Int J Gynecol Obstet 2018; 143 (Suppl. 2): 37–50 wileyonlinelibrary.com/journal/ijgo  | 37

DOI: 10.1002/ijgo.12612

F I G O C A N C E R R E P O R T 2 0 1 8

Cancer of the corpus uteri

Frédéric Amant1,2,3,* | Mansoor Raza Mirza4 | Martin Koskas5 | Carien L. Creutzberg6

ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsuse,distributionandreproductioninanymedium,providedtheoriginalworkisproperlycited.©2018TheAuthors.International Journal of Gynecology & ObstetricspublishedbyJohnWiley&SonsLtdonbehalfofInternationalFederationofGynecologyandObstetrics

1DivisionofGynecologicOncology,UniversityHospitalsGasthuisberg,Leuven,Belgium2CenterforGynecologicOncologyAmsterdam,NetherlandsCancerInstitute,Amsterdam,Netherlands3CenterforGynecologicOncologyAmsterdam,AmsterdamUniversityMedicalCenters,Amsterdam,Netherlands4DepartmentofOncology,Rigshospitalet,CopenhagenUniversityHospital,Copenhagen,Denmark5DivisionofGynecologicOncology,BichatUniversityHospital,Paris,France6DepartmentofRadiationOncology,LeidenUniversityMedicalCenter,Leiden,Netherlands

*CorrespondenceFrédéricAmant,CenterforGynecologicOncologyAmsterdam,AmsterdamUniversityMedicalCenters,Amsterdam,Netherlands.Email:frederic.amant@uzleuven.be

AbstractEndometrial cancer is the most common gynecological malignancy in high-incomecountries.Althoughtheoverallprognosisisrelativelygood,high-gradeendometrialcancershave a tendency to recur. Recurrence needs to be prevented since the prognosis forrecurrentendometrialcancerisdismal.Treatmenttailoredtotumorbiologyistheoptimalstrategy to balance treatment efficacy against toxicity. Standard treatment consists ofhysterectomy and bilateral salpingo-oophorectomy. Lymphadenectomy (with ongoingstudiesofsentinelnodebiopsy)enablesidentificationoflymphnodepositivepatientswhoneedadjuvanttreatment,includingradiotherapyandchemotherapy.Adjuvantradiotherapyisused forStage I–IIpatientswithhigh-risk factorsandStage III lymphnodenegativepatients. In advanced disease, a combination of surgery to no residual disease andchemotherapyresultsinthebestoutcome.Surgeryforrecurrentdiseaseisonlyadvocatedinpatientswithagoodperformancestatuswitharelativelylongdisease-freeinterval.

K E Y W O R D S

Chemotherapy;Corpusuteri;Endometrialcancer;FIGOCancerReport;Gynecologiccancer;Radiotherapy;Surgery

1  | STAGING

1.1 | Anatomy

1.1.1 | Primary site

Theuppertwo-thirdsoftheuteruslocatedabovetheinternalorificeoftheuterus istermedthecorpus.Thefallopiantubesenterattheupperlateralcornersofaninversepear-shapedbody.Theportionofthemuscularorganthatisabovealinejoiningthetubouterineorificesisreferredtoasthefundus.

Cancerofthecorpusuteri isusuallyreferredtoasendometrialcancer,whicharisesfromtheepithelial liningoftheuterinecavity.Itsfirstlocalextensionconcernsthemyometrium.Cancersarisinginthestromalandmuscletissuesofthemyometriumarecalleduter-ine sarcomas and are not discussed in this overview (readers aredirectedtothechapteronuterinesarcomasinthisSupplementbyMbatanietal.1).

1.1.2 | Nodal stations

Thelymphaticsystemofthecorpusuteriisformedbythreemainlym-phatictrunks:utero-ovarian(infundibulopelvic),parametrial,andpresa-cral.Theycollectivelydrainintothehypogastric(alsoknownasinternaliliac),externaliliac,commoniliac,presacral,andpara-aorticnodes.Directmetastasestothepara-aorticlymphnodesareuncommon.Thisissur-prisinggiven thatadirect routeof lymphaticspread fromthecorpusuteri to thepara-aorticnodes through the infundibulopelvic ligamenthasbeensuggestedfromanatomicalandsentinellymphnodestudies.

1.1.3 | Metastatic sites

Thevagina,ovaries,andlungsarethemostcommonmetastaticsites.

1.2 | Rules for classification

SurgicalstagingofendometrialcancerreplacedclinicalstagingbytheFIGOCommitteeonGynecologicOncologyin1988andagainrevised

38  |     AmAnt Et AL.

in2009.Rulesforclassificationincludehistologicverificationofgrad-ingandextentofthetumor.

1.3 | Histopathology

1.3.1 | Histopathologic types (according to WHO/International Society of Gynecological Pathology classification)

Alltumorsaretobemicroscopicallyverified.Thehistopathologictypesofendometrialcarcinomasare2:

1. Endometrioid carcinoma: adenocarcinoma; adenocarcino-ma-variants(withsquamousdifferentiation;secretoryvariant;villoglandular variant; and ciliated cell variant).

2. Mucinousadenocarcinoma.3. Serousadenocarcinoma.4. Clearcelladenocarcinoma.5. Undifferentiatedcarcinoma.6. Neuroendocrinetumors.7. Mixed carcinoma (carcinoma composed of more than onetype,withatleast10%ofeachcomponent).

Apartfromtheclassificationofendometrialcarcinoma,carcinomaoftheendometriumcomprisesmixedepithelialandmesenchymaltumorsincluding:

1. Adenomyoma2. Atypicalpolypoidadenomyoma3. Adenofibroma4. Adenosarcoma5. Carcinosarcoma:currentlycarcinosarcomas,inwhichbothepithe-lial andmesenchymal components aremalignant and aggressivetumors,areconsideredmetaplasticcarcinomas,andaretreatedasaggressivecarcinomas.

Endometrialcancershavetraditionallybeenclassifiedinoneofthefollowingtwocategories:

1. Types1 (grade1 and 2 endometrioid carcinoma) are the mostcommon endometrial cancers. They may arise from complexatypical hyperplasia and are linked to excess of estrogen stim-ulation. As they are usually diagnosed at early stages, theypresent a relatively good prognosis.

2. Types2are the least commonendometrial tumors.They includegrade3endometrioidtumorsaswellastumorsofnonendometri-oid histology, and develop from atrophic endometrium. Type2tumorsarelesshormonesensitive.Sincetheyarediagnosedinlaterstages,theyaregenerallymoreaggressiveandhaveapoorerprog-nosisthanType1endometrialcancer.

However, the Cancer Genome Atlas studies have identified fourmolecular subgroups characterized, respectively, by POLE mutation,

mismatchrepairdeficiency,TP53mutation,andacopynumberlowgroupwithoutaspecificdrivermutation,eachwithadistinctprognosis.3,4

1.3.2 | Histopathologic grades (G)

1. GX: Grade cannot be assessed.2. G1:Welldifferentiated.3. G2:Moderatelydifferentiated.4. G3:Poorlyorundifferentiated.

Degreeofdifferentiationoftheadenocarcinomaisanotherbasisforclassificationcarcinomaofthecorpus,whicharegroupedasfollows:

1. G1: less than5%of anonsquamousornonmorular solidgrowthpattern.

2. G2:6%–50%ofanonsquamousornonmorularsolidgrowthpattern.3. G3: greater than 50% of a nonsquamous or nonmorular solidgrowthpattern.

