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Cytoreductive Nephrectomy in Metastatic Papillary Renal Cell Carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

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Cytoreductive

Nephrectomy

in

Metastatic

Papillary

Renal

Cell

Carcinoma:

Results

from

the

International

Metastatic

Renal

Cell

Carcinoma

Database

Consortium

Jeffrey

Graham

a

,

J.

Connor

Wells

a

,

Frede

Donskov

b

,

Jae

Lyun

Lee

c

,

Anna

Fraccon

d

,

Felice

Pasini

e

,

Camillo

Porta

f

,

I.

Alex

Bowman

g

,

Georg

A.

Bjarnason

h

,

D.

Scott

Ernst

i

,

Sun

Young

Rha

j

,

Benoit

Beuselinck

k

,

Aaron

Hansen

l

,

Scott

A.

North

m

,

Christian

K.

Kollmannsberger

n

,

Lori

A.

Wood

o

,

Ulka

N.

Vaishampayan

p

,

Sumanta

K.

Pal

q

,

Toni

K.

Choueiri

r,1

,

Daniel

Y.C.

Heng

a,1,

*

aTomBakerCancerCentre,UniversityofCalgary,Calgary,Canada;bAarhusUniversityHospital,Aarhus,Denmark;cUniversityofUlsanCollegeofMedicine,

AsanMedicalCenter,Seoul,RepublicofKorea;dCDCPererzoli,PeschieradelGarda,Italy;eOncologiaMedicaOspedaleSantaMariadellaMisericordia,

Rovigo,Italy;fUniversityofPavia,Pavia,Italy;gUTSouthwesternMedicalCenter,Dallas,TX,USA;hSunnybrookResearchInstitute,Toronto,Canada;iLondon

HealthSciencesCentre,London,Canada;jYonseiUniversityCollegeofMedicine,Seoul,RepublicofKorea;kUniversityHospitalsLeuven,LeuvenCancer

Institute,Leuven,Belgium;lPrincessMargaretCancerCentre,Toronto,Canada;mUniversityofAlberta,CrossCancerInstitute,Edmonton,Canada;nBritish

ColumbiaCancerAgency,Vancouver,Canada;oQEIIHealthSciencesCentre,Halifax,Canada;pKarmanosCancerCenter,Detroit,MI,USA;qCityofHope

ComprehensiveCancerCenter,Duarte,CA,USA;rDana-FarberCancerInstitute,HarvardMedicalSchool,Boston,MA,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 : e u o n c o l o g y . e u r o p e a n u r o l o g y. c o m Articleinfo Articlehistory: AcceptedMarch14,2019 AssociateEditor: GianlucaGiannarini Keywords: Kidneycancer

Metastaticrenalcellcarcinoma Papillary

Cytoreductivenephrectomy

Abstract

Background: There is evidence that cytoreductive nephrectomy (CN) may be beneficial in metastatic renal cell carcinoma (mRCC). This has been studied predominantly in clear-cell RCC, with more limited data on the role of CN in patientswithpapillaryhistology.

Objective: TodeterminethebenefitofCNinsynchronousmetastaticpapillaryRCC.

Design, setting, and participants: Using theInternational Metastatic RenalCell Carcinoma Database Consortium (IMDC)database, a retrospectiveanalysis was performedforpatientswithpapillarymRCCtreatedwithorwithoutCN.

Outcomemeasurementsandstatisticalanalysis: Medianoverallsurvival(OS)and progression-free survival (PFS) were determined for both patient groups. Cox regressionanalysiswasperformedtocontrolfor imbalancesinindividualIMDC riskfactors.

Resultsandlimitations: Intotal,647patientswithpapillarymRCCwereidentified, of whom353 hadsynchronousmetastaticdisease. Of these,109 patients were treated with CN and 244 were not. The median follow-up was 57.1mo (95% confidenceinterval[CI]32.9–77.8)andtheOSfromthestartoffirst-linetargeted therapy for the entire cohort was 13.2mo (95% CI 12.0–16.1). Median OS for patients with CN was16.3mo, compared to 8.6mo (p<0.0001) in theno-CN group.WhenadjustedforindividualIMDCriskfactors,thehazardratio(HR)of

1 Theseauthorscontributedequallytothiswork.

*Correspondingauthor.DepartmentofOncology,TomBakerCancerCentre,UniversityofCalgary, 133129thStreetNW,CalgaryT2N4N2,Canada.Tel.:+14036717750.

