Intravesical Therapy in Patients with Intermediate-risk Non–muscle-invasive Bladder Cancer: A Systematic Review and Network Meta-analysis of Disease Recurrence

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Review

–

Bladder

Cancer

Intravesical

Therapy

in

Patients

with

Intermediate-risk

Non

–muscle-invasive

Bladder

Cancer:

A

Systematic

Review

and

Network

Meta-analysis

of

Disease

Recurrence

Ekaterina

Laukhtina

a,b,y

,

Mohammad

Abufaraj

a,c,y

,

Abdallah

Al-Ani

c

,

Mustafa

Rami

Ali

c

,

Keiichiro

Mori

a,d

,

Marco

Moschini

a,e,f

,

Fahad

Quhal

a,g

,

Reza

Sari

Motlagh

a,h

,

Benjamin

Pradere

a

,

Victor

M. Schuettfort

a,i

,

Hadi

Mostafaei

a,j

,

Satoshi

Katayama

a,k

,

Nico

C. Grossmann

a,l

,

Harun

Fajkovic

a,m

,

Francesco

Soria

n

,

Dmitry

Enikeev

b

,

Shahrokh

F. Shariat

a,b,c,m,o,p,q,

*

,

European

Association

of

Urology-Young

Academic

Urologists

(EAU-YAU):

Urothelial

carcinoma

working

group

a_Department_of_Urology,_{Comprehensive}_Cancer_Center,_Medical_University_of_Vienna,_Vienna,_Austria;b_Institute_for_Urology_and_Reproductive_Health, SechenovUniversity,Moscow,Russia;c_Division_of_Urology,_Department_of_Special_Surgery,_Jordan_University_Hospital,_The_University_of_Jordan,_Amman, Jordan;d_Department_of_Urology,_The_Jikei_University_School_of_Medicine,_Tokyo,_Japan;e_Department_of_Urology,_Luzerner_{Kantonsspital,}_Lucerne, Switzer-land;f_Department_of_Urology_and_Division_of_Experimental_Oncology,_Urological_Research_Institute,_Vita-Salute_San_Raffaele,_Milan,_Italy;g_Department_of Urology,KingFahadSpecialistHospital,Dammam,SaudiArabia;h_Men_’s_Health_and_Reproductive_Health_Research_Center,_Shahid_Beheshti_University_of MedicalSciences,Tehran,Iran;i_Department_of_Urology,_University_Medical_Center_{Hamburg-Eppendorf,}_Hamburg,_Germany;j_Research_Center_for_Evidence BasedMedicine,TabrizUniversityofMedicalSciences,Tabriz,Iran;k_Department_of_Urology,_Okayama_University_Graduate_School_of_Medicine,_Dentistry_and PharmaceuticalSciences,Okayama,Japan;l_Department_of_Urology,_University_Hospital_Zurich,_Zurich,_Switzerland;m_Karl_Landsteiner_Institute_of_Urology andAndrology,Vienna,Austria;n_Division_of_Urology,_Department_of_Surgical_Sciences,_San_Giovanni_Battista_Hospital,_University_of_Studies_of_Torino,_Turin, Italy;o_Department_of_Urology,_Weill_Cornell_Medical_College,_New_York,_NY,_USA;p_Department_of_Urology,_University_of_Texas_{Southwestern,}_Dallas,_TX,_USA; q_Department_of_Urology,_Second_Faculty_of_Medicine,_Charles_University,_Prague,_Czech_Republic

a v ai l a b l e a t w w w . s c i e n c e d i r e c t . c o m

j o u r n al h o m e p a g e : w w w . e u r o p e an u r o l o g y . c o m / e u f o c u s

Articleinfo Articlehistory:

AcceptedMarch10,2021 AssociateEditor:RichardLee

Keywords:

Non–muscle-invasivebladder cancer Bladdercancer Intermediaterisk Intravesicaltherapy Networkmeta-analysis Abstract

Context: Patientswithintermediate-risknon–muscle-invasivebladdercancer(NMIBC)

may pose a clinical dilemma without an agreed evidence-based decision tree for

personalizedtreatment.

Objective: Toperformasystematicreviewandnetworkmeta-analysis(NMA)to

sum-marizeavailableevidenceontheoncologicoutcomesofintravesicaltherapyinpatients

withintermediate-riskNMIBC.

Evidence acquisition: The MEDLINE, EMBASE, and ClinicalTrials.gov databases were

searchedinOctober 2020accordingtothePreferredReporting ItemsforSystematic

ReviewsandMeta-analysesstatement.Studiesweredeemedeligibleiftheyreportedon

oncologic outcomes in patients with intermediate-risk NMIBC treated with

trans-urethral resection ofbladdertumorwithand withoutintravesicalchemotherapyor

bacillusCalmette-Guérin(BCG)immunotherapy.

Evidencesynthesis: Twelvestudieswereincludedinaqualitativesynthesis(systematic

review);threeweredeemedeligibleforaquantitativesynthesis(NMA).AnNMAofﬁve

different regimens was conducted for the association of treatment with the 5-yr

y_These_authors_contributed_equally_to_this_work.

*Correspondingauthor. DepartmentofUrology, ComprehensiveCancerCenter, ViennaGeneral Hospital,MedicalUniversityofVienna,WähringerGürtel18–20,1090,Vienna,Austria.

