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Initialmanagementoflowriskgestationaltrophoblasticneoplasia

Officialreprintfrom UpToDate
www.uptodate.com 2015UpToDate

Initialmanagementoflowriskgestationaltrophoblasticneoplasia
Authors
RossSBerkowitz,MD
DonaldPeterGoldstein,
MD
NeilSHorowitz,MD

SectionEditor
BarbaraGoff,MD

DeputyEditors
SandyJFalk,MD,FACOG
DonSDizon,MD,FACP

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jan2015.|Thistopiclastupdated:Jan08,2015.
INTRODUCTIONGestationaltrophoblasticdisease(GTD)definesagroupofconditionsthatarisefroman
aberrantfertilizationevent.WhenGTDrecursorthereisevidenceofmetastaticdisease,itiscalledgestational
trophoblasticneoplasia(GTN)andcomprisesfoursubtypesofdisease:

Invasivemole
Choriocarcinoma
Placentalsitetrophoblastictumor(PSTT)
Epithelioidtrophoblastictumor(ETT)

TheinitialtreatmentoflowriskGTNisdiscussedhere.ThepathologyofGTN,epidemiology,clinical
manifestations,andstagingofGTNarediscussedseparately.Inaddition,themanagementofhighriskand
recurrentGTNarealsodiscussedseparately.
(See"Hydatidiformmole:Epidemiology,clinicalfeatures,anddiagnosis".)
(See"Gestationaltrophoblasticdisease:Pathology".)
(See"Hydatidiformmole:Management".)
(See"Gestationaltrophoblasticneoplasia:Epidemiology,clinicalfeatures,diagnosis,staging,andrisk
stratification".)
DEFINITIONOFLOWRISKDISEASETheriskfordiseaseprogressionandresistancetosingleagent
chemotherapyforwomenwithgestationaltrophoblasticneoplasia(GTN)isdefinedbytheInternational
FederationofGynecologyandObstetrics(FIGO)stagingandtheWorldHealthOrganization(WHO)riskscoring
systems(table1).Lowriskdiseaseischaracterizedbyanyoneofthefollowing:
FIGOstageIGTNThisischaracterizedasapersistentlyelevatedhumanchorionicgonadotropin(hCG)
leveland/ortumorconfinedtotheuterus
StageIIorIIIGTNwithaWHOriskscore<7
FurtherdiscussionofhighriskGTNiscoveredseparately.(See"Initialmanagementofhighriskgestational
trophoblasticneoplasia",sectionon'Definitionofhighriskdisease'.)
APPROACHTOTREATMENTMostpatientswithlowriskgestationaltrophoblasticneoplasia(GTN)are
curedwithsingleagentchemotherapy,usingeithermethotrexate(MTX)oractinomycinD(ActD).Becauseof
theoverallexcellentprognosis,immediatetreatmentwithmultiagentregimensisgenerallynotnecessary,and
inourexperience,singleagentchemotherapyismostoftenutilizedwithsuccess.However,somereports
suggestthatpatientswithprognosticscoresof5or6maybeatanincreasedriskofresistancetosingleagent
chemotherapy,withupto70percentofthesepatientsrequiringcombinationchemotherapytoachieve
remission.Studiesareongoingtotrytobetterdefinewhich"lowrisk"patientsmayparticularlybenefitfrom
primarycombinationchemotherapy[1,2].
PatientswithlowriskGTNhaveanoverallexcellentprognosiswithsurvivalratesof100percentaftertreatment,
althoughthismayrequireadditionaltreatments(includingtheuseofcombinationchemotherapyregimensif
theybecomeresistanttosingleagenttherapy)[35].Theprincipleofsequentialtherapyutilizesonesingle
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agentinitially,thenanalternatesingleagentifresistancetothefirstdrugdevelops(asdeterminedbyaplateau
orreelevationofthehumanchorionicgonadotropin[hCG]level)duringtreatment.
Thepotentialroleofaseconddilatationandcurettageinlieuofchemotherapyhasbeenevaluatedinseveral
studies,buttheresultshavebeenconflicting[69].Asdiscussedlaterinthissection,asecondcurettagemay
beareasonableoptioninlieuofchemotherapyinselectedpatients.However,theonlyrandomizedtrialinvolved
only64women.Thisstudydemonstratedsurgicalcurein38percentbutprogressionin55percent,including
twopatientswhodevelopedlungmetastases[9].
Ofnote,becauseplacentalsitetrophoblastictumor(PSTT)andepithelioidtrophoblastictumor(ETT)are
relativelyresistanttochemotherapy,patientswithnonmetastaticPSTTandETTaregenerallytreatedwith
hysterectomy.Althoughtherearecasereportsofselectedpatientstreatedsuccessfullywithlocalresectionand
preservationoffertility,hysterectomyremainstheoptimaltreatmentinmostcases.(See"Initialmanagementof