E-mailaddress:daniel.heng@ahs.ca (DanielY.C.Heng).

https://doi.org/10.1016/j.euo.2019.03.007

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1. Introduction

Despite impressive advances in treatment, renal cell carcinoma(RCC)remainsasignificantglobalhealthissue, with approximately 30% of patients presenting with advanceddisease [1]. The treatmentlandscapefor meta-staticRCC(mRCC)hasundergoneadramatictransformation inrecentyearsbecauseoftheintroductionofmolecularly targetedtherapiesandnovelimmuno-oncology(IO)agents

[2].Despitethesetherapeuticadvances,themanagementof mRCC still requires a multimodal approach, with the incorporation of systemic targeted and IO therapies, as well as selected use of radiation therapy and surgical interventions.

Theevidenceforsurgicalresectionoftheprimaryrenal tumorin synchronousmetastaticdisease isderivedfrom bothobservationalstudiesandrandomizedtrials.Evidence supporting the use of cytoreductive nephrectomy (CN) comesfromdata fromprospectivetrialsintheeraofIFN therapy,aswellasretrospectivestudies performedinthe more modern,targeted therapyera. Apooled analysis of two prospective randomized clinical trials demonstrated thatCNfollowedbyIFNtreatmentwasassociatedwith a 5.8-moincreaseinoverallsurvival(OS)whencomparedto IFN alone (13.6 vs 7.8mo) [3]. Similarly, retrospective analysesofreal-worldmRCCdatasetshavealsosuggesteda survival benefit from CN among patients treated with targetedtherapy [4,5]. By contrast,the recentlyreported phase3CARMENAclinicaltrialdemonstratedthattargeted therapywithsunitinib alonewasnoninferiorto nephrec-tomyfollowedbysunitinibinInternationalmRCCDatabase Consortium (IMDC) intermediate- and poor-risk patients with clear cell histology [6]. In general, the potential benefitsofCNmustbebalancedcarefullywiththepossible complicationsandmorbidityofthisprocedure.

Themajorityofthesestudieshavefocusedprimarilyon clearcellRCC(ccRCC),themostcommonRCChistological subtype.Therearemorelimiteddataregardingtheroleof CNinnon–clear-cellRCC(nccRCC).WithinnccRCC pathol-ogy,themostcommonsubtypeispapillaryRCC,accounting forapproximately10–15%ofRCCcases.PapillaryRCChas unique biological and clinical features compared to traditionalccRCChistology[7].Thisincludesmorefrequent genetic mutations in MET and FH, rather than the VHL alterations seen in ccRCC. Clinically, papillary RCC is

characterized by diverse outcomes, with both indolent andaggressivetumors.Thus,theroleofCNinpapillaryRCC maydifferwhencomparedtoitsccRCCcounterpart.Given this context, this study was designed to determine the benefitofCNinsynchronousmetastaticpapillaryRCCusing theIMDCdatabase.

2. Patientsandmethods

2.1. Patientpopulation

Patientdatawerecollectedretrospectivelyfrom38internationalcancer centersincludedintheIMDC.TheIMDCisalarge,multi-institutionalset comprisingdataforpatientswithmetastaticRCC[8].Inclusioncriteria forthisstudywerepatientswithmetastaticRCCandpapillaryhistology. We further divided this cohort into patients treated with targeted therapywithoutahistoryofnephrectomy,andthosetreatedwithCN, defined as nephrectomy performed after diagnosis of synchronous metastaticdiseaseorwithin90dbeforediagnosisofmetastaticdisease [5].

Datawerecollectedusinguniformdatabasesoftwareandtemplates. Baseline demographic, clinical, and laboratory data were collected, including variablesfound tohaveprognosticsignificance.Laboratory valueswerestandardizedagainsttheirrespectiveinstitutionupperlimit ofnormal(ULN)andlowerlimitofnormal(LLN)valuesasnecessary. Outcomesmeasuredincluded(OS),progressionfreesurvival(PFS),and objectiveresponserate(ORR)tofirst-linetherapy.Thedataincluded patientsaccruedbetween2005andOctober2017.Thisstudyreceived institutionalreviewboardapprovalfromeachparticipatingcenter.

2.2. Statisticalanalysis

The primary outcome of this study was OS, defined as time from initiationoffirst-linetargetedtherapytothedateofdeathorcensoredat lastfollow-up.A secondaryoutcomewasPFS,definedas timefrom initiationoftargetedtherapytothedateofprogression,drugcessation, orcensoredatlastfollow-up.MedianOSandPFSdistributionswere estimatedusingthe Kaplan-Meiermethod.Coxproportionalhazards regressionwasusedtodeterminehazardratios(HRs)afteradjustment forbaselineprognosticvariables.ThisincludedadjustingfortheIMDC prognosticfactors:hemoglobinbelowtheLLN,correctedcalciumgreater thantheULN,neutrophilsabovetheULN,plateletsgreaterthantheULN, Karnofskyperformancestatus(KPS)<80%,andtimefromdiagnosisto treatmentof<1yr.TheIMDCprognosticfactorshavebeenvalidatedin metastaticpapillaryRCC[9].AdjustedHRsandcorrespondingpvalues arereported.StatisticalanalyseswereperformedwithSASv.9.4(SAS Institute,Cary,NC,USA),withstatisticalsignificancesetatp<0.05 (two-sidedtest).

death for CN was 0.62 (95% CI 0.45–0.85; p=0.0031). Limitations include the retrospectivenatureoftheanalysis.

Conclusions: TheuseofCNinpatientswithmRCCandpapillaryhistologyappears tobeassociatedwithbettersurvivalcomparedtonoCNafteradjustmentforrisk criteria.SelectionofappropriatecandidatesforCNiscrucial.Aclinicaltrialinthis rarepopulationmaynotbepossible.

Patient summary: In a population of patients with advanced papillary kidney cancer,wefoundthatsurgicalremovaloftheprimarykidneytumorwasassociated withbetteroverallsurvival.

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3. Results

Atthetimeofanalysis,atotalof8798patientswithmRCC were included in the overall IMDC data set. Within this population,647patientswereidentifiedashavingpapillary histology.Ofthissubset,538underwentnephrectomy.Those who had a prior nephrectomy and then subsequently developed metastatic disease were excluded (n=294) to isolate patients with synchronous metastatic disease. The finalnumbersfortheanalysisincluded109patientswithout CNand244withCN.Themediannumberofpatientsincluded bythecontributinginstitutionswasnine.Themedian follow-upforallpatientswas57.1mo(95%confidenceinterval[CI] 32.9–77.8).ThemedianOSfromthestartoffirst-linetargeted therapyfortheentirecohortwas13.2mo(95%CI12.0–16.1).

Table1comparesbaselinecharacteristicsfortheCNand no-CNgroups.Table2summarizesthetypeoftargetedtherapy received and the number of subsequent lines of therapy. PatientswhounderwentCNweremorelikelytobeyounger (p=0.0001)withbetterperformancestatus(p=0.0231).There wasalsoahighernumberofbonemetastasesintheCNgroup (p=0.0281).Theproportionsoftype1andtype2histology weresimilarbetweenthetwogroups(p=0.902).Sunitinib was the mostcommon first-line targetedtherapy used inboth groups.TheORRtofirst-linetherapydidnotdifferbetweenCN andno-CN(12%vs5.9%;p=0.2847).

ThemedianOSfortheCNgroupwas16.3mo,compared to 8.6mo in the no-CN group (Fig. 1; p<0.0001). On multivariableanalysisadjustedforIMDCprognosticfactors, theHRfordeathwas0.62(95%CI0.45–0.85;p=0.0031), translatingintoa38%decreaseintheriskofdeathwithCN. After adjusting for additional prognostic imbalances in-cluding theIMDCcriteria, age,and thepresence ofbone metastases, the HR improved to 0.55 (95% CI 0.39–0.78; p=0.0006).Withregardto secondaryoutcomes,PFSalso

appeared to be prolonged in the CN group at 5.1mo, comparedto3.4mointheno-CNgroup(Fig.2;p=0.0344). AfteradjustingfortheIMDCfactors,theHRforPFSwas0.82 (95%CI0.61–1.10;p=0.1822).Whenageandthepresenceof bonemetastaseswereaddedtotheregressionmodel,the HR for PFS was 0.73 (95% CI 0.53–1.01; p=0.0555). For comparative purposes, we performed an analysis of CN versusno-CNintheccRCCpopulation.InthisccRCCsubset, median OS was 21.8mo in the CN group, compared to 10.0mointheno-CNgroup(p<0.0001).

Wealsoperformedasubgroupanalysisbydividingthe CN cohort into immediate systemic therapy (defined as within 90d of surgery) and delayed systemic therapy (definedas>90dfromCN)groups.Therewasnosignificant survivaldifferencebetweenthesetwosubgroups.

4. Discussion

TheroleofCNinthecontemporarymanagementofadvanced kidneycancerhasbeenwellstudiedinretrospectivestudies,

Table2–BaselinetreatmentcharacteristicsfortheCNandno-CN groups. NoCN (N=109) CN (N=244) pvalue First-linetherapy,n/N(%) Sunitinib 59/109(54) 134/244(55) Sorafenib 3/109(2.8) 31/244(13) Temsirolimus 25/109(23) 31/244(13) Pazopanib 12/109(11) 19/244(7.8) Other 10/109(9.1) 29/244(12) Second-linetherapy,n/N(%) 43/109(39) 137/244(56) 0.0037 Third-linetherapy,n/N(%) 17/109(16) 58/244(24) 0.0828 Fourth-linetherapy,n/N(%) 4/109(3.7) 16/244(6.6) 0.2783 CN=cytoreductivenephrectomy.

Table1–BaselinecharacteristicsfortheCNandnon-CNgroups. NoCN (N=109) CN (N=244) pvalue Male,n(%) 86/109(79) 173/244(71) 0.1163

Medianage(yr) 67 59 0.0001

Karnofskyperformancestatus<80%,n/N(%) 28/90(31) 41/214(19) 0.0231

Diagnosistotargetedtherapy<1yr,n/N(%) 99/109(91) 204/244(84) 0.0723

Calcium>ULN,n/N(%) 16/89(18) 30/193(16) 0.6072 Hemoglobin<LLN,n/N(%) 69/99(70) 136/216(63) 0.2445 Neutrophils>ULN,n/N(%) 25/98(26) 38/209(18) 0.1383 Platelets>ULN,n/N(%) 26/98(27) 42/213(20) 0.1769 Histologicsubtype,n/N(%) 0.902 Type1 6/41(14.6) 13/94(13.8) Type2 35/41(85.4) 81/94(86.2) Livermetastases,n/N(%) 21/105(20) 50/207(24%) 0.4082 Bonemetastases,n/N(%) 30/107(28) 86/212(41%) 0.0281 Brainmetastases,n/N(%) 3/106(2.8) 5/204(2.5%) 0.8417

Morethanonesiteofmetastasis,n/N(%) 87/108(81) 169/222(76.1%) 0.3653

IMDCriskgroup,n/N(%) 0.2627

Favorablerisk 4/78(5.1) 10/175(5.7)

Intermediaterisk 37/78(47) 101/175(58)

Poorrisk 37/78(47) 64/175(37)

CN=cytoreductivenephrectomy;ULN=upperlimitofnormal;LLN=lowerlimitofnormal;IMDC=InternationalMetastaticRenalCellCarcinomaDatabase Consortium.

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analysesofreal-worlddata,andrandomizedcontrolledtrials. Priorretrospectiveanalysesofdifferentdatasets,including the IMDC and the National Cancer Data Base, have consistently revealed that CN appears to offer a survival benefitinccRCC[5,10].

Although more limited than the literature on ccRCC, previous retrospective analyses have also suggested a benefitofCNinnccRCC[11,12].Itisimportanttonotethat nccRCCrepresentsadiversespectrumofpathologicaland clinicalentities,withpapillaryRCCbeingthemostcommon subtype. Aizer et al. [12] analyzed the role of CN in metastatic nccRCC using the Surveillance, Epidemiology, andEnd Results (SEER) database.In this more heteroge-neous population, CN was associatedwith lower cancer-specificandall-causemortality(HR0.45,95%CI0.37–0.55; p<0.001).Marchionietal.[11]alsoexaminedtheroleofCN innccRCCpatients usinganupdatedanalysis oftheSEER

database. They again demonstrated a cancer-specific mortality benefit with CN (HR 0.38, 95% CI 0.30–0.47; p<0.001).Inasubgroupanalysislookingatpatientswith papillaryRCC,CNwasalsoassociatedwithbetter cancer-specific mortality(HR 0.40,95%CI 0.30–0.53; p<0.001). None of thesestudies adjustedfor potentialconfounders such as IMDC criteria, specifically for the time between diagnosisandsystemictherapy.

Theresultsofouranalysisforpatientswithexclusively papillaryRCCareconsistentwiththesefindings.Incontrast totheSEERdatabase,theIMDCisabletocontrolformore specificprognosticvariables,includingperformancestatus at initiationof systemictherapyandbiochemical param-eters.Inourstudy,thegroupreceivingCNwereyoungerand had better performance status, probably reflecting an element of bias in surgical selection. We demonstrated that patients undergoing CN had significantly better OS,

Fig.1–Kaplan-Meiercurveforoverallsurvival(OS)fortheCNandno-CNgroups.CN=cytoreductivenephrectomy;HR=hazardratio;CI=confidence interval;IMDC=InternationalMetastaticRenalCellCarcinomaDatabaseConsortium.

Fig.2–Kaplan-Meiercurveforprogression-freesurvival(PFS)fortheCNandno-CNgroups.CN=cytoreductivenephrectomy;HR=hazardratio; CI=confidenceinterval;IMDC=InternationalMetastaticRenalCellCarcinomaDatabaseConsortium.

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evenwhencontrollingforprognosticimbalancesbetween thesegroups, including performancestatus, age,and the IMDCriskfactors.APFSbenefitinfavorofCNdidnotmeet statistical significance in the multivariable analysis. The proportion of type 1 and type 2 histology was similar betweenthesetwogroups,whichisimportantgiven the clinical significanceofthese subtypes. Tothebest of our knowledge,ourstudyrepresentsthelargestmultivariable analysisexploringCNinpapillaryRCC.Giventhatadvanced papillary RCC typically has lower response rates to traditionalVEGFtargetedtherapies,itmay beeven more importanttoachievelocaltumorcontrolandcytoreduction inthistumorsubtype[13].

In contrast to these findings, the recently reported CARMENArandomizedcontrolledtrial demonstratedthat sunitinibtherapyalone appearedto benoninferiorto CN followed by sunitinib in patients with intermediate and poorrisk[6].Theresultsinthesunitinib-alonegroupwere noninferiortothoseintheCNfollowedbysunitinibgroup withregardtoOS(stratifiedHRfordeath,0.89,95%CI0.71– 1.10;upperboundofthe95%CIfornoninferiority,1.20). Importantly,theCARMENAtrialexcludedpatientswith nccRCCandbydefinitionexcludedpatientswithfavorable risk.Inaddition,patientsrandomizedinthistrialmaynot accurately reflect ideal CN candidates in a real-world setting, possibly because of a perceived lack of clinical equipoise[14].Thiswasevidentintheslowaccrualtothe trial,whichrequiredareductioninitssamplesize,andthe unusuallyhighnumberofIMDCpoor-riskpatientsinthe cohort(43%).PriorstudiesusingtheIMDCdatabasehave suggestedthatpatientswithpoorerrisk,includingthose with four or more IMDC risk factors, do not appear to derivebenefitfromCN[5].Thus,utilizationofCNinthis poor-risk population may have helpedthe trial meet its noninferiorityendpoint.The efficacyofsystemictherapy inpapillaryRCCissuboptimal,highlightingtheimportance of CN as a potential therapeutic strategy in metastatic disease.

Ingeneral,CNmaybeconsideredforpatientswithgood performancestatusandlimitedorslow-growingmetastatic disease.Symptomaticpatientswithongoinghematuriaor flank pain may also benefit from CN. It is important to discussthesecasesinamultidisciplinary tumorboardto considerCNfeasibility, comorbidities,andan estimateof theoverall prognosisto gainaninsightinto whetherthe patientswillbenefitfromsurgery.Thus,forpatientswith papillaryRCC,carefulpatientselectionforCNiscrucial.

Anotherrandomized trial (SURTIME trial)randomized mRCC patients to immediate CN followed by sunitinib versus delayed CN after three cycles of initial sunitinib

[15,16].AtrendtowardsbetterOSforthosewithdeferred nephrectomy was observed. This may in part be due to patientselectionafterinitialsunitinib,inthatpatientswho hadafavorabletumorresponsewenton toCN,whileCN wasaborted for those whohad progressivedisease. This trialmaygivetreatingphysiciansthecomfortthatdelaying adecisiononCNmaybereasonable,especiallyforpatients with intermediateor poor risk. Similar to the CARMENA trial,SURTIMEincludedpatientswithccRCConly,andthus

may not be fully generalizable to those with nccRCC or papillaryhistology.

Limitationsofourstudyincludetheretrospectivenature oftheanalysisandthepresenceofinherent,unmeasured confounders that could not be adjusted for, despite multivariableanalysis.Selectionbiasisanotherimportant limitationthatisintrinsictotheretrospectivedesignofthe study. The IMDC uses a consecutive patient series to minimize selectionbias. Giventheselimitations, acausal relationshipbetweenCNandsurvivalcannotbedefinitively established.Therewasnocentralpathologyreview,asthis wasamulti-institutionalstudy.Ourdatasetonlyincludes patientswhoarereceivingactivesystemictherapy,andthus does not include patients with mRCC undergoing active surveillance. Owing to low patient numbers, we were unable to perform a subgroup analysis looking at the relationshipbetweenanumberofindividualIMDCfactors andbenefitfromCN.Wewerealsounable toaccountfor outcomes such as perioperative mortality and surgery-relatedmorbidity.

5. Conclusions

Insummary,inourdatasetitappearsthatCNisassociated withbettersurvivalinmetastaticpapillaryRCC,evenwhen controllingforknownprognosticimbalancesbetweenthe groups.Giventhelowerresponseratestotargetedtherapyin papillary RCC, achieving local tumor control may be particularly important in this pathologicalsubtype. Asin themorecommonlystudiedccRCCpopulation,selectionof patientsforCNwillbecritical.Unfortunately,aprospective clinicaltrialinthisraresubgroupmaynotbepossible.Asthe treatmentlandscapeformRCCevolves,itwillbeimportantto reevaluate therole ofCN inpapillary RCC,particularly in combinationwithnovelIOandMETtargetedtherapy.

Authorcontributions:DanielY.C.Henghadfullaccesstoallthedatain thestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Allauthors. Acquisitionofdata:Allauthors.

Analysisandinterpretationofdata:Heng,Graham. Draftingofthemanuscript:Heng,Graham.

Criticalrevisionofthemanuscriptforimportantintellectualcontent:All authors.

Statisticalanalysis:Heng,Graham. Obtainingfunding:None.

Administrative,technical,ormaterialsupport:Heng,Graham. Supervision:Heng.

Other:None.

Financial disclosures: Daniel Y.C.Heng certifies that all conflicts of interest, including specific financial interests and relationships and affiliationsrelevanttothesubjectmatterormaterialsdiscussedinthe manuscript(eg,employment/affiliation,grantsorfunding, consultan-cies,honoraria,stockownershiporoptions,experttestimony,royalties, orpatentsfiled,received,orpending),arethefollowing:JaeLyunLeehas receivedhonorariafromAstellasPharma,Bristol-MyersSquibb,Novartis, andPfizer;hasactedinaconsultingoradvisoryroleforAstellasPharma, AstraZeneca,andEisai;andhasreceivedresearchfundingfrom Bristol-MyersSquibb,Exelixis,Janssen,Novartis,Pfizer,andRoche/Genentech.

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CamilloPortahasactedinaconsultingoradvisoryroleforBristol-Myers Squibb,Eisai,EUSAPharma,Ipsen,Janssen,Novartis,Peloton Therapeu-tics,andPfizer. GeorgA.Bjarnasonhasreceivedhonorariafromand actedinaconsultingoradvisoryroleforBristol-MyersSquibb,Novartis, andPfizer;hasreceivedinstitutionalresearchfundingfromMerckand Pfizer; and has received travel and accommodation expenses from NovartisandPfizer.D.ScottErnsthasactedinaconsultingoradvisory roleforAstraZeneca/MedImmune,Bristol-MyersSquibb,Merck,Novartis Canada Pharmaceuticals, and Roche Canada. Benoit Beuselinck has receivedhonorariaformAmgen,Bayer,Janssen,andPfizer.ScottA.North hasreceivedhonorariafromAstellasPharma,Janssen-Ortho,Novartis, Pfizer,andSanoCanada;hasactedinaconsultingoradvisoryrolefor AstellasPharma,AstraZeneca,JanssenOncology,Merck,Novartis,Pfizer, Roche Canada, and Sanofi Canada; and has received institutional researchfundingfromAstellasPharma,AstraZeneca,Janssen,Novartis CanadaPharmaceuticals,RocheCanada,andSanofiCanada.ChristianK. Kollmannsberger has received honoraria from Bristol-Myers Squibb, Novartis,andPfizer;hasactedinaconsultingoradvisoryroleforAstellas Pharma,Bristol-MyersSquibb,Novartis,Pfizer,andSeattleGenetics;and hasreceivedtravelandaccommodationexpensesfromNovartisand Pfizer.LoriA.Woodhasreceivedinstitutionalresearch fundingfrom AragonPharmaceuticals, AstraZeneca,Bristol-Myers Squibb, Exelixis, Merck,Novartis,Pfizer,andRocheCanada.UlkaN.Vaishampayanhas receivedhonorariafromAstellasPharma,Bayer,Bristol-MyersSquibb, Exelixis,Genentech,Janssen,Novartis,Pfizer,andSanofi;hasactedina consultingoradvisoryroleandparticipatedinaspeakers’bureaufor AstellasPharma,Bayer,Bristol-MyersSquibb,Exelixis,Genentech/Roche, andPfizer;andhasreceivedresearch fundingfromAstellasPharma, Bristol-MyersSquibb,Exelixis,Novartis,andPfizer.SumantaK.Palhas receivedhonorariafromAstellasPharma,Medivation,andNovartis;has actedinaconsultingoradvisoryroleforAstellasPharma,Aveo, Bristol-MyersSquibb,Eisai,Exelixis,Genentech,Ipsen,MyriadPharmaceuticals, Novartis,andPfizer;andhasreceivedresearchfundingfromMedivation. ToniK.ChoueirihasreceivedhonorariafromNCCNandUpToDate;has actedinaconsultingoradvisoryroleforAlligent,AstraZeneca,Bayer, Bristol-Myers Squibb, Cerulean Pharma, Eisai, Exelixis, Foundation Medicine, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics, Pfizer, Prometheus Laboratories,andRoche/Genentech; hasreceived institutionalresearchfundingfromAgensys,AstraZeneca,Bristol-Myers Squibb, Celldex, Exelixis, GlaxoSmithKline, Merck, Novartis, Peloton Therapeutics,Pfizer,Roche/Genentech,andTRACONPharma;andhas receivedtravelandaccommodationexpenseswhenactinginanadvisory orconsultingrole.DanielY.C.Henghasactedinaconsultingoradvisory roleforAstellasPharma,Bristol-MyersSquibb,Janssen,Novartis,and Pfizer; andhas receivedinstitutionalresearch funding from Bristol-MyersSquibb,Exelixis,Novartis,andPfizer.Theremainingauthorshave nothingtodisclose.

Funding/Supportandroleofthesponsor:None.

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Figura

Table 2 – Baseline treatment characteristics for the CN and no-CN groups. No CN (N = 109) CN(N= 244) p value First-line therapy, n/N (%) Sunitinib 59/109 (54) 134/244 (55) Sorafenib 3/109 (2.8) 31/244 (13) Temsirolimus 25/109 (23) 31/244 (13) Pazopanib 12/
Fig. 1 – Kaplan-Meier curve for overall survival (OS) for the CN and no-CN groups. CN = cytoreductive nephrectomy; HR = hazard ratio; CI = confidence interval; IMDC = International Metastatic Renal Cell Carcinoma Database Consortium.

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