Tel.:+4314040026150;Fax:+4314040023320.

E-mailaddress:shahrokh.shariat@meduniwien.ac.at(S.F.Shariat).

Pleasecitethisarticleinpressas:LaukhtinaE,etal.IntravesicalTherapyinPatientswithIntermediate-riskNon–muscle-invasive

https://doi.org/10.1016/j.euf.2021.03.016

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1. Introduction

Bladder cancer is the sixth most commonly diagnosed cancerworldwide[1,2].Approximately75%ofbladder can-cer patients present with non–muscle-invasive bladder cancer (NMIBC) [3]. NMIBC is a heterogeneous disease associatedwithawidearrayofoncologicoutcomes,which warrantsanaccurateandpracticalriskstratification strat-egyfortreatmentplanningandpatientcounseling[4]. Sev-eralmodels,suchasthoseoftheEuropeanOrganizationfor Research and Treatment of Cancer (EORTC) [5] and Club UrologicoEspanodeTratamientoOncologico[6],havebeen proposedfor stratifyingpatients withNMIBC interms of recurrence and progression risk. However, despite their ease of use, the predictive accuracy of these models is limited by intragroup heterogeneity among patients

[7].Moreover,themodelsdonottakeintoaccountadverse pathologicfeatures, suchaslymphovascularinvasionand varianthistologies,thatareassociatedwithmoreaggressive disease and poor response to intravesical therapy [8– 12].Consequently,optimaldecision-makingremains chal-lenging,especiallyforpatientswithintermediate-risk dis-ease,thelargestriskgroupamongNMIBCpatients.

Currently, adjuvant intravesical immunotherapy with bacillusCalmette-Guérin(BCG)orintravesical chemother-apyisthestandardofcareforpatientswith intermediate-and high-risk NMIBC [13]. Since treatment options and follow-uparedependentonriskstratification,patientswith intermediate-riskNMIBCarevulnerabletoinadequate ther-apyowingtothepoorlydefinedandoverlappingdiagnostic criteria [13]. However, unnecessary adverse events and costsassociatedwithtreatmentmayoutweighthepossible benefitsforpatientswithintermediate-riskNMIBC. Conse-quently,patientswithintermediate-riskNMIBCmayposea clinicaldilemma withoutan agreedevidence-based deci-siontreeforpersonalizedtreatment.

Theprimaryaimofthissystematicreviewandnetwork meta-analysis (NMA) was to determine the oncologic

outcomesofintravesicaltherapyamongpatientswith inter-mediate-riskNMIBC.Suchfindingswouldhelpin decision-making,patientcounseling,andtrialdesign.

2. Evidenceacquisition

2.1. Protocol

ThissystematicreviewandNMAwereconductedaccording tothePreferredReportingItemsforSystematicReviewsand Meta-analyses(PRISMA)extensionstatement fornetwork meta-analysis [14]. The study protocol was registered a prioriontheInternationalProspectiveRegisterof System-aticReviews(PROSPERO;registrationIDCRD42020212851).

2.2. Datasourcesandsearches

TheMEDLINE,EMBASE,andClinicalTrials.govdatabaseswere searchedinOctober2020toidentifystudiesreportingonthe oncologicoutcomesofintravesicaltherapyforpatientswith intermediate-riskNMIBC.Acomprehensivesystematic liter-aturesearchwasindependentlyperformedbytwoauthors. Terms and keywords suchas urinary bladder neoplasms, non–muscle-invasivebladdercancer,intermediaterisk non-–muscle-invasive bladder cancer, NMIBC, oncologic out-comes, local recurrence,disease-free survival, and overall survivalwereusedtoperformthesearch.Theprimary out-comesofinterestwereoncologicoutcomes,including pro-gression-freesurvival(PFS),recurrence-freesurvival(RFS), disease-freesurvival(DFS),andoverallsurvival(OS).

Afterremovingduplicates,twoindependentreviewers screened thetitlesandabstracts.Any citation thateither reviewerthoughtshouldbeincludedorforwhich suitabil-ity for inclusionwas unclear was identified for full-text screening.Subsequently,fulltextsofeligiblearticleswere reviewed forfinal inclusionanddata extraction.Any dis-crepancy during the primary and secondary literature screeningswereresolvedbyreferringtotheseniorauthor.

recurrence risk. Chemotherapy with maintenance was associated with a lower

likelihoodof5-yrrecurrencethanchemotherapywithoutmaintenance(oddsratio

[OR] 0.51, 95% credible interval [CI] 0.26–1.03). Immunotherapy, regardless of

whetherafull- orreduced-doseregimen,was notassociatedwithasigniﬁcantly

lowerlikelihoodof 5-yrrecurrencewhencompared withchemotherapywithout

maintenance(OR0.90,95%CI0.39–2.11vsOR0.93,95%CI0.40–2.19).Analysisofthe

treatmentrankingrevealedthatchemotherapywithmaintenancehadthelowest

5-yrrecurrencerisk(Pscore0.9666).

Conclusions: Ouranalysisindicatesthatchemotherapywithamaintenanceregimen

confersasuperioroncologicbeneﬁtintermsof5-yrrecurrenceriskcomparedto

chemotherapy without maintenance in patients with intermediate-risk NMIBC.