highriskgestationaltrophoblasticneoplasia",sectionon'Placentalsiteorepithelioidtrophoblastictumor'and
'PatientswithPSTTorETTorwhodonotdesirefertilitypreservation'below.)
MethotrexateOftheavailableagents,weadministerMTXinitiallybecauseitiseffective,welltolerated,
convenientforthepatient,andcosteffective[1,1015].MTXhasbeenadministeredinavarietyofscheduleswith
orwithoutfolinicacid(FA),whichisusedtoprotectfromMTXrelatedtoxicity.(See"Majorsideeffectsoflow
dosemethotrexate".)
Oftheregimensstudied,inourpractice,weadministerMTXFAasaneightdayregimenratherthanother
schedulesbecauseitisbotheffectiveandassociatedwithminimaltoxicitiesforthepatient.Wereviewedour
experiencewithMTXFAin185patientswithlowriskGTNwiththefollowingresults[10]:
Completeremissionwasachievedin88percent,whichincludes90percentofpatientswithstageI
diseaseand68percentofpatientswithstagesIItoIIIlowriskGTN.Notably,of23patientswithMTX
resistantdisease,61percentachievedremissionwithActD,andtheremaining39percentachieved
remissionwithcombinationchemotherapy.
AfterthreeconsecutiveweeksofnondetectablehCGvalues,onlytwo(1.2percent)patientswith
nonmetastaticdiseasedevelopedtumorrecurrence.Resistancewasmorecommoninpatientswith
choriocarcinoma,metastases,andpretreatmenthCGlevelsof>50,000mIU/mL.
Inaseparatestudythatincluded250patients,thisregimenwasassociatedwithmildtoxicity,andtherewere
nocasesofalopeciareported[16].Otherfindingsofthisstudyincludedthat:
Nauseaoccurredinlessthan15percentofalltreatmentcycles,withvomitingseeninlessthan5percent.
Onefourthofallpatientsdevelopedgrade1or2mucositis.
Onefourthofthesepatientsdevelopedgrade1or2conjunctivitis.
Hematologictoxicitywasmildandinfrequent,withgrade3or4neutropeniaorthrombocytopeniaoccurring
inlessthan1percentoftreatmentcycles.
DosingThereisnouniversalconsensusontheoptimaldosingregimenforMTX.However,atour
institution,weprefertheMTXFAeightdayregimenfortheprimarytherapyoflowriskGTN.Inthisregimen,
MTXisdosed1mg/kgasanintramuscular(IM)orintravenous(IV)injectionandadministeredondays1,3,5,
and7.FAisadministered24hoursaftereachdoseofMTXtoprotectnormalcellsfrompotentialtreatment
relatedtoxicityasaresultofinhibitionoffolatemetabolisminducedbyMTX.(See'Isthereanoptimalregimen?'
below.)
OtherregimensthatutilizeMTXareoftenadministeredtothispopulation.Giventhelackofhighqualitydata
comparingthedifferentschedulesforMTXadministration,thesearealsoreasonableoptions:
MTXfivedayregimenTheadministrationofMTX,0.3to0.5mg/kg,IMorIV,forfiveconsecutivedays
everytwoweekswasoriginallydescribedin1956[1719]andistheregimenofchoiceattheBrewer
TrophoblasticDiseaseCenterinChicago(USA)[20].Otherdataemphasizethatmaintainingdose
intensityisimportanttotheefficacyofthisregimen[21].
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WeeklyMTXWeeklyIMinjectionofMTXatadoseof30to50mg/m2hasbecomeawidelyused
regimenintheUnitedStates[22,23].TreatmentisrepeateduntiltheserumhCGlevelbecomes
undetectable(<5mIU/mL),afterwhichconsolidationtherapyisrecommended.Thisregimenwasoriginally
introducedundertheauspicesoftheGynecologicOncologyGroup(GOG)asthemostcosteffective
amongalternativeregimenswhenefficiency,toxicity,andcostweretakenintoconsideration.Themain
disadvantageofthisregimenisthelengthoftimeittakestoachieveremission,whichinsomecaseshas
takenupto15to20weeklytreatments,particularlywhenusedtotreatpatientswithlowriskmetastatic
disease.
HighdoseMTXHighdoseinfusionofMTX,100mg/m2IVpushfollowedbya12hourcontinuousinfusion
at200mg/m2,hasalsobeenusedasinitialtherapyforpatientswithlowriskGTN[12,24].FA(15mg
dose)isadministeredorallybeginning24hoursafterthestartoftheinitialMTXdoseandcontinuedevery
12hoursforsixdoses.Althoughthisregimenisassociatedwithalowercompleteremissionrateof69
percentinpatientswithlowriskdisease,itofferssomeadvantagesintermsofitsshorterdurationof
treatment,whichisparticularlyimportantforthosepatientswhoresidealongdistancefromthetreating
institution.
