nonresponsetotherapy. TheConsensusGroupdiscussedthekeyquestionswhere therewasadearthofinformationfromtrialsandwherenewand additionaldatawereneeded.Throughconsensus,thegroupfocused onquestionsofbroadinterest,whichcouldadvanceknowledgeand weremostlikelytoattractintergroupandinternationalcollabora- tions.Theseareoutlinedbelow: PreventionofEndometrioidEndometrial Carcinoma Asdiscussedabove,EINseemstobeaprecursorlesionto endometrioidendometrialcarcinoma.Arelativeexcessofestrogen, whetherendogenousorexogenous,toprogesteronecanresultin thedevelopmentofEIN.Severaltrialstoevaluatethetherapeutic bene“tofprogestinsinthetreatmentofEINwerediscussed.The “rst,GOG-0224,randomizeswomenwithEINtocontinuous(me- gestrol,40mgtwiceadayfor12weeks)orcyclic(megestrol,80mg twiceadayfor12weeks,2weekson/2weeksoff)progestinsfor 3monthsbeforehysterectomy.Theprimaryendpointofinterest isthepresenceorabsenceofEINinthehysterectomyspecimen. Afollow-upstudywouldcompareacommerciallyavailable progesterone-releasingintrauterinedevice,Mirena,tothebest- performingarmofGOG-0224. ForwomenwithLynchsyndrome,whofaceahighlifetime riskofEC,TheUKNCRIisundertakingthePOETtrial,which randomizeseligiblewomeneithertotheMirenaortoobservation. Theprimaryoutcomeisdevelopmentofatypicalhyperplasiaor EC,whicheverisdetected“rst.Womeninbotharmswillbeob- servedfor12monthswithtransvaginalscanning T uterinebiopsy, upto36months. TreatmentofEndometrialCarcinoma Adjuvanttherapyafterprimaryhysterectomy. Asdiscussedabove,thereseemtobe3broadapproaches toprimarysurgeryandstagingworldwide,namely,hysterectomy aloneformostpatients,hysterectomyandstaginglymphadenec- tomyformostpatients,andhysterectomywithstaginglymphade- nectomyforpatientsthoughtatsuf“cientlyhighriskfornodal metastasis.Thegroupendeavoredtodesigntrialsthatmighten- rollpatientswithandwithoutsurgicalstagingforvariousrisk groups. Forwomenwithdiseaseapparentlycon“nedtotheuterusat timeofhysterectomy(FIGOstageI Y II),s everaltrialswere discussed.Overall,thegoalsofthesestudieswastodelineatethe appropriaterolesforadjuvantpelvicRT,vaginalbrachytherapy, systemicchemotherapy,andlymphnodedissectioninthispatient population.CurrentlyopentoaccrualisthePORTEC3trial,which randomizeswomentopelvicRTversuschemoradiationandconsol- idationchemotherapy.EligibilityincludesFIGOIBandIC/grade 3,II(occult)grade3,IIIAorIIC,endometrioid,andstagesIBto IIICclearcellorseroushistologicsubtype.Chemoradiationin- cludesconcurrentcisplatin50mg/m 2 ondays1and22;aftercom- pletionofchemoradiation,womenwillreceive4additionalcycles ofcarboplatin(AUC5)andpaclitaxel175mg/m 2 thriceweekly. Theplannedaccrualof800willdetecta10%differencein5-year overallsurvivalwith80%power. Oneproposedtrialwouldrandomizewomenwithnode- negativeECde“nedasathighriskofrecurrencetopelvicRTor chemotherapyplusvaginalbrachytherapy.Theywouldbestrati- “edonthebasisoflymphnodeevaluation,whetherimagingor surgicaldissection.Asecondproposalwouldrandomizewomen whohadundergonehysterectomybutnotlymphnodedissection tosurgicalstagingandchemotherapyforpositivenodesorpelvic RTandchemotherapywithoutsurgicalstaging. ConsolidationTherapyAfterHysterectomyfor FIGOStageIIIDisease Therecentstudiesdocumentingaroleforsystemicchemo- therapyinwomenwithadvancedECthrowintoquestionthebene“ts oflocalradiationtreatment.Theproposedtrialwouldrandomize womentosystemicchemotherapywithorwithoutradiationtherapy targetedtotheknownorsuspectsitesofdiseaseinthepelvisand/ orpara-aorticregion. TreatmentofIsolatedPelvicRecurrence