Treatment of climacteric symptoms in survivors of gynaecological cancer

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Maturitas82(2015)295–297

ContentslistsavailableatScienceDirect

Maturitas

j ourna l h o me pa g e :w w w . e l s e v i e r . c o m / l o c a t e / m a t u r i t a s

Review

article

Treatment

of

climacteric

symptoms

in

survivors

of

gynaecological

cancer

Nicoletta

Biglia

∗

,

Valentina

Elisabetta

Bounous,

Luca

Giuseppe

Sgro,

Marta

D’Alonzo,

Martina

Gallo

UnitofObstetricsandGynaecology,MaurizianoUmbertoIHospital,DepartmentofSurgicalSciences,UniversityofTurin,Turin,Italy

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received11June2015

Receivedinrevisedform3July2015 Accepted6July2015

Keywords:

Gynaecologicalsurvivors

Hormonereplacementtherapy(HRT) Ovariancancer

Endometrialcancer Cervicalcancer

a

b

s

t

r

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t

Differenttreatments(surgery,radiotherapy,chemotherapy)forgynaecologicalcancersmaycause ovar-ianfailureorincreasemenopausalsymptoms.Thereisawidespreadreluctanceamongphysiciansto prescribehormonereplacementtherapy(HRT)tothesurvivorsofgynaecologicalcancer.Thisreview analysestheuseofHRTandofalternativetherapiesinsuchwomen.Squamouscervicalcancerisnot estro-gendependentandthusHRTisnotcontraindicated.Whileacautiousapproachtohormone-dependent canceriswarranted,forwomentreatedfornon-hormone-relatedtumoursalternativetreatmentsfor menopausalsymptomsshouldbegivendueconsideration,asanyreluctancetoprescribeHRTforthem hasneitherabiologicalnoraclinicalbasis.InstudiesofHRTforsurvivorsofendometrialandovarian cancer,forinstance,noevidenceofincreasedriskwasfound,althoughnodeﬁnitiveconclusionscanyet beformulated.ThepositiveeffectofHRTonqualityoflifeseemstooutweightheunfoundedsuspicionof anincreasedriskofrecurrenceofnon-hormone-relatedtumours.Effectivenon-hormonalalternativesfor vasomotorsymptomsareselectiveserotoninreuptakeinhibitorsandselectiveserotonin–norepinephrine reuptakeinhibitors.

Contents

1. Introduction...295

2. Discussion...296

2.1. Endometrialcancer...296

2.2. Uterinesarcomas...296

2.3. Cancerofthecervix...296

2.4. Ovariancancer...296

2.4.1. Alternativestohormonetreatment ... 297

Researchagenda...297 Conﬂictofinterest ... 297 Fundinginformation...297 Authorscontribution...297 References...297 1. Introduction

Duetoadvancesintreatment,manywomenwith gynaecolog-icalcancerssurvivelongaftertheirprimarysurgery,andthusthe

∗ CorrespondingAuthor:NicolettaBiglia,ObstetricsandGynaecology,Mauriziano UmbertoIHospital,DepartmentofSurgicalSciences,UniversityofTurin,Largo Turati62,10128Turin,Italy.Fax:+39115082683.

E-mailaddress:nicoletta.biglia@unito.it(N.Biglia).

long-termconsequencesofestrogendeprivationmayaffecttheir qualityoflife(QoL).

Hotﬂushes(HFs)arethemostfrequentlyreportedmenopausal symptoms,followedbyinsomnia,vaginaldrynessanddyspareunia. Systemichormonereplacementtherapy(HRT)isthemosteffective strategyinreducingmenopausalsymptomsinhealthywomen[1]. However,manyphysiciansarereluctanttoprescribeHRTto sur-vivorsofgynaecologicalcancers,regardlessofexacttumortype anddiseasestage,becauseofthelackofinternationalguidelines andthefearofmedicallitigationifawomandoesgoontosuffera recurrencewhiletakingHRT[2].

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296 N.Bigliaetal./Maturitas82(2015)295–297 ThisarticlereviewsclinicalstudiesontheuseHRTaswellas

alternativetherapiesformenopausalsymptomsingynaecological cancersurvivors.

2. Discussion

2.1. Endometrialcancer

Endometrialcancer(EC)isanestrogen-dependentdiseasewith afavourableprognosis.Thus,relievingmenopausalsymptomsis importantformaintainingagoodQoL.

Ina13-yearfollow-upanalysisofdatafromtheWomen’sHealth Initiative(WHI)[3],a reducedriskofECinhealthywomenwas observed withcombined estrogen–progestogen HRT (HR=0.67, 95%CI0.49–0.91).However,therewasconcernregardingHRTfor womenpreviouslytreatedforECbecauseofthefearthat,evenafter uterusremoval,estrogensmaystimulatethegrowthofoccultfoci oftumourcells.

