Fertility preservation after fertility-sparing surgery in women with borderline ovarian tumours

(1)

HAL Id: hal-02926007

https://hal.archives-ouvertes.fr/hal-02926007

Submitted on 31 Aug 2020

HAL is a multi-disciplinary open access

archive for the deposit and dissemination of

sci-entific research documents, whether they are

pub-lished or not. The documents may come from

teaching and research institutions in France or

abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire HAL, est

destinée au dépôt et à la diffusion de documents

scientifiques de niveau recherche, publiés ou non,

émanant des établissements d’enseignement et de

recherche français ou étrangers, des laboratoires

publics ou privés.

Fertility preservation after fertility-sparing surgery in

women with borderline ovarian tumours

S. Khiat, M. Provansal, P. Bottin, J. Saias-Magnan, Catherine

Metzler-Guillemain, Blandine Courbiere

To cite this version:

S. Khiat, M. Provansal, P. Bottin, J. Saias-Magnan, Catherine Metzler-Guillemain, et al..

Fertil-ity preservation after fertilFertil-ity-sparing surgery in women with borderline ovarian tumours.

Euro-pean Journal of Obstetrics & Gynecology and Reproductive Biology, Elsevier, 2020, 253, pp.65-70.

�10.1016/j.ejogrb.2020.07.053�. �hal-02926007�

(2)

Full

length

article

Fertility

preservation

after

fertility-sparing

surgery

in

women

with

borderline

ovarian

tumours

S. Khiat

a

,

M. Provansal

b

,

P. Bottin

a

,

J. Saias-Magnan

a

,

C. Metzler-Guillemain

a,c

,

B. Courbiere

a,d,

*

a

Assistance-PubliquedesHôpitauxdeMarseille(AP-HM),PôleFemmes-Parents-Enfants,CentreClinico-biologiqueAMP-CECOS,PlateformeCanceretFertilité ONCOPACA-Corse,Marseille,France

b

InstitutPaoli-Calmettes,DepartmentofMedicalOncology,CRCM,Marseille,France c_Aix_Marseille_Univ,_INSERM,_Marseille_Medical_Genetics_(MMG),_U1251,_Marseille,_France d

AixMarseilleUniv,CNRS,IRD,IMBE,AvignonUniversité,Marseille,France

ARTICLE INFO

Articlehistory: Received1May2020

Receivedinrevisedform23July2020 Accepted27July2020

Availableonlinexxx

Keywords:

Borderlineovariantumour Fertilitypreservation Oocytecryopreservation Pregnancy

ABSTRACT

Objective:Topresentacaseseriesofwomenwithborderlineovariantumours(BOTs)whounderwent oocytevitriﬁcationinadditiontofertility-sparingsurgery.

Studydesign:ObservationalstudyofallwomenreferredtoaFrenchfertilitypreservationunitbetween 2015and2019forcounsellingregardingafertilitypreservation(FP)strategyafterBOTfertility-sparing surgery.Alleligiblewomenunderwentoneormorecyclesofcontrolledovarianstimulation(COS)using anantagonistprotocol,followedbyoocyteretrieval.MetaphaseII(MII)oocyteswerevitrified. Results:Twenty-fivewomenwithBOTswerereferredduringthestudyperiod.Amongthem,11women underwentatleastonecycleofCOS.Onehundredandseven MIIoocyteswerevitrified.Themean numberofvitrifiedMII oocytesperwomanwas9.7(standarddeviation 5.2).Fivelive birthswere reportedduringfollow-upoffourwomenwithvitrifiedoocytes:threespontaneouspregnancies,one in-vitrofertilizationcyclewithfreshembryotransfer,andonelivebirthafterreturnofvitrifiedoocytes. Conclusion:ConservativesurgeryforBOTsoffersahighspontaneouspregnancyratebuthasahigherrisk ofrelapsethanradicaltreatment.Furthermore,womenwhoundergoconservativeBOTsurgeryhavea higherriskofsurgery-inducedprematureovarianfailure.OocytecryopreservationafterCOSappearsto beaneffectivetechniqueaftertheconservativemanagementofBOTsinwomenofreproductiveage. Althoughtheavailableshort-termdataarereassuring,furtherlong-termstudiesevaluatingthesafety andcost-effectivenessofthissystematicFPstrategyafterBOTfertility-sparingsurgeryarerequired.