Isthereanoptimalregimen?Therearenohighqualitydatatoestablishauniversallyapplied
standardregimen.However,theavailabledatasuggestthatMTXadministeredonafiveoreightdayscheduleis
moreeffectivethaneithertheweeklyIMorintermittentcontinuousIVinfusionregimens[12,25].
TworetrospectivecasestudiescomparedfivedayMTXandeightdayMTXFAprotocolsinpatientswithlowrisk
GTN,andonefoundnodifferenceinremissionratesofapproximately76percent[13].Anotherstudyreportedan
only72percentremissionrateinpatientstreatedwithMTXFAascomparedwitha92percentremissionratein
patientsreceivingMTXalone[26].
ActinomycinDWewillgenerallyadministerActDtopatientswhodonotachieveremissiontoMTX[3,4]it
isnotedthattheseagentshavebeenusedinthissequencesince1965[2729].Althoughsomedatasupport
theadministrationofActDintheinitialtreatmentsetting,itismoreoftenusedassecondlinetherapyin
patientswithMTXresistance,orwhentherearecontraindicationstotheuseofMTXduetotheincreased
toxicityassociatedwithActD,particularlyhyperemesis,alopecia,andtheriskoflocaltissueinjuryif
extravasationoccurs.
Becauseoftheissuesassociatedwithtoxicity,ActDadministeredin"pulsed"dosingisgenerallyused(1.25
mg/m2biweekly),althoughitcanalsobeadministeredasanIVpush(10to12mcg/kgdailyforfivedaysevery
otherweek).[3034].TheprimaryremissionrateforpatientswithnonmetastaticpostmolarGTNis78and88
percentforthepulsedandfivedayregimens,respectively[35].
MethotrexateversusactinomycinDWhilewepreferMTXasinitialtherapy,thereisnoconsensus
regardingwhatshouldbethefavoredprimarysingleagentregimeninlowriskGTN.Anumberofdifferent
regimensutilizingMTXandActDappeartohaveexcellentactivity.
MultipletrialshavecomparedMTXandActDregimensfortreatmentoflowrisk,nonmetastaticGTN,including
twosmallrandomizedtrialspublishedin2009[36]and2011[37].A2012metaanalysisthatincludedfive
studiesconcludedthatActDwasassociatedwithsignificantlyhighercureratesthanMTX(relativerisk0.64,
95%CI0.540.76)withoutdifferencesintoxicity[4].However,therewassubstantialheterogeneityinthis
analysisduetothevariousschedulesofMTX(asaweeklyinjection,fivedayinjection,andtheeightday
schedule)andActD(biweeklypulsedIVandthefivedayIVdosing)includedandthenumberofpatients
includedintheanalysiswassmall(n=517).Therefore,wearenotconfidentintheconclusivenessofthismeta
analysis.
BothMTXandActDareassociatedwithhematologictoxicity,requiringthathematologicindicesbecarefully
monitoredduringtherapy.Inaddition,bothagentsareexcretedbythekidneyandassuch,patientsshouldhave
normalrenalfunctionconfirmedpriortoeachtreatment.MTXishepatotoxic,however,sointhepresenceof
abnormalliverfunctiontests,ActDshouldbeusedpreferentially.
OtheragentsTwoothersingleagentsareinuse,primarilyinAsia,forthetreatmentofpatientswithlowrisk
GTN:etoposideand5fluorouracil(5FU).
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EtoposideSingleagentetoposide(VP16)isanacceptableoptionforprimarytherapyforlowrisk
disease[3840].Singleagentetoposideatadoseof100mg/m2,IV,dailyforfivedaysevery10dayshas
alsobeenusedasanothereffectivemonotherapyregimenforpatientswhoprogressdespiteMTX
treatment[41].
Althoughitappearstobehighlyeffective,itsusewaslimitedbyconcernsregardingtheriskofsecondary
malignancy.StudiesconductedwiththeCharingCrossHospitalhadreportedthatpatientsreceivingmore
than2000mg/m2havearelativeriskof16.6forleukemia,5.8forbreastcancer,4.6forcoloncancer,and
3.4formelanoma[42].However,anupdateofdatafromCharingCrossHospitalbasedon30,638patient
yearsoffollowupindicatesthatthismaynotbethecasefollowingtreatmentwithetoposide,therelative
riskforasecondtumorwas0.9[43].
Whethertheconcernforasecondarymalignancyisjustifiedisnotnecessarilyclear,especiallysincethe
cumulativedoseof2000mg/m2israrelyrequired[44].
5fluorouracil5FUatadoseof30mg/kgdailyfor10daysevery28dayshasbeenthepreferred
singleagentregimenforlowriskGTNinChina,withcompleteremissionratesof86and93percent.
Toxicityisreportedtobemild[4547].IthasalsobeenusedintheUSaspartofcombination
chemotherapyforthemanagementofhighriskdisease[48].
ConsolidationtherapyAftercompleteremissionisattained,consolidationtherapyshouldbeadministered
topreventrelapse.Thisgenerallyconsistsofthreecoursesofthelasteffectiveregimen.
Therearefewdatatoinformtheoptimalnumberofcyclesthatshouldbeadministeredinthissetting.However,
datafromtheNetherlandsandUnitedKingdomcomparingtwoversusthreeconsolidationcyclesofMTXFA
reportedthatpatientstreatedwithtwocourseshadahigherrelapseratethanthosetreatedwiththree[49].(See
'Definingremission'below.)
MONITORINGDURINGTREATMENTAllwomenwithgestationaltrophoblasticneoplasia(GTN)shouldbe
monitoredwithserialmeasurementsofserumhumanchorionicgonadotropin(hCG)atthestartoftreatmentand
thenatweeklyintervalsduringtherapy.
DefiningremissionAdiseaseremissionrequiresthreeconsecutiveweeklynormalhCGvalues(lessthan5
mIU/mL).Treatmentshouldthenbecontinuedforthreeconsecutivecoursesofthelasteffectiveregimento
reducetheriskofrelapse.(See'Consolidationtherapy'above.)
PersistentorprogressivediseasePersistentorprogressiveGTN(orchemotherapyresistance)isdefined
asanincreaseoraplateauintwoconsecutivehCGvaluesoveratwoweekinterval[50].Othergenerally
acceptedcriteriaincludedetectionofnewmetastases[1].
TheapproximatebiologichalflifeofhCGis1.5to3days,andserumlevelsshouldfallexponentially(byatleast
onelogwithin18days).Aslowerrateofdeclinesuggeststhepossibilityofchemoresistance,althoughthereis
noconsensusorclearguidelineastotheoptimalcutofffordeterminingchemoresistanceorthemanagementof
patientswithaslowerthanexpectedtumormarkerdecline[5153].
Persistentdiseaseismorecommoninpatientswhohavehadrepeatedmolarpregnancies(incidence,11
percentafteroneand29percentaftertwocompleteorpartialmoles)[54].Arepeatmolarpregnancyisnot,
however,necessarilyanindicationforchemotherapy.Inonereport,chemotherapywasonlynecessaryin6
percentofsecondmolarpregnancies[55].Themanagementofthesepatientsisdiscussedseparately.(See
"Managementofresistantorrecurrentgestationaltrophoblasticneoplasia".)
POSTTREATMENTSURVEILLANCEAfterremissionisachieved,serumhumanchorionicgonadotropin
(hCG)shouldbemeasuredmonthlyuntilmonitoringhasshownoneyearofnormalhCGlevels[56,57].
Approximately85to95percentofrecurrencesoccurwithinthefirst18monthsandareusuallydetectedasnew
elevationsinserumhCG[58].
FERTILITYANDPREGNANCYGiventhatgestationaltrophoblasticneoplasia(GTN)oftenaffectswomenin
theirreproductiveyears,itisimportantthatissuesrelatedtofertilityandpregnancybepartofthesubsequent
managementofpatientsaftertreatmenthascompleted.
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ContraceptionFollowingsuccessfultreatment,allwomenshouldbemonitoredusingserialhumanchorionic
gonadotropin(hCG)foratleast12months[56,57].Anewpregnancyduringthisperiodwouldmakeitdifficultor
impossibletointerprethCGresultsandwouldcomplicatemanagement.Therefore,itisessentialthatwomen
usecontraceptionfortheentiredurationofsurveillance.
Estrogenprogestincontraceptivesarepreferredbecauseoftheirlowfailurerateandrelativelylowincidenceof
irregularbleeding,sincethissymptommayraiseconcernaboutrecurrence.Tworandomizedtrialsfoundno
increaseintheriskofGTNinwomenwhousedestrogenprogestinpillsfollowingamolarpregnancy[59].There
isalsonoevidencethattheuseoforalcontraceptivesinfluencesthecourseofGTN.(See"Overviewoftheuse
ofestrogenprogestincontraceptives".)
Barriermethodsmaybeused,buthavelesscontraceptiveefficacy.Inaddition,inourpractice,weadvise
againstuseofintrauterinedevicesbecausethereisariskofuterineperforationwithintrauterinecontraceptive
devices,particularlyinpatientsinwhomthereisuterineinvasion.
SubsequentpregnancyPatientswhoachieveasustainedremissionaftertreatmentforlowriskGTNcan
expectnormalreproductivefunction,andweadvisethatpatientsmayattempttoachievepregnancyafter12or
moremonthsofnormalhCGlevels[6063].
InareviewfromtheNewEnglandTrophoblasticDiseaseCenter(NETDC)betweenJuly1965andDecember
2013of667pregnanciesinwomenwhosubsequentlybecamepregnantaftertreatmentforGTN,pregnancy
outcomeswereasfollows(table2)[63]:

Livetermbirths(66.9percent)
Spontaneousabortions(18.3percent)
Prematuredeliveries(6.6percent)
Therapeuticabortions(4.2percent)
Stillbirths(1.5percent)
Repeatmolarpregnancies(1.5percent)
Ectopicpregnancies(1percent)

Importantly,theuseofchemotherapyforlowriskGTNdoesnotappeartobeassociatedwithanincreasein
congenitalmalformations[60,6271].IntheexperienceoftheNETDCreportedabove,congenitalanomalies
(majorandminor)weredetectedinonly12of500births(1.4percent)thesevaluesarecomparablewiththe
generalgestationalpopulation.
ForwomenwithapriorhistoryofGTN,followingcompletionofapregnancy,weadviseallpatientshaveanhCG
levelmeasuredatthesixweekpostpartum(orpostabortal)checkuptoensurecompleteremissionandthe
absenceofoccultGTN.Theplacentashouldbeexaminedcarefullyandsentforevaluationbyapathologistif
anyabnormalityissuspected.
PregnancybeforecompletionoffollowupPatientsoccasionallybecomepregnantbeforetheirfollowup
hasbeencomplete,despiteadvicetousecontraception.
EarlypregnancyaftertreatmentforGTNcandelaydiagnosisofdiseaserecurrence,asmostrecurrencesoccur
betweenthreeandsixmonthsaftercompletingtreatment[58,72].Whenthisoccursandthepregnancyis
desired,wemonitorthedevelopingfetusandplacentawithsonogramsat6and10weeksofgestation.Ifthe10
weeksonogramappearsnormal,thereislittlelikelihoodofrecurrence[73].Furthermore,pregnanciesoccurring
beforehCGfollowupiscompleteappeartohavenoincreasedriskofabnormalities[74].
PSYCHOSOCIALISSUESWomenwhodevelopgestationaltrophoblasticneoplasia(GTN)mayexperience
significantmooddisturbance,maritalandsexualproblems,andconcernsoverfuturefertility.BecauseGTNisa
consequenceofpregnancy,patientsandtheirpartnersmustconfrontthelossofapregnancyatthesametime
theyfaceconcernsregardingmalignancy.Patientscanexperienceclinicallysignificantlevelsofanxiety,
fatigue,anger,confusion,sexualproblems,andconcernforfuturepregnancythatlastforprotractedperiodsof
time.Patientswithmetastaticdiseaseareparticularlyatriskforpsychologicaldisturbancesandneed
assessmentsandinterventionsbothduringtreatmentandafterremissionisattained[7577].
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SPECIALSCENARIOSWhilemostpatientswithlowriskgestationaltrophoblasticneoplasia(GTN)willbe
curedwithsingleagentchemotherapy,thereareafewscenarioswherechemotherapymaynotbenecessary.
Thesearereviewedbelow.
PersistentelevatedhCGlevels(quiescentGTN)SomewomenwithahistoryofGTNornonmolar
pregnancyhaveaconsistentlylowlevelofhumanchorionicgonadotropin(hCG)(<200mIU/mL)without
detectabledisease.ThisconditionisoftenreferredtoasquiescentGTN,andisdiscussedindetailseparately.
(See"Hydatidiformmole:Management",sectionon'PersistentlowhCG(quiescentGTN)'.)
PersistentuterinebleedingTreatmentwithaseconddilationandcurettage(D&C)isinvestigational,andin
ourexperience,thevastmajorityofpatientswithpostmolarGTNhavelocallyinvasivedisease.Thus,itisour
practicetoperformarepeatD&Conlyformanagementofpersistentuterinebleedingwithtransvaginal
ultrasoundevidenceofresidualmolartissue,ratherthanasprimarytreatment[78].
D&ChasalimitedroleasatreatmentforGTN.InthesettingofsuspectedGTN,D&Cisusedonlyinfrequently
asadiagnosticprocedure.Inaddition,itistheprimarytreatmentforamolarpregnancy.(See"Gestational
trophoblasticneoplasia:Epidemiology,clinicalfeatures,diagnosis,staging,andriskstratification",sectionon
'Uterinecurettage'and"Hydatidiformmole:Management".)
ForsomepatientswithstageIGTN(table1)followingamolarpregnancy,D&Calonehasbeenproposedasan
alternativetochemotherapy.However,thereareconflictingdataonitsefficacyandnocomparativestudieswith
primarychemotherapy.TheonlyprospectivedataregardingD&CfortreatmentofGTNarefromastudy
conductedbytheGynecologicOncologyGroup(GOG)trial[9].Of64womenenrolled(allofwhomwere
previouslyuntreatedforGTN),88percenthadapriorhistoryofacompletemole.Aspresentedatthe2014
AnnualMeetingonWomen'sCancers:
Thesurgicalcure(definedastheabsenceofariseorplateauinthehCGlevelforsixmonthspost
evacuation)was38percent.
Progressionofdiseasewasseenin55percent,includingtwopatientswhodevelopedlungmetastases.
