Murat Akand, Ralf Veys, Dieter Ost, Kathy Vander Eeckt, Frederic Baekelandt, Raf Van Reusel, Pieter Mattelaer, Loic Baekelandt, Ben Van Cleynenbreugel, Steven Joniau et al.
Article https://doi.org/10.3390/cancers16213653
cancers
Article
CohortProfile:VZNKUL–NMIBCQualityIndicatorsProgram: AFlemishProspectiveCohorttoEvaluatetheQualityIndicators intheTreatmentofNon-Muscle-InvasiveBladderCancer
MuratAkand 1,2 ,RalfVeys 3,DieterOst 4,KathyVanderEeckt 4,FredericBaekelandt 5,RafVanReusel 6 , PieterMattelaer 7,LoicBaekelandt 1,2 ,BenVanCleynenbreugel 1,2,StevenJoniau 1,2 andFrankVanderAa 1,2,*
1 DepartmentofUrology,UniversityHospitalsLeuven,3000Leuven,Belgium; murat.akand@uzleuven.be(M.A.);loic.baekelandt@uzleuven.be(L.B.); ben.vancleynenbreugel@uzleuven.be(B.V.C.);steven.joniau@uzleuven.be(S.J.)
2 LaboratoryofExperimentalUrology,Urogenital,AbdominalandPlasticSurgery,Departmentof DevelopmentandRegeneration,KULeuven,3000Leuven,Belgium
3 DepartmentofUrology,AZGroeninge,8500Kortrijk,Belgium;ralf.veys@azgroeninge.be
4 DepartmentofUrology,AZSintBlasius,9200Dendermonde,Belgium;dieter.ost@azsintblasius.be(D.O.); kathy.vandereeckt@azsintblasius.be(K.V.E.)
5 DepartmentofUrology,AZSint-LucasBrugge,8310Brugge,Belgium;f.baekelandt@telenet.be
6 DepartmentofUrology,AZTurnhout,2300Turnhout,Belgium;raf.vanreusel@azturnhout.be
7 DepartmentofUrology,AZOostendeDamiaan,8400Oostende,Belgium;pieter.mattelaer@azoostende.be
* Correspondence:frank.vanderaa@uzleuven.be;Tel.:+32-16-34-69-45;Fax:+32-16-34-69-31
Citation: Akand,M.;Veys,R.;Ost,D.; VanderEeckt,K.;Baekelandt,F.;Van Reusel,R.;Mattelaer,P.;Baekelandt, L.;VanCleynenbreugel,B.;Joniau,S.; etal.CohortProfile:VZNKUL–NMIBCQualityIndicatorsProgram: AFlemishProspectiveCohortto EvaluatetheQualityIndicatorsinthe TreatmentofNon-Muscle-Invasive BladderCancer. Cancers 2024, 16,3653. https://doi.org/10.3390/ cancers16213653
AcademicEditor:KeChen
Received:18September2024
Revised:14October2024
Accepted:22October2024
Published:29October2024
Copyright: ©2024bytheauthors. LicenseeMDPI,Basel,Switzerland. Thisarticleisanopenaccessarticle distributedunderthetermsand conditionsoftheCreativeCommons Attribution(CCBY)license(https:// creativecommons.org/licenses/by/ 4.0/).
SimpleSummary: Bladdercanceristheninthmostcommonlydiagnosedformofcancerinbothsexes worldwideandthefifthinEurope.Themostcommonform,non-muscle-invasivebladdercancer,is highlyprevalentwithhighrecurrenceratesandhaswiderangeofoutcomesthatispartiallydueto thevariabilityinthetreatmentdelivered.Therefore,somerecommendationshavebeendonebythe EuropeanAssociationofUrologytostandardizetheirmanagement.Severalqualitycontrolindicators havebeenproposedtomonitortheadherenceofurologistsandhospitalstotheserecommendations. AqualitycontrolindicatorprogramhasbeeninitiatedinthehospitalsthatareapartoftheFlemish HospitalNetworkinJune2013usingaspecificprospectiveregistry.Wehaverecentlypublishedthe firstanalysisofthesequalitycontrolindicators,whichshowedsignificantdifferencesbetweenthe hospitals.Beforepublishingthesecondanalysiswithmorepatientsandadditionalqualitycontrol indicators,weaimedtodescribethecharacteristicsofthecohortinthisstudy.
Abstract:Purpose: Bladdercancer(BC)isaheterogeneousdiseasewithvaryingoutcomes,influencedbydiseaseheterogeneityandvariabilityintreatmentandfollow-up.Riskgroupshavebeen establishedfornon–muscle-invasiveBC(NMIBC)tostandardizetherapy,andseveralqualitycontrol indicators(QCIs)monitoradherencetotheseriskgroup-basedguidelines.However,controversial resultshadbeenobtainedregardingtheoncologicalbenefitsoftheseQCIsuntilrecenthigh-quality studiesfromlargeregistriesshowedtheirusefulness.ToimproveadherencetotheEuropeanAssociationofUrology(EAU)GuidelinesandbenchmarkcurrentcareinFlemishhospitalswithinVlaams Ziekenhuisnetwerk–KULeuven(VZNKUL),aQCIprogramforNMIBCwasinitiatedin2013.This studyaimstodescribethedemographic,clinical,andtreatmentdataofpatientsenrolledinthis program. Participants: TheVZNKUL–NMIBCQualityIndicatorsProgramRegistryisaprospective cohortincludingpatientstreatedandfollowedupwithatsevenacademicandnon-academicFlemish hospitalssinceJune2013.Datacollectionincludespatientcharacteristics,tumordata,treatment, andoncologicaloutcomes. Findingstodate: FromJune2013toDecember2020,4744transurethral resectionsofbladdertumors(TURBTs)from2237uniquepatientswereanalyzed.Mostpatients(80%) weremenwithamedianageof73.ThemediantimefromdiagnosistoTURBTwas19days.Asingle tumorwasdetectedin37%ofTURBTs.Tumorslargerthan3cmwerefoundin20.8%ofcases.In 46%ofTURBTs,areTURBTwasscheduledaccordingtoguidelines.Thecomplicationrateswere 7.5%and2.4%forbladderperforationandbleeding,respectively.Postoperativesingleintravesical instillationofchemotherapy(SIVIC)wasadministeredto56.9%of1533indicatedpatientswitha
mediantimetoadministrationof4.7h.Amongthecohort,60.4%hadNMIBC,and9.3%hadmuscleinvasiveBC.Of972high-riskpatients,60.7%receivedadequateBCGinduction,while39.4%received adequatemaintenance.AfterBCGinduction ± maintenance,39.7%weretumor-free,with17.7% recurrenceand4%progressiontomuscle-invasiveBC.BCGtreatmentwasterminatedearlyfor17% ofpatientsduetointolerance.Earlycystectomywasperformedfor2.4%oftheBCG-naïvepatients, and27.7%ofpatientswithBCGfailureunderwentaBCGrechallenge.Forintermediate-riskpatients, 2.1%receivedadequateBCG,and23%receivedintravesicalchemotherapy.Themedianfollow-up was57months.Five-yearrecurrence-free,progression-free,cancer-free,overall,andcancer-specific survivalrateswere53%,91.6%,89%,70.6%,and95.6%,respectively,fortheNMIBCpatients.Of 400non-metastaticMIBCpatients,217(54.3%)underwentradicalcystectomy(RC),ofwhom46% receivedneoadjuvantchemotherapy,while18(4.5%)refusedRC,and74(18.5%)wereconsidered unfitforthesurgery. Futureplans: TheVZNKUL–NMIBCQualityIndicatorsProgramRegistry willcontinuecollectingdatatoevaluateQCIsandmonitortreatmentquality,enablinghospitalsto benchmarktheirperformanceandimprovepatientcare.Additionally,theregistry’sreal-worlddata cansupportresearchandinternationalcollaboration. Trialregistration: Thestudywasregisteredon ClinicalTrials.gov(NCT04167332).