1.3.3 | Pathologic grading notes

Notablenuclearatypia(pleomorphismandprominentnucleoli),inap-propriateforthearchitecturalgrade,raisesthegradeofagrade1orgrade2tumorby1.However,thisshouldnotbedonetooeasilyasgrade2willthenloseitsdiscriminativepower.5

Mostauthorsconsiderserousandclearcellcarcinomashighgradebydefinition.

Gradingofadenocarcinomaswithsquamousdifferentiationisallo-catedaccordingtothenucleargradeoftheglandularcomponent.

1.4 | FIGO staging classification

Table1 shows the currentFIGOstaging classification for cancerofthecorpusuteri.Comparisonof thestagegroupingswith theTNMclassificationisrepresentedinTable2.

1.4.1 | Regional lymph nodes (N)

1. NX: Regional lymph nodes cannot be assessed.2. N0:Noregionallymphnodemetastasis.3. N1:Regionallymphnodemetastasistopelviclymphnodes.4. N2:Regional lymphnodemetastasis topara-aortic lymphnodes,withorwithoutpositivepelviclymphnodes.

1.4.2 | Distant metastasis (M)

1. MX: Distant metastasis cannot be assessed.2. M0:Nodistantmetastasis.3. M1: Distant metastasis (includes metastasis to inguinal lymphnodesorintraperitonealdisease).

     |  39AmAnt Et AL.

1.4.3 | Rules related to staging

Duringstaging,distance fromtumor toserosashouldbemeasured.Otherfeaturesshouldalsobereportedinthepathologicreportofthehysterectomy specimen. For instance, the presence of lymphovas-cularspaceinvasion(LVSI)shouldalsobeindicated,aspatientswithLVSI-positivetumorshaveasignificantlyworseprognosis,especiallyif

extensiveLVSIisfound.6ThedistinctionmadeusingLVSIstatuscouldbemorerelevant thanthedistinctionbetweenStagesIAand IBforpredictingsurvivalinStageIendometrialcancer.7

As aminimum, any enlarged or suspicious lymph nodes shouldberemovedinallpatients.Forhigh-riskpatients(grade3,deepmyo-metrial invasion, cervical extension, serous or clear cell histology),complete pelvic lymphadenectomy and resection of any enlargedpara-aorticnodesisrecommended.

Clinicalstaging,asdesignatedbyFIGOin1971,appliestoasmallpercentageofcorpuscancersthatareprimarilytreatedwithradiationtherapy. In those instances, the designation of that staging systemshouldbenoted.

2  | INTRODUCTION

2.1 | Incidence

Endometrial cancer represents the sixth most common malignantdisorderworldwide.Anestimated320000newcasesarediagnosedwiththismalignancyannually.High-incomecountrieshaveagreaterincidenceofendometrialcancer(5.9%)comparedwithlow-resourcecountries (4.0%), although specificmortality is higher in the latter.Thecumulativeriskofendometrialcanceruptotheageof75yearshasbeenestimated as1.6% for high-income regions and0.7% forlow-income countries.8 This might be attributable to high ratesof obesity and physical inactivity—two major risk factors in high-incomecountries.Specifically,elevatedestrogenlevelsareknowntobe themost likely cause of the increased risk of endometrial can-cer forpostmenopausalobesewomen.9Conversely,physicalactiv-ity and long-termuse of continuous combined estrogen–progestintherapyareassociatedwithareducedriskofendometrialcancer.10,11 Interestingly,obesityisassociatedwithearlierageatdiagnosis,andwith endometrioid-type endometrial cancers. Similar associationswere not observedwith nonendometrioid cancers, consistentwithdifferentpathwaysoftumorigenesis.12

NorthAmericaandEuropehavethehighestincidenceofendome-trialcancer,whereitisthemostfrequentcancerofthefemalegenitaltractandthefourthmostcommonsite inwomenafterbreast, lung,andcolorectalcancer.13

In Europe, it represents the eighth most common cancer deathinwomen,with a reported23700womendying in 2012.7 InNorthAmerica, it is the sixthmost frequent cause of death,with approxi-mately55000newcasesand11000estimatednewdeathseachyear.3

Thetwomajorfactorsthatcontributetoanincreaseintheinci-denceofendometrialcancerinhigh-incomecountriesareincreasedprevalence of obesity and extended life expectancy. Other deter-minants—such as thewidespread decrease in use of estrogen plusprogestinmenopausal hormone therapy—have also been proposedasthecauseoftheincreasedincidenceratesforendometrialcancerinNorthAmerica.14

MortalityratesforendometrialcancershowedadecreaseinmostEuropean Union member states among women born before 1940.

TABLE  1 Cancerofthecorpusuteri.

FIGO Stage

Ia Tumorconfinedtothecorpusuteri

IAa Noorlessthanhalfmyometrialinvasion

IBa Invasionequaltoormorethanhalfofthemyometrium

IIa Tumorinvadescervicalstroma,butdoesnotextendbeyondtheuterusb

IIIa Localand/orregionalspreadofthetumor

IIIAa Tumorinvadestheserosaofthecorpusuteriand/oradnexaec

IIIBa Vaginalinvolvementand/orparametrialinvolvementc

IIICa Metastasestopelvicand/orpara-aorticlymphnodesc

IIIC1a Positivepelvicnodes

IIIC2a Positivepara-aorticnodeswithorwithoutpositivepelviclymphnodes

IVa Tumorinvadesbladderand/orbowelmucosa,and/ordistantmetastases

IVAa Tumorinvasionofbladderand/orbowelmucosa

IVBa Distantmetastasis,includingintra-abdominalmetastasesand/oringuinalnodes)

aEitherG1,G2,orG3.bEndocervicalglandularinvolvementonlyshouldbeconsideredasStageIandnolongerasStageII.cPositive cytology has to be reported separately without changing thestage.

TABLE  2 Cancerofthecorpusuteri:FIGOstagingcomparedwiththeTNMclassification.a

FIGO Stage

Union for International Cancer Control (UICC)

T (tumor) N (lymph nodes) M (metastasis)

I T1 N0 M0

IA T1a N0 M0

IB T1b N0 M0

II T2 N0 M0

III T3 N0–N1 M0

IIIA T3a N0 M0

IIIB T3b N0 M0

IIIC1 T1–T3 N1 M0

IIIC2 T1–T3 N1 M0

IVA T4 AnyN M0

IVB AnyT AnyN M1

aCarcinosarcomasshouldbestagedascarcinoma.

40  |     AmAnt Et AL.