Auterineperforationoccurredinonepatient,whichwasmanagedconservatively.
RiskfactorsforfailureofsecondcurrettageincludedpatientswithaWorldHealthOrganization(WHO)
scoreof5to6andage>39or<19.
Althoughthiswasasmallstudy,itsuggeststhatasecondD&Calonemaybeareasonabletreatmentoption,
especiallyforwomenwhodonotwishtoinitiatechemotherapy.However,weawaitfinalpublicationofthisstudy
tofurtherassessthisoptionforpatientswiththisinherentlycurabledisease.
Similarly,aretrospectivestudy(n=544)foundthat68percentofpatientswithGTNwhounderwentD&C
enteredaspontaneousremission,andnopatientsrequiredahysterectomyforperforation[8].Inthatstudy,risk
factorsfordiseaseprogressionafterD&CincludedhistologicevidenceofpersistentGTNandhCGlevelsabove
1500mIU/mL.
Incontrast,someinvestigatorshavereportedthatrepeatcurettageinducesremissionorinfluencestreatmentin
lessthan20percentofpatients,withuterineperforationoccurringin4.8to8percent[7,79].
PatientswithPSTTorETTorwhodonotdesirefertilitypreservationPatientswithInternational
FederationofGynecologyandObstetrics(FIGO)stageI(nonmetastatic)GTN(table1)whodonotwishto
preservefertilitymaybetreatedwithprimaryhysterectomy.
Placentalsitetrophoblastictumor(PSTT)andepithelioidtrophoblastictumor(ETT)arerelativelyresistantto
chemotherapybaseduponourclinicalexperience,andpatientswithstageIdiseasearegenerallytreatedwith
hysterectomy[80].Baseduponobservationaldata,itappearsthatpatientswithPSTTorETTconfinedtothe
uterusmaybecuredwithprimaryhysterectomyalonewithoutadjuvantchemotherapy,makingthisareasonable
optionforprimarymanagementinthesepatients.Casereportsindicatethatlocalresectionmaybesuccessful
incarefullyselectedpatientswhowishtopreservefertility[8184].
However,thereishighriskofoccultpulmonarydisease(estimatedtooccurin40percentofpatientswith
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presumednonmetastaticdisease[85,86])inGTNingeneral,andinvasivemoleorchoriocarcinomais
chemosensitive.Inacaseseriesof33womenwithGTNfromourpractice,treatmentwithhysterectomyand
onecycleofsingleagentchemotherapyresultedinsustainedremissioninallpatients[80].Chemotherapycan
besafelyadministeredwithoutincreasingperioperativemorbidity[87].Baseduponthesefactors,forwomen
withstageIchoriocarcinomaorinvasivemoletreatedwithhysterectomy,wesuggestonecycleofsingleagent
chemotherapy(eitherintravenous[IV]infusionofmethotrexateandfolinicacid[MTXFA]orbolusactinomycinD
[ActD]).AdjunctivechemotherapyisnotutilizedinpatientswithPSTTorETTatthetimeofhysterectomy
becauseoftherelativechemoresistanceofthesetumors.
PatientstreatedwithprimaryhysterectomyshouldbefollowedwithhCGlevelspostoperatively,andtreatedwith
chemotherapyifhCGispersistentlyelevated.(See'Posttreatmentsurveillance'above.)
PROGNOSISTheprognosisforpatientswithlowriskgestationaltrophoblasticneoplasia(GTN)isexcellent,
andcureratesapproach100percent[12,23,24,88],althoughthismayrequiresubsequenttreatmenttoachieve
cure.Thisisshowninthefollowingstudies:
Inananalysisof624patientstreatedforstageIGTNattheNewEnglandTrophoblasticDiseaseCenter
(NETDC)betweenJuly1965andDecember2013,83percentachievedcompleteremissionwithprimary
singleagentchemotherapy.Curewasobtainedwithadditionaltherapyinallotherpatientsandincluded
primaryhysterectomy(n=35)andsubsequentmultiagentchemotherapywithorwithoutsurgical
intervention(n=104).Theseresultsaresummarizedinthetable(table3).
Inaseparateanalysisof175patientswithlowriskstageIIandIIIGTNtreatedattheNETDC,allpatients
ultimatelywerecured.However,21percentrequiredsecondlinemultiagentregimensforresistantdisease
toattainremission.Theseresultsaresummarizedinthetable(table4).
DIAGNOSISOFRECURRENTDISEASEPatientswithlowriskgestationaltrophoblasticneoplasia(GTN)
havealessthan5to10percentriskofrecurrence[58,72].Thisisusuallymarkedasariseinthehuman
chorionicgonadotropin(hCG)levelatamediantimeofsixmonthssinceendoftherapy,irrespectiveofthe
InternationalFederationofGynecologyandObstetrics(FIGO)stage[89].Riskfactorsforrecurrenceinmost
studiesappeartoberelatedtoalargeinitialtumorburden,inadequateprimarytherapy,andinpatientswho