Regardlessofthedoseregimen,immunotherapywithBCGdoesnotappeartobe

superior to chemotherapyin patients with intermediate-risk NMIBC in term of

diseaserecurrence.However,owingtothelackofcomparativestudies,thereisan

unmetneedforwell-designed,large-scaletrialstovalidateourﬁndingsandgenerate

robustevidenceondiseaserecurrenceandprogression.

Patientsummary: A maintenance scheduleof chemotherapyreducestherate of

long-termrecurrenceofbladdercancerthathasnotinvadedthebladdermuscle.

Chemotherapy inserted directly into the bladder and immunotherapy without

maintenanceschedulesseemtohavelimitedbeneﬁtinpreventingcancerrecurrence.

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2.3. Eligibilitycriteria

We included randomized controlled trials (RCTs) that reported on oncologic outcomes of intravesical therapy forpatientswithintermediate-riskNMIBC.PICOS (popula-tion,intervention,control,outcomes,andstudydesign)for thisstudywasasfollows:patientswithintermediate-risk NMIBCaccording to theEuropeanAssociationof Urology (EAU)ortheAmericanUrologicalAssociation(AUA) guide-lines,treatedwithtransurethralresectionofbladdertumor (TURBT)andintravesicalchemotherapyorimmunotherapy (BCG)comparedtoacontrolgroupincludingpatients trea-tedwithTURBTaloneorcohortsreceivingsingleadjuvant therapy.Theoutcomeswereoncologicoutcomes,including PFS,RFS,DFS,and/orOS.

Weexcludedreviews,letters,editorials,animalstudies, study protocols, case reports, meeting abstracts, replies fromauthors,briefcorrespondence,andarticlesnot pub-lishedinEnglish.Furthermore,weexcludedstudiesthatdid notprovidedataregardingtheoncologicoutcomes. Refer-encesofallthepapersincludedwerescannedforadditional studiesofinterest.

2.4. Dataextraction

Datafromeachstudywereindependentlyextractedbytwo reviewers.Extracteddataincludedthefollowing:study iden-tifiers,studydesign,numberofparticipants,numberof par-ticipantswithindifferentNMIBCriskstrata,oncologic out-comes,anddemographicandclinicalcharacteristicsofthe patients.Subsequently,thehazardratio(HR)and95% confi-denceintervalfortheoncologicoutcomeswereretrieved.

2.5. Risk-of-biasassessment

Theriskofbias(RoB)wasevaluatedaccordingtotheRiskof BiasinNon-randomizedStudiesofInterventions(ROBINS-I) tool.Thistoolisbasedonsevendomainsthatincludebias duetoconfounding,participantselection,classificationof interventions,deviations from the intendedintervention, missingdata,measurementofoutcomes, andselection of thereportedresult(Supplementary Table1).The RoBfor each study was assessed independently by two authors. Disagreementswereresolvedviaconsultationwiththe co-authors.

2.6. Statistical analyses

NMAwas usedfor simultaneous comparisonof the 5-yr recurrenceriskformultipletreatmentstrategiesand pool-ingofdirectandindirectevidence.Forassessmentofthe 5-yrrecurrencerisk,arm-basedanalyseswereperformedto estimatetheoddsratio(OR)ofthe5-yrrecurrenceriskand 95%credibleinterval(CI)fromtherawdatapresentedinthe manuscriptsincluded[15].Therelativerankingofthe dif-ferenttreatmentsforeachoutcomewasestimatedusingthe Pscore,whichcanbeconsideredafrequentistanalogtothe surfaceunderthecumulativerankingcurves[16,17]. Net-workplotswereusedtoillustrate theconnectivityofthe

treatmentnetworksintermsof5-yrrecurrencerisk.Rv1.14, framework 2.21 (R Foundation for Statistical Computing, Vienna,Austria)wasusedfortheNMA.

3. Evidencesynthesis

3.1. Description of the studies included

The literaturesearchidentified522unique references.Of these, 192 were excluded because of duplication and 255 becauseofunrelatedoutcomes during thescreening process (Fig.1). Of the 75 full-text articles assessed for eligibility,63wereexcludedbasedontheselectioncriteria. Twelve studieswere finallyincludedinthequalitative synthesis(systematicreview)[18–29];threeweredeemed eligibleforquantitativesynthesis(NMA)[18,26,27].Table1

summarizesthecharacteristicsofthestudies.

Wefoundsignificantheterogeneityacrossthestudiesin termsoftreatmentusedforpatientswithintermediate-risk NMIBC.Tenstudiesreporteddataondifferentintravesical therapy regimens [18,19,22–29]. Among chemotherapeu-tics, epirubicin was used in four studies, mitomycin C (MMC) in three, and pirarubicin in one.Immunotherapy with BCGwasusedinfour studies.Two studiesreported outcomesforlaservaporizationofbladdertumor(LVRBT) comparedtoTURBT[20,21].

3.2. Principalfindings

3.2.1. Oncologic outcomes

Intermsofoncologicoutcomes,all12studiesreportedon the recurrence rate [18–29], eight reported data on the progression rate [18,19,23,24,26–29], and only two reported on survival outcomes such as OS and cancer-specificsurvival(CSS)[26,28].Table2summarizes oncol-ogic outcomes such as recurrence and progression rates amongthestudies.