Introduction

Borderlineovariantumours(BOTs)areararegroupofovarian tumours that differ from carcinoma in the absence of stromal invasion[1,2].BOTs havea goodprognosis,and 10-yearoverall survivalis>90%[3].Theaverageageofonsetis45years,whichis 20 years younger than the average age of onset of invasive epithelialovariancancer;one-thirdofpatientswithBOTsareof childbearing age [4]. Standard treatment involves bilateral salpingo-oophorectomywithorwithouthysterectomy,andleads to permanent suppression of endocrine and exocrine ovarian

function.Considering thegoodprognosisofBOTandtheglobal trendtopostponemotherhood,fertilitypreservation(FP)remains a majorconcernforthesewomen.Fertility-sparingsurgerywas proposedin1988byLim-Tanetal.,whofirstdescribedcystectomy orunilateralsalpingo-oophorectomywiththeaimofreducingan impairment in the ovarian reserve and enabling spontaneous pregnancy[5].Theoncologicsafetyofconservativemanagement ofBOTshasbeenwelldocumented,anddespiteahigherriskof recurrencecomparedwithradicaltreatment,nodifferenceshave beenobservedin10-yearoverallsurvivalrates[6].However,these recurrencesleadtoadditionalsurgeriesathighriskofdecreasing theovarianreserve,andconservativetreatmentdoesnotappearto fullypreservefertility.Several FPtechniques,suchascontrolled ovarian stimulation (COS) for oocyte vitrification, have been proposedinwomenwithBOTs,butlimiteddataareavailableon thefeasibility,safetyandeffectivenessofthistechnique[7–9].This article presents thefirst case series of women withBOTs who * Corresponding author at: Pôle Femmes-Parents-Enfants, Centre

Clinico-Biologique d’AMP-CECOS, PlateformeCanceret FertilitéONCOPACA-Corse, AP-HM,LaConception,147bdBaille,13005Marseille,France.

E-mailaddress:blandine.courbiere@univ-amu.fr(B. Courbiere).

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

(3)

underwentFPthroughCOSforoocytevitriﬁcationafter fertility-sparing surgery. Speciﬁc FP strategies of potential use after conservativesurgeryinthispopulationarediscussed.

Materialsandmethods

Aretrospectiveobservationalstudycollectedmedicaldatafrom women with BOTs who were referred to a French fertility preservationunitfrom2015to2019,regardlessofthehistological typeoftheBOT.Allwomenhadundergoneatleastoneovarian surgeryforBOTbeforecounselling.COSwasofferedtowomenwho had complete surgerywithout stromalmicroinvasion at anato-mopathology.Theaimofcounsellingwastoinformwomenofthe rateofspontaneouspregnancywithoutFP,andaboutthebenefits, limitsandrisksofoocytevitrification.Moreover,informationwas given about the chance of a live birth using vitrified–thawed oocytes,takingaccountof thewoman’sageand thenumber of vitrifiedoocytes.Coboetal.reportedanongoingpregnancyrateof 35.7%andalivebirthrateof41.1%inwomenaged35yearswho cryopreservedforoncologicalindications.Before35yearsofage, thecumulativeprobabilityoflivebirthinoncologicalindicationsis 9.1%forfivecryopreservedoocytes,35.8%foreightcryopreserved oocytes, 42.9% for 10 cryopreserved oocytes and 61.9% for 12 cryopreservedoocytes[10].

Afterapersonalizedcounsellingsession,andinagreementwith theoncologicteamandthepatient,COSwasinitiatedonDay2of the woman’s cycle using daily subcutaneous injections of recombinant follicle-stimulating hormone (rFSH). A gonadotro-pin-releasing hormone antagonist was co-administered daily, beginningonDay5,topreventthesurgeofluteinizinghormone. Oocytematurationwas triggered with0.3mg triptoreline 36 h prior to transvaginal oocyte retrieval under local or general anaesthesia. Metaphase II (MII) oocytes were vitriﬁed using a closedsystem(VitKitFreeze,IrvineScientiﬁc,SantaAna,CA,USA). According tothe number ofMII oocytescryopreserved, one or morecyclesofCOSwereproposedtoaccumulatemorethan10 matureoocytes.ThisstudywasapprovedbytheEthicsCommittee atAixMarseilleUniversity(N _{2019-17-10-003).}

Results

Intotal,25womenwithBOTswerereferredtoourcentreforFP counsellingafter undergoingtheirﬁrst fertility-sparing surgery. Their median age was 27.5 5.6 years. Most women had an International Federation of Gynaecology and Obstetrics (FIGO) stageItumour(80%,n=20).Theotherﬁvewomenweretreatedfor FIGOstageIIItumourswithnon-invasiveperitonealimplants.Ten women had prior unilateral oophorectomy (40%); that was associated with contralateral cystectomy for bilateral BOT for twowomen. Ninewomen had unilateral cystectomy(36%) and sevenwomenhadbilateralcystectomy(28%).Theserumlevelof anti-Müllerian hormone (AMH) after conservative surgery was availablefor 15women {mean7.8 [standard deviation(SD)8.6 pmol/l]}.

Thecharacteristicsofthe11womenwhochosetocryopreserve theiroocytesarereportedinTable1.Inthisgroup,themedianage was265.7years.Anassessmentofovarianreserveshowed a meanserumAMHlevelof9.7(SD9.8)pmol/landameanantral folliclecountof5.3(SD2.8).Amongthese11women,eightonly hadoneovaryremainingaftersurgery.