AbouthalfofwomenwithrecurrentEChavetheirrecur- renceslimitedtothepelvis.Treatmentapproacheshaveincluded KitchenerandTrimble InternationalJournalofGynecologicalCancer & Volume19,Number1,January2009 138 * 2009IGCSandESGO Copyright @ 2009 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited. PelvicRadiotherapyandChemoradiation Bothradiationtherapyandchemotherapyhaveshownacti- vityinpreventingrecurrenceofEC,althoughtheirutilityvariesas tositesoffailure.Trialsevaluatingdifferentmodalitiesoftreat- mentintheadjuvantsettinghavebeencomplicatedbyheteroge- neitybothofriskofrecurrenceandmostlikelysitesforrecurrence. Weneedtodeterminehowbesttointegrateradiationandchemo- therapyafterprimarysurg

erytotakeadvantageofbothmodalities. PelvicRT,bothexternalbeamandbrachytherapyaloneor incombination,hasbeenwidelyusedformanyyearsasadjuvant therapyinunstagedwomen,witheitherintermediate(stageIC/IIA, grades1 Y 2)orhighrisk(stageIC,grade3),aswellasinstaged womenwithpositivenodesandstagedwomenwithnegativenodes butotherhigh-riskfactors.Ithasalsobeenusedforunresecta- ble,advanceddiseaseinthepelvis.ThreerandomizedtrialsofRT forintermediate-riskdiseasehavebeencompleted:theNorwegian trial,PORTEC1,andGOG-99. 14,15,20 Thesealldemonstrateda reductioninpelvicrecurrencebutnoeffectonoverallsurvival.Risk factorsforrecurrenceweregrade3disease,depthofinvasion,lym- phovascularspaceinvasion,stageIC,andaged60yearsorolder. ThePORTEC2trialiscurrentlyevaluatingwhetherpelvicexternal beamtherapycanbesafelyreplacedbybrachytherapywithresults expectedlate2008.Inlightofthesetrials,therehasbeenareduc- tionintheuseofadjuvantRTforintermediate-riskdisease.The principalchallengenowisachievinghighersurvivalratesinwomen withhigh-riskdiseasebyvirtueofageandprimarytumorfeatures whetherunstagedorwithnegativenodesorthosefoundtohave nodalmetastases. InarecentlypublishedItaliantrial,345womenwithstages IC/II(grade3)andstageIIIwererandomizedtoCAPorpelvicRT. 21 Nodifferenceinoverallsurvivalwasfound,butRTdelayedpelvic relapseandchemotherapydelayeddistalrelapse.Arecentphase 2trialfromtheUnitedStatestestedconcurrentchemoradiation (cisplatin,50mg/m 2 )withadjuvantcisplatin/paclitaxel(4cyclesof cisplatin50mg/m 2 andpaclitaxel175mg/m 2 ). 22 Thiswasfeasible, andat4years,disease-freesurvivalwas81%,indicatingcandida- tureforaphase3trial.Onthisbasis,thePORTEC3trialopenedas acollaboratingPORTEC/NCRIintergroupstudy.Itisplanned torandomize800womenwithhigh-riskdiseasetoeitherexternal beamRTorRT+concurrentcisplatin(weeks1and3)followed by4cyclesofcarboplatinandpaclitaxel(175mg/m 2 ).Theprimary endpointwillbeoverallsurvival. WholeAbdominalRadiotherapy TherationaleforwholeabdominalRT(WART)isthatthe abdominalcavityisthecommonestsiteoftreatmentfailureina numberofstudiesinvolvingwithadvanceddisease,whichincluded womenwithserousandclearcelltumors.Upto30grayiswell tolerated,withshieldingofthekidneys.Inoneofthelargestre- portedstudies,132womenweretreatedwithWARTincluding 68%withstageIIIand45%withserousorclearcelltumors. 23 Disease-freesurvivalat5and10yearswas55%and45%,respec- tively;siteofrelapsewastheabdominalcavityin59%.Toxicity included14%withgastrointestinalgrades3to4and2%renal. InGOG-122,WARTwascomparedwithadriamycin/cisplatin inaphase3trialinvolving396womenwithstageIIIandIVendo- metrialcarcinomaandlessthan2-cmresidualdisease. 