3.2.1.1.Recurrencerisk. Allstudiesincludedreportedtherisk

ofrecurrencefordifferenttreatmentstrategiesforpatients with intermediate-riskNMIBC (Table 2). Regarding intra-vesicalchemotherapy,Nayaetal[24]reportedthatamong patients with intermediate-riskNMIBC, the3-yrRFSrate was worse for those who received a single immediate installationofpirarubicincomparedtothosewhoreceived additionalinstillationsofpirarubicin.Kellyetal[23]found thatcelecoxibaddedtoastandard-of-caresingle intrave-sicalMMCinstillationwithin24hfollowingTURBTdidnot improve3-yrRFS.

RegardingintravesicalimmunotherapywithBCG,Gupta etal[22]reportednodifferenceinrecurrenceratebetween patientstreatedwithmonthlyBCGfor12dosesandpatients receivingBCGmaintenanceaccordingtotheSWOG proto-col.Likewise,Oddensetal[25]reportedthatpatientswith intermediate-riskNMIBCtreatedwithafull-doseschedule do not benefit from 1 yr of maintenance BCG therapy. Comparingtheefficacyofmaintenancewithchemotherapy andBCG,Sylvesteretal[28]reportedstatisticallysignificant worseoutcomesintermsof9.2-yrrecurrenceanddistant

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metastasesratesforpatientsreceivingepirubicincompared tothosereceivingBCG(bothwith3-yrmaintenance).

Two studies comparedthe effectivenessof LVRBTand TURBT followed by intravesical therapy. Xu et al [20]

reportednosignificant differencein2-yrrecurrencerates between KTP laser and standard TURBT, both following pirarubicininstillations.Zhangetal[21]didnotfind differ-encesin1-and3-yrrecurrenceratesbetweenLVRBTwith thulium laser and TURBT; in both groups, surgery was followedbyepirubicininstillations.

Insummary,accordingtothecurrentliterature, chemo-therapywithmaintenanceseemstoreducetherecurrence rateamongpatientswithintermediate-riskNMIBC,while1 yrofmaintenanceBCGtherapydoes notappearto affect recurrence outcomes in these patients. Different endo-scopicproceduresalso donot demonstratedifferences in recurrence risk among patients with intermediate-risk NMIBC.

3.2.1.2.Progressionrisk. Eightofthestudiesincludedreported

dataontheprogressionrate(Table2).Sylvesteretal[28]did notfindastatisticallysignificantdifferencein9.2-yr pro-gression rate between patients receiving epirubicin and

those receivingBCG (bothwith 3-yrmaintenance). Simi-larly,Ojeaetal[26]didnotfindadifferenceinprogression ratesamongpatientswithintermediate-riskNMIBCtreated withMMCorfullorlowdosesofBCG(27mgand14.5mg). Kelly etal[23]foundthatcelecoxibdidnotdecreasethe progressionratemorethanasingleimmediateintravesical MMC instillation alone in intermediate-risk NMIBC. The current data indicate that intravesical therapies do not differintermsoftheprogressionrate.However,thesedata need to be supported by well-designed and controlled large-scaletrials.

3.2.1.3. Survival outcomes. Among survival outcomes,OS and

CSSwerereportedintwostudiesofpatientswith intermedi-ate-riskNMIBCtreatedwithepirubicin,BCG,orMMC.Data from the EORTC trials[28]showed all-cause mortality of 38.8% among patients treated with epirubicin with 3-yr maintenance,comparedto30.3%amongthosetreatedwith BCG3-yrmaintenance(HR0.79,95%CI0.58–1.09;p=0.14); cancer-specificmortalitywas7.1%and2.4%,respectively(HR 0.35,95%CI0.14–0.86;p=0.02).Ojeaetal[26]found cancer-specificmortality of 4.7%, 3%, and 3.6%among patientstreated withMMC,BCG27mg,andBCG14.5mg,respectively,ina

Fig.1–Flowdiagramofthestudyselectionprocedureforthesystematicreviewandnetworkmeta-analysis.

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studywithmedianfollow-upofapproximately5yr.Infact, thereareonlylimiteddataonsurvivaloutcomesforpatients withintermediate-riskNMIBC.Nevertheless,BCGappearsto haveamarginalbenefitcomparedtochemotherapyinterms oflong-termOSandCSS.

3.3. Networkmeta-analysis

Forquantitativesynthesisin theNMA,therapy regimens from three studies were categorized into groups as fol-lows: (1) chemotherapy as standard regimen ([total of Table1–Characteristicsofstudiesreportingoncologicoutcomesforpatientswithintermediate-risknon–muscleinvasivebladdercancer

Study Country Study

design Patients (IR/total) IRpatients inTxarm 1/Txarm2

Treatmentarm1 Treatmentarm2 DeﬁnitionofIR Follow-up

Bosschieter2017[18] Netherlands RCT 413/2243 190/223 Immediate

instillationofMMC afterTURRT InstillationofMMC delayedfor2wk afterTURBT Primary,solitary pTa/pT1G3OR recurrent, solitarypTa/pT1 G1–3tumors,no concomitantCIS Median32mo (IQR17–51) Ojea2017[26] Spain RCT 430/430 BGC27mg:142 BCG13.5mg:139 MMC:149 BCG27mg,BCG 13.5mg MMC30mg TaG2andT1G1– 2,no concomitantCIS MMC:52.6mo 27mgBCG: 57.3mo 13.5mgBCG: 61.2mo