Keywords: bladdercancer;non-muscle-invasive;registry;qualityindicator;recurrence;progression; prospective;survival;treatment
1.Introduction
Bladdercancer(BC)istheninthmostcommonlydiagnosedformofcancerinboth sexesworldwideandthefifthinEurope[1,2].InBelgium,2364newcasesofBCwere diagnosedin2013,whichisexpectedtoriseto2900by2025[3].Asimilaranticipationhas beenexpressedbytheWorldHealthOrganization(WHO),suggestingthatthenumber ofBCcasesanddeathswouldalmostdoubleinthenearfuture,paralleltotheincrease inlifeexpectancy[4].AlthoughBCismorecommonlyseenin(predominantlywhite) males,females,andBlackindividualsaremorefrequentlydiagnosedwithadvanced-stage disease[5,6].MostBCcasesareurothelialcarcinoma(UC)insubtype,andapproximately 75%ofthesearenon–muscle-invasiveBC(NMIBC).Thediseaseishighlyprevalentdue toitsindolentnaturalhistoryandhighrecurrencerate[7].MostBCcasesareassociated withexternalriskfactors,ofwhichapproximately50%arecausedbytobaccosmoking.At thesametime,occupationalcarcinogenexposureisasignificantriskfactorforasubsetof patients,especiallyinindustrializedcountries[8].
Eventhoughourinsightintothisdisease’smolecularmechanism(s)hasincreased significantlyinthelastdecade,muchisstillunknownaboutthiscomplexdisease.Itswide rangeofoutcomesisattributedtotheintrinsicdiseaseheterogeneityandthevariabilityin deliveredtreatmentandfollow-up.Tostandardizetherapybasedontheriskofdisease recurrenceand/orprogression,severalprognosticmodelshavebeendeveloped.The EuropeanAssociationofUrology(EAU)hasproposedcategorizingpatientsintofourrisk groups:low-,intermediate-,high-,andveryhigh-risk[9–12].Utilizingthisprognostic riskstratification,theEAUGuidelinesOfficehaspublisheditsrecommendationsforthe diagnosis,treatment,andfollow-upofNMIBCpatients[7].Despitetheseguidelines,it hasbeenconsistentlyobserved,bothinEuropeandglobally,thatadherencetotherecommendedguidelinesissuboptimal[13–18].Furthermore,theefficacyoftheseguidelinesin improvingoncologicaloutcomeshasnotbeenwidelydemonstrated.Someretrospective studieshavereportedthatadherencetoguideline-recommendedpractices,suchassecond transurethralresectionofthebladdertumor(TURBT),adjuvantbacillusCalmette–Guérin (BCG)maintenancetreatment,andregularcystoscopicsurveillance,significantlyimpacts recurrence-freesurvival(RFS)andrecurrence/progressionrates[15,19,20].Recently,Mariappanetal.publishedresultsfromtheScottishBladderCancerQualityPerformance IndicatorsInfluencingOutcomes,PrognosisandSurveillance(ScotBCQualityOPS)project,
whichdemonstratedforthefirsttimethatachievingpredefinedqualitycontrolindicator(QCI)targetsinbenchmarkingcentersreducedrecurrenceandprogressionratesin NMIBC[21].
AQCIprogramspecifictoNMIBCwasinitiatedatthreeFlemishhospitals,with aspecificregistryestablishedinJune2013,aimingtoincreaseadherencetotheEAU Guidelinesandtobenchmarkthecurrentstandardofcareatthehospitalsaffiliatedwith VlaamsZiekenhuisnetwerk–KULeuven(VZNKUL;FlemishHospitalNetwork)[22].Since then,patientsundergoingTURBThavebeenprospectivelyregisteredinthisdatabase acrosssevenparticipatinghospitalswith,onaverage,morethan700TURBTSformorethan 600uniquepatientsperyearduringthelastfiveyears.Apartfromincreasingadherenceto theEAUGuidelinesandbenchmarkingtheparticipatinghospitals,thisQCIprogramalso aimstofindanswerstoseveralresearchquestions,suchasthoseconcerningtheeffectof guidelineadherenceonrecurrence/progressionratesandsurvivaloutcomesandreasons fornon-compliance.ThefirstanalysisofsixQCIs(completeresection[CR]status,presence ofdetrusormuscle[DM]inthespecimen,postoperativesingleintravesicalinstillationof chemotherapy[SIVIC],repeatTURBT[reTURBT],startofBCGinductiontherapy,and performingTURBTwithinsixweeksafterdiagnosis)fromthefirstthreeparticipating hospitalswasrecentlypublished.Thisanalysisrevealedthatthequalityofreportingand compliancewiththeseQCIsweresuboptimal,withsignificantvariabilitybetweencenters. Moreover,postoperativeSIVICcorrelatedwithRFS[23].
Inthisarticle,wedescribetheVZNKUL–NMIBCQualityIndicatorsProgramcohort andreportonpatientandtumorcharacteristicsatenrollment,surgicaltreatmentinformation,adjuvanttherapypatterns,follow-up,andsurvivalinformationpriortopublishingthe secondanalysisonQCIs.Thisstudywillrevealcomprehensiveinsightsintopatientand treatmentcharacteristicswithreal-worlddatabeforeanalyzingtheguidelinesadherence andtheirimpactondiseaseoutcomes.
2.CohortDescription
Thisprospectiveregistrystartedatoneacademicandtwonon-academichospitalsin Flanders,utilizingaspecificallydevelopedelectroniccasereportform(eCRF)forTURBT. ThiseCRFwasembeddedintheelectronicpatientfilesystemknownasKlinischWerkstation(KWS).Theregistryprotocolwasapprovedbytheinstitutionalreviewboard(Clinical TrialsCenterUZLeuven)inJune2013,anditwasapprovedbytheEthicsCommittee ResearchUZ/KULeuvenafterseveralamendments(approvalnumber:S55725,approval date:6June2014).Writteninformedconsentwasobtainedfromeveryincludedpatient. ThisregistryhasbeenregisteredatClinicalTrials.gov(NCT03973671),andthedetailsofits developmenthavebeenpreviouslypublishedelsewhere[22].Toencompassmoreaspects ofthemanagementofNMIBCpatients,threeadditionaleCRFshavebeenimplemented(for bladderinstillations,follow-up,andmultidisciplinaryteammeetings[MDT]).Thenumber ofparticipatinghospitalshasincreasedtoseven.Theselectionofthecenterswasvoluntary, anditdependednotonthevolumeofTURBTstheyperformedbutontheirwillingnessto participateandusetheeCRFs.Thisapproachensuredcoverageacrossbothacademicand non-academic,aswellaslow-andhigh-volume,centers.
ThenumbersofTURBTs,bladderinstillations,follow-ups,MDTs,anduniquepatients sincetheinceptionofeachformarelistedinSupplementaryTablesS1–S4,categorized peryearandcenter.Thesedatademonstrateanincreaseinthenumberofregistered proceduresandpatientsovertime,attributabletothegrowingnumberofparticipating centersandimprovedcompliancewithusingtheeCRFs.Aimingtoincreasethequality ofcareandprovideabenchmarkforparticipatingcenters,thisprogramwillcontinue indefinitely,contingentonthevoluntaryparticipationofthecenters.Here,wereport onpatientsregistereduptotheendof2020inordertoachieveconcordancewiththe upcomingnewanalysesonQCIs.Additionally,reTURBTsforthesepatientsuptothe pointofdataextractionhavebeenincludedtoprovidemoreinsightintotheirlongitudinal diseasetrajectory.
