Radical prostatectomy for locally advanced and high-risk prostate cancer: A systematic review of the literature

(1)

Progrèsenurologie(2018)28,875—889

Disponibleenlignesur

ScienceDirect

www.sciencedirect.com

LITERATURE REVIEW

Radical prostatectomy for locally advanced and high-risk prostate cancer: A systematic review of the literature

Prostatectomie totale pour cancer de prostate a haut risque et localement avancé : revue de littérature

G. Delporte

^a^,∗

, F. Henon

^a

, G. Ploussard

^b^,^c

, A. Briganti

^d

, J. Rizk

^a

, F. Rozet

^e

, K. Touijer

^f

, A. Ouzzane

^a

aDepartmentofurology,CHRUdeLille,hôpitalClaude-Huriez,59037Lille,France

bInstitutuniversitaireducancerdeToulouse,Oncopole,31100Toulouse,France

cDepartmentofurology,Saint-JeanLanguedochospital,31400Toulouse,France

dDepartmentofurology,Vita-SaluteuniversitySanRaffaele,Milan,Italy

eDepartmentofurology,institutMutualisteMontsouris,75014Paris,France

fUrologyService,DepartmentofSurgery,MemorialSloanKetteringCancerCenter,NewYork, NY,USA

Received14January2018;accepted9August2018 Availableonline24September2018

KEYWORDS High-risk;

Oncologicoutcomes;

Prostatecancer;

Radical prostatectomy;

Survival

Summary

Context.—Theroleofradicalprostatectomy(RP)inhigh-riskprostatecancer(PCa)isincreas- ing.

Purpose.—Toreviewtheexisting literatureanddeterminethevalue ofRP inhigh-riskand locallyadvancedPCa.

Documentarysource.—MEDLINE,EmbaseandtheCochraneCentralRegisterofControlledTrials weresearchedfrom01/2000through05/2016accordingtothePRISMAguidelines.

Selectionofstudies.—Forty-twostudiesdescribingoutcomesofRPamong52,546patientswith high-riskandlocallyadvancedPCa.

∗Correspondingauthor.Departmentofurology,Lilleuniversityhospital,rueMichelPolonovski,59000Lille,France.

E-mailaddress:gauthier.delporte@hotmail.fr(G.Delporte).

https://doi.org/10.1016/j.purol.2018.08.007

(2)

876 G.Delporteetal.

Results.—Mortalitywasapproximately0—1%andClavien≥3complicationsrangedfrom1.8%

to12%.Biochemicalrecurrence-freeandmetastasis-freesurvivalrangedfrom40to94%and90 to96.1%at5yearsandfrom27to68%and64.4to85.1%at10years,respectively.Overalland cancerspeciﬁcsurvivalrangedfrom55.2to98.6%and89.8to100%at5yearsandfrom58to 84%and65to96%at10years,respectively.The12-mocontinenceratesrangedfrom32%to 96.2%andtheerectilefunctionrecoveryrangedfrom60%to64%.

Limits.—Studieswereheterogeneousespeciallyregardingthedeﬁnitionofhigh-riskdisease andtheuseofadjuvanttreatments.

Conclusions.—TheutilizationofRPinhigh-riskandlocallyadvancedPCaisincreasing.Existing datasupporttheadvantagesofRPinthisgroupofpatients.However,uniformityindeﬁnitions andindicationsareaprerequisiteinordertoestablishitsroleasanimportanttherapeuticarm inamultimodalitymanagementstrategy.

MOTSCLÉS Hautrisque; Résultats oncologiques; Cancerdeprostate; Prostatectomie; Survie

Résumé

Contexte.—Lerôledelaprostatectomietotale(PT)danslecancerdelaprostate(CaP)àhaut risqueestenaugmentation.

Objectif.—DéterminerlaplacedelaPTdansleCaPàhautrisqueetlocalementavancé.

Sourcesdocumentaires.—MEDLINE, Embase etleregistrecentraldes essaiscontrôlésdela Cochraneontétéanalysédejanvier2000àmai2016selonlesdirectivesPRISMA.

Sélectiondesétudes.—Quarante-deux études rapportant les résultats de la PT chez 52546patientsatteintsdeCaPàhautrisqueetlocalementavancés.

Résultats.—Lamortalitéétaitd’environ0—1%.LescomplicationsClavien≥3allaientde1,8% à12%.Lasurviesansrécidivebiochimiqueetsansmétastasesvariaitde40à94%etde90à 96,1%à5ansetde27à68%etde64,4à85,1%à10ans,respectivement.Lasurvieglobale etspéciﬁque variaitde55,2à98,6%etde89,8à100%à5ansetde58à84%etde65à 96%à10ans,respectivement.Lestauxdecontinenceà12moisvariaientde32%à96,2%.La récupérationdelafonctionérectilevariaitde60%à64%.

Limitesdutravail.—Les études étaient hétérogènes,en particulier en ce qui concerne la déﬁnitiondelamaladieàhautrisqueetl’utilisationdetraitementsadjuvants.

Conclusion.—Les donnéesexistantessoutiennent lesavantagesde laPT danscegroupe de patients.L’uniformitédesdéﬁnitionsetdesindicationsestuneconditionpréalablepourétablir son rôle en tant que bras thérapeutique important dans une stratégie de prise en charge multimodale.

Introduction

Prostatecancer(PCa)isthemostcommoncancerdiagnosed inmenintheUnitedStates,andthesecondmost-common cause of cancer-speciﬁc mortality. The discovery of PSA inthe late 1970sandits subsequentuse asa population- screeningtoolhashadprofoundeffectontheepidemiology of the disease. Consequently, PSA screening has led to an increase in the proportion of men diagnosed withlow stageand low grade diseasewith an estimated lead-time bias of approximately 11 years. The proportion of men withadvanced riskfeatureshowever, hasremainedstable over time. Recent controversies regarding PSA screening has also led to a stage migration toward more high-risk PCadiagnosedinrecentyears.Accuratepre-treatmentrisk assessmentforthesehigh-riskPCacasesischallengingand thereisnouniversallyacceptedclassiﬁcation.Thereare3

well-deﬁnedpredictorsofdiseaseoutcomeaftertreatment:

clinicaltumorstage,Gleasonscoreofthediagnosticbiopsy specimen, and serum PSA level. The deﬁnition of high- riskprostate cancerisusuallybasedontheseparameters.

D’Amicoetal.firstcombinedthemascategoricalvariables andpatientswithPSAabove20ng/mLorGleasonscoreofat least8orclinicalstageofatleastT2cweredefinedashigh- risk. Sincethen, other high-risk classifications have been proposed,basednotonlyonriskgroupingbutalsoonpatient riskstratificationