Does the Unexpected Presence of Non-organ-confined Disease at Final Pathology Undermine Cancer Control in Patients with Clinical T1N0M0 Renal Cell Carcinoma Who Underwent Partial Nephrectomy?

Kidney

Cancer

Does

the

Unexpected

Presence

of

Non-organ-confined

Disease

at

Final

Pathology

Undermine

Cancer

Control

in

Patients

with

Clinical

T1N0M0

Renal

Cell

Carcinoma

Who

Underwent

Partial

Nephrectomy?

Umberto

Capitanio

*,

Grant

D.

Stewart

,

Tobias

Klatte

,

Bulent

Akdogan

,

Marco

Roscigno

,

Martin

Marszalek

,

Paolo

Dell’Oglio

,

Emanuele

Zaffuto

,

Oscar

Rodriguez

Faba

,

Maciej

Salagierski

,

James

Lingard

,

Marco

Carini

,

Idir

Ouzaid

,

Maria

Carmen

Mir

,

Francesco

Montorsi

,

Luigi

Filippo

Da

Pozzo

,

Christian

Stief

,

Andrea

Minervini

,

Sabine

D.

Brookman-May

a_{UnitofUrology,UniversityVita-Salute,SanRaffaeleScientificInstitute,Milan,Italy;}b_{DivisionofExperimentalOncology,UrologicalResearchInstitute,}

IRCCSSanRaffaeleScientificInstitute,Milan,Italy;c_{EdinburghUrologicalCancerGroup,UniversityofEdinburgh,WesternGeneralHospital,Edinburgh,UK;} d_{MedicalUniversityofVienna,Vienna,Austria;}e_{HacettepeUniversity,Ankara,Turkey;}f_{PapaGiovanniXXIIIHospital,Bergamo,Italy;}g_{Donauspital,Vienna,}

Austria;h_{FundacioPuigvert,Barcelona,Spain;}i_{Kent&CanterburyHospital,Canterbury,UK;}j_{AziendaOspedalieroUniversitariaCareggi,Florence,Italy;} k_{BichatUniversityHospital,Paris,France;}l_{HospitaldelMar-ParcdeSalutMar-IMIM,Barcelona,Spain;}m_{DepartmentofUrology,Ludwig-Maximilians}

UniversityMunich,CampusGrosshadern,Munich,Germany;n_{JanssenPharmaResearchandDevelopment,LosAngeles,CA,USA}

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

AssociateEditor:JamesCatto

Keywords: Renalcancer Kidneycancer Partialnephrectomy Radicalnephrectomy Cancercontrol Upstaging Abstract

Background: Anon-negligibleproportionofindividualsdiagnosedwithcT1renalcell carcinoma (RCC)are upstaged to pT3a at finalpathology. Few data ononcological outcomesforthesepatientsareavailabletodeterminewhetherpartialnephrectomy (PN)mightjeopardisecancercontrol.

Objective: Toassess,withinaninternationalmulti-institutionalcollaboration,whether PNmightunderminecancercontrolrelativetoradicalnephrectomy(RN)inRCCpatients withunexpectedpT3adisease.

Design,setting,andparticipants: Internationalmulti-institutionalcollaboration includ-ingpatientswithcT1abN0M0–pT3aRCC.

Intervention: PNorRN.

Outcome measurements and statistical analysis: We used Kaplan-Meier analyses, before and after propensity-score matching, to evaluate differences in metastatic progression(MP)andcancer-specificmortality(CSM)ratesduringfollow-up. Univari-ableandmultivariableCoxregressionanalyseswereusedtoassesspredictorsofMPand CSM.

Resultsandlimitations: Overall,309patientswithcT1abN0M0RCC(cT1aN0M0,n=107, 34.6%; cT1bN0M0, n=202, 65.4%) had pT3a disease according to final pathology. Patientsweretreated witheitherPN (n=71, 23%)orRN (n=238,77%).MPat1, 2, and5yrwasdetectedin9.1%,13.3%,and24.1%ofpatients,respectively.CSMwas3.5%, 10.7%,and18.4%at1,2,and5yr,respectively.Aftermatching,nodifferenceintermsof

1y_{Currentaffiliation:AcademicUrologyGroup,UniversityofCambridge,Addenbrooke’sHospital,}

Cambridge,UK.