Improvedcancertreatmentandaccesstohealthcarehavebeensug-gestedascontributingtothisdecreaseincancermortality.8

2.2 | Pathophysiology

Endometrial cancer researchhasgainedsomemomentum in recentyears and insights obtained from those studies have significantimplications in the clinic. Endometrioid adenocarcinoma progressesthroughapremalignantphaseofintraepithelialendometrialneoplasiainalargeproportionofcases.15Otherhistologictypessuchasserousand clear cell carcinoma arise as a result of a sequence of geneticmutations.Mutationsinthetumorsuppressorp53havebeenshowntoplayapivotalroleinserousendometrialcancer.16

2.3 | Diagnosis

Theutilityofpopulationscreeningforendometrialcancerremainstobe fully substantiated.17 Transvaginal ultrasound (TVS) is a possiblescreeningtest,asitisreasonablysensitiveandspecific.Screeningisonly recommended for high-risk groups, such as those with Lynchtype2syndromewithawishforfertilitypreservation,beforethedeci-sionforprophylactichysterectomyismadeatalaterage.18Inthesecases, endometrial surveillance is performed by aspiration biopsyand transvaginal ultrasonography starting from the age of 35years(annuallyuntilhysterectomy).Prophylacticsurgery(hysterectomyandbilateral salpingo-oophorectomy),preferablyusingaminimally inva-siveapproach,shouldbediscussedattheageof40asanoptionforLynchtype2syndromemutationcarrierstopreventendometrialandovariancancer.19

After physical examination, endometrial cancer is usually sus-pectedwith ultrasound—an effective first testwith a high negativepredictivevaluewhentheendometrialthicknessislessthan5mm.20 Specifically,combinationoftransvaginalultrasoundwithendometrialbiopsiesobtainedbycurettagehasbeenshowntohaveanegativepre-dictivevalueof96%.20Whenabiopsyisrequired,thiscanbeobtainedusually as anofficeprocedureusing a numberof disposable instru-mentsdevelopedforthispurpose.Inpatientswithdiagnosticuncer-tainty,hysteroscopymaybeperformed,andwithflexibleinstrumentscanalsobedonewithout recourse togeneral anesthesia.However,theprognosticroleofcells thatare transtuballyflushedduringhys-teroscopyremainsuncertain.Anesthesiamightbenecessaryincasesofcervicalstenosisor ifpatient tolerancedoesnotpermitanofficeprocedure.Individualswhosepelvicexaminationisunsatisfactorymayalsobeevaluatedwith transvaginalorabdominalultrasound to ruleoutconcomitantadnexalpathology.

Afterahistopathologicdiagnosisofendometrialadenocarcinoma,otherfactorsneedtobeassessed.Theseincludethelocalextentofthetumor,evidenceofmetastaticdisease,aswellasperioperativerisk.

Thepathologyreportfromendometrialsamplingshould indicateatleastthetumortypeandgradeofthelesion.Overallthereisonlymoderateagreementontumorgradebetweenpreoperativeendome-trialsamplingandfinaldiagnosis,withthelowestagreementforgrade2 carcinomas. Agreement between hysteroscopic biopsy and final

diagnosisishigherthanfordilatationandcurettage;however,itisnotsignificantlyhigherthanforofficeendometrialbiopsy.21

Fullbiochemistry(renalandliverfunctiontests),andbloodcountalsorepresentroutinetestsinthediagnosisofcorpusuterinecancers.AchestX-rayisoftenperformedasit isauniversallyavailable, low-costexaminationandtheconsequencesofdetectinglungmetastases,althoughrareinearlystagedisease,aresignificant.SerumCA125maybeofvalueinadvanceddiseaseforfollow-up.Evaluationformetasta-sisisusefulparticularlyinpatientswithabnormalliverfunctiontests,andclinicalfindingssuchasparametrialorvaginaltumorextension.Inhigh-riskpatients,CT-basedimagingofthechest,abdomen,andpelvisorPET-CTmayhelpdeterminethesurgicalapproach.Cystoscopyand/orproctoscopymaybehelpful if direct extension to thebladderorrectumissuspected.

3  | PROGNOSTIC TUMOR CHARACTERISTICS FOR HIGH- RISK DISEASE

Its early presentation following postmenopausal bleeding results inagenerallygoodprognosis,butitshouldbetreatedusingevidence-basedprotocols, andwhereappropriate,byexpertmultidisciplinaryteams.Fourmainhistopathologiccriteriaarerecommendedtodeter-minehigh-riskdisease:

1. Tumor grade3 (poorly differentiated).2. Lymphovascularspaceinvasion.3. Nonendometrioid histology (serous, clear cell, undifferentiated,smallcell,anaplastic,etc.).

4. Cervicalstromalinvolvement.

MRIscanningandintraoperativefrozensectionrepresentthemostaccuratemeansofassessingboththedepthofmyometrialinvasionandcervicalinvolvement.22–24AlthoughCTandMRIareequivalentintermsof evaluating nodalmetastases, neither is suitable to replace surgicallymphnodeassessment,whichprovideshistological confirmation.25,26 PET-CTisthebestimagingmethodtoevaluatelymphnodeanddistantmetastases,andcouldbeconsideredinhigh-riskoradvancedstagedis-ease.TheroleofPET-MRIiscurrentlybeinginvestigated.

Nonsurgical staging for endometrial cancer, where extrauterinediseaseexists,isinherentlyinaccurate.Thisisparticularlythecaseforthe detection of small nodal involvement, intraperitoneal implants,andadnexalmetastasis.

4  | SURGICAL STAGING PROCEDURE FOR ENDOMETRIAL CANCER

Stagingofendometrialcancerwaschanged fromclinical tosurgicalin1988,bytheFIGOGynecologicOncologyCommittee.Thisrecom-mendationhasledtoconsiderabledebateandefforttodefinesurgicalstagingproceduresthatcanbeimplementedinternationally.Agener-allyrecommendedprotocolincludesopeningoftheabdomenwitha

     |  41AmAnt Et AL.

verticalmidline incision andperitonealwashings taken immediatelyfromthepelvisandabdomen,followedbycarefulexplorationoftheintra-abdominalcontents.Theomentum,liver,peritonealcul-de-sac,andadnexalsurfacesshouldbeexaminedandpalpatedforanypos-siblemetastases.Theseproceduresshouldbefollowedbycarefulpal-pationforsuspiciousorenlargednodesintheaorticandpelvicareas.However,laparoscopicprocedureshaveincreasinglybeenintroducedas standard, especially for early stage disease, as these have beenproven safe and reduce acute treatment-related complications.27,28 The recommended standard surgical procedure is an extra-fascialtotal hysterectomy with bilateral salpingo-oophorectomy. Adnexalremovalisrecommendedevenifthetubesandovariesappearnormal,astheymaycontainmicrometastases.Inpremenopausalwomenwithlow-gradeearlystagedisease,ovarianpreservationcouldbeconsid-ered.29,30Vaginalcuffremovalisnotadvised,noristhereanybenefitfromexcisingparametrialtissueintheusualcase.Whereobviouscer-vicalstromalinvolvementisdemonstratedpreoperatively,amodifiedradicalhysterectomyhasbeenhistoricallyperformed.However,thereis consensus (ESMO-ESGO-ESTRO) that simple hysterectomy withfreemarginstogetherwithpelvicandpara-aorticlymphadenectomymaybesufficient.31