2.1.DemographicandMedicalHistoryInformation
Whilereportingonthecohort,wegroupedtheNMIBCpatientsaccordingtotherisk stratificationoutlinedintheEAU2019Guidelines(low-,intermediate-,andhigh-risk). Atsomepoints,thehighest-risksubgroupwithinthehigh-riskgroupwasspecifically highlighted[24].Patientsdiagnosedwithmuscle-invasivebladdercancer(MIBC)were presentedasaseparategroup.Patients’ageswererecordedatthetimeofthefirstregistered TURBT.TheAmericanSocietyofAnesthesiologists(ASA)scoreonphysicalstatuswas manuallyretrievedfromtheanesthesiologyreportofthefirstregisteredTURBT(from availablepatients).TheCharlsoncomorbidityindex(CCI)atthetimeofthefirstregistered TURBTwaseitherretrievedfromtheMDTform(forthecentersusingthiseCRF)ormanuallycalculatedbythoroughlyevaluatingpatients’electronicmedicalrecords.Smoking statusandhistoryofpelvicradiotherapyweremanuallyextractedfrompatients’electronic medicalrecords.Patientswhohadceasedsmokingatleastsixmonthsbeforethefirst registeredTURBTwerecategorizedasformersmokers.
2.2.SurgicalandAdjuvantTreatmentInformation
Macroscopictumorcharacteristicsandsurgicaldatawereretrievedautomatically fromthesurgeryform,whichallcentersused.Pathologicaldatawereretrievedeither fromtheMDTform(forthecentersusingthiseCRF)ormanuallyfromthepathology reportsofeachTURBT.TumorstageandgradewerereportedusingtheAmericanJoint CommitteeonCancer(AJCC)Tumor-Node-Metastasis(TNM)staging(8thedition)andthe WHOclassification(1973and/or2004/2016),respectively.Dataonadjuvantintravesical treatments(BCGandchemotherapy)wereeitherretrievedfromtheinstillationforms(for thecentersusingthiseCRF)ormanuallyfrompatients’follow-upfiles.AdequateBCG exposurewasdefinedaccordingtotheFoodandDrugAdministration(FDA)criteria, whichspecifyatleastfiveoutofsixinstillationsoftheinductioncourseplusatleasttwo outofthreeinstillationsinthefirstcycleofmaintenancetherapyoratleastfiveoutofsix instillationsofinitialinductioncourseplusatleasttwooutofsixinstillationsofthesecond inductioncourse[25].ThecategoriesofBCGfailureweredefinedaccordingtotheEAU GuidelinesasBCG-refractorytumor,BCG-relapsingtumor,BCG-unresponsivetumor,BCG intolerance,andMIBC[24].Forpatientswithrecurrenthigh-risktumors,wepragmatically establishedinclusion/exclusioncriteriatodecidewhetherthatrecurrencecouldbeused fortheBCG-relatedanalyses.PatientswhohadreceivedatleastadequateBCGtreatment afterahigh-risktumorepisodeandremainedtumor-freeforatleasttwoyearsfromthe completionordiscontinuationofBCGtreatmenttillrecurrencewereconsiderednew casesfortheanalysis.Conversely,patientswhodidnotreceiveorreceivedinadequate BCGinstillationswerere-includedintheanalysisiftheyexperiencedahigh-risktumor recurrencewarrantingBCGtreatmentatleastoneyearafterthediscontinuationofBCGor thedetectionoftheirprevioustumor.Wealsoadoptedapragmaticstratificationofdisease outcomesfornon-BCG-treatedpatientstoreflectpatientoutcomesbetter.Thisincludedthe followingcategories:norecurrence,low-grade(LG)recurrence(TaLGtumors),high-grade (HG)recurrence(TaHGandTistumors),T1tumors(representingtumorupstagingfor TaLG,TaHG,andTis),muscle-invasivedisease,andmetastaticdisease.Allotherdata parametersreportedherewereautomaticallyretrievedfromtheregistry’seCRFs.
2.3.Follow-UpandSurvivalInformation
RecurrencewasdefinedasthereappearanceofatumorofanyT-stageandgrade, whileprogressionwasdescribedasatumorwithaT-stageofatleastT2ormetastatic disease.PatientsarebeingfollowedupwithaccordingtothemostrecentEAUGuidelines recommendationsrelevanttotheirriskgroups.ThetimebetweenthedatesofTURBT andrecurrenceatthelevelofsurgicalinterventionwasdefinedasRFS.Caseswithout recurrencewerecensoredatthetimeofthenextTURBT(reTURBT)orthelastfollow-up. ThetimebetweenthedateofthefirstTURBTandthedatesofprogression,cystectomy,and deathfromanycausewerecalculatedasprogression-freesurvival(PFS),cystectomy-free
survival(CFS),andoverallsurvival(OS),respectively.Theseweredefinedatthepatient level.Caseswithouttherespectiveeventswerecensoredatthelastfollow-up.Cancerspecificsurvival(CSS)wasthetimebetweenthedateofthefirstTURBTandthedateof deathduetoBC,alsodefinedatthepatientlevel.Deathfromothercauseswastreatedasa competingevent,andpatientswhowerealivewerecensoredatthelastfollow-up.
2.4.StatisticalAnalysis
Kaplan–MeierestimateswereusedtoconstructPFS,CFS,andOScurves.ThecumulativeincidencefunctionwasusedforCSS.SurvivalcurvesforRFSwerederivedfroma CoxmodelusingtherobustsandwichestimateofLinandWeitoaccountfortheclustering ofinterventionsamongpatients[26].Continuousvariablesweresummarizedasthemedianandinterquartilerange(IQR),andcategoricalvariableswereshownasthefrequency count(n)andpercentage.AnalyseswereperformedusingSASsoftware(SASSystemfor Windows,version9.4,SASInstituteInc.,Cary,NC,USA).
3.FindingstoDate
3.1.PatientCharacteristics
Afterexcludingsurgeriesperformedforpalliativepurposes(forpatientswithmetastatic diseaseorthoseunabletoundergoradicalcystectomy[RC]),bladdertumorsotherthan UC,otherpelviccancers,andbenignconditions,atotalof4744TURBTsfor2237unique patientswereanalyzed(Figure 1 andSupplementaryTableS5).Approximately80%of thepatientsweremen,and70%wereeitheractiveorformersmokers.Themedianageat thefirstregistrationwas73years(range:29–101),with62.7%ofthepatientsolderthan 70years.AllpatientcharacteristicsarepresentedinTable 1
Figure1. FlowchartoftheincludedandexcludedTURBTs/patients.
Table1. Patientcharacteristics.
Allvaluesaregivenas n (%),otherwisementioned.ASA:AmericanSocietyofAnesthesiologists;BCG:bacillus Calmette–Guérin;CCI:Charlsoncomorbidityindex;IQR:interquartilerange;UTUC:uppertracturothelialcarcinoma.