*Correspondingauthor.UnitofUrology,IRCCSSanRaffaeleScientificInstitute,ViaOlgettina60, 20132Milan,Italy.Tel.:+390226437286;Fax:+390226437298.

E-mailaddress:umbertocapitanio@gmail.com(U.Capitanio). http://dx.doi.org/10.1016/j.euf.2017.02.020

1. Introduction

Themajorityofpatientscurrentlydiagnosedwithrenalcell carcinoma (RCC) harbour small, organ-confined tumours

[1].Inthissetting,internationalurologicalguidelines rec-ommenddifferentmanagementoptions,rangingfrom sur-veillance to nephron-sparing surgery, such as partial nephrectomy(PN)[2–4].Forsmallrenalmasses,PNreduces theriskof cardiovascularmorbidity[5]andis associated withbetterfunctionaloutcomes[6–10]comparedtoradical nephrectomy (RN) withoutcompromising cancer control

[11]. However, a non-negligibleproportion ofindividuals treatedwithPNshowinvasionofperirenalsinusfattissue or involvement of the inner renal blood vessels at final pathology and thus are upstaged to stage pT3a [12– 14]. The clinical impact of such upstagingis debated. In addition,onlyafewsmallstudieshaveformallyevaluated theimpactofsurgicalapproach(PNvsRN)ononcological outcomes among patients with cT1 disease who experi-enced upstaging to pT3a, and these comprise extremely limitedpatientcohorts[12–14].

To bridge this gap, we used the largest multi-institu-tionalcohortofpatientswithclinicalT1abN0M0RCC trea-ted with PN or RN for whom final pathology revealed unexpectedpT3adiseasetoinvestigatethehypothesisthat PNdoes notcompromisecancercontrolrelativeto RNin thissubsetofpatients.

2. Patientsandmethods 2.1. Studypopulation

Forourretrospectiveanalysisweusedamulti-institutionaldatabaseof surgicallytreatedRCCpatientsfromtenEuropeantertiarycarecentres. Specifically,thestudycohortconsistedofindividualsdiagnosedwith RCCandtreatedwith eitherRNorPN between 1988and2015.All individualswerepreoperativelystagedascT1N0M0andwerestaged aspT3aatfinalpathology.Individualswithbilateralkidneycanceror withmonolateralmultifocaltumourswerenotconsidered.

2.2. Clinicalandpathologicalevaluation

TNMstageswereassignedaccordingtothe2009AmericanJoint Com-mitteeonCancer/UnionInternationaleContreleCancerclassification [2]. Cases before the introduction of the most recent classification schemewerereclassi_fied.Clinicaltumoursizewasbasedonpreoperative imagingandde_finedasthegreatesttumourdiameterincentimetres. StagecT1wasdefinedinaccordancewiththe2009TNMclassificationfor RCC:tumourof7cminthegreatestdimension,limitedtothekidney,

andwithoutradiographicsignsofextensiontotheperinephrictissueor themajorveins[2].Surgerywasperformedwithin3mofromclinical staging.Allspecimenswereevaluatedbyanexperienceduropathologist ateachtreatinginstitution.Patientswereevaluatedat3moaftersurgery andsubsequentlyaccordingtoindividualisedfollow-upschedules com-prisingatleasttwoannualvisits.

2.3. Outcomes

The joint primary outcomes were metastaticprogression (MP) and cancer-specificmortality(CSM).MPwasdefinedasretroperitonealnodal recurrenceorsystemicrecurrence(skeletaland/orvisceralrelapse)at imagingduringfollow-up.PatientswhodiedfromRCCwerede_finedas havingCSM.CSMwasdefinedbytheattendingurologistoroncologist who followed the patient and/or from information on the death certificate.

2.4. Statisticalanalyses

Descriptivestatisticswereusedtocategorisethebaselinecharacteristics amongpatientstreatedwitheitherPNorRN.Frequenciesand propor-tionswerereportedforcategoricalvariables.Mean,medians,and inter-quartilerangeswerereportedforcontinuousvariables.Mann-WhitneyU testsandx2_{testswereappliedtoassessthestatisticalsignificanceof}

differencesinmediansandproportions,respectively.

Theeffectoftreatmenttype(PNvsRN)onMPandCSMwasassessed intheoverallcohort.Actuarialsurvivalratesatvarioustimepointsafter PNandRNwerecalculated.

Toaccount forpossibledifferencesbetweenthe twogroups that mightberelatedtodifferencesinthesurgicalapproach, propensity-score matching wasperformed. Specifically, propensity scores were computedusingalogisticregressionmodelthatevaluatedtheoddsof receivingPNversusRNaccordingtoclinicaltumoursize,age,andyearof surgery. The nearest-neighbour method, with a calliper width of 0.2 timesthestandarddeviationofthe logitanda1-to-1matching ratio,wasused.Aftermatching,Kaplan-Meierplotswereusedto graph-icallydepictthesurvivalratesobservedforthematchedcohorts. Differ-encesintheratesofMPandCSMweretestedusingthelog-ranktest.

Totestthehypothesisthattreatmenttype(PNvsRN)mayaffectthe riskofMPandCSMaftersurgery,multivariateCoxregressionanalyses wereperformedintheunmatchedcohortafteradjustingforallclinical andpathologicalcovariates.

Allstatisticaltestsweretwo-sidedwithalevelofsigni_ficancesetat p<0.05.AnalyseswereperformedusingSPSS version20(IBMCorp., Somers,NY,USA)forstatisticalcomputingandtheRsoftware environ-mentforgraphics(version3.3.0;www.r-project.org).

3. Results

Overall, among 3863 patients with a clinically defined diagnosis of T1abN0M0 RCC, 309 (8%) harboured pT3a MPorCSMwasobservedbetweenthePNandRNcohorts(bothp>0.3).Onmultivariable analysis,type ofsurgery(PNvsRN)was notanindependentpredictorofeitherMP (p=0.3)orCSM(p=0.4).Limitationsincludetheretrospectivedesign.

Conclusions: In patientswithunexpected pT3aRCC at final pathology,PN doesnot appeartojeopardisecancercontrolwithregardtoMPandCSM.

Patientsummary: Cancercontrolissimilarbetweenpatientstreatedwithremovalof the entire kidney and those with only partial removal, even if the final histology examination demonstrates a tumour that is unexpectedly not confined within the kidney.

disease at final pathology (cT1aN0M0, n=107, 34.6%; cT1bN0M0, n=202, 65.4%). Patients were treated with either PN (n=71, 23%) or RN (n=238, 77%). Relative to RN,PNcasesweretreatedmorerecently(p<0.001,Table1) andhadsmallermasses(mediantumoursize3.0vs5.5cm, p<0.001)and alowerproportion ofhigh Fuhrmangrade (G3–4 29.6 vs 47.1%).An open, laparoscopic, androbotic approachwasusedin72.9%,2.8%,and24.3%ofPNcases,and 60.7%,36.5%,and2.8%ofRNcases,respectively.No signifi-cant differences were observed between the PN and RN groups with regard to patient age and the presence of necrosisorsarcomatoidfeatures(Table1).pT3awasdefined accordingtothepresenceofperirenalfatinvasiononlyin 82.1%ofPN and43.6%ofRNpatients (p<0.001; Table1). Onlysix patients (1.9%) had positive surgical margins at finalpathology(0.8vs5.6%forRNvsPN;p=0.01).

Aftermeanfollow-upof52mo(55moforRNvs43mo forPN),localrecurrencewasrecordedinsixRNcases(2.8%) andtwoPNcases(2.9%).MPat1,2,and5yrwasobservedin 9.1%,13.3%,and24.1%ofcases,respectively(Fig.1A).CSM was3.5%,10.7%, and 18.4% at1,2, and5 yr,respectively

(Fig. 2A).After matching,no differences in MPand CSM wereobservedbetweenthePNandRNgroups(bothp>0.3; Figs.1Band2B).

In multivariable analyses for MP prediction, clinical tumoursize(hazardratio[HR]1.4,95%confidenceinterval [CI]1.0–1.8;p=0.02)andsarcomatoidfeatures(HR4.3,95% CI 1.1–16.3; p=0.003) were independent predictors. In multivariable analyses forCSM prediction,ageatsurgery (HR1.1,95%CI1.0–1.1;p=0.005)andclinicaltumoursize (HR1.4,95%CI1.1–1.9;p=0.03)wereindependent predic-tors.Type ofsurgery(PNvsRN)wasnot anindependent predictorofeitherMP(p=0.3)orCSM(p=0.4;Table2). 4. Discussion

InternationalguidelinesrecommendthatRCCpatientswith organ-confined tumours should undergo PN whenever technicallyfeasible,whichallowsadequatecancercontrol and the preservation of functional parenchyma [2–4,15]. Thebenefitsofthisapproachintermsofthegeneralhealth of patients during the follow-up period have been well Table1_–Clinicalandpathologicalcharacteristicsof309patientstreatedwithpartialnephrectomy(PN)orradicalnephrectomy(RN)for clinicalcT1abN0M0renalcellcarcinomaforwhompathologyrevealedunexpectedpT3adisease.

Variable PN(n=71,23%) RN(n=238,77%) pvalue Clinicalcharacteristics Age(yr) 67(60–76) 66(58–74) 0.6 Yearofsurgery 2010(2006–2012) 2006(2001–2009) <0.001 Tumorsize(cm) 3.0(2.2–4.4) 5.5(4.2–6.5) <0.001 Clinicalstage,n(%) <0.001 cT1aN0M0 53(74.6%) 54(22.7%) cT1bN0M0 18(25.4%) 184(77.3%) Pathologicalfeatures pT3asubclassification(%) <0.001 PFIonly 82.1 43.6 SFIonly 14.9 24.1

PFI+SFIorPFI/SFI+RVI 3.0 32.3

Surgicalmargins(%) 5.6 0.8 0.01

Fuhrmangrade3–4(%) 29.6 47.1 0.009

Sarcomatoidfeatures(%) 1.5 1.8 0.8

Necrosis(%) 26.1 37.6 0.1

SFI=sinusfatinvasion;PFI=perinephricfatinvasion;RVI=renalveininvasion.

Table2–MultivariableCoxregressionanalysespredictingmetastaticprogressionandcancer-specificmortality.

Variable Metastaticprogression Cancer-specificmortality

HR(95%CI) pvalue HR(95%CI) pvalue

Age 1.0(1.0–1.1) 0.07 1.1(1.0–1.1) 0.005 Yearofsurgery 1.0(0.9–1.0) 0.6 1.0(0.9–1.1) 0.5 Tumoursize 1.4(1.0–1.8) 0.02 1.4(1.0–1.9) 0.03 Fuhrmangrade3–4 1.9(0.9–3.8) 0.08 1.8(0.8–4.2) 0.2 Sarcomatoidfeatures 4.3(1.1–16.3) 0.03 4.7(0.8–25.0) 0.07 Necrosis 1.1(0.6–2.3) 0.7 1.2(0.5–2.7) 0.7 pT3asubclassification 0.2 0.7

SFIonlyvsPFIonly 0.9(0.3–2.3) 0.6(0.2–2.0)

PFI+SFIorPFI/SFI+RVIvsPFIonly 1.7(0.8–3.6) 0.9(0.4–2.3)

Surgicalmargins 2.3(0.3–18.4) 0.9 2.7(0.4–15.1) 0.3

Treatmenttype

PNvsRN 0.5(0.1–1.8) 0.3 0.6(0.1–2.3) 0.4

HR=hazardratio; CI=confidence interval;SFI=sinus fat invasion;PFI=perinephric fat invasion;RVI=renal veininvasion;PN=partial nephrectomy;

established [5–11]. However, preoperative assessment of clinical stage may sometimes underestimate the actual tumourburden, leadingto apathological upstagingwith potential detrimental effects on a patient’s prognosis in relation to pathological tumour stage [16]. For approxi-mately10–20%ofpatientswithdiseasestagedascT1N0M0, final pathology reveals unexpected non-organ-confined disease(pT3a)owingtothepresenceofmicroscopic inva-sion of the renal vein and/or of the perirenal/sinus fat

[14,17,18]. Computed tomography imaging has sensitivity of59–88%andspecificityof71–93%inpredictingthe pres-enceofpT3disease[19].Ithasbeensuggestedthatcancer

control could be jeopardised relative to RN for this pT3 upstaginginpatientswhohaveundergonePN[12–14,20]. Manyreportshavealreadyassessedpotentialpredictors ofunfavourablecharacteristicsatfinalpathologyinpatients treatedwithPN[18,20,21].Forinstance,Gorinand collea-gues[13]evaluatedtheearlyoncologicalendpointof recur-rence-free survival (RFS) in patients with RCC upstaged fromcT1topT3a,butonlyinthespecificsettingofrobotic PN. Only 41 patients (4.8%) were upstaged to pT3a. The 24-moRFSestimatesforcT1andpT3atumourswere99.2% and 91.8%, respectively (p=0.003). Factors associated with tumourupstagingincludedhightumourcomplexity

Fig.1–Kaplan-Meieranalysesofmetastaticprogression-freesurvival

accordingtosurgicaltreatment(partialvsradicalnephrectomy)(A)

beforeand(B)afterpropensity-scorematching.CE=cumulativeevents;

NR=numberatrisk.

Fig.2–Kaplan-Meieranalysesofcancer-specificmortality-freesurvival

accordingtosurgicaltreatment(partialvsradicalnephrectomy)(A)

beforeand(B)afterpropensity-scorematching.CE=cumulativeevents;

(nephrometry score), increasing preoperative tumour diameter,andhilarlocation[13].Balletal.[18]investigated predictors associated with adverse pathology, defined as highpathologicalgradeand/orpT3adisease,among771cT1 RCC cases. Male gender, tumour size >4cm, and high tumourcomplexityscorewere independentpredictors of adversepathologyfollowingPN. Thesestudies andothers focused on upstaging only; however, very few data are available for comparison of cancer control between PN and RN in upstaged patients. Nayak et al. [14] assessed the risk of progression in The Canadian Kidney Cancer Information System including 1448 clinically defined T1 RCCcases. Overall,134patients haddisease upstagingto pT3a(n=66PNandn=68PN).Aftermedianfollow-upof 23mo,the3-yrRFSwas76%inupstagedpatientscompared to 93% in those with no upstaging (p<0.001). Unfortu-nately,multivariable analyses comparing theeffectofPN versusRNinthesubgroupofpatientswithupstagingcould not be performed because of the limited sample size

[14].Jeldresandcolleagues[22]performeda multi-institu-tional matched comparison betweenPN (n=30) and RN (n=63)casesandfoundnosignificantcancer-specific sur-vivaldifferencesafterPNforpT3alesions(HR2.5;p=0.9). Owing to the small cohort size, a subgroup analysis of cT1N0M0patientscouldnotbeundertaken.

SubgroupanalysesforcT1patientsarerarelyreportedin theliterature,andareexclusivelyinsmallcohortsofpatients. Ohetal.[12]carriedoutaretrospectivecomparisonofPN versusRNforpatientswithpT3aM0RCCwhohad under-gone surgery atfive institutions inKorea (2000–2010). A subgroup analysis of 63 cT1a patients upgraded to pT3a revealedsimilarRFSratesbetweenPNandRNgroups.

To the best of our knowledge, the present study has evaluated thelargest patientcohort availableto datefor thecurrenttopic.Weareunawareofpreviousreportsbased onlargerpatientsamplesorofanypreviousanalysisthat relied on propensity-score matching of cohorts. Several questions might be raised by the current study. First, althoughfutureinvestigationsareneededtodrawa defini-tiveconclusion,itmightbeaskedwhethertheuseoffrozen sections during PN is needed in patients with clinically low-risk,organ-confined,smallrenalmasseswhensimilar oncologicaloutcomesmightbeexpectedregardlessofthe surgicalprocedure.Second,itmightbehypothesisedthat RNmightnotnecessaryinpatientswithunexpectednon– organ-confineddiseaseatfinalpathology.Third,itappears thatthe surgical procedure should not bea factor when assessingthemostadequatefollow-upscheduleafter sur-gery.Unfortunately,allthosehypothesescanonlybe for-mallyvalidatedinprospectivesettings,whichare unachie-vableatpresent.

Ourstudyisnotdevoidof limitations.First,the retro-spectivenaturemustbeconsidered.Asaconsequence,itis conceivablethatunmeasuredvariablesforpatient charac-teristics might have affected the results. Second, the RN groupcomprisedindividualswithlargerandpossiblymore complextumours,forwhichsurgicalchallengesmighthave influenced the decision to perform RN instead of PN. In addition,PN patients weremore representedinthe later

yearsofthestudy.However,yearofsurgerywasincludedin our multivariable analyses to adjust for potential biases relatedtodifferentlengthsoffollow-up.Third,thelackof centralreviewforimagingandpathologyspecimen evalu-ation must also beconsidered. Specifically, theability to correctlyperformanadequateclinicalstagingdependson theimagingtechnique(computedtomographyvsmagnetic resonanceimaging),theexperienceoftheradiologist,and theprotocolsusedateachinstitution.

5. Conclusions

Using alarge multi-institutional cohortof cT1N0M0RCC patients, we investigated whether PN might undermine cancercontrolwhen unanticipatedpT3adisease isfound at final pathology. In this specific scenario, despite the presence of unexpected non–organ-confined disease, PN doesnotseemtojeopardisecancercontrol.

Authorcontributions:UmbertoCapitaniohadfullaccesstoallthedata inthestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Capitanio.

Acquisitionofdata:Capitanio,Stewart,RodriguezFaba,Klatte,Akdogan, Roscigno, Marszalek, Dell’Oglio, Zaffuto, Salagierski, Ouzaid,Lingard, Carini,Mir,Montorsi,DaPozzo,Stief,Minervini,Brookman-May. Analysisandinterpretationofdata:Capitanio,Dell’Oglio,Zaffuto. Draftingof themanuscript:Capitanio, Stewart,Klatte,Dell_’Oglio, Mir, Brookman-May.

Critical revision of the manuscript for important intellectual content: Capitanio,Stewart,RodriguezFaba,Klatte,Akdogan,Roscigno, Marsza-lek,Dell’Oglio,Zaffuto,Salagierski,Ouzaid,Lingard,Carini,Mir,Montorsi, DaPozzo,Stief,Minervini,Brookman-May.

Statisticalanalysis:Capitanio,Dell_’Oglio,Zaffuto. Obtainingfunding:None.

Administrative,technical,ormaterialsupport:None.

Supervision: Capitanio, Stewart, Rodriguez Faba, Klatte, Akdogan, Roscigno, Marszalek, Dell’Oglio, Zaffuto, Salagierski, Ouzaid,Lingard, Carini,Mir,Montorsi,DaPozzo,Stief,Minervini,Brookman-May. Other:None.

Financialdisclosures:UmbertoCapitaniocertifiesthatallconflictsof interest, including specific financial interests and relationships and affiliationsrelevanttothesubjectmatterormaterialsdiscussedinthe manuscript(eg,employment/affiliation,grantsorfunding, consultan-cies,honoraria,stockownershiporoptions,experttestimony,royalties, orpatents_filed,received,orpending),arethefollowing:None. Funding/Supportandroleofthesponsor:None.

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