Thesafetyofendoscopic surgery for the treatmentofendome-trialcancerhasalsobeenthesubjectofconsiderabledebate.Recentstudieshavedemonstrated that laparoscopic removalof theuterusandadnexaeappearstobesafe.For instance,notmanydifferenceshavebeenreportedintermsofmajorcomplicationsbetweenabdom-inalhysterectomyandlaparoscopicallyassistedvaginalhysterectomy(LAVH)or total laparoscopichysterectomy (TLH).Additionally, lapa-roscopic interventionsareassociatedwithsignificantdecreasedriskof major surgical adverse events, shorter hospital stays, less pain,and faster recoveries.32–34 Owing to the demonstrated oncologicalsafety of the laparoscopic approach,28,35 hysterectomy and bilat-eral salpingo-oophorectomyby this route is recommended in thosepatientswithnocontraindicationsto laparoscopy(e.g. large-volumeuterus).Theendoscopicroutealsoappearssafeinhigh-riskendome-trial cancer.36Thisapproachcanbeaccompaniedbya laparoscopiclymphadenectomy, if surgical staging is to be undertaken. Roboticsurgeryformorbidlyobesepatientsrepresentsavaluableoptionforexperiencedsurgeons.Intheseinstances,surgicalmanagementusingroboticsissafeandpresentsfewerperioperativecomplicationscom-paredwithopensurgery.37Furthermore, retrospectivestudieshavesuggestedequivalentoncologicoutcomescomparedwithtraditionallaparoscopic surgery.38,39

The utility of lymphadenectomy of the pelvic and para-aorticareas isdisputed, albeit it is currentlymandated through the stag-ingsystem.Currently,itisadvisedthatcompletelymphadenectomyis reserved for caseswith high-risk features. In contrast, selectivenode sampling has been deemed dubious as a routine approach.Sincemanyindividualswithendometrialcancerareobeseorelderly,with concomitant medical problems, clinical judgment is requiredtodetermineifadditionalsurgeryiswarranted.Anydeeplyinvasivetumor or radiological suggestionof positive nodes is an indicationforretroperitoneallymphnodeevaluation,whichmightbefollowed

byremovalofanyenlargedorsuspiciousnodes.Documentationofpositive nodes identifies a high-risk population and helps to tailoradjuvant treatment. Nodal resection also allows identification ofnode negative patients, potentially reducing the need for externalbeamradiotherapy.19

Several parameters advocate for aortic node sampling. Theseinclude suspicious aortic or common iliac nodes, grossly positiveadnexae,grosslypositivepelvicnodes,andhigh-gradetumorsshow-ingfullthicknessmyometrialinvasion.Patientswithclearcell,papillaryserous,orcarcinosarcomahistologicsubtypesarealsocandidatesforaorticnodesampling.

5  | WHO SHOULD PERFORM THE SURGERY?

Full surgical staging is not required for low-risk tumors, defined aswell-differentiated tumorswith less than 50%myometrial invasion,with positive nodes in less than 5% of cases. Women with thesetumorscanbesafelyoperatedonbyageneralgynecologist.Patientsatgreaterriskofextrauterinediseasewhomayrequirelymphadenec-tomy should, in contrast, be operated on by gynecological oncolo-gists.Careprovidedbygynecologiconcologistshasbeenassociatedwithbettersurvivalinhigh-riskcancers40andresultsinefficientuseofhealthcareresourcesandminimizationofthepotentialmorbidityassociatedwithadjuvantradiation.41

Athoroughpreoperativeassessment,withparticularattentiontothe pathology and to radiological features has been defined as themost effective strategy for the triaging of these patients. Triagingfor lymphadenectomy is alsopossibleduring surgery. Intraoperativeassessmentmainlyinvolvesassessmentofmyometrialinvasion.22,24,39 Gradingon frozen section ispossible, though suboptimal comparedwithpreoperativegrading.24

Concerningsentinellymphnodebiopsy,severalkeysurgicalpointsshouldberespected42:

1. Expertise of the surgeon and attention to technical detail.2. Superficialanddeepcervicalinjectionofdye.3. Completeevaluationoftheperitonealcavity(sentinellymphnodemappingisforclinicalStageI,apparentuterine-confineddisease).

4. Sentinellymphnodedissectionbeginswithevaluationoftheretro-peritonealspacesandidentificationofthesentineldrainagepath-waysthatemanatefromtheparametria,followedbyexcisionofthemostproximallymphnodesinthesentinelpathway.

5. Anysuspiciouslymphnodesshouldberemovedregardlessofsen-tinel lymphnodemappingand frozensectionanalysismay influ-ence the decision to perform para-aortic lymphadenectomy insome cases.

6. Performance of hemipelvic side-specific lymphadenectomy formappingfailurehasbeenshowntoreducefalse-negativestaging.

7. Enhancedpathologyevaluationofsentinellymphnodeswithserialsectioningand immunohistochemistrystains increasesthedetec-tionoflow-volumemetastasis.

42  |     AmAnt Et AL.

6  | WHEN SHOULD SURGERY BE PERFORMED?

Theeffect ofwaitingtime for surgical stagingon survival outcomeforendometrialcanceriscontroversial.Ithasbeensuggestedthatalongerwaiting time for surgical stagingwas associatedwithworsesurvivaloutcomesinuterinecancer43andthedelaybetweendiagno-sisandsurgeryshouldnotexceed6weeks.44However,whenfocus-ingontype1endometrialcanceronly, thewaitingtimeforsurgicalstagingwasnotassociatedwithdecreasedsurvivaloutcome,presum-ablyowingtoitsindolentgrowthandresultingexcellentprognosis.45

7  | IS LYMPHADENECTOMY THERAPEUTIC?

Lymphadenectomyisrequiredforaccuratestaging,yetitstherapeu-ticbenefitsremaincontroversial.Historically,onecase–controlstudysuggestedthatlymphadenectomymaybebeneficialtherapeutically46 and another showed it improved prognosis even in node-positivewomen.47Anotherretrospectivestudysuggestedthatcompletelym-phadenectomy increases survival inpatientswithgrade3 tumors.48 Incontrast, twomajor trialsof large-scalecohortshaveshownthatpelvic lymphadenectomy offers no therapeutic benefits comparedwith no lymphadenectomy.49,50 These studies, however, have beencriticizedforseverallimitingfactors.First,limitedeffortwithrespectto the extent of dissection and lymph node evaluation was made.Second,ahighproportionoflow-riskpatientsinthesestudiesmighthaveskewedtheresults.Finally,nodirectdecisiononadjuvantther-apybasedonlymphadenectomywasdesignedaspartoftheproto-cols.Atpresent, lymphadenectomyisprimarilyusedforstagingandshouldbeconsideredinwomenwithhigh-riskfactors.51Aninterna-tionaltrialoftheroleoflymphadenectomytodirectadjuvanttherapyforhigh-riskendometrialcancer (STATEC)hasrecentlystarted.TheongoingENGOT-EN2-DGCGtrial(NCT01244789)aimstoshedlightintothisissuebycomparingsurvivalinpatientswithStageIgrade3endometrioid endometrial cancer, StageI and II type2 endometrialcancer,orStageIIendometrioidendometrialcancerandwithoutmet-astaticnodeafterrandomizationforadjuvantchemotherapy.

In a retrospective study, para-aortic lymphadenectomy resultedinanimprovedoutcomeinintermediateandhigh-riskpatientswhencomparedwithpelviclymphadenectomyalone.52Alimitingfactorofthisstudywasthatadjuvanttherapywasnotcomparableinthetwogroups.Inpatientswhounderwentbothpelvicandpara-aorticlymph-adenectomy,77%receivedchemotherapyasopposedtoonly45%inthepelviclymphadenectomygroup.Thisuncertaintyisthereasonwhyaddition of para-aortic lymphadenectomy is recommended if pelviclymphadenectomy is being done, and explains different approachesamongdifferentcenters.

Sentinel lymphnodemappinghasbeen introduced intothesur-gical stagingofendometrialcancerwith thegoal to reducemorbid-ity associatedwith comprehensive lymphadenectomy and toobtain

prognostic information from lymph node status. A recent meta-analysisreportedoveralldetectionrateshigherthan80%,with50%bilateral pelvic node detection rate and 17% para-aortic detectionrate.53Useofindocyaninegreenincreasesthebilateraldetectionratecomparedwithbluedye.Additionally,cervicalinjectionincreasesthebilateralsentinel lymphnodedetectionratebutdecreasesthepara-aorticdetectionratecomparedwithalternativeinjectiontechniques.The sensitivity of sentinel lymph nodemapping to detectmetasta-ses is higher than90%, reaching almost100% in ameta-analysis.53 Randomizedstudieshavesuggested that sentinel lymphnodemap-pingcansafelyreplacelymphadenectomyinthestagingofendome-trialcancer.54,55

Apartfromthehistoricaldistinctionbetweentype1and2endo-metrial cancer,various approaches (genomic and immunochemistry)have been conducted to better predict prognosis and subsequentlyadapttherapy.TheCancerGenomeAtlasResearchNetworkidentifiedfourgroupsofendometrialcarcinomasbasedongenomic features.4 Similarly,many immunohistochemicalmarkershavebeen studied todifferentiate between low- and high-risk endometrial carcinomas.SeveralstudieshavetriedtodevelopmoreapplicablevariantsoftheTCGAclassificationbyusingimmunohistochemicalmarkersandDNAsequencing techniques that can be doneon formalin-fixed, paraffinembeddedtissues.56,57L1celladhesionmolecule(L1CAM)wasintro-duced as a promising biomarker for identification of patients withpooroutcome,whichhasbeenconfirmedinsubsequentstudies.58–60 Markersof thep53pathway,16hormone receptorexpression,61 andmicrosatelliteinstability,62areseveraloftheotherrelevantbiomarkerstopredictprognosisofendometrialcancer.Variousapproachescom-bining genomic characterization and biomarkers expression providepromisingresultstotailoradjuvanttherapy.63–65

8  | ADJUVANT TREATMENT

Atpresent,theindicationforadjuvantradiationtherapyisbasedonthepresenceof risk factors. Low-riskdisease (StageI, grade1or2withnoorsuperficialmyometrialinvasion)doesnotrequireadjuvantradiation therapy. Thiswasdemonstrated in aDanish cohort studyoflow-riskwomen,inwhichsurgeryaloneresultedina96%5-yearsurvival.66A seminalNorwegian trial,67which included621womentreatedaftersurgerywithvaginalbrachytherapy,indicatedthatover-all survivalwasnot improvedbyadditionalexternalbeam radiationtherapy (EBRT). This study, however, showed that adjuvant radio-therapyreducedtheriskofpelvicrecurrence.Threeotherlargeran-domizedtrials(PORTEC-1trial,68theUSGOG#99trial,69andtheUKMRCASTECtrial70)studyingthebenefitsofpelvicradiationtherapyasadjuvanttherapytosurgeryhavesupporteditsindicationonlyforhigh-riskpatients.ThemainfindingfromthesetrialsisthesignificantreductionintheratesofvaginalandpelvicrecurrenceafterEBRT,butwithoutaddedsurvivalbenefit. In contrast,EBRTadded to the riskoflong-termmorbidity.Thepatientswithoutlymphadenectomyana-lyzed inthePORTECandASTECtrialspresentedsimilarrecurrenceandsurvivalratestothosewithdocumentednode-negativediseasein

     |  43AmAnt Et AL.

theGOG#99trial.Additionally,PORTEC-1illustratedthatmostpelvicrelapseswerelocatedinthevaginalvault(75%),andthatsalvagerateswerehighinwomenwhohadnothadpreviousradiationtherapy.71

Othertrialshaveinvestigatedthevalueofradiationasanadjuvanttherapyinhigh-riskpatients.ThePORTEC-2trialcomparedtheadju-vantvalueoftworadiationapproaches,EBRTandvaginalbrachyther-apy,in427womenwithhigh/intermediateriskfactors.Thepatientswere randomized to EBRT or vaginal brachytherapy.72 This trialshowedthatvaginalbrachytherapyhadexcellentvaginalcontrolrates(<2%at5yearsforbothEBRTandvaginalbrachytherapygroups),withminimaladverseeffectsandsignificantlybetterqualityoflife.Qualityof lifeofpatients inthebrachytherapygroupremainedthesameasthoseofanage-matchednormalpopulation.73Sincethisseminaltrial,vaginalbrachytherapyhasreplacedEBRTasstandardadjuvanttreat-mentforpatientswithhigh/intermediateriskfactors.

However,inlow-riskpatients,adjuvantradiationtherapydoesnotleadtoabettersurvival.InaDanishstudy,omissionofanyEBRTorvag-inalbrachytherapyforhigh/intermediateriskdiseaseledtoanincreaseinrecurrencerates (22%for intermediateriskdisease,ofwhich15%locoregional)without affecting survival rates.74A patient preferencestudyshowedthatpatient’spreferencesarebiasedtowardatreatmentpreventing relapse.75 However, even treating all women with high/intermediate risk factors (grade1–2withdeep invasion) is stillover-treatment.ThecurrentlyongoingPORTEC-4atrialinvestigatestheuseof combined clinicopathologic, immunohistochemical, and molecularmarkers to determine the use of adjuvant vaginal brachytherapy orobservation,keepingEBRTonlyforthosewithhigh-riskfactors.

Since adjuvant radiotherapy alone and adjuvant chemotherapyalonehaveshownsimilarimpactonoverallorrelapse-freesurvivalinpatientsoperatedonforendometrialcancer,76,77severalstudieshaveinvestigatedtheeffectofsequentialcombinationofchemotherapyandradiotherapy.Ameta-analysispoolingtheresultsoftworandomizedtrials(NSGO-EC-9501/EORTC-55991andMaNGOILIADE-III)inves-tigatingthetherapeuticvalueofcombiningadjuvantplatinum-basedchemotherapywithEBRTinpatientswithriskfactors(grade3ordeepinvasionoradversehistologies)foundasignificant9%improvementinprogression-freesurvival(69%vs78%at5years;HazardRatio[HR]0.63)withtheadditionofchemotherapytoEBRT,andatrendfora7%improvementin5-yearoverallsurvival(75%vs82%;HR0.69,P=0.07).

Three other large randomized trials (GOG#249, GOG#258,PORTEC-3) are currently underway to support and expand onthosefindings.TherandomizedGOG-249trial,whichrecruited601patientswithStageI–IIendometrialcancerwithhigh/intermediateorhigh-risk factors,comparedvaginalbrachytherapyplus threecyclesof carboplatin-paclitaxel chemotherapy with pelvic EBRT alone;results showednodifferences in relapse-free survival between thearms,while therewasbetterpelvic control in thepelvicEBRTarmandmoreacutetoxicityinthechemotherapyarm.Fromthistrial,theauthorsconcludedthatforStageI–IIendometrialcancerwith(high)riskfeatures,pelvicEBRTisstill thestandardofcare.78About50%ofthetrialpopulationhadgrade1–2diseasewithabaseline5-yearsurvivalof86%–91%andfor thesepatients,vaginalbrachytherapyalonemightbepreferable.