defaultedonpotentialtreatmentsornoncompliantfollowup.
Forpatientsdiagnosedwithrelapse,reimagingwithchest,abdominal,andpelviccomputedtomography(CT)
scansandbrainmagneticresonanceimaging(MRI)shouldbeperformed.Considerationshouldbegiventothe
useofpositronemissiontomography(PET)scanningtodistinguishactivediseasefromfibrotictumornodules.
Inadditiontoreestablishingabaselineforfuturetreatment,thesestudiesareimportanttodetermineifsurgery
isanoption[90,91].TheapproachtopatientswithpersistentorrecurrentGTNisdiscussedseparately.(See
"Gestationaltrophoblasticneoplasia:Epidemiology,clinicalfeatures,diagnosis,staging,andriskstratification".)
SUMMARYANDRECOMMENDATIONS
Gestationaltrophoblasticdisease(GTD)definesagroupofconditionsthatarisefromanaberrant
fertilizationevent.WhenGTDrecursorthereisevidenceofmetastaticdisease,itiscalledgestational
trophoblasticneoplasia(GTN).(See'Introduction'above.)
Lowriskdiseaseischaracterizedbyanyoneofthefollowing:InternationalFederationofGynecologyand
Obstetrics(FIGO)stageIGTN,whichischaracterizedasapersistentlyelevatedhumanchorionic
gonadotropin(hCG)leveland/ortumorconfinedtotheuterusorFIGOstageIIorIIIGTNwithaWorld
HealthOrganization(WHO)riskscore<7.(See'Definitionoflowriskdisease'above.)
ForpatientswithlowriskGTN,werecommendsingleagentchemotherapyratherthancombination
chemotherapy(Grade1B)(see'Approachtotreatment'above).Wesuggestsingleagentmethotrexate
(MTX)ratherthanactinomycinD(ActD)(Grade2C).WesuggestMTXbeadministeredonaneightday
regimen,alternatingwithfolnicacid(FA)(Grade2C).(See'Methotrexate'above.)
AllwomenwithGTNshouldbemonitoredwithserialmeasurementsofserumhCGatthestartoftreatment
andthenatweeklyintervalsduringtherapy.(See'Monitoringduringtreatment'above.)
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AdiseaseremissionrequiresthreeconsecutiveweeklynormalhCGvalues(lessthan5mIU/mL).For
patientswhoachievearemission,wesuggestconsolidationtherapy(Grade2C).Inourpractice,this
consistsofthreecyclesofthelasteffectiveregimentoreducetheriskofrelapse.(See
'Consolidationtherapy'above.)
PersistentorprogressiveGTN(orchemotherapyresistance)isdefinedasanincreaseoraplateauin
twoconsecutivehCGvaluesoveratwoweekintervalorthedetectionofnewmetastases.(See
'Persistentorprogressivedisease'aboveand"Managementofresistantorrecurrentgestational
trophoblasticneoplasia".)
Afterremissionisachieved,serumhCGshouldbemeasuredmonthlyuntilmonitoringhasshownoneyear
ofnormalhCGlevels.(See'Posttreatmentsurveillance'above.)
ContraceptionisrequiredfortheentiredurationofposttreatmenthCGfollowup.Estrogenprogestin
contraceptivesareaneffectiveoptionanddonotappeartoimpactthecourseofGTN.(See'Contraception'
above.)
Forwomenwithpersistent/invasiveGTNsolelyonthebasisofapersistentlyelevatedhCGsixmonths
aftermolarevacuation,wesuggestobservation,providedtheyarewillingandabletofollowacareful
scheduleofsurveillancewithbloodtestseverytwoweeks(Grade2C).Patientswhoarenotcandidatesfor
observationforwhateverreasonshouldbetreatedwithsingleagentchemotherapy.(See'Persistent
elevatedhCGlevels(quiescentGTN)'above.)
ForpatientswithstageIplacentalsitetrophoblastictumor(PSTT)orepithelioidtrophoblastictumor(ETT),
wesuggestprimaryhysterectomyaloneratherthanprimarychemotherapy(Grade2C).However,local
resectionisreasonableinwomenwhowishtopreservefertility.(see'PatientswithPSTTorETTorwhodo
notdesirefertilitypreservation'above)
ForthosewithstageIchoriocarcinomaorinvasivemole,hysterectomyisareasonableoption.Forthose
whochoosehysterectomy,wesuggestonecourseofsingleagentchemotherapyatthetimeof
hysterectomyratherthannochemotherapy(Grade2C).(see'PatientswithPSTTorETTorwhodonot
desirefertilitypreservation'above)
TheprognosisforpatientswithlowriskGTNisexcellent,andcureratesapproach100percent,although
thismayrequiresubsequenttreatmenttoachievecure.(See'Prognosis'above.)
ThediagnosisofrecurrentdiseaseisusuallymarkedasariseinthehCGlevel.Themediantimefor
recurrenceissixmonths,irrespectiveoftheFIGOstage.(See'Diagnosisofrecurrentdisease'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic3242Version19.0