24 Theresults showedsuperiorityforchemotherapy(hazardratio,0.71;95% con“denceinterval,0.54 Y 0.94),althoughtherewasanexcessof neurologicG 1 Y 2 andcardiactoxicity,with8treatment-related deathscomparedwith4intheWARTarm.Eighty-fourpercent completedWARTcomparedwith62%forchemotherapy.Almost twiceasmanywomenwhohadRTrecurredoutsidetheabdomen (18.3%)comparedwithAP(9.8%).Weshouldnote,however,that thesurvivalcurvesforthe2armshavegrowntogetherwithtime. AlthoughWARTisgenerallywelltolerated,itsroleintheman- agementofECisnotclear. VaginalBrachytherapy Therationaleofvaginalbrachytherapyisthatvaginalcuff recurrenceisanimportantsiteofpelvicrecurrence,andthistype oftreatmentisverywelltolerated.Instudiesreportingvaginalbra- chytherapyforadjuvanttreatmentofstageIdisease,vaginalcontrol approaches100%.InPORTEC1,73%ofrecurrencesamongnon- irradiatedpatientsinvolvedthevaginalcuff.Vaginalbrachythe- rapycouldsubstituteforexternalbeamradiationifpelviccontrol rateswerenotcompromisedand,forhigher-riskdisease,couldbe combinedwithchemotherapy.AnAmericansurveyofASTROand AmericanBrachytherapySocietymembersproduced551comple- tedresponses. 25 Mostreportedincreasedreferralforvaginal brachytherapywithalmostalltreatingtheuppervaginaonly. Almost70%ofpatientsweretreatedwithhigh Y doseratebra- chytherapy.ThePORTEC2trialwilldeterminewhetherbrachy- therapycansafelyreplaceexternalbeamRTforintermediate-risk disease.Futuretrialscouldcombinevaginalbrachytherapywith chemotherapyandbetterde“nitionofthetechnicalaspectsof therapy. Chemotherapy Treatmentofadvanced/recurrentECneedstotakeaccount oftheproportionofwomenwhomaybeobese,previouslyirra- diated,andelderly.Amongwomenwhohavenotyetreceivedche- motherapy,responseratesinexcessof20%havebeenseenwith thefollowingdrugs:doxorubicin/epirubin,paclitaxel/docetaxel, andcisplatin/carboplatin. 26 Tworandomizedtrialshavecompared doxorubicinwithdoxorubicin/cisplatin.Responserateswere higherforthecombination(27%vs45%;17%vs43%)witha medianoverallsurvivalof9monthsforthecombinationarmsin bothtrials. GOG-177comparedthecombinationofdoxorubicinand cisplatinwithdoxorubicin/cisplatinandpaclitaxelwithF-CSFsup- port.Therewasanoverallsurvivalbene“t.Theresponseratewas 57%forthetripletcomparedwith34%forthedoublet.Theme- dianoverallsurvivalrateswere15.3and12.3months,respective- ly,buttherewasexcessneurotoxicitywiththe3-drugcombination. Theless-toxiccombinationofcarboplatinandpaclitaxelhasbeen evaluatedinseveralphase2trialswithresponseratesinexcessof 60%.Thiscombination,whichisnowwidelyusedinthecommu- nity,isnowbeingcomparedwithdoxorubicin/cisplatin/paclitaxel forwomenwithstageIIIandIVdiseases(GOG-209). RoleofEndocrineTherapy Thesexsteroidhormonesprogesteroneandestrogenbind tospeci“creceptorswiththeresultingcomplexenteringthenucleus andleadingtospeci“cpatternsofgeneexpression,whichleadto speci“cphenotypiceffects,forexample,progesteroneleadstoen- dometrialcelldifferentiation. Endocrinetherapyhasbeenshowntohavesomeactivity inadvanced/recurrentECformorethan40years.Inclinicaltrials ofsingle-agentprogestogens(GOG-48andGOG-81),response ratesofapproximately20%wereachievedwithhigherresponse ratesinPR-positiveandlower-gradetumors. 27 Combinationsof progestogensandtamoxifen(whichincreasesprogesteronerecep- torexpressionandmaythereforecounteractresistancetopro- gestogens)havebeenassessed.Phase2trialsofsuchcombination strategies(GOG-119andGOG-153)havedemonstratedoverall responseratesof33%and27%,progression-freesurvivalof3 InternationalJournalofGynecologicalCancer & Volume19,Number1,January2009 ECStateoftheScienceMeeting * 2009IGCSandESGO