In the PORTEC-3 trial, patients with high-risk StageI–II (32%grade3and29%serousorclearcellcancer)orwithStageIII(45%)endometrial cancerwere randomly allocated to pelvic EBRT aloneor EBRTwith two concurrent cycles of cisplatin inweeks1 and4ofEBRT,followedbyfourcyclesofcarboplatinandpaclitaxel.Atamedianfollow-upof60.2months,therewasnosignificantdifferenceinoverallsurvivalbetweenthearms,butasignificantdifference infailure-free survival, with women in the combined chemoradio-therapy arm having 7% higher failure-free survival (76% vs 69%;P=0.022).79WomenwithStageIIIdiseasehadthehighestabsolutebenefit of chemoradiotherapy, with 5-year failure-free survival of69%versus58%forradiotherapyalone(P=0.03).Thelargemajorityofrecurrenceswereatdistantsites(22%vs28%)andpelvicrecur-rencewas rare. In view of the toxicity of chemoradiotherapywithsignificantlymoregrade3–4adverseeventsduringandaftertreat-mentandapersistinghigherrateofgrade2sensoryneuropathyatlongerterm,itcanbeconcludedthatthecombinedschedulecannotberecommendedasanewstandardofcareforStageI–IIdisease,butwomenwithStageIIIendometrialcancershouldbecounseledaboutthefailure-freesurvivalbenefit.

IntherandomizedGOG-258trialforStageIIIandStageIV(resid-ualdisease<2cmallowed),813patientswererandomizedtoreceiveeitherchemoradiotherapyasusedinPORTEC-3orsixcyclesofcar-boplatinandpaclitaxelwithout radiotherapy.80Additionof radiationtherapy to chemotherapy did not improve overall or progression-free survival, but the rate of pelvic (7%vs 3%;HR0.36) and para-aorticnodal relapse (21%vs10%;HR0.43)wassignificantlyhigherinthechemotherapyalonearm.IntheongoingENGOT-EN2-DGCG-trial, patientswith node-negative endometrial cancerwith high-riskfeatures are randomized to adjuvant chemotherapy (six cycles ofcarboplatin-paclitaxel)orobservation,withorwithoutbrachytherapyinbotharms.Thistrialcouldprovidesomeanswerstothequestionsregardingoptimaluseandoptimalschedulesofadjuvanttherapyforwomenwithhigh-riskendometrialcancer.

Insummary,adjuvantradiationtherapyisdiscouragedinlow-riskpatientsandindicatedinhigh-riskpatients.Specifically,patientswithgrade1–2tumorsandnomorethan50%myometrialinvasion,orforthosewithonlyasingleriskfactor,adjuvantradiotherapyisnotrec-ommended.Forpatientswithhigh/intermediateriskfactors(atleasttwoofthefactors:age>60years,deepmyometrialinvasion,grade3,serous or clear cell histology, LVSI), vaginal brachytherapy alone ispreferabletoEBRT,providingexcellentvaginalcontrolwithoutimpact-ing on quality of life. In patientswith higher-risk StageI–II disease(grade3anddeepinvasionand/orLVSI,unfavorablehistologies,unfa-vorablemolecularfactors),pelvicEBRTremainsthestandardofcare.Overall,theneedforEBRTdecreaseswhensurgicalstagingidentifiesnode-negativedisease.19Surgicalstagingalsoallowsclinicianstoiden-tifynode-positive(StageIII)diseasethatbenefitsfromadjuvantther-apy.ForwomenwithStageIIIendometrialcancer,thecombinationofadjuvant chemotherapy and radiation therapy seemsmost effectivetomaximizerecurrence-freesurvival.Ongoingandnewstudieswithmoreindividualassessmentofmolecularfeatureswillinvestigatetheirroleindirectingadjuvanttreatment.

44  |     AmAnt Et AL.

9  | PROGESTOGEN THERAPY

Although the use of progesterone therapy has been widelyrecognized in the past, a meta-analysis of six randomized tri-als totalizing 3339 women has shown no survival benefit foradjuvantprogestogentherapyinendometrialcancer.81Asubse-quentlypublishedrandomizedtrialof1012womenalsofailedtodemonstrateanysurvivalbenefit.82However,hormonaltherapycanprovideprolongedremissionofmetastaticdiseaseinwomenwith grade 1 and/or ER/PR receptor-positive disease. Wherepossible,ER/PRshouldbedeterminedonabiopsyoftherecur-rent tumor because the hormone receptor status may changeovertime.83

10  | STAGE I I

10.1 | Occult Stage II disease

TherapeuticmanagementofpatientswithclinicallyoccultStageIIdis-easeissimilartothatofpatientswithStageIdisease.

10.2 | Clinical overt Stage II disease

In these cases, radical hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, and selec-tiveaorticnodedissectionhavebeenhistoricallyusedasprimarytreatment.However, it is important tonote that this strategyhasbeenpoorlysupportedbythemedicalliterature.Resultsofoneofthe few retrospective studies could not find any survival benefitfrom radical hysterectomy for patientswith suspected gross cer-vical involvement in comparison with simple or modified radicalhysterectomy.31,84 Surgical treatment in patients with suspectedgrosscervicalinvolvementiscurrentlyunderevaluation,asradicalhysterectomy increases the risk of adverse events. PreoperativeMRI scanning is advisable to exclude bladder involvement andensurelocalresectability.Studiesindicateexcellentresultsforthisapproach,withnobenefitfromtheadditionofradiationforpatientswithnegativenodes.85,86Adjuvantradiotherapyisusuallyreservedfor patientswith involved nodes or other adverse factors and/orcloseorinvolvedsurgicalmargins.

However,neoadjuvanttherapyfollowedbyalessextensivesimplehysterectomycanrepresentanalternative.Ifsurgeryisnotconsideredfeasible because of tumor extension and/or inmedically inoperablepatients,fullpelvicradiotherapyandintracavitarybrachytherapy,asincervicalcancer,maybeemployedeitherpreoperativelyordefinitivelywithhighdiseasecontrolandsurvivalrates.87,88

11  | STAGE I I I

MostpatientswithStageIIIendometrialcanceraremanagedbycom-pletesurgicalresectionofallpelvicand/ornodaldisease,followedbypostoperativeEBRTand/orchemotherapy.

Asprimarytumorsofboththeovaryandtheendometriummaybepresent inpatientswithpresumedStage IIIdiseasewithadnexalinvolvement, full surgicalstagingandexpertpathologicexaminationofthespecimenisrecommendedinthesecases.

AdjuvanttreatmentisindicatedforwomenwithStageIIIdiseaseasdetailedinSection8above.

Patients with clinical Stage III endometrial carcinoma in whichsurgicalresection isnotpossiblearetreatedprimarilybypelvic irra-diation, with or without chemotherapy.89 Once therapy has beencompleted, exploratory laparotomy should be considered for thosepatientswhosediseasenowappearstoberesectable.

12  | STAGE IV

Optimal management in women with StageIV endometrial cancerincludes cytoreductive surgery, which is associated with superioroverallsurvivaloutcome.90 Inadvanceddisease,neoadjuvantchem-otherapy isalsoanoption,particularly ifpostoperativemorbidity isconsideredlikelyand/orascitesispresent.91Aftersurgery,platinum-basedchemotherapyshouldbeconsidered,basedonthetrialscitedabove.Patientswithevidenceofextra-abdominalmetastasesareusu-allymanagedwithsystemicplatinum-basedchemotherapy,orhormo-naltherapyifgrade1and/orreceptorpositive.