Amongthe14womenwhodidnotchoosetocryopreservetheir oocytes,eightdeclinedFPafterapersonalizedcounsellingsession. Giventhelackofdataregardingthelong-termriskofCOS,fearof increasingtheriskofrelapsewasthemainreasonwhypatients declinedtheofferof FP.Twowomenwerecontra-indicated for COS:onebecauseofaconcurrentlupusﬂare-up,andtheotherfor

suspicionofassociatedovarianmicroinvasion.Twowomenwished topostponetheCOScycle,andtwopatientsdidnotstartCOSas scheduledforpersonalreasons.

Outcomeofoocytecryopreservation

TheresultsofCOScyclesarepresentedinTable2.Themean durationofCOScycleswas10.8(SD2)days,andthemeantotal doseofgonadotropinrequiredwas3680(SD1120)IU.Onehundred and fifty-sixoocyteswereharvested, and107MIIoocytes were vitrified.ThemeannumbersofretrievedoocytesandMIIvitrified oocytes per woman were 14.1 (SD 6.7) and 9.7 (SD 5.2), respectively.Fifty-fourpercentofwomen(n=6/11)cryopreserved 10 oocytes. One woman underwent five COS cycles, three patientsunderwent three or two cycles, and four women only underwentone cycle.AsingleCOS cyclewas sufficient fortwo women (Patients 8 and 10), and more than 10 oocytes were retrieved.Themediandurationoffollow-upafterCOSwas1615 months(7–48).

Fertilityoutcome

FertilityoutcomeissummarizedinTable3.Duringfollow-up, fourwomenachievedalivebirthandonewomanhadtwobabies. One woman (Patient 1) wanted to use her cryopreserved oocytes. In May 2015, this 29-year-old patient was initially diagnosed withserous bilateral BOT withperitoneal spread. A rightsalpingo-oophorectomy,omentectomyand leftcystectomy wereperformedbeforeFP.Abloodtestofhormonelevelsbefore COSshowedadiminishedovarianreserveonDay3ofhercycle, FSHof9UI/l,estradiol(E2)of92pmol/LandAMHof5.3pmol/L. BetweenSeptember2015andJanuary2016,threecyclesofCOSled tovitriﬁcationof12MIIoocytesfromtheresidualleftovary.In March 2016, after oncological counselling, surgical radical treatment was completed with left salpingo-oophorectomy. Approximately 2 months later, hormone replacement therapy wasprescribedforembryotransfer(ET):4mgoforalE2perdayfor 13 days until endometrial thickness >8 mm. Next, 600 mg of vaginalprogesteronewasadministereddaily3daysbeforeDay3 ET. In May 2016, four oocytes were warmed and four diploid embryos were obtained after intracytoplasmic sperm injection (ICSI).Duetoahistoryoftwocaesareansections,asingleETwas performedandtwoadditionalembryoswerefrozen.Nopregnancy was obtained. In August2016, a second ETof a single frozen– thawedembryoledtoasingletonpregnancy.A3760-ghealthygirl wasbornbycaesareansectionat38weeksofpregnancy.InJune 2020, this patient had not experienced any recurrence, and underwentsonographicfollow-upevery6months.

Patient5wasa27-year-oldwomanwhowasreferredafterher firstsurgeryofbilateralserousBOT,treatedwithleft oophorecto-myandrightcystectomy.BloodtestsofovarianreserveonDay2of hercycleshowedFSHof8.6UI/l,E2of28pmol/landAMHof12.5 pmol/l.Thetotalantralfolliclecountwas6.Afterthreecyclesof COS between 2015 and 2017, only _five MII oocytes were cryopreserved.Twoyearslater,shedesiredapregnancy. Sponta-neouspregnancywasnotpossibleduetoarighthydrosalpinx.Due to the low number of cryopreserved oocytes and a sufficient ovarianreserve(AMH9.3pmol/l),anewCOScyclewasperformed for ICSI–in-vitro fertilization (IVF). Two mature oocytes were retrievedandfertilized,andledtothetransferoftwofreshdiploid Day3embryos.Thepatientachievedasingletonpregnancywitha 3360-ghealthynewborn.

Twowomen reported spontaneouspregnancies after oocyte cryopreservation.Onewoman(Patient10)achievedtwo sponta-neouspregnancieswithtwotermdeliveries1and 3yearsafter conservative BOT management. The second woman (Patient 6) 2 S.Khiatetal./EuropeanJournalofObstetrics&GynecologyandReproductiveBiology253(2020)xxx–xxx

(4)

achievedaspontaneouspregnancywithahealthybabybornby caesareansectionatterm.Todate,follow-upofthesewomenhas notdetectedrecurrenceat,respectively,48and12monthssince COS.Forthesetwowomen,theirvitriﬁedoocytes(13andsixMII oocytes,respectively)provideanadditionalchanceofpregnancyin theeventofadecreasedovarianreserveinducedbyfurthersurgery orapostponeddesireforfutureparenthood.