3.2.SurgicalCharacteristics
AmongtheanalyzedTURBTs,1702wereperformedasthefirstTURBTforaprimary tumor,while528werereTURBTforpatientsregisteredforthefirsttime.Together,for primaryandrecurrenttumors,themediantimefromdiagnosistoTURBTwas19days,and themedianoperationdurationwas20min.Remarkably,visualenhancementtechniques (suchasbluelightfluorescenceornarrow-bandimaging)wereusedinonlyapproximately 10%oftheoperations.Ofthe1146indicatedTURBTs,reTURBTwasplannedfor527(46%) cases,ofwhich91.2%couldbeperformed.Thecomplicationratesof7.5%and2.4%for bladderperforationandbleeding,respectively,wereconsistentwiththeliteraturedata.Out of1533indicatedpatients,postoperativeSIVICwasrequestedfor62.4%,ofwhom56.9% receivedit.Themediantimefromrequesttoreceiptwas282min(4.7h;IQR:3.2–7.8h). Otherperi-operativecharacteristicsarepresentedinTable 2.Thereasonsfornotrequesting postoperativeSIVICin32.6%oftheindicatedpatientsarelistedinTable 3.Asignificant majorityofthecases(86.9%)werediscussedatanMDT.
Table2. Peri-operativecharacteristics.
TimefromDxtoTURBT (days)
median(IQR)(min–max)
Operationduration (minutes) median(IQR)(min–max)
Useofvisualenhancement
Total n =4744
19(10–37) (0–375)
20(15–30) (1–301)
No423189.2% Yes,Hexvix4699.9% Yes,NBI140.3% Unknown300.6%
Macroscopicalappearanceoftumor Superficial397683.8% Invasive61913% NK/NR1493.2%
Macroscopicallycompleteresection a No2187.4% Yes267491% NK/NR/NA471.6%
Table2. Cont.
reTURBTplanned b
c
PostoperativeSIVIC_requested d
PostoperativeSIVIC_ordered d
PostoperativeSIVIC_received d
TimetoSIVIC e (minutes) median(IQR)(min–max)
TimefromTURBTtoPR f (days) median(IQR)(min–max) 5(3–7) (1–64)
CasesdiscussedinMDT g 287586.9%
TimefromTURBTtoMDT h (days) median(IQR)(min–max) 12(7–19) (1–139)
TimefromPRtoMDT i (days) median(IQR)(min–max) 7(3–12) (0–134)
Follow-uptime (months) median(IQR)(min–max) 57(35–83) (0–136)
Allvaluesaregivenas n (%),otherwisementioned.Dx:diagnosis;IQR:interquartilerange;max:maximum; MDT:multidisciplinaryteammeeting;min:minimum;NA:notapplicable;NBI:narrow-bandimaging;NK:not known;NR:notreported;PR:pathologyreport;reTURBT:repeatTURBT;SIVIC:singleintravesicalinstillationof chemotherapy;TURBT:transurethralresectionofthebladdertumor. a Total n =2939(TURBTswithT0,Tx,Tis, ≥T2,andinconclusiveresultandreTURBTsforadrandombiopsy,scartissue,andnodetrusormuscleinprevious TURBTexcluded). b Total n =1146(TURBTswithincompleteresection,macroscopicallyinvasivetumor,no urothelialcarcinoma,historyofhigh-risktumor/BCGinstillationandreTURBTsforadrandombiopsy,scartissue, andnodetrusormuscleinpreviousTURBTexcluded). c Total n =527(TURBTswithaplannedreTURBT,outof 1146TURBTswithareTURBTindication). d Total n =1533(TURBTswithincompleteresection,macroscopically invasiveappearance,suspicionofnotumor,historyofprevioushigh-gradetumorand/orBCGinstillationand reTURBTsforadrandombiopsy,scartissue,andnodetrusormuscleinpreviousTURBTexcluded). e Total n =673 (forthehospitalswithavalueofNA,datawereavailableforonlyfewerthanfivepatientspercenter;therefore, notcalculated). f Total n =4259(TURBTswithoutavailabledataexcluded). g Total n =3011(TURBTswithT0,Tx, Tis,inconclusiveresult,andnoPRexcluded). h Total n =2872(TURBTswithoutavailabledataexcluded). i Total n =2839(TURBTswithoutavailabledataexcluded).
Table3. ReasonsfornotrequestingpostoperativeSIVIC. Reasons
Allvaluesaregivenas n (%).MMC:MitomycinC;SIVIC:singleintravesicalinstillationofchemotherapy;TURP: transurethralresectionoftheprostate.
3.3.TumorCharacteristics
ThemediannumberoftumorsresectedperTURBTwastwo,with37%oftheTURBTs havingasingletumorand20.8%exceeding3cmintheirlargestdimension.Thetumors weremainlylocatedonthelateralwallsofthebladder(19.9%forboththeleftandright sides),whiletheinvolvementoftheprostaticlogeoccurredonlyin3.2%ofcases.An NMIBC(Tis,Ta,andT1)wasdetectedin60.4%oftheTURBTs,whileMIBCwaspresent in9.3%.TheWHO2004/2016tumorgradingsystemwasmorefrequentlyusedthanthe WHO1973system,with27.2%oftumorsclassifiedasHGtumorsundertheWHO2004/2016 system.Bothgradingsystemswereappliedtoonly25%of3311indicatedTURBTs.Ten (2.3%)muscle-invasivetumorsand59(8.7%)T1tumorswereclassifiedaseitherLGor grade1/2.ThedistributionofthetumorsaccordingtotheEAUriskstratificationwas7.9%, 44%,31.3%,and16.8%forlow-,intermediate-,high-,andhighest-risktumors.Patients werecategorizedinthesameriskgroupsaccordingtotheirfirstregisteredTURBTin14.3%, 36.9%,28.6%,and20.3%,respectively.DMwassampledin66.9%oftheindicatedTURBTs. Concomitantcarcinomainsitu(CIS)andlymphovascularinvasion(LVI)werereportedin 10.3%and2.8%ofthetumors,respectively.Varianthistologywasdetectedin9.7%ofthe tumors,withsquamous,glandular,andmicropapillarybeingthemostcommon.Further detailsontumorcharacteristicsandthedistributionofthevarianttypesarelistedinTable 4 andSupplementaryTableS6,respectively.
Table4. Clinicalandhistopathologicaltumorcharacteristics.
Total n =4744
Tumorsize ≤1cm126526.6% 1–3cm128027%
Tumornumber median(IQR)(min–max) 2(1–3) (1–50)
Tumormultiplicity
Tumorlocalization a
Totaltumornumberperlocalization a
Base b 97613.4%
Posteriorwall120116.5%
Dome89912.3%
Anteriorwall3314.5%
Leftwall144719.9%
Rightwall144819.9%
Bladderneck74910.3%
Prostaticloge2343.2%
Base b 151413%
Posteriorwall203017.4%
Dome169614.5%
Anteriorwall5955.1%
Leftwall211218.1%
Rightwall228319.5%
Bladderneck11079.5%
Prostaticloge3422.9%
Tumorshape NK/NR/NA88718.7% Pws1282.7% Pbb/N/S328369.2% Flat4469.4%
Tumorgrade(WHO1973)
Tumorgrade(WHO2004/2016)
PRswithbothgradingsystems d
Tumor-gradereporting e
Riskstratification(atTURBTlevel) g
Riskstratification(atpatientlevel) h Low-risk25914.3% Intermediate-risk67036.9% High-risk52028.6% Highest-risk36820.3%
ConcomitantCISpresent i 30910.3%
Detrusormuscleinspecimen j Notpresent33821.1% Present106966.9%
Table4. Cont.
Allvaluesaregivenas n (%),otherwisementioned.CIS:carcinomainsitu;IQR:interquartilerange;G:grade; HG:highgrade;LG:lowgrade;LVI:lymphovascularinvasion;max:maximum;min:minimum;N:nodular tumor;NA:notapplicable;NK:notknown;NR:notreported;Pbb:papillarytumor,broad-based;PR:pathology report;PUNLMP:papillaryurothelialneoplasmoflowmalignantpotential;Pws:papillarytumorwithstalk; S:sessiletumor;WHO:WorldHealthOrganization. a Total n =4017(reTURBTsforadrandombiopsy,scar tissue,incompletepreviousTURBT,andnodetrusormuscleinpreviousTURBTexcluded). b Baseincludestrigon andureterorifices. c Inconclusiveincludesbiopsy/coagulationartifactandnoviabletissue/mucosa. d Total n =3311 (TURBTswithT0,inconclusiveresult,andnoPRexcluded). e Total n =2866(TURBTswithT0,Tx, ≥T2, inconclusiveresult,andnoPRexcluded). f OnlytheWHO1973gradingsystemwasused(fortheothers,both gradingsystemswereused). g Total n =3294(TURBTswithT0,Tx, ≥T2,andinconclusiveresultexcluded). h Total n =1817(accordingtothefirstregisteredTURBT,patientswithT0,Tx, ≥T2,andinconclusiveresultexcluded). i Total n =3011(TURBTswithT0,Tx,Tis,inconclusiveresult,andnoPRexcluded). j Total n =1599(TURBTs withT0,Tx,Tis,TaLG/G1-2,inconclusiveresult,andnoPRandreTURBTsforadrandombiopsyandscartissue excluded). k Total n =3305(TURBTswithT0,Tx,inconclusiveresult,andnoPRexcluded). l Total n =1643 (TURBTswithT0,Tx,Tis,TaLG/G1-2,inconclusiveresult,andnoPRexcluded).
3.4.AdjuvantSurgicalandIntravesicalTreatmentCharacteristics
Of76TaHGtumorsforwhichareTURBTwasperformed,residual TaHG,TaLG,andTis tumorsweredetectedin14(18.4%),8(10.5%),and7(9.2%)cases,respectively.Additionally, 46(60.5%)weretumor-free(T0),and1(1.3%)casewasupstagedtoT1disease.Of251T1 tumorsthatunderwentreTURBT,residualT1,TaHG,TaLG,and Tistumorsweredetected in51(20.3%),23(9.2%),16(6.4%),and32(12.7%)specimens,respectively.UpstagingtoT2 diseasewasobservedin23(9.2%)cases,and106(42.2%)were tumor-free(T0)(Figure 2).
Figure2. DistributionofthepathologicalresultsofthereTURBTsperformedforTaHG(n =76)and T1(n =251)tumors(madeat SankeyMATIC.com).HG:highgrade;HR:high-risk(todefinethepart ofthetumorgroupforwhichreTURBTwasperformed);LG:lowgrade.
Of972patientsforwhomhigh-riskBCGwasindicated(Tis,TaHG,T1),BCGinduction wasplannedfor79%,and60.7%underwentadequateBCGinduction.Maintenancetherapy wasplannedfor45.2%ofthesepatients,with39.4%receivingadequateBCGmaintenance. Thedistributionofpatientsreceiving1-,2-,and3-yearmaintenancetherapywas14.9%, 6.5%,and3%,respectively.Only7.4%ofallBCG-indicatedHRpatientsreceivedintravesicalchemotherapy(mainlyMitomycinC),primarilyduetoineligibilityforBCGdue tointoleranceorcomorbiditiesandalsoinfluencedbyrecentBCGshortages.Detailed informationaboutadjuvantintravesicaltreatmentsispresentedinTable 5 andFigure 3.
Table5. AdjuvantintravesicaltreatmentstatusofBCG-indicatedtumors.
Allvaluesaregivenas n (%). a 2-year:maintenancemorethan1yearbutlessthanorequalto2years. b 3-year: maintenancemorethan2yearbutlessthanorequalto3years. c Onlyforintermediate-risktumors.BCG:bacillus Calmette-Guérin,HG:highgrade,HR:high-risk,IR:intermediate-risk.
AfterBCGinductionwithorwithoutmaintenancetreatment(completedprotocolor not),26%ofthepatientsachievedsuccessfuloutcomes.Thissuccessrateincreasedto39.7% whenpatientswhoexperiencedintolerancewithoutrecurrencewereincluded,withhigher ratesobservedintheTisgroup(47.4%)comparedtootherriskgroups.While17.7%of thepatientsexperiencedrecurrence(refractoryorrelapsing),progressiontoMIBCwas observedin4%ofpatientsandmetastaticdiseasein0.9%.Meanwhile,intoleranceledtoan earlyterminationoftreatmentfor17%ofpatients.ThemanagementofHRtumorsandthe resultsofintravesicalBCGinstillationsforeachgroupandintotalaredetailedinTable 6 andFigure 3.EarlyRCwasperformedfor2.4%ofBCG-naïvetumors,withthehighest rateseeninTistumors(5.9%),typicallywithinamediantimeof40daysfromthedecision takenattheMDTtoperformsurgery.Remarkably,intravesicalchemotherapywasutilized morethantwiceasfrequentlyforTaHGtumorscomparedtoT1tumorsandnearlythree timesasfrequentlycomparedtoTistumors.
EarlyRC(45%)andBCGrechallenge(26.5%)werethetwomostfrequentlychosen managementoptionsafterBCGfailure.However,outof99patientsforwhomRCwas planned,72(72.7%)underwentsurgery(withamediantimeof48daysfromMDTto surgery).ThereasonsfornotproceedingwithRCincludedpatientrefusalin9(9.1%) cases,medicalunfitnessin16(16.2%),andthedetectionofmetastasisduringstagingor progressionduringneoadjuvantchemotherapy(NAC)in2(2%)cases.BCGrechallenge wasparticularlyfavoredforTispatients.Furtherdetailsregardingthemanagementof patientswithBCGfailurearesummarizedinTable 7
Cont.
Cont.
Cont.
Figure3. SankeydiagramsshowingtheproportionsoftheadjuvantBCGinstillationsandtheresultsofBCGtreatmentfor(a)BCG-indicatedT1tumors(n =478),(b) BCG-indicatedTaHGtumors(n =376),(c)BCG-indicatedTistumors(n =118),and(d)BCG-indicatedallHRtumors(n =972)(madeat SankeyMATIC.com).AIC: adjuvantintravesicalchemotherapy;BCG:bacillusCalmette–Guérin;eRC:earlyradicalcystectomy;HG:highgrade;HR:high-risk;induc:induction;LG:lowgrade; maint:maintenance;MIBC:muscle-invasivebladdercancer;Pt:patient;w/:with;w/o:without.
T1( n =478)
TaHG( n =376)
Tis( n =118)
AllHRtumors( n =972)
Table6. Managementofhigh-risktumorsandresultsofintravesicalBCGtreatments.