As neoadjuvant chemotherapy is the treatment of choice inadvanced-stagedisease, aswell as in relapseddisease, several stud-ies have investigated the optimal combinations of chemotherapeu-ticagents that represent themosteffectiveneoadjuvant therapy forStageIVendometrialcancerpatients.Asthecombinationsofdoxorubi-cin,cisplatin,andpaclitaxel(TAP)92andcarboplatinandpaclitaxelhavebeenshowntobemosteffective,thesehavebeenthemoststudied.The former,however, ismuchmore toxicand resulted in treatment-relateddeaths.AcomparativetrialoftheGOG,randomizingtoeitherTAPorcarboplatin-paclitaxelchemotherapyhasshownbothschedulestohavesimilarefficacy,whilecarboplatin-paclitaxelwaspreferredforlowermorbidity;fullresultshavenotyetbeenpublished.93

Tworandomizedtrialshavecompareddoxorubicinmonotherapyversusdoxorubicin–cisplatindoublet.94,95Superiorityofthecombina-tionchemotherapy intermsofprogression-freeandoverallsurvival,withmanageabletoxicity,wasconfirmedinbothstudies.Doxorubicin–cisplatin doublet versus doxorubicin–cisplatin–paclitaxel triplet wastested inaphase III randomizedtrial.92Thetriplet regimenresultedinasignificantlysuperiorprogression-freesurvival,althoughthisregi-menprovedtobetootoxic,withtreatment-relateddeathsdespitetheuseofgrowthfactors.

The carboplatin–paclitaxel doublet has been tested in severalphaseIIstudiesinadvanced-stageorrelapseddisease,demonstratingaresponserateof65%–75%andprogression-freesurvivalofabout14months.96–98The interimresultsoftheGOG-0209trial,anonin-ferioritytrialcomparingthecombinationofdoxorubicin,cisplatin,andpaclitaxel (TAP) and G-CSF versus carboplatin and paclitaxel, showthat the carboplatin and paclitaxel doublet is not inferior toTAP.98 Thebettertolerabilityprofileofcarboplatin–paclitaxelhasledtothe

     |  45AmAnt Et AL.

recommendationoftheuseofcarboplatinandpaclitaxelasthestan-dardforadjuvanttreatmentinStageIIIandIVdisease.

Pelvic radiotherapy in StageIV disease is sometimes consideredtoprovide local tumor control. Similarly, it has alsobeen suggestedthatpatientswithvaginalbleedingorpain froma local tumormass,orwithlegedemaduetolymphnodeinvolvement,shouldbetreatedwithpelvicradiotherapy.Palliationofbrainorbonemetastasescanbeeffectivelyobtainedwithshortcourses(1–5fractions)ofradiotherapy.

13  | SPECIAL CONSIDERATIONS

13.1 | Diagnosis post hysterectomy

Several therapeutic management problems have been reported toarise from post hysterectomy diagnosis. This is particularly true incaseswheretheadnexaehavenotbeenremoved,whichmostoftenarises following vaginal hysterectomy for pelvic organ prolapse.Recommendations for further postoperative therapy are based onknownrisk factors forextrauterinediseaserelatedto thehistologicgrade and depth of myometrial invasion. Individuals with grade3lesions,deepmyometrialinvasion,orLVSImaybecandidatesforaddi-tionalsurgerytoremovetheadnexae,oradjuvantEBRT.Patientswithagrade1or2 lesionwithminimalmyometrial invasionandnoLVSIinvolvementgenerallyrequirenofurthertherapy.

13.2 | Medically inoperable patients

Themost common reasons for endometrial carcinoma to be deemedmedicallyinoperablearemorbidobesityandseverecardiopulmonarydis-ease.Insuchcases,uterinebrachytherapyisadvisedandhasbeenshowntoachievecure rates inexcessof70%. In thepresenceofprognosticfactorssuggestingahighriskofinvolvednodesitcanbecombinedwithEBRT.88PrimaryradiationtherapyformedicallyinoperablepatientswithclinicalStageIandIIendometrialadenocarcinomaprovidesdiseasecon-trol,withfewerthan16%ofsurvivingpatientsexperiencingrecurrence.99

For patients with a well-differentiated lesion, contraindicationsto general anesthesia, and who are unsuitable for radiotherapy,high-doseprogestinsmaybeused.Trialsusingintrauterinehormonereleasingdevicesinsteadoforalprogestinsareunderway.Inpatientswithcontraindicationstohigh-doseprogestins,theuterinehormonereleasingdevicecanbeconsidered.

13.3 | Diagnosis in young women

Since endometrial carcinoma is uncommon in women the age of35years,diagnosisduringthereproductiveyearsshouldbemadewithcaution,andgrade1endometrialcarcinomamaybeconfusedwith severe atypical hyperplasia. In these women, considerationshouldbegiven to anestrogen-relatedunderlying condition suchas a granulosa cell tumor, polycystic ovaries, or obesity. Fertilitypreservation isonly recommended ingrade1endometrioidendo-metrial cancer not invading the myometrium (as determined byMRI).19 Progestins such as megestrol acetate (160–320mg/d) or

medroxyprogesterone acetate (400–600mg/d) may be appropri-ate in these situations. The safety of such an approach has beenreported in several studies, for grade 1 endometrial adenocarci-nomaandatypicalhyperplasia.100Fewstudiesreportedthesafetyof fertility-sparing management of grade2 endometrial can-cer.101However,arecent largeretrospectiveanalysisreportedanincreasedriskassociatedwithuterinepreservationinpatientswithgrade2 and 3 endometrial adenocarcinoma and suggested suchmanagementshouldbe limited intime.29Equivocal lesionsshouldbeexaminedbyanexperiencedpathologist. In casesof completeresponse,conceptionmustbeencouragedandreferraltoafertilityclinicisrecommended.Althoughtheliteraturedescribessuccessfuloutcomes,fatalrecurrencesofendometrialcancerafteraconserv-ative approach have been reported; as such, the patientmust beinformedabout thenonstandard treatment.Hysterectomy shouldberecommendedoncechildbearingiscomplete.

Ovarianpreservation,inpatientswithgrade1intramucosalendo-metrial adenocarcinoma, might represent a beneficial therapeuticoption, as thismanagementwas not associatedwith an increase incancer-relatedmortalityinthelargestsampleavailable.30

14  | FOLLOW- UP

The objectives of follow-up care for treated endometrial cancerpatients are toprovide reassurance,diagnoseearly recurrence, andcollect data. The clinical and cost-effectiveness of follow-up imple-mentationhasbeenaddressed internationally inoneprospective102 andseveralretrospectivestudies.103–105Overall,thesestudiesfoundthat about 75% of recurrences in endometrial cancer patients aresymptomatic and 25% asymptomatic. Neither recurrence-free noroverallsurvivalwasimprovedinasymptomaticcasescomparedwiththosedetectedatclinicalpresentation.Most(65%–85%)recurrenceswerediagnosedwithin3yearsofprimarytreatment,and40%ofrecur-renceswerelocal.Anotherimportantfindingofthosestudieswasthattheuseofroutinefollow-upPapsmearsandchestX-raysisnotcost-effective.Given thehigh salvage rate following radiotherapy, ithasbeen suggested that nonirradiated patients are a group thatwouldbenefitfromregularfollow-uptodetectearlyvaginalrecurrence.106

Twosystematicreviews107,108documentedevidencefortheutil-ity of follow-up examinations, and concluded that follow-up shouldbepracticalanddirectedbysymptomsandpelvicexamination.Thesestudiesalsorecommendreductioninthefrequencyoffollow-upvisitsforlow-riskpatients.Giventhelowriskofrecurrence,vaginalcytologycan be omitted, resulting in reduced healthcare costs.109 It appearsthatvisual inspection is sufficient, since positive cytology ismerelydiagnosedincasesofsymptomaticrecurrence.104,110,111

Morerecently,studiesofminimalfollow-up(nurseled,telephonebased)afterthefirstyearhavebeendoneandresultsareawaited.112,113 Firstresultssuggestgoodpatientacceptabilityoncepromptaccesstoevaluationincaseofsymptomsisensured.

Follow-up care should also include patient counseling as thesepatients are at risk of second cancers following their primary

46  |     AmAnt Et AL.

endometrial cancer. For instance, the estimated incidence rate ofLynch syndrome in an unselected endometrial cancer population is3%–6%.114Routinepathologicscreeningofmismatchrepairdeficien-ciesintheendometrialcancerspecimen,similartocolorectalcancer,hasbeenadvocatedandisincreasinglybeingintroducedinpractice.115 However, in most women with mismatch repair deficiency this iscausedbyMLH1promoterhypermethylationandatestofthisbeforereferringapatienttoaclinicalgeneticistisrecommended.Survivorsofendometrialcancerhaveathree-foldincreasedriskofsecondcancerwhencomparedwithamatchedpopulation.Thisriskincreaseseemsmainlyrelatedtolifestylefactorsandgeneticsusceptibility.116 These womenshouldbecounseledonexerciseandweightlossprograms.

15  | RECURRENCE

The therapeuticmanagement for localized recurrences includes sur-gery,radiationtherapy,oracombinationofboth.Thechoiceofthesestrategies depends on the primary therapy. Screening for distantmetastases should be performed before deciding on curative treat-ment. If primary therapy consisted of surgery alone, radiotherapyrepresentsaneffectivesalvagestrategyincasesofvaginalorcentralpelvicrecurrence.Inthesecases,acombinationofEBRTandbrachy-therapy, preferably image guided, is usually required. Large recur-rences should be evaluated for excision, followed by radiotherapy.Alternatively,chemotherapymaybeconsideredtodecreasethevol-umeof the recurrenceandhence improve thechancesof completesurgicalresection.AdditionalchemotherapywithradiotherapyisbeingevaluatedinanongoingGOGtrial.Extendedsurgerymaybejustified,especiallyinpatientswhohavehadpriorradiationtherapy.However,radicalsurgerywithin irradiatedfields (especially inthecaseofside-wall recurrence) frequently results in significant morbidity, such astreatment-resistant pain and fistula formation. The results of pelvicexenteration inproperly selected cases (central recurrenceswithoutsignsofdistantspread)aresimilartothoseobtainedincervicalcancer.Overall,survivalratesinwell-selectedpatientsareintheorderof50%.

Nonlocalized recurrent tumors are usually treatedwith proges-tintherapy:medroxyprogesteroneacetate50–100mgthreetimesadayormegestrolacetate80mg2–3timesaday.Treatmentiscontin-uedaslongasthediseaseisstableorinremission.Maximumclinicalresponsemayonlybeobservedthreeormoremonthsaftertherapyinitiation.Platinum-basedchemotherapy(cisplatinanddoxorubicin,orcarboplatinandpaclitaxel)hasbeenrecommendedforpatientswithadvancedorrecurrentdisease,notamenabletocurebysurgeryand/orradiotherapy.96,117Severalongoingtrialsarecurrentlyinvestigatingtheclinicalapplicabilityoftargetedtherapiesinpatientswithnonlo-calizedrecurrenttumors

16  | RECOMMENDATIONS FOR PRACTICE

 1. A definitive tissue diagnosis must be obtained preoperatively.This will result in better selection of the surgical approach,

andhelptodifferentiatetumorsatlow-andhigh-riskoflymphnode metastasis. Imaging might be used to determine depthofmyometrial invasion, cervical involvement, and lymph nodeenlargement. Level of Evidence C

  2. AlthoughlymphadenectomyinclinicalStageIendometrialcan-cerdecreasesrecurrence,ithasnoimpactonoverallorrelapse-freesurvival.Level of Evidence A.Intheclinic,lymphadenectomyshouldbeperformedforstagingonlyinhigh-riskcases.Thereislittleevidence tosupporta therapeuticbenefit,but itmaybeusedtoselectwomenwithpositivenodesforadjuvanttherapyandreducetheneedforEBRTinnode-negativepatients.Level of Evidence C

  3. InpatientswithStageIendometrialcancerwithlow-,intermedi-ate-, or high/intermediate risk features, adjuvant radiotherapyhas no impact on survival, but significantly reduces the rate ofpelvicrecurrence.Level of Evidence A.Inhigh-riskpatients,vagi-nalbrachytherapyeffectivelyreducestheriskofvaginalrelapse.Level of Evidence A.EBRTshouldbeconsideredinpatientswithpresumedStageI–IIdiseasewithstrongadversefactors,positivenodes,oradvancedstagediseasetoensurepelviccontrol.Level of Evidence A

  4. Theadditionofadjuvantchemotherapytoradiotherapyinpatientswithhigh-riskdiseaseimprovesprogression-freesurvival,butanoverallsurvivalbenefitisunproven.Level of Evidence A

  5. Adjuvant chemotherapy for patientswith early stage, high-riskdiseaseshouldonlybeconsideredforthosewithserouscancersandafterindividualpatientcounseling(noprovenbenefitinover-allsurvival),andpreferablybedonewithinclinicaltrials.

  6. ChemotherapyisamoreeffectivestrategycomparedwithwholeabdominalradiationinpatientswithStageIVdiseaseandabdomi-naldiseasewithresidualnoduleslessthan2cmdiameter.Level of Evidence A

  7. Targetedtherapyinendometrialcancershouldbefurtherdevel-opedandonlyconsideredwithinclinicaltrials.

  8. Theuseofadjuvanthormonaltherapy(progestogen)hasnotbeenproperlysubstantiated.Level of Evidence A

  9. High-riskandadvancedstageendometrialcancerpatientsshouldbemanagedwherepossiblebyagynecologicaloncologist,work-ingwithinamultidisciplinaryteam.Level of Evidence A

10. Patientswithendometrialcancerarefrequentlyoldandfrail,andthisshouldbetakenintoconsiderationwhenprescribingadjuvanttherapy.Professionalconsensus

AUTHOR CONTRIBUTIONS

Allauthorscontributedequallytothismanuscript.

ACKNOWLEDGMENTS

Thischapterupdatesthe informationpublished intheFIGOCancerReport2015(AmantF,MirzaMR,KoskasM,CreutzbergCL.Cancerofthecorpusuteri.Int J Gynecol Obstet.2015;131(Suppl.2):S96–104).

     |  47AmAnt Et AL.

CONFLICTS OF INTEREST

Theauthorshavenoconflictsofinteresttodeclare.

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