OnecaseofBOTrecurrencewasreportedafteronecycleofCOS intheFP group(Patient4).This28-year-oldwomanwithFIGO stageIIIAunilateralserousBOTreceivedunilateralcystectomyby laparoscopywithexcision ofcaecalandperitonealnon-invasive implantsandomentectomy.OnecycleofCOSenabled cryopreser-vationoffourMIIoocytes.NinemonthsafterCOS,shepresented withipsilateralrelapseandunderwentoophorectomy.Shedidnot wishtoperformasupplementaryCOScycle.Fivemonthslater,she presented with contralateral relapse that was treated with contralateraloophorectomy. After36 monthsof follow-up, this patient hasnot experiencedrecurrence, continuesto be moni-tored, and does not currently wish to use her cryopreserved oocytes.

Discussion

BOTsoccurinyoungwomenwhohavenotalwayscompleted theirfamilies,andthepreservationoftheirlong-termfertilityisa paramountchallenge. Oocyte cryopreservation appears tobe a feasibleandefficientFPtechniqueinwomenofreproductiveage afterconservativesurgeryforBOT.Totheauthors’knowledge,this isthefirstreportedcase seriesof womenwithBOTs whohave benefitedfromthisFPstrategy.Thefirstlivebirthwasreportedby Porcuetal.in2008,andtheauthorsbelievethatthepresentstudy reportsthesecondlivebirthafterreturningcryopreservedoocytes toawomanfollowingBOTsurgery[8].

Fertility-sparing surgery effectively preserves fertility and allows spontaneous pregnancies. The cumulative spontaneous pregnancy rate is 50–60% after conservative surgery [6,11]. Nevertheless,therecurrencerateishigherafterthisconservative strategy,andisevaluatedat20_–30%[12,13].Despitethehigherrisk of recurrence, nodifferencein survivalrate hasbeenobserved, which remains at>90%,andtherisk ofprogression toinvasive carcinomaappearstobelow,estimatedat2_–3%[1].Inwomenwith bilateralBOTs,whichaccountfor40%ofserousBOTs,arandomized controlledtrialcomparedbilateralcystectomywithoophorectomy pluscontralateralcystectomy.At11-yearfollow-up,womenwho underwentbilateralcystectomyhadasignificantlyshortertimeto firstlivebirthandahigherrelativerate(RR)oflivebirth[RR=8.05 (95%confidenceinterval1.20–9.66;p<0.01)].TheRRofrecurrence didnotdiffersignificantlybetweenthetwogroups,butthetimeto firstrecurrencewassignificantlyshorterforthebilateral cystec-tomygroup(16.2monthsvs48months;p<0.01)[14,15].Recent Frenchguidelinesalsorecommendbilateralcystectomyinwomen with bilateral BOTs who wish to preserve their fertility [16]. Despite theefficiency of fertility-sparingsurgery,theincreased rate of relapse carries a higher risk of additional surgery than radicaltreatment.Everyovariansurgicalprocedurerisksreducing theovarianreserveandinducingprematureovarianinsufficiency [17]. In a cohort study by Chevrot et al. with 52 women of childbearing age, the pregnancy rate after conservative BOT treatment was 63%, but 26% of women required postoperative assistedreproductivemedicinetoconceive[18].Inaretrospective cohortstudyof535womenwhounderwentconservativesurgery, DelleMarchetteetal.showedthateachovariansurgeryreduced theprobabilityofachievingaspontaneouspregnancyby40%[11]. Considering the global trend to postpone motherhood in developed countriesand thehigh survivalrate of womenwith early-stage BOTs, additionalFP techniques shouldbeofferedto Table1

Characteristicsofwomenwhocryopreservedoocytesafterconservativesurgeryforborderlineovariantumour(BOT).

Patient no. Age (years) Localization FIGO stage Histological type

Ovariansurgerypriortooocyte cryopreservation

Follow-upafteroocyte cryopreservation Durationof follow-up (months) 1 29 BilateralBOTs+ non-invasiveimplants intheomentum

IIIA Serous Unilateralrightoophorectomy, omentectomy,leftcystectomy

Radicalsurgerywithleftoophorectomy afterCOS(threecycles)andoocyte vitriﬁcation.Returnofvitriﬁedoocytes. Livebirth(girl,3760g,38GW)after ICSI–IVFonfrozen–thawedoocytes

48

2 18 UnilateralBOT+ peritonealimplants

IIIA Serous Unilateralleftoophorectomy, omentectomy

Norecurrence 24

3 21 UnilateralBOT IA Mucinous Unilateralrightoophorectomy Norecurrence 7 4 28 UnilateralBOT+non

invasiveperitonealand caecalimplants

IIIA Serous Unilateralleftcystectomy,resectionof peritonealimplants

Recurrenceat9months:treatedbyleft oophorectomy.Contralateral recurrenceat14months:radical treatmentbyrightoophorectomy

12

5 27 BilateralBOTs IB Serous Unilateralrightoophorectomy, contralateralcystectomy

Contralateralrecurrenceat12months: conservativetreatmentwithrecurrent cystectomyonleftovary.Livebirth(girl, 3360g,39GW)afterCOS,oocyte pick-upfromtheremainingovary.ICSI–IVF (twoMIIoocytes)andfreshembryo transfer

36

6 27 UnilateralBOT IA Serous Unilateralleftoophorectomy Norecurrence.Spontaneouspregnancy –livebirth36monthsaftersurgery

36

7 25 UnilateralBOT IA Serous Unilateralleftcystectomy Norecurrence 7 8 38 UnilateralBOT IA Endometrioid Unilateralrightcystectomy Norecurrence 16 9 21 BilateralBOTs IB Serous Unilateralrightoophorectomy,

contralateralleftcystectomy

Norecurrence 24

10 26 UnilateralBOT IA Mucinous Unilateralrightoophorectomy Norecurrence.Spontaneouspregnancy –livebirths12and36monthsafter surgery

48

11 19 UnilateralBOT IA Mucinous Unilateralrightoophorectomy Norecurrence 14 FIGO,InternationalFederationofGynaecologyandObstetrics;COS,controlledovarianstimulation;ICSI–IVF,intracytoplasmicsperminjection–in-vitrofertilization;GW, gestationalweeks;MII,metaphaseII.

(5)

womenwhobeneﬁtedfromconservativemanagementandwho wishtopostponematernity[19].Todate,onlyafewcasereports havebeenpublishedthatreportadditionalFPstrategiesforwomen withBOTs.Gallotetal.reported‘emergency’IVFforawomanwith in-situFIGOstageIIIBOTwhoachievedalivebirthafterradical surgicaltreatmentandafrozen–thawedembryotransfer(ET)[20]. Oocyteretrievalwasperformed2daysbeforebilateral oophorec-tomy.Sixteen MIIoocyteswereharvested andfertilized,and 10 embryos were cryopreserved. Three other case reports have describedBOTFPusingin-vitromaturationofimmatureoocytes [7,21,22]. In two cases, in a context of radical surgery for BOT

recurrence,oocyteswereharvestedexvivoinalaboratoryfromthe excisedovariantissueandwerefertilizedafterin-vitromaturation. Twolivebirthswerereportedafterfrozen–thawedETissuedfrom maturedoocytes[21,22].

Totheauthors’knowledge,onlyafewcasereportsofoocyte cryopreservation after conservative BOT surgery and COS have beenpublished[8,23].TheﬁrstlivebirthwasdescribedbyPorcu etal.,who reporteda 26-year-oldwomanwitha FIGOstageIA serous BOT treated with salpingo-oophorectomy [8]. After a disease-freedelayof2years,COSwasperformedandsevenmature oocytes were cryopreserved. She presented with recurrence 6 Table2

Resultsofcontrolledovarianstimulation(COS)cyclesforoocytecryopreservationinwomenwhounderwentconservativesurgeryforborderlineovariantumours.

Patientno. BaselineAMH level,(pmol/l)

Antralfollicle count

Stimulation cycles

Totaldoseofgonadotropins requiredforstimulation(IU)

PeakE2level (pmol/l) Oocytes retrieved(n) Cryopreserved MIIoocytes(n) 1 10 7 Cycle1 4125 1575 6 5 Cycle2 3750 1000 5 4 Cycle3 3375 468 3 3 14 12 2 NA 9 Cycle1 2700 488 7 4 Cycle2 2700 488 10 7 Cycle3 2100 554 8 7 25 18 3 1.3 3 3600 485 1 1 4 3.9 5 2400 1400 9 4 5 12.5 8 Cycle1 3000 3966 3 2 Cycle2 2400 537 3 2 Cycle3 2400 1345 2 1 8 5 6 2.9 NA Cycle1 4500 300 8 3 Cycle2 4800 201 6 3 14 6 7 13.5 8 Cycle1 4200 586 8 5 Cycle2 3900 265 10 7 18 12 8 7.8 8 4050 2596 16 15 9 0.4 NA Cycle1 6300 841 0 0 Cycle2 4950 1395 3 0 Cycle3 4950 1563 3 3 Cycle4 4950 699 8 4 Cycle5 4950 924 9 6 23 13 10 NA 10 Cycle1 3000 1588 9 7 Cycle2 3300 926 7 6 16 13 11 35.7 NA 2000 3000 12 8

AMH,anti-Müllerianhormone;E2,estradiol;MII,metaphaseII;NA,notavailable.

Table3

Fertilityoutcomeofwomenwhocryopreservedoocytesafterconservativesurgeryforborderlineovariantumours(BOTs).

Patientno. Characteristics Fertilityoutcomes 1 29-year-oldwomenwithbilateralserousFIGOstageIIIA

tumourwithnon-invasiveimplantsintheomentumtreatedby rightoophorectomy,leftcystectomyandomentectomy.FP strategywasdiscussedwithoncologists:severalCOScyclesfor bankingoocytesontheremainingleftovary,immediately followedbyleftoophorectomy

ThreecyclesofCOS–12MIIcryopreservedoocytes.Returnof cryopreservedoocytes2monthsafterleftoophorectomy.Onelivebirth afterICSI–IVFonfrozen–thawedoocytesandembryotransferafter endometrialpreparationwithhormonereplacementtherapy(3760-g healthygirl,38GW)

5 27-year-oldwomenwithbilateralserousFIGOstageIBtumour treatedbyleftoophorectomyandrightcystectomy

ThreecyclesofCOSafterﬁrstBOTsurgery–ﬁveMIIcryopreserved oocytes.NorecurrenceafterCOS.Thirty-fourmonthsafterBOTsurgery, desireforpregnancy:IVFbecauseofbilateralhydrosalpinxanddespite alowresidualovarianreserve(AMH9.3pmol/l).OneCOScyclewas performedforICSI–IVF,pick-upoftwomatureoocytesandtransferof twofreshembryos.Livebirthofa3360-ghealthyboyat39GW 6 27-year-oldwomenwithunilateralleftserousFIGOstageIA

tumourtreatedbyunilateraloophorectomy

TwocyclesofCOS–sixMIIcryopreservedoocytes.Norecurrenceafter COS.Onespontaneouspregnancyandonelivebirth36monthsafter BOTsurgery.Nooocytereturn

10 26-year-oldwomenwithunilateralmucinousFIGOstageIA tumourtreatedbyunilateralrightoophorectomy

TwocyclesofCOS–13MIIcryopreservedoocytes.Twospontaneous pregnanciesandtwolivebirths(1and3yearsafterBOTsurgery).No oocytereturn.NorecurrenceafterCOS

FIGO,InternationalFederationofGynaecologyandObstetrics;COS,controlledovarianstimulation;ICSI–IVFintra-cytoplasmicsperminjection–in-vitrofertilization;MII, metaphaseII;GW,gestationalweeks;FP,fertilitypreservation;AMH,anti-Müllerianhormone.

(6)

months later and a contralateral salpingo-oophorectomy was performed.The patientwished touseheroocytes4 yearslater, resultinginatwinpregnancy,andtwohealthygirlswerebornat38 weeksof gestation.Otherstrategies describedCOS within-situ BOT, immediately followed on the day of oocyte pick-up by oophorectomyandex-vivooocyteretrievalforin-vitromaturation [9,24]. Noreportsof theuseof thesefrozenoocyteshavebeen publishedtodate.This‘one-shot’FPtechniquedoesnotallowthe patienttoundergorepeatedcyclesofCOSwhichmightbeusefulto increase the number of cryopreserved oocytes, particularly for womenwhohaveundergoneone ormoreovariansurgeries.As described by Fillipi et al., COS could also be discussed upon recurrence, before a new conservative surgery. This approach provides the advantages of conservative treatment and allows bettertargetingofwomenwitharealneedforoocyte cryopreser-vation.Indeed,therearenodatatodatethathavestudiedthe cost-effectivenessofCOS foroocytecryopreservationgiven thehigh rateof spontaneouspregnanciesafterconservativeBOTsurgery [23].

Availableevidencesuggeststhattheuseofinfertilitydrugsfor ovarianstimulationissafeinwomenwithBOTsaftersurgery.The recurrenceratedoesnotappeartobehigherinwomenwhohad bothconservativesurgeryandinfertilitydrugs.Themeta-analysis of Daraï et al. reported 105 women who were treated with infertilitydrugsafterconservativeBOTsurgery[6].Therecurrence ratewas27%,similartowomentreatedwithconservativesurgery whodidnotreceiveinfertilitydrugs.Denschlagetal.reporteda recurrencerateof19%inasystematicreviewincluding62women who received ovarianstimulation afterconservative BOT treat-ment[25].Basilleetal.studiedthestimulatoryeffectofFSHorE2 onin-vitroculturedBOTcells [26].Nodifferenceingrowthwas observedbetweenexposedandcontrolcells,despitethepresence ofhormonalreceptorsonBOTcells,suggestingthatgonadotropins mightbeusedinwomenafterconservativesurgeryforBOT.Data are not available on the safety of COS in women with in-situ ovariantumours.

Key points of the FP strategy in women with BOTs are summarized in Table 4. As histopathological analysis of the ovarian cyst is necessary to eliminate an invasive carcinoma, complete removal of theovarian tumour should be performed beforeFP[27].AsrecommendedbytheguidelinesoftheAmerican Society of Clinical Oncology, physicians caring for women of reproductiveagewithBOTsshouldrefertheirpatientstoafertility preservationunitforcounsellingpriortotheﬁrstrecurrenceto assess their ovarian reserve and inform women about the possibilitiesofFP. Alldecisionsshouldbediscussedin a multi-disciplinarymeeting[28,29].TheauthorsproposeanFPstrategy

for womenwith BOTs inwhich one ormore cycles of COSare performedtopreserveatleast10–15oocytesandpreservefuture fertilityafterthefirstconservativesurgery.AssuggestedbyCobo etal.,thepreservationof12vitrifiedoocytespriorto35yearsof ageresultsinacumulativelivebirthrateof61.9%[10].Thisstrategy shouldbeproposedtowomen,regardlessofwhetherornotthey haveacurrentdesireforpregnancy.However,largercohortstudies withalongdurationoffollow-upareneededtoevaluatethe cost-effectivenessofasystematicFPstrategyafterthefirstBOTsurgery. Conclusion

Although spontaneous fertility is >50% after conservative surgery, additional FP approaches are needed due toa risk of recurrence inwomen who wish topostpone motherhood. This articlereportstheﬁrstcaseseriesofwomenwhohavepreserved theirfertilitybyoocytecryopreservationfollowing conservative BOT surgery.In the authors’opinion, performing repeated COS cyclesforoocytecryopreservationaftertheﬁrstconservativeBOT surgery represents an interesting and safe strategy, allowing oocytebankingandthepossibilityofradicalsurgeryinthecaseof recurrence.However,althoughtheseshort-termdataare reassur-ing, further long-term studies evaluating the safety and cost-effectivenessofthissystematicFPstrategyfollowingBOT fertility-sparingsurgeryarerequired.

Funding None.

DeclarationofCompetingInterest Nonedeclared.

References

[1]MoriceP,UzanC,FauvetR,GouyS,DuvillardP,DaraiE.Borderlineovarian tumour:pathologicaldiagnosticdilemmaandriskfactorsforinvasiveorlethal recurrence.LancetOncol2012;13:e103–115.

[2]VasconcelosI,Darb-EsfahaniS,SehouliJ.Serousandmucinousborderline ovariantumours:differencesinclinicalpresentation,high-risk histopatho-logical features, and lethal recurrence rates. Br J Obstet Gynaecol 2016;123:498–508.

[3]TrimbleCL,KosaryC,TrimbleEL.Long-termsurvivalandpatternsofcarein womenwith ovariantumors of lowmalignant potential. GynecolOncol 2002;86:34–7.

[4]SkírnisdóttirI,GarmoH,WilanderE,HolmbergL.Borderlineovariantumorsin Sweden1960–2005:trendsinincidenceandageatdiagnosiscomparedto ovariancancer.IntJCancer2008;123:1897–901.

[5]Lim-TanSK,CajigasHE,ScullyRE.Ovariancystectomyforserousborderline tumors:afollow-upstudyof35cases.ObstetGynecol1988;72:775–81. [6]DaraïE,FauvetR,UzanC,GouyS,DuvillardP,MoriceP.Fertilityandborderline

ovariantumor:a systematicreviewofconservativemanagement,riskof recurrenceandalternativeoptions.HumReprodUpdate2013;19:151–66. [7]HuangJYJ,BuckettWM,GilbertL,TanSL,ChianR-C.Retrievalofimmature

oocytesfollowedbyinvitromaturationandvitriﬁcation:acasereportona newstrategyof fertility preservationinwomenwith borderlineovarian malignancy.GynecolOncol2007;105:542–4.

[8]PorcuE,VenturoliS,DamianoG,etal.Healthytwinsdeliveredafteroocyte cryopreservationandbilateralovariectomyforovariancancer.ReprodBiomed Online2008;17:265–7.

[9]FatemiHM,KyrouD,Al-AzemiM,etal.Ex-vivooocyteretrievalforfertility preservation.FertilSteril2011;95:1787e15–7.

[10]CoboA,García-VelascoJ,DomingoJ,PellicerA,RemohíJ.Electiveand onco-fertility preservation: factors related to IVF outcomes. Hum Reprod 2018;33:2222–31.

[11]DelleMarchetteM,CeppiL,AndreanoA,etal.Oncologicandfertilityimpactof surgicalapproachforborderlineovariantumourstreatedwithfertilitysparing surgery.EurJCancer2019;111:61–8.

[12]TinelliR,TinelliA,TinelliFG,CicinelliE,MalvasiA.Conservativesurgeryfor borderlineovariantumors:areview.GynecolOncol2006;100:185–91. [13]Uzan C, Kane A, ReyA, Gouy S,Duvillard P, MoriceP. Outcomes after

conservativetreatmentofadvanced-stageserousborderlinetumorsofthe ovary.AnnOncolOffJEurSocMedOncol2010;21:55–60.

Table4

Keypoints forpreserving fertility inwomen ofreproductiveage treatedfor borderlineovariantumours(BOTs)

1.Informationshouldbeprovidedtowomenabouttheriskofadecreasein ovarianreserveinducedbysurgicaltreatmentofBOTs

2.Fertilitycounsellingshouldbeofferedsystematicallytowomenof reproductiveagewithBOTs

3.Conservativesurgicaltreatmenthelpstopreservefertilityinwomenwith early-stageBOTsandallowsahighrateofspontaneouspregnancies 4.Duetoahigherriskofrecurrence,conservativesurgicaltreatmentmaylead

torepeatedovariansurgeriesthatjustifyofferingacomplementaryFP technique

5.WhenconservativeBOTtreatmentisindicated,ovarianstimulationshouldbe consideredaftercompleteremovaloftheBOT

6.PerformingoneornumerousCOScyclestocryopreservematureoocytesafter theﬁrstconservativeBOTsurgerymayensureoocytepreservationinthecase ofrecurrence

BOT,borderlineovariantumour;FP,fertilitypreservation;COS,controlledovarian stimulation.

(7)

[14]Palomba S, Zupi E, Russo T, et al. Comparison of two fertility-sparing approachesforbilateralborderlineovariantumours:arandomizedcontrolled study.HumReprod2007;22:578–85.

[15]PalombaS,FalboA,DelNegroS,etal.Ultra-conservativefertility-sparing strategyforbilateralborderlineovariantumours:an11-yearfollow-up.Hum Reprod2010;25:1966–72.

[16]CanlorbeG,LecointreL,ChauvetP,AzaïsH,FauvetR,UzanC.[Borderline ovarian tumours: CNGOF guidelines for clinical practice – therapeutic managementofearlystages].GynecolObstetFertilSenol2020,doi:http:// dx.doi.org/10.1016/j.gofs.2020.01.016.

[17]PergialiotisV,ProdromidouA,FrountzasM,BitosK,PerreaD,Doumouchtsis SK.Theeffectofbipolarelectrocoagulationduringovariancystectomyon ovarianreserve:asystematicreview.AmJObstetGynecol2015;213:620–8. [18]ChevrotA,PougetN,BatsA-S,etal.Fertilityandprognosisofborderline

ovariantumorafterconservativemanagement:resultsofthemulticentric OPTIBOTstudybytheGINECO&TMRGgroup.GynecolOncol2020;157:29–35. [19]MillsM,RindfussRR,McDonaldP,teVeldeE.ESHREReproductionandSociety TaskForce.Whydopeoplepostponeparenthood?Reasonsandsocialpolicy incentives.HumReprodUpdate2011;17:848–60.

[20]GallotD,PoulyJL,JannyL,etal.Successfultransferoffrozen–thawedembryos obtainedimmediatelybeforeradicalsurgeryforstageIIIaserousborderline ovariantumour:casereport.HumReprod2000;15:2347–50.

[21]UzelacPS,DelaneyAA,ChristensenGL,BohlerHCL,NakajimaST.Livebirth followinginvitromaturationofoocytesretrievedfromextracorporealovarian tissue aspiration and embryo cryopreservation for 5 years. Fertil Steril 2015;104:1258–60.

[22]PrasathEB,ChanMLH,WongWHW,etal. Firstpregnancyandlivebirth resultingfromcryopreservedembryosobtainedfrominvitromaturedoocytes afteroophorectomyinanovariancancerpatient.HumReprod2014;29:276–8. [23]FilippiF,MartinelliF,SomiglianaE,FranchiD,RaspagliesiF,ChiappaV.Oocyte cryopreservationintwowomenwithborderlineovariantumorrecurrence.J AssistReprodGenet2020;37:1213–6.

[24]Bocca S, Dedmond D, Jones E, Stadtmauer L, Oehninger S. Successful extracorporealmatureoocyte harvestingafterlaparoscopicoophorectomy followingcontrolledovarianhyperstimulation forthepurposeoffertility preservationinapatientwithborderlineovariantumor.JAssistReprodGenet 2011;28:771–2.

[25]DenschlagD,vonWolffM,AmantF,etal.Clinicalrecommendationonfertility preservationinborderlineovarianneoplasm:ovarianstimulationandoocyte retrievalafterconservativesurgery.GynecolObstetInvest2010;70:160–5. [26]BasilleC,OlivennesF,LeCalvezJ,etal.Impactofgonadotrophinsandsteroid

hormonesontumourcellsderivedfromborderlineovariantumours.Hum Reprod2006;21:3241–5.

[27]RaadJ,RollandL,GrynbergM,CourbiereB,D’argentEM.[Borderlineovarian tumours:CNGOFguidelinesforclinicalpractice–fertility].GynecolObstet FertilSenol2020,doi:http://dx.doi.org/10.1016/j.gofs.2020.01.020.

[28]OktayK,HarveyBE,PartridgeAH,etal.Fertilitypreservationinpatientswith cancer:ASCOclinicalpracticeguidelineupdate.JClinOncol2018;36:1994– 2001.

[29]MangiliG,SomiglianaE,GiorgioneV,etal.Fertilitypreservationinwomen withborderlineovariantumours.CancerTreatRev2016;49:13–24. 6 S.Khiatetal./EuropeanJournalofObstetrics&GynecologyandReproductiveBiology253(2020)xxx–xxx