Serretta2010[27] Italy RCT 482/482 237/245 5weekly

instillationsofEpi (postTUR+ immediateEpi) 5weekly instillations+ 10monthly instillationsofEpi (postTUR+ immediateEpi)

EAUguidelines Median48mo

(range3–78)

Elsawy2018[19] Egypt RCT 52/236 28/24 IntravesicalEpi

(postTURBT)

TURBTalone Primary/

recurrent

papillarybladder

cancer,>1cm

Mean29mo

Gupta2020[22] India RCT 14/78 7/7 MonthlyBCGfor

12doses BCGfollowingthe SWOGprotocol Multiple/ recurrent low-gradetumors Duration1yr

Kelly2018[23] UK RCT 126/472 69/57 Twicedaily

celecoxibpost TURBT+MMC(IR) orBCG(HiR) Placebopost TURBT+MMC(IR) orBCG(HiR)

(IQR36–57)

Naya2018[24] Japan RCT 68/113 35/33 Singleimmediate

postTURBT intravesical instillationofTHP IntravesicalTHP chemotherapy weeklyfor8wk

Oddens2012[25] Netherlands RCT 789/1355 1/3dose,1yr:192

FD,1yr:191v 1/3dose,3yr:218 FD,3yr:188 1/3doseBCG+1-yr maintenancepost TUR FDBCG+1-yr maintenancepost TUR 1/3doseBCG+3-yr maintenancepost TUR FDBCG+3-yr maintenancepost TUR MultipleT1,G1-2 tumors,<10 tumors,no concomitantCIS Median7.1yr Sylvester2009[28] Europe (Belgium) RCT 497/837 BCG:161 BCG+INH:166 Epi:170 BCGaloneorBCG plusINH Epi Singleor multiple,primary orrecurrent,T1, G1-2tumors,no concomitantCIS Median9.2yr

Turkeri2010[29] Turkey RCT 143/143 68/75 Singleinstillation

ofEpipostTURBT

Doubleinstillations

ofEpipostTURBT

Primaryand solitaryor multiple(3)Ta (G2–3)orT1 (G1–2)tumors; noconcomitant CIS Duration16.9mo

Xu2015[20] China RCT 116/193 56/60 KTPlaser+THP TURBT+THP EAUguidelines NR

Zhang2015[21] China RCT 87/292 43/44 LVRBT+Epi TURBT+Epi EAUguidelines Duration36mo

BCG=bacillusCalmette-Guérin;CIS=carcinomainsitu;EAU=EuropeanAssociationofUrology;Epi=epirubicin;FD=fulldose;G=grade;HiR=highrisk;INH

=isoniazid;IQR=interquartilerange;IR=intermediaterisk;KTP=potassium-titanyl-phosphate;LVRBT=laservaporesectionofbladdertumor;MMC=

mitomycinC;RCT=randomizedcontrolledtrial;SWOG=SouthwesternOncologyGroup;THP=pirarubicin;TUR/TURBT=transurethralresectionofbladder

tumor;Tx=treatment.

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6 instillations of epirubicin: immediate epirubicin after TURBT+5weeklyinstillations]or[totalof9installations with MMC 40 mg: immediatewithin 24 h after TURBT instillation+ 3 weeklyinstillations + 5monthly instilla-tions]); (2)chemotherapyasadelayedregimen (total of 9installationswithMMC40mg:instillationstarting2wk afterTURBT+3weeklyinstillations+5monthly instilla-tions);(3)chemotherapyasanextendedregimen([totalof 16instillationsof epirubicin:immediateepirubicin after TURBT+5weeklyinstillations+10monthlyinstillations] OR[MMC30mggivenonceaweekfor6wkfollowedby another 6 instillations given once every 2 wk during 12wk];(4)immunotherapyatfulldose(BCG27mggiven onceaweekfor 6wkfollowedbyanother6instillations given onceevery2wkduring 12wk); and(5) immuno-therapyatareduceddose(BCG13.5mggivenonceaweek for 6wk followed by another 6 instillations given once every2wkduring12wk).Thenetworksofeligible com-parisonsaregraphicallyrepresentedinanetworkplot of theassociationoftreatmentregimenwith5-yrrecurrence risk in Figure 2. Network plots show interconnections between different therapy regimens (represented by a node). Connections between different therapy regimens arerepresentedbylinks;numbersindicatethenumberof studies.

AnNMAofthefiveintravesicaltherapyregimenslisted abovewasconductedwithregardtothe5-yrrecurrencerisk inintermediate-riskNMIBC(Fig.3).Chemotherapyinthe extendedregimenwasassociatedwithalowerlikelihoodof 5-yrrecurrencecomparedtochemotherapyinthestandard regimen(OR0.51,95%CI0.26–1.03).Bycontrast,adelayed

Fig.2–Networkplotshowingtheassociationoftreatmentwiththe

5-yrrecurrenceriskinintermediate-risknon–muscle-invasivebladder

cancer.Theplotshowsinterconnectionsbetweendifferenttherapy

regimens(representedbyanode).Connectionsbetweendifferent

therapyregimensarerepresentedthroughlinks,andthenumbers

indicatethenumberofstudies.