BCGResult AdequateBCG 214(44.8%) Nomaint. 113(23.6%)
Success95 (19.8%) 24(5%)
BCGinductionnotplanned/notreceived 151(31.6%)
AIC(23;4.9%) NT(114;23.8%) eRC(14;2.9%)
Intolerancew/orecurrence58 (12.1%) 16(3.4%)Norecurrence9(2%)56 (11.8%) 11(2.3%)
Intolerancew/recurrence10(2.1%)9(1.9%)
TaLG1(0.2%)13(2.8%)-Refractory25(5.2%)37(7.7%)TaHG1(0.2%)8(1.6%)-Relapsing5(1.1%)--Tis2(0.4%)8(1.6%)-MIBC8(1.7%)22(4.6%)T15(1.1%)8(1.6%)-Metastasis5(1.1%)2(0.4%)MIBC4(0.8%)13(2.8%)-Patientdied a 8(1.7%)3(0.6%)Metastasis1(0.2%)8(1.6%)3(0.6%)
BCGresult AdequateBCG 114(30.3%) Nomaint. 87(23.1%)
Success55 (14.6%) 41 (10.9%)
Recurrence
BCGinductionnotplanned/notreceived 175(46.5%)
AIC(43;11.5%) NT(130;34.6%) eRC(2;0.5%) Intolerancew/orecurrence33(8.8%)8(2.1%)Norecurrence17(4.5%)43 (11.4%) 2(0.5%)
Intolerancew/recurrence6(1.6%)3(0.8%)
TaLG7(1.9%)28(7.5%)-Refractory7(1.9%)25(6.7%)TaHG3(0.8%)33(8.8%)-Relapsing7(1.9%)6(1.6%)Tis10(2.7%)6(1.6%)-MIBC3(0.8%)2(0.5%)T13(0.8%)8(2.1%)-Metastasis--1(0.3%)MIBC3(0.8%)10(2.7%)-Patientdied a 3(0.8%)1(0.3%)Metastasis--2(0.5%)--
BCGresult AdequateBCG 55(46.6%) Nomaint. 40(33.9%)
Success24 (20.3%) 14 (11.9%)
Recurrence
BCGinductionnotplanned/notreceived 22(18.6%)
AIC(5;4.2%)NT(10;8.4%)eRC(7;5.9%)
Intolerancew/orecurrence17 (14.4%) 1(0.8%)Norecurrence1(0.8%)4(3.4%)7(5.9%)
Intolerancew/recurrence2(1.7%)2(1.7%)
TaLG1(0.8%)1(0.8%)-Refractory4(3.4%)14 (11.9%) TaHG-----Relapsing4(3.4%)6(5.1%)Tis1(0.9%)3(2.5%)-MIBC2(1.7%)2(1.7%)T12(1.7%)---Metastasis--1(0.8%)MIBC--2(1.7%)-Patientdied a 2(1.7%)--Metastasis------
BCGresult AdequateBCG 383(39.4%) Nomaint. 240(24.7%)
Success174 (17.9%) 79(8.1%)
Recurrence
BCGinductionnotplanned/notreceived 348(35.8%)
AIC(71;7.3%) NT(254;26.1%) eRC(23;2.4%)
Intolerancew/orecurrence108 (11.1%) 25(2.6%)Norecurrence27(2.8%)103 (10.6%) 20(2.1%)
Intolerancew/recurrence18(1.9%)14(1.4%)
TaLG9(0.9%)42(4.3%)-Refractory36(3.7%)76(7.8%)TaHG4(0.4%)41(4.2%)-Relapsing16(1.7%)12(1.2%)Tis13(1.4%)17(1.8%)-MIBC13(1.3%)26(2.7%)T110(1%)16(1.6%)-Metastasis5(0.5%)4(0.4%)MIBC7(0.7%)25(2.6%)-Patientdied a 13(1.3%)4(0.4%)Metastasis1(0.1%)10(1%)3(0.3%)
Recurrence
Allvaluesaregivenas n (%).PercentagesarecalculatedaccordingtothenumberofallBCG-indicatedpatients ineachgroupandintotal.Somepercentagesarerounded. a Patientdiedduringthetreatment.AIC:adjuvant intravesicalchemotherapy,BCG:bacillusCalmette-Guérin,eRC:earlyradicalcystectomy,HG:highgrade,HR: high-risk,LG:lowgrade,MIBC:muscle-invasivebladdercancer,NT:nottreated,w/:with,w/o:without.
T1
n=116
TaHG
n=59
Tis
n=36
All tumors n=211
Table7. Furtherfirst-linemanagementofpatientswithBCGfailure.
Intolerancew/rec.19(15.3%)3(15.8%)4(21.1%)1(5.2%)3(15.8%)8(42.1%)
Refractory62(53.4%)12(19.4%)18(29%)3(4.8%)-29(46.8%)
Relapsing5(4.2%)1(20%)2(40%)--2(40%)
MIBC30(27.1%)5(16.7%)---25(83.3%)
Intolerancew/rec.9(14.3%)5(55.6%)1(11.1%)--3(33.3%)
Refractory32(57.1%)7(21.8%)12(37.5%)2(6.3%)-11(34.4%)
Relapsing13(20.7%)9(69.2%)1(7.7%)--3(23.1%)
MIBC5(7.9%)2(40%)---3(60%)
Intolerancew/rec.4(10.3%)1(25%)3(75%)---
Refractory18(43.6%)1(5.9%)10(58.9%)-1(5.9%)6(29.4%)
Relapsing10(35.9%)3(30%)5(50%)--2(20%)
MIBC4(10.3%)1(25%)---3(75%)
Intolerancew/rec.32(14.1%)9(28.1%)8(25%)1(3.1%)3(9.4%)11(34.4%)
Refractory112(52.7%)20(17.8%)40(35.7%)5(4.5%)1(0.9%)46(41.1%)
Relapsing28(14.6%)13(46.3%)8(28.6%)--7(25%)
MIBC39(18.6%)8(20.5%)---31(79.5%)
Total211(100%)50(23.7%)56(26.5%)6(2.9%)4(1.9%)99(45%)
Allvaluesaregivenas n (%).Thepercentagesformanagementoptionsrefertothetotalnumber(n)ofthatrow, whilethepercentagesof n refertothetotalnumberofpatientsinthesubgroup.BCG:bacillusCalmette-Guérin, Cx:cystectomy,HG:highgrade,MIBC:muscle-invasivebladdercancer,w/rec.:withrecurrence.
Amongthe1063intermediate-riskpatients,BCGinductionwasplannedforonly 3.9%,whereasonly2.1%receivedadequateBCGinductionplusmaintenance.Intravesical chemotherapywasadministeredto245patients(23%),ofwhom226(21.3%)receivedfive ormoreinstillations(range:5–18).Only14(1.3%)completed1-yearmaintenance.Detailed dataregardingadjuvantintravesicaltreatmentsareprovidedinTable 5
3.5.MIBCPatientCharacteristics
PrimaryMIBCwasdetectedin322(14.4%)patients,ofwhom39(12.1%)weremetastatic atthetimeofdiagnosis.Additionally,117patients(5.2%)werediagnosedwithsecondary MIBC.Ofthe217patients(54.3%)whounderwentRC,100(46%)receivedNAC.Eighteen patients(4.5%)refusedtheoperation,and74(18.5%)weredeemedunfitforsurgery.Thirty patients(7.5%)underwentbi-/trimodalitytreatment.Thecharacteristicsofthepatients withMIBCaresummarizedinTable 8.
3.6.Follow-UpandSurvival
Duringamedianfollow-upof57months(IQR:35–83),recurrencewasobserved following40.8%oftheTURBTs.Among1817patients,153(8.4%)experienceddisease progression,and191(10.5%)underwentRC.BCwasthecauseofdeathin97patients(5.3%), while586patients(32.3%)diedfromothercauses.ForNMIBCpatients,the5-yearRFS,PFS, CFS,OS,andCSSestimateswere53%,91.6%,89%,70.6%,and95.6%,respectively.These figures,alongwith2-and10-yearsurvivalestimatesforallpatientsandriskgroups,are detailedinTable 9 andillustratedinFigure 4.Duringthesamefollow-upperiod,37patients (1.65%)developedametachronousupperurinarytracturothelialcarcinoma(UTUC),while 5outof125patients(4%)withapriorUTUChistorydevelopedametachronoustumorin theircontralateralupperurinarytract.
Table8. TumorcharacteristicsandtreatmentofpatientswithMIBC.
Allvaluesaregivenas n (%),otherwisementioned.BSC:bestsupportivecare;FU:follow-up;MIBC: muscle-invasivebladdercancer;NAC:neoadjuvantchemotherapy;RC:radicalcystectomy;RT:radiotherapy; UC:urothelialcancer a Total n =2237(uniquepatientnumber). b Total n =251(T1patientsunderwentreTURBT). c Total n =400(non-metastaticMIBCpatients). d Total n =217(patientsunderwentRC).