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GRAPHICS
FIGOStagingofGestationalTrophoblasticNeoplasia(GTN)and
modifiedWHOPrognosticScoringSystemasadaptedbyFIGO

Stage
I

Diseaseconfinedtothe
uterus

Stage
II

GTNextendsoutsideof
theuterus,butislimited
tothegenitalstructures

Stage
III

GTNextendstothelungs,
with
or
withoutgenitaltract
involvement

Stage
IV

Allothermetastaticsites

Thestageshouldbefollowed
bythesumoftheriskfactors
(eg,III:5)

Riskfactor

Score

Age(years)

<40

40

Antecedent
pregnancy

Mole

Abortion

Term

Interval
(months)*

4to6

7to
12

>12

Pretreatment
serumhCG
(mIU/mL)

<10 3

10 3to
10 4

10 4
to
10 5

>10 5

Largesttumor

<3cm

3to4

5cm

(including
uterus)

cm

Siteof
metastases

Lung

Spleen,
kidney

GI
tract

Brain,
liver

Numberof
metastases

1to4

5to8

>8

Priorfailed
chemotherapy

Single
drug

2
drugs

FIGO:InternationalFederationofGynecologyandObstetricsWHO:WorldHealthOrganization
hCG:humanchorionicgonadotropin.
*Interval(inmonths)betweenendofantecedentpregnancyandstartofchemotherapy.

Originalfiguremodifiedforthispublication.BerkowitzRS,GoldsteinDP.Currentmanagementof
gestationaltrophoblasticdiseases.GynecolOncol2009112:654.Tableusedwiththepermissionof
ElsevierInc.Allrightsreserved.
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Outcomesfollowingsubsequentpregnancyinwomentreatedfor
gestationaltrophoblasticneoplasiaattheNewEnglandTrophoblast
Center,1965to2013
Outcome

Number

Percent

Totalpregnancies

667

100

Totaldeliveries

500

Termlive

446

66.9

Pretermlive

44

6.6

Stillbirth

10

1.5

Congenitalanomalies

12

1.4

123

18.3

28

4.2

1.0

10

1.5

Spontaneousmiscarriage
Inducedabortion
Ectopic
Repeatmolarpregnancy
Graphic97193Version1.0

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OutcomesoftreatmentforlowriskstageIgestational
trophoblasticneoplasiaattheNewEnglandTrophoblasticCenter,
1965to2013
StageIresults

Initialtherapy

Numberofpatients

Numberofremissions

624

624(100percent)

520(83.3percent)

SequentialMTX/ActD

478

Combination

35

Resistanttherapy

104(16.7percent)

Combination
chemotherapy

78

Hysterectomy/local
resection

19

Other

chemotherapy*
Hysterectomy

MTX:methotrexateActD:actinomycinDMAC:methotrexate,actinomycinD,cyclophosphamide
EMA:etoposide,methotrexate,actinomycinDCO:cyclophosphamideplusvincristine.
*MAC.

Withadjunctivechemotherapy.
MAC,EMA,EMA/CO.

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OutcomesoftreatmentforlowriskstageIItoIIIgestational
trophoblasticneoplasiaattheNewEnglandTrophoblasticCenter,
1965to2013
StageIIresults

Numberofpatients

Numberofremissions

37

37(100percent)

Lowrisk

21

21(100percent)

Initialtherapy

17(80.9percent)

SequentialMTX/ActD

16

Combination
chemotherapy*

Resistanttherapy

4(19.1percent)

Combination

chemotherapy*
Salvagetherapy

StageIIIresults

Numberofpatients

Numberofremissions

228

228(100percent)

Lowrisk

154

154(100percent)

Initialtherapy

121(78.6percent)

SequentialMTX/ActD

114

Combination
chemotherapy

Resistanttherapy

33

33(21.4percent)

SequentialMTX/ActD

Combination
chemotherapy

33

Twopatientsalivewithdiseaseonedeath.
MTX:methotrexateActD:actinomycinDMAC:methotrexate,actinomycinD,cyclophosphamide
EMA:etoposide,methotrexate,actinomycinDCO:cyclophosphamideplusvincristineEP:
etoposide,cisplatin.
*MAC,EMA,EMA/CO.
EMA/CO,EMA/EP.
MAC,EMA,EMA/CO.
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Initialmanagementoflowriskgestationaltrophoblasticneoplasia

Disclosures
Disclosures:RossSBerkow itz,MDNothingtodisclose.DonaldPeterGoldstein,MDNothingto
disclose.NeilSHorow itz,MDNothingtodisclose.BarbaraGoff,MDNothingtodisclose.SandyJ
Falk,MD,FACOGEmployeeofUpToDate,Inc.DonSDizon,MD,FACPEmployeeofUpToDate,Inc.
Contributordisclosuresarereview edforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreview process,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.
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