Table2–Progressionandrecurrenceratesforpatientswithintermediate-risknon–muscleinvasivebladdercancer

Study Progression Recurrence

Bosschieter2017[18] 15of413ptsexperiencedDP 3-yrRR20%forimmediateMMCinstillationvs32%fordelayedMMC

installation

Ojea2017[26] DPrate9.4%forMMC,9.9%forBCG27mg,and

12.9%forBCG14.5mg

RR38.9%forMMC,26.8%forBCG27mg,and36%forBCG13.5mg

Serretta2010[27] 10ptsprogressedtomuscle-invasivedisease(3in

5weeklyEpiinstillationsarmvs7inextendedEpi

schedulearm)

3-yrRFR54.4%for5weeklyEpiinstillationsvs62.1%forextendedEpi

schedule(p=0.11)

3-yrRFS62.7%for5weeklyEpiinstillationsvs69.5%forextendedEpi

schedule

Elsawy2018[19] DP1eventinintravesicalEpiarmvs0eventsin

TURBTalonearm

Recurrence:4eventsinintravesicalEpiarmvs4eventsinTURBTalonearm

Gupta2020[22] NR Recurrence:0/7formonthlyBCGfor12dosesvs1/7forBCGpertheSWOG

protocol(p=0.3)

Kelly2018[23] DP3pts(4.3%)treatedwithTURBT+MMC(IR)or

BCG(HiR)+celecoxibvs1pt(1.7%)treatedwith

TURBT+MMC(IR)orBCG(HiR)+placebo(p=0.6).

3-yrRFR52%forTURBT+MMC(IR)orBCG(HiR)+celecoxibvs50%for

TURBT+MMC(IR)orBCG(HiR)+placebo(HR0.90,log-rankp=0.7).

Naya2018[24] DPnotnotedduringthisperiodinanypatient 3-yrRFS63.4%forsingleimmediateTHPinstallationvs86.1%foradditional

THPinstallations(log-ranktest,p<0.01)

Oddens2012[25] NR DFIfor1/3BCGdose:106events/192ptsfor1-yrmaintenancevs97events/

218ptsfor3-yrmaintenance(HR1.35,95%CI1.03–1.79)

DFIforfullBCGdose:72events/191ptsfor1-yrmaintenancevs81events/

188ptsfor3-yrmaintenance(HR0.88,95%CI0.64–1.21)

Sylvester2009[28] 9.2-yrDP7.1%forEpivs4.0%forBCG(HR0.56,95%

CI0.26–1.23;p=0.14)

DPorDM13.5%forEpivs5.2%forBCG(HR0.39,

95%CI0.21–0.73;p=0.002)

9.2-yrRR58.8%forepirubicinvs40.1%forBCG(HR0.59,95%CI0.45–0.76;p

<0.001)

DM8.8%forepirubicinarmvs3.7%forBCG(HR0.42,95%CI0.20–0.90;p=

0.027)

Turkeri2010[29] Gradeandstageprogression:1.5%forsingle

instillationvs4%fordoubleinstillation(p=0.165)

RR14.7%forsingleinstillationvs21.3%fordoubleinstillation(p=0.305)

Xu2015[20] NR 2-yrRR26.8%forlaser+THPvs30%forTURBT+THP

Zhang2015[21] NR 1-yrRR54.5%forTURBT+Epivs51.2%forLVRBT+Epi(HR0.935,95%CI

0.62–1.42;p=0.752)

3-yrRR68.2%forTURBT+Epivs65.1%forLVRBT+Epi(HR0.933,95%CI

0.59–1.47;p=0.762)

BCG=bacillusCalmette-Guérin;CI=conﬁdenceinterval;DFI=disease-freeinterval;DM=distantmetastasis;DP=diseaseprogression;Epi=epirubicin;HiR=

highrisk;HR=hazardratio;IR=intermediaterisk;LVRBT=laservaporesectionofbladdertumor;MMC=mitomycinC;NR=notreported;THP=pirarubicin;

TURBT=transurethralresectionofbladdertumor;pt=patient;RFR=recurrence-freerate;RFS=recurrence-freesurvival;RR=recurrencerate.

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chemotherapyregimenwasnotassociatedwith a signifi-cantly lower likelihood of 5-yr recurrence compared to standardchemotherapy(OR0.92,95%CI0.58–1.48). Simi-larly, compared to a standard chemotherapy regimen, immunotherapy,regardlessofwhetheratafullorreduced dose,wasnotassociatedwith asignificantlylower likeli-hoodof5-yrrecurrence(OR0.90,95%CI0.39–2.11,andOR 0.93,95%CI0.40–2.19,respectively).Accordingtothe anal-ysisoftreatmentranking,itishighlylikelythat chemother-apyintheextendedregimenhasthelowestrateofthe5-yr recurrence(Pscore0.9666).Thetreatmentrankingofother therapiesispresentedinSupplementaryTable2.