Cont.
Figure4. SurvivalcurvesofNMIBCpatientsaccordingtoriskgroups. (a)Recurrence-freesurvival. (b)Progression-freesurvival.(c)Cystectomy-freesurvival.(d)Overallsurvival.(e)Cancer-specificsurvival.
Table9. Two-,five-,andten-yearsurvivalestimatesforallNMIBCpatientsandsubgroups.
2-YearRFSPFSCFSOSCSS
5-yearRFSPFSCFSOSCSS
Allvaluesaregivenaspercentages(%)and95%confidenceintervals.CFS:cystectomy-freesurvival;CSS: cancer-specificsurvival;NMIBC:non-muscle-invasivebladdercancer;OS:overallsurvival;PFS:progression-free survival;RFS:recurrence-freesurvival.
4.Discussion
TheVZNKUL–NMIBCQualityIndicatorsProgramRegistryisaprospectivecohort of4104uniquepatientswithBC(asof1May2024)whoweretreatedwithTURBTplus adjuvantintravesicalinstillations(ifindicated)andfollowedupwithaccordingtotheir pathologicalstageandriskstratification.BeingthefirstofitskindinBelgiumforBC, thisregistryoffersauniqueresourcetogaininsightintothequalityofthecareprovided toNMIBCpatients.Itenablesthebenchmarkingofparticipatingcentersregardingtheir adherencetoQCIs,anditfacilitatestheprovisionofregularfeedbacktothesecenters. ThisfeedbackhelpsimplementnecessaryimprovementsinQCIsforwhichsuboptimal orbelow-thresholdcompliancehasbeendetected.Additionally,theregistrycanserveas atoolforevaluatingtheoutcomesofsurgicalandadjuvanttreatmentsandtheireffects ononcologicaloutcomes,asitprovidesinvaluablereal-worlddatarepresentingdifferent hospitalsettings.
Inthiscohort,thefrequencyofNMIBC,distributionofpatients’gender,andmedian ageatdiagnosiswereconsistentwiththeliterature,asexpected.Themajorityofpatients underwentsurgerywithinsixweeksofdiagnosis,whichisaguideline-recommended threshold.Remarkably,boththeWHO1973andWHO2004/2016tumorgradingsystems wereusedinonly25%ofthereports.Thereareinconsistentresultsforusingthethree-tier (WHO1973)versusthetwo-tier(WHO2004/2016)tumorgradingsystem.However,the mostrecentEAUGuidelinesrecommendusingahybridgradingsystemthatsubdivides grade2tumorsintoLGandHGcategories[7].Giventhatmoreresearchisneededto determinethemostbeneficialgradingsystem,usingbothgradingsystemsforeachTURBT wouldbeadvisable.
ReTURBTwasplannedforonly46%ofthe1146indicatedpatients,while42%actually underwenttheprocedure.Whilethisrateappearslow,itisdifficulttodrawdefinitive conclusionswithoutanestablishedthresholdforthisratio.Althoughnotsystematically recordedinourregistry,areviewofpatients’filesindicatedthatthemainreasonsfor omittingreTURBTweresurgeonorpatientpreference,oftenbecauseofthepatient’sage, generalhealthstatus,orcomorbidities.Giventheongoingdebateabouttheaddedvalue ofperformingreTURBT,furtherresearchisneededtoidentifyspecificpatientsubgroups inwhichitcouldbesafelyomitted,therebyminimizingtheeconomicandpsychological burdenofNMIBCtreatment.
PostoperativeSIVICwasrequestedfor62.4%ofthepatientsbytheoperatingurologistsattheendofsurgery,and56.9%receivedthetreatment.Thisfallsbelowthearbitrarily identifiedthresholdof60%setbyMariappanetal.andtheRESECTregistry[21].The primaryreasonfornotadministeringSIVICwasthesurgeons’discretion,assomeurologistsbelieveitisnotnecessaryorbeneficialforsomepatients.Othersignificantreasons includedbladderperforation(19%),verydeep/extensiveresection(13%),andtheneed forcontinuousirrigation(mainlyduetobleeding—9%).Thesefactorsaredirectlyrelated toperforminganoptimalandsafeTURBT.Itisobviousthat,regardlessoftheirexperiencelevel,urologistsandresidentsshouldbebetteracquaintedwithtipsandtricksfor performingacompleteandsafeTURBTandunderstandingtheoncologicalbenefitsof SIVIC.Themediantimeof4.7htoreceivepostoperativeSIVICisconsistentwiththe recommendationof6hoftheEAUGuidelines.However,thisresultshouldbeinterpreted cautiously,asitwascalculatedfromthedataofonlytwocenters,withthehighestnumber ofincludedpatients.
Regardingadjuvantintravesicaltreatment,althoughBCGinductionwasplanned for79%of972BCG-indicatedHRpatients,only60.7%receivedadequateBCGinduction. Almostone-fifthofthepatientsforwhomBCGinductionwasplannedcouldnotreceive thetreatmentduetocomorbidities,generalstatus,age,intolerance,theBCGshortage,and theCOVID-19pandemic.Thenumbersofpatientsforwhommaintenancewasplanned andthosewhoreceivedadequateBCGmaintenancewereevenlower,at45.2%and40.1%, respectively.Itisworthnotingthatsomecentershaveusedafour-cycleregime(at3,6, 9,and12months)forone-yearBCGmaintenance,whileothershavefollowedthethree-
cycleregime(at3,6,and12months),asrecommendedbytheEAUGuidelines[7].Our ratesofpostoperativeSIVICuseandadjuvantBCGtreatmentwerehigherthanthose reportedintheCOBLAnCEcohortfromFrance,whichhasbeenrecentlypublished[27]. AswehaveobservedanincreaseinpostoperativeSIVICuseinourfirstanalysis,we thinkcreatingtheregistryspecificallyforQCIsandtheinherentHawthorneeffectmight explainthedifferenceinourcohort.Additionally,discussingthemajorityofthepatients (86.9%)atMDTlikelycontributedtothisrate.OfthepatientswhoreceivedatleastBCG induction,39.7%weretumor-freewhenthosewhohadearlyterminationofBCGtreatment butexperiencednorecurrencewereconsidered.Ontheotherhand,asubstantialportionof thepatients(17.3%)experiencedBCGintolerance,whichcouldhaveaffectedsuccessrates. Asexpected,planninganRC(oranearlyRC)wasthemostpreferredtreatmentafterBCG failure.Nonetheless,morethanone-fourthofthepatientsscheduledforthisprocedure couldnotundergosurgeryduetounfitnessorarefusalofthiscomplexoperation.
Interestingly,theuseofadjuvanttreatmentforintermediate-riskpatientswasobserved tobesuboptimal.Of1063intermediate-riskpatients,only2.1%receivedadequateBCG inductionplusmaintenance.Thislowratecanbeattributedtothelessfrequentpreference ofurologiststogiveBCGtothisgroup,whichdoesnotexperienceHGtumorsaccording tothepreviousriskstratificationoftheEAUGuidelines,andtherecentBCGshortage. Intravesicalchemotherapywasgiventoonly23%ofthepatients,with21.3%receiving adequateinductiontherapy.Hereagain,weobservedthatsomecentersadministeredfive instillations,astheycountedthepostoperativeSIVICasthefirstdoseoftheinduction scheme,whiletheothersgavesix.Remarkably,only1.3%ofallindicatedpatientscompleteda1-yearmaintenancescheme.Asintermediate-riskNMIBCconsistsoftumorswith varyingcharacteristicsandoutcomes,makingitaveryheterogeneousgroup,theserates emphasizetheneedforfurtherstudiestodefinewhichintermediate-riskpatientswould benefitmostfromadjuvantBCGorchemotherapytreatment.