Theresultsofseveralsmallobservationalstudiesare reassur-ing.In thestudybyCreasman,47patientswithstageIECused conjugatedestrogenbyoralorvaginalroutesforamedianof26 months.Alowerrecurrencerate(2.1%versus14.9%oftheplacebo group)andsigniﬁcantlongerdisease-freesurvival(DFS)andoverall survival(OS)wereseenintheestrogen-treatedgroup[4].

Lee[5]compared44stageIECsurvivorsusingoralestrogens withorwithoutcombinedprogestogenwith99controls.No recur-rencewasobservedintheHRTgroup,while8%ofpatientsinthe controlgrouprelapsed.However,selectionbiaswaspresentsince HRTwasprescribedonlytolow-riskpatients(stageIA,IBgrade1 or2)while37%ofcontrolshadhigh-riskdisease(stageICgrade3). InthestudybyChapman[6],62patientswithstageIorstage IIECreceivedHRTatamediantimeaftersurgeryof8monthsand 61similarpatientsdidnotreceiveHRT.Nosigniﬁcantdifferences intherecurrencerateorinOSwereobservedbetweenthetwo groups.

Surianoetal.[7]evaluated75womentreatedforstageI–IIIEC whoreceivedHRTand75matchedcontrols.IntheHRTgroupa lowerrecurrencerate(1%)wasobserved(14%inthecontrolgroup); moreover,HRTusershadasigniﬁcantlylongerDFS.

Ahyanetal.[8]compared50patientsreceivingcombinedHRT 4–8weeksaftersurgeryand52matchedcontrols,alltreatedfor stageIorstageIIEC;norecurrencewasobservedintheHRTgroup, whereas,onecontrolexperiencerecurrence.

Theonly prospectiverandomized controlled trial(RCT) was fromtheGynecologicOncologyGroup(GOG)[9].Itinvolved1236 womentreatedforECrandomizedtoestrogensaloneortoplacebo, butitwasclosedprematurelyafterpublicationoftheWHIstudy [10].Themajorityoftheenrolledpatientshadwelldifferentiated endometrioidEC;91%hadlessthan50%myometrialinvasion.No signiﬁcantdifferenceinrecurrenceratewasobserved,beingvery lowinbothgroups(2.1%inthe618HRTusersversus1.9%inthe placebogroup).

Allthesestudieswereincludedinarecentmeta-analysis[11] thatfoundnosigniﬁcantincreasedriskofrecurrenceinthe896EC survivorsemployingHRTcomparedwiththe1079controls.

AsregardsthetypeofHRT,therewasaprotectiveeffectof com-binedHRT(OR:0.23;95%CI:0.08–0.66)onECrecurrence,whereas, therewasnosucheffectforestrogen-onlyHRT(OR:0.35;95%CI: 0.06–2.10).However,inthestudieswhereaprogestinwasadded [5–7],withtheexceptionofAyhanetal.[8],onlyhalfoftheHRT usersreceivedit.Forthisreason,itremainsunclearwhetherthe additionofprogestinstrulyinhibitsthestimulatoryeffectof estro-genontumorcells.

TheselectionofhealthierandyoungerwomentobeginHRTmay explaintheprotectiveeffectofHRTonrecurrenceinECsurvivors seeninobservationalstudies.

The minimum disease-free period before any HRT may be startedisstillcontroversial.SincemostrecurrentECsoccurwithin 2 yearsof theinitialdiagnosis,some authorssuggest thatHRT shouldnotbestartedearlierthanthat[12].However,inmost stud-iespatientsreceivedHRTsooner[4–7]andinthestudybyAhyan etal.[8]HRTwasstartedimmediatelyaftersurgery.

Theavailableguidelinesareconﬂicting,whichunderminestheir usefulness.Forinstance,theNorthAmericaMenopauseSociety[1] statesthatHRTisnotrecommendedinwomenwithahistoryof ECandsuggeststhatprogestogenaloneshouldbeconsideredfor themanagementofHFs,evenifnolong-termdataareavailable. Incontrast,theNationalComprehensiveCancerNetwork(NCCN) Panel[13]statesthatestrogen-onlyHRTisareasonableoptionfor patientswhoareatlowriskoftumourrecurrence,butthattheexact therapyshouldbeindividualisedanddiscussedindetailwiththe patient.

Inconclusion,nodeﬁnitiveconclusionscanbedrawn,sinceno long-termRCTshave beenconducted.Patientsshouldbe coun-seledonanindividualbasisandgiveninformationonthelimited evidencefromtheliterature.

2.2. Uterinesarcomas

Amonguterinesarcomas(carcinosarcomas,leiomyosarcomas, adenosarcomas,endometrialstromalsarcomas),onlyendometrial stromalsarcomasareconsideredtobeestrogendependentandHRT shouldbeavoided[2].

2.3. Cancerofthecervix

TheroleofHRToncervicalcancer(CC)dependsonthetumour histotype.SquamousCCisnotconsideredtobeestrogen respon-siveandHRTdoesnotseemtohavearole inhumanpapilloma virus(HPV)replication.InthestudybyPloch[14]on120women treatedforstageIorstageIICC(80womentreatedwithHRTand40 non-treated),HRTproducednochangeineitherOSorDFS.Cervical adenocarcinomasaccountfor15%ofallCCsandaredependenton estrogenstimulationinthesamewayasEC.

2.4. Ovariancancer

Most ovarian epithelial cancers (OC) appear in menopausal womenanddiseaseprognosisispoor,withlessthan30%ofpatients withstageII–IVtumoursalive5yearsafterdiagnosis.Nonetheless, maintainingagoodQoLisofcourseimportant.

AvailabledataonHRTuseinhealthywomenandOCriskare conﬂicting.TheWHItrialdidnotﬁndanyincreaseinriskofOCfor HRTusers[10].However,ameta-analysisof52studies[15]found anincreasedriskofOCinhealthyHRTusers.

PublishedstudiesonHRTuseafterOCtreatmentshowno neg-ativeinﬂuenceondiseaseprognosisandagreatimprovementin QoL[16–19].

Eeles et al. [16] compared 78 OC survivors using HRT with 295controlsand found nodifferences in OS and DFS between thetwogroups.IntheonlyRCT[17],130OCsurvivorswere ran-domlyassigned toreceiveestrogen-onlyHRTornot6–8weeks aftersurgery.NostatisticallysigniﬁcantdifferencesinDFSandOS werefoundbetweenthetwogroups(32recurrencesintheHRT groupversus41recurrencesinthecontrolgroup).Inastudyby Ursic-Vrscaj etal.[18],24 OCsurvivors treatedwithHRTwere compared with48 non-users andnodetrimentaleffecton out-comewasobservedinHRTusers.Thelargestprospectivestudywas publishedbyMascarenasetal.[19],whoanalysedtheOSof649

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N.Bigliaetal./Maturitas82(2015)295–297 297 survivorsofinvasiveOCandof150patientstreatedforborderline

ovariantumor(BOT)accordingtoHRTusebeforeandafter diag-nosis.InwomenwithinvasiveOC,therewasnooveralldifference in5-yearOSaccordingtoHRTusebeforediagnosis(HR0.83,95% CI0.65–1.08)butabetterOSwasobservedforpatientswhoused HRTafterdiagnosis(HR0.57,95%CI50.42–0.78).ForBOTpatients, noassociationwasfoundbetweenOSandHRTusebeforeorafter diagnosis.BOTsareknowntohavealowpotentialformalignancy andthereforecarryabetterprognosisthaninvasiveOC.

EachOChistotype(high-gradeserous,endometrioid,clearcell, mucinousandlow-gradeserouscarcinomas)isadistinctdisease, withdifferentriskfactors,hormoneresponsivenessandprognosis. Inparticular,endometrioidOCisestrogensensitiveandresidual diseaseaftertreatmentcouldbestimulatedbyHRT.

TheoverallconsensusisthatHRTshouldbeconsideredinOC patientswhoexhibittroublesomemenopausalsymptoms[2]. 2.4.1. Alternativestohormonetreatment

For HFs, the most effective treatments are selective sero-toninreuptakeinhibitorsandselectiveserotonin–norepinephrine reuptakeinhibitors[20];mostoftherelevantstudieshavebeen performed on breast cancer survivors. Several recent studies in healthy women have suggested thatvaginal laser treatment may be effective for dyspareunia and vaginal atrophy, but no RCTsare available. Bisphosphonates and the selectiveestrogen receptor modulator (SERM) raloxifene may be good alterna-tivesforboneprotection.Lifestylemodiﬁcationsuchasdietand physical exercise can be considered for cardiovascular protec-tion.

Researchagenda

Consensusguidelinesareneeded.MoreRCTsonlargersamples areneededtodrawdeﬁnitiveconclusions.

Conﬂictofinterest

NBigliahadaﬁnancialrelationship(memberofadvisoryboards and/orconsultant)withGedeonRichter,ItalfamarcoandShionogi Ltd.Theotherauthorsdeclarethattheyhavenoconﬂictofinterest.

Fundinginformation

Theauthorshavereceivednofundingforthisarticle

Authorscontribution

Allauthorsdeclarethathaveparticipatedinthisworkandthat haveseenandapprovedtheﬁnalversion.

NicolettaBiglia:Scientiﬁcresponsible,manuscriptpreparation, manuscript,supervision.

ValentinaElisabettaBounous:Manuscriptpreparation.

LucaGiuseppeSgro:Manuscriptsupervision. MartaD’Alonzo:Manuscriptrevision. MartinaGallo:Manuscriptrevision.

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