3.4. Discussion

We performedasystematic reviewofthe oncologic out-comesofintravesicaltherapyforpatientswith intermedi-ate-riskNMIBC.Wealso performedanNMAtoindirectly compare the association of different intravesical therapy regimenswiththe5-yrrecurrencerisk.Thisapproachledto severalinterestingfindings.

First, according to our results, chemotherapy in the extendedregimen(withmaintenance)wasassociatedwith thelowestlikelihoodof5-yrrecurrence forpatientswith intermediate-riskNMIBC.Therefore,immediate intravesi-calchemotherapyinstillationafterTURBTandthenfiveor six weekly instillations followed by prolonged monthly instillations or instillations given once every 2 wk for a fewmonthsistheregimenthatprovidesthebestlong-term oncologicoutcomesintermsofrecurrencein intermediate-riskNMIBC.ThissupportstheAUAguidelines recommend-ing 6 wk of induction intravesical chemotherapy with maintenanceforanunspecifieddurationin intermediate-risk NMIBC [30]. At the same time, some of the studies includedreportedintravesicalchemotherapywith mainte-nanceforupto12wkthatisnottheregimenrecommended by the current guidelines. This therapy might be used accordingtohistoricrecommendationsbeforethecurrent treatment strategies. Nevertheless, ouranalysis does not reflect the impact of intravesical therapy on progression risk, whichmay also pose achallenge in identifying the optimaltreatmentoptionsforintermediate-riskNMIBC.

Second,wefoundthatchemotherapydelayedfor2wk afterTURBTwasnotsignificantlyassociatedwithalower likelihoodof5-yrrecurrencewhencomparedtostandard chemotherapyinintermediate-riskNMIBC.TheEAU guide-lines indicate that repeat chemotherapy instillations

improve RFS for patients with intermediate-risk NMIBC regardlessofaprevioussingleinstillationimmediatelyafter TURBT [13]. Sylvester et al [31] reported that a single instillationofchemotherapyimmediatelyafterTURBT com-pared to TURBT alone reduces the risk of recurrence in NMIBC, except for patients at high risk of recurrence because of its lack of efficacy in this subgroup. In their meta-analysis, Sylvester et al also provide evidence that theuseofpostoperativeirrigationalsoreducesrecurrences, whichcanbeexplainedbyaroleinpreventingimplantation ofcirculatingtumorcellsatthesiteofresection. Unfortu-nately, dataonpostoperative irrigationuseinthestudies includedinourNMAarelacking.Moreover,nostudyhas reportedresultsforcombinationtherapy,althoughitwas previouslyshownthatcombinationtherapymightprovide prophylacticadvantageintermsofrecurrencewhen com-paredtoBCGtherapyaloneforpatientswith intermediate-andhigh-riskNMIBC[32].

Interestingly, immunotherapy with BCG, regardless of the doses used, was not associated with a significantly lower likelihood of5-yr recurrence compared to chemo-therapyfor patientswithintermediate-riskNMIBCinour analysis. Hence, it seems that BCG instillations do not providelong-termbenefitsoverchemotherapyin interme-diate-riskNMIBC.Thisisparticularlyimportantbecauseof thecurrentworldwideshortageofBCG[33].Incontrastto ourresults,apreviousmeta-analysisfoundthat27mgBCG was moreeffective than13.5 mg BCGin reducingtumor recurrences (riskratio0.66,95%CI 0.49–0.89; p= 0.006)

[34].Astrametalincludedbothintermediate-andhigh-risk NMIBC withoutsubgroup analysis intheir meta-analysis, whileourNMAincludedonlypatientswith intermediate-riskNMIBC.However,itshouldbestressedthatthearticle includedinourNMAdidnotusethemaintenanceschedule ofBCGtherapy,whichwasshowntobemoreeffectivein preventingrecurrence.Forexample,Hanetal[35] recom-mendedadjuvantintravesicalBCGwithmaintenance ther-apyforpatientswithpapillarycarcinoma.Chemotherapyor BCGpluschemotherapywasnotbetterthanBCGalonein preventingtumorrecurrence[35].Supportingtheseresults, anothermeta-analysisshowedthatmaintenanceBCGwas superiortoMMCinpreventingdiseaserecurrence[36].The discrepancyintheseresultscanprobablybeattributedto theinclusionofallNMIBCpatientsregardlessofriskgroup. Nevertheless,asboththeEAUandAUAguidelines recom-mend 1-yrBCG maintenancein intermediate-riskNMIBC

[13,30], most of the studies included highlight the poor compliancewithNMIBCguidelinesworldwide[37].

Another challenge in interpreting the results of the studiesincludedisthelackofdataonsomerelevant clini-copathologicfeatures.Thestudiesincludeddidnottakeinto accountadversepathologicfeaturessuchastumorextent and variant histology, which are associated with worse oncologicoutcomesandsuboptimalresponseto intravesi-cal therapies [12,38–40]. The introduction of immune checkpoint inhibition (CPI) and its combinations might provideafurtherunderstandingoftheroleofintravesical therapyin intermediate-riskNMIBC.Afew ongoingtrials areevaluatingtheroleofintravesicalCPIin

intermediate-Fig.3–Forestplotshowingtheassociationoftreatmentwiththe5-yr

recurrenceriskinintermediate-risknon–muscle-invasivebladder

cancer.OR=oddsratio;CI=confidenceinterval.