Notably,thisstudyrevealedthatintermediate-riskNMIBCpatientsexhibitedthe poorestRFSoutcomes.However,forothersurvivaloutcomes,thisgroupfellbetweenthe low-riskandhigh-risksubgroups,asanticipated.Theuseofthe2019EAUGuidelinesfor riskstratificationmayhaveinfluencedthisresult.Importantly,thesefindingshighlightthe well-establishedheterogeneityofintermediate-risktumorsandunderscorethelimitations ofpreviousEAUclassificationsinrobustlydefiningsubgroups.Thisalsosuggeststhat incorporatingadditionalfactors,asproposedintheInternationalBladderCancerGroup’s scoringsystemandsubstratificationmodel,couldenhancepatientstratificationandguide moretailoredadjuvanttreatmentdecisions[28].
Ofthe2237patientsintheregistry,14.4%werediagnosedwithMIBCattheinitial diagnosis,while117(5.2%)developedsecondaryMIBC.Therateofpatientswithprimary MIBCisslightlylowerthanreportedintheliterature.However,therateof46%for receivingNACoutof217RCpatientswasexplicitlydifferentfromtheliteratureandthe COBLAnCEcohort.ThishigherNACratecouldbeattributedtoseveralfactors.Apart fromparticipatinginaQCIprogramandtheinherentHawthorneeffect,thetreatmentof thesepatientsbyurologistssubspecializedinonco-urologyinamultidisciplinarysetting likelycontributedtothemorefrequentuseofNAC.
Ourcohortapproachis,ofcourse,notdevoidoflimitations.Thisregistryrequiresa specificelectronicfilesystem(KWS),orthesoftwaremustbeadaptedtointegratewithother hospitalelectronicsystems,necessitatingadditionalfinancial,labor,andtimeinvestments. Currently,onlyonecenterisprospectivelycollectingbodilymaterials(urine,blood,and fresh-frozentumortissue).However,itisimportanttonotethattheprimarygoalofthis projectisnotbiosamplecollection.Thisaspecthasrecentlystartedatonecenter,with planstoexpandthebiosamplecollectiontoothercenters.Thelackofacentralreviewof pathologyreportscanbecountedasanotherlimitation.However,asthisproject’smain aimistoreportonQCIsandreal-worlddata,webelieveacentralreviewisnotessential. Moreover,suchareviewisimpractical,asthisprojectisintendedtocontinueindefinitely. Nevertheless,tumorspecimensaretypicallyevaluatedbypathologistsexperiencedin
uropathology,andmostcasesarediscussedatMDTs,whichwebelievemitigatesthis limitation.Last,asthisregistrywascreatedspecificallyforQCIs,theinherentHawthorne effectmighthaveaffectedtheresults.
5.Conclusions
ThecohortoftheVZNKUL–NMIBCQualityIndicatorsProgramservesasaninvaluablesourcenotonlyforassessingadherencetoQCIsbutalsoforevaluatingtreatment patternsandoutcomesinareal-worlddatasetting.ThiscohortandQCIprogramare instrumentalinincreasingthequalityofthetreatmentNMIBCpatientsreceive,improving ourunderstandingofthecourseofNMIBCunderguideline-recommended,state-of-the-art care,andaddressingunmetneedsinNMIBCmanagement.ByreportingonthisQCI registrycohort,weaimtofostercollaborationwithotherinternationalprojectsfordataand biosamplesharingandtofacilitateperforming(multidisciplinary)scientificstudies.
SupplementaryMaterials: Thefollowingsupportinginformationcanbedownloadedat https: //www.mdpi.com/article/10.3390/cancers16213653/s1:TableS1:(a)numberofTURBTspercenter peryear;(b)numberofuniquepatientsforTURBTspercenterperyear.TableS2:(a)numberof follow-upspercenterperyear;(b)numberofuniquepatientsforfollow-upspercenterperyear. TableS3:(a)numberofmultidisciplinaryteammeetingspercenterperyear;(b)numberofunique patientsformultidisciplinaryteammeetingspercenterperyear.TableS4:(a)numberofbladder instillationspercenterperyear;(b)Numberofuniquepatientsforbladderinstillationspercenterper year.TableS5:(a)distributionofbenignconditions;(b)distributionofbladdercancersotherthan urothelialcarcinoma;(c)distributionofcancersotherthanbladdercancer.TableS6:distributionof thecaseswithavarianthistologytype.
AuthorContributions: Studyconceptanddesign:M.A.,F.V.d.A.andS.J.Acquisitionofthedata: B.V.C.,R.V.,D.O.,K.V.E.,F.B.,R.V.R.,P.M.andF.V.d.A.Analysisofthedata:M.A.Draftingofthe manuscript:M.A.Criticalrevisionofthemanuscriptforimportantintellectualcontent:F.V.d.A., S.J.,M.A.,B.V.C.,R.V.,D.O.,K.V.E.,F.B.,R.V.R.,P.M.andL.B.Administrative,technical,ormaterial support:M.A.andB.V.C.Supervision:F.V.d.A.andS.J.Allauthorshavereadandagreedtothe publishedversionofthemanuscript.
Funding: Thisresearchreceivednoexternalfunding.
InstitutionalReviewBoardStatement: ThisstudyinvolvedhumanparticipantsandwasapprovedbyEthicsCommitteeResearchUZ/KULeuven(approvalnumber:S55725;approvaldate: 6June2014).
InformedConsentStatement: Notapplicable.Patientsandthepublicwerenotinvolvedinthe design,conduct,reporting,ordisseminationplansofthisresearch.
DataAvailabilityStatement: Dataareavailableuponreasonablerequest.Researchersmayrequest accesstodatabycontactingthecorrespondingauthor.
Acknowledgments: ThismanuscriptispartofthedoctoralthesisofMuratAkand.StevenJoniauisa seniorclinicalresearcherattheResearchFoundationofFlanders(FWO).
ConflictsofInterest: Theauthorsdeclarenoconflictofinterest.
Abbreviations
AJCCAmericanJointCommitteeonCancer
ASAAmericanSocietyofAnesthesiologists
BCBladdercancer
BCGBacillusCalmette–Guérin
CCICharlsoncomorbidityindex
CFSCystectomy-freesurvival
CISCarcinomainsitu
COBLAnCEACohorttoStudyBladderCancer
CRCompleteresection
CSSCancer-specificsurvival
DMDetrusormuscle
EAUEuropeanAssociationofUrology
eCRFElectroniccasereportform
FDAFoodandDrugAdministration
HGHighgrade
IQRInterquartilerange
KWSKlinischWerkstation
LGLowgrade
LVILymphovascularinvasion
MDTMultidisciplinaryteam
MIBCMuscle-invasivebladdercancer
NACNeoadjuvantchemotherapy
NMIBCNon-muscle-invasivebladdercancer
OSOverallsurvival
PFSProgression-freesurvival
QCIQualitycontrolindicator
RCRadicalcystectomy
RESECT TransurethralREsectionandSingle-instillationintra-vesicalchemotherapy EvaluationinbladderCancerTreatment
reTURBTRepeatTURBT
RFSRecurrence-freesurvival
SIVICSingleintravesicalinstillationofchemotherapy
TNMTumor-node-metastasis
TURBTTransurethralresectionofthebladdertumor
UCUrothelialcarcinoma
UTUCUppertracturothelialcarcinoma
VZNKULVlaamsZiekenhuisnetwerk–KULeuven
WHOWorldHealthOrganization
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