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riskNMIBC:thephase1/2 PemBlatrial iscomparing the safety,tolerability,andefficacy of intravesicalor intrave-nous pembrolizumab (NCT03167151). In addition, in the currenteraofpersonalizedmedicine,molecularbiomarkers arepromisingtoolsforpredictingpatientresponseto intra-vesicalchemotherapyandimmunotherapy[41].However, noneofthestudiesincludedprovideddataonbiomarkers expressionortheirpredictiverole.Webelievethat tissue-basedandurine-basedmolecularbiomarkersholdpromise forchangingthemanagementofintermediate-riskNMIBC. ThemainstrengthofoursystematicreviewandNMAis that,tothebestofourknowledge,itisthefirsttoevaluate oncologicoutcomesofintravesicaltherapyforpatientswith intermediate-risk NMIBC. Nevertheless, there are several limitations.Themainlimitationisthesignificant heteroge-neity across the studies in terms of different treatment regimensanddefinitionsofoutcomes(endpoints).Hence, anNMAwasfeasibleonlyamongthreestudiescomparing differentintravesicaltherapystrategiesandonlyforthe 5-yrrecurrencerisk.However,thelong-termsurvival differ-encesmaybebiasedbythetreatmentreceivedafter recur-rence.Second,thesmallsamplesizeinmostofthestudies included may have limited the power of the studies to revealclinicallysignificantfindings.Third,the heterogene-ityinriskstratificationdefinitionunderlinesthenecessity forstandardizedcriteriatofacilitateaccurate decision-mak-ing. Fourth, inconsistenciesin the interventionregimens andevaluationofthecurativeeffectinthetrialsincluded mightaffectthegeneralizabilityofourresultsforpatients with intermediate-riskNMIBC becauseof different treat-mentregimens andaheterogeneouscasemix.Moreover, thearticlesincludedoncelecoxibandcomparisonoflaser andstandardTURBTtechniquesmightprovidemixedand unclear messages to readers. These treatments are not widely used and current guidelines do not recommend them.However,patientsinthesestudiesunderwent intra-vesicalinstillationinadditiontocelecoxibreceivedduring singleintravesicalMMCinstillationfollowingTURBT. Like-wise,lasertherapywasfollowedbyintravesicalinstillation. Weincludedthesestudiesinthequalitativeevidence syn-thesisbecausetheymatchedourinclusioncriteria(articles on patients with intermediate-risk NMIBC treated with TURBTand/or intravesical therapy).Nevertheless, we did notincludetheminthequantitativeanalysisforthereasons mentioned above. Although indirect treatment compari-sonshavebeenusedandvalidatedtocompareoutcomes from RCTs, this approach falls short of a head-to-head treatmentcomparison.Thus,directandwell-designed com-parativetrialsare requiredtovalidate thefindingsofour study.

4. Conclusions

Ouranalysisindicatesthatintravesicalchemotherapywith amaintenanceregimenconfersasuperioroncologicbenefit intermsof the5-yrrecurrence riskcomparedto chemo-therapywithoutmaintenanceforpatientswith intermedi-ate-risk NMIBC. Use of a single immediate intravesical

instillationofchemotherapydidnotresultinaclear reduc-tion inthe recurrence rate. Regardlessof dose regimens, intravesical BCG immunotherapy does not appear to be superiortochemotherapyforpatientswith intermediate-risk NMIBC. However, owing to the lack of comparative studies,there isanunmet needfor well-designed, large-scale trials to validate our findings and generate robust evidenceondiseaserecurrenceandprogression.

Authorcontributions:EkaterinaLaukhtinahadfullaccesstoallthedata inthestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Shariat,Abufaraj,Laukhtina. Acquisitionofdata:Al-Ani,Ali.

Analysisandinterpretationofdata:Laukhtina,Abufaraj. Draftingofthemanuscript:Laukhtina,Abufaraj.

Criticalrevisionofthemanuscriptforimportantintellectualcontent:Mori, Moschini,Quhal,Motlagh, Pradere,Schuettfort,Mostafaei,Katayama, Grossmann,Soria.

Statisticalanalysis:Laukhtina,Mori. Obtainingfunding:None.

Administrative,technical,ormaterialsupport:None. Supervision:Shariat,Abufaraj,Enikeev,Fajkovic. Other:None.

Financialdisclosures:EkaterinaLaukhtinacertifiesthatallconflictsof interest, including speci_fic _financial interests and relationships and af_filiationsrelevanttothesubjectmatterormaterialsdiscussedinthe manuscript(eg,employment/affiliation,grantsorfunding, consultan-cies,honoraria,stockownershiporoptions,experttestimony,royalties, orpatentsfiled,received,orpending),arethefollowing:None. Funding/Supportandroleofthesponsor:None.

Acknowledgements:EkaterinaLaukhtinaandVictorM.Schuettfortare supported byanEUSPScholarshipfromthe EuropeanAssociationof Urology.NicoC.GrossmannissupportedbytheZurichCancerLeague. DeclarationofCompetingInterest:Theauthorsreportnodeclarationsof interest.

AppendixA. Supplementarydata

Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10. 1016/j.euf.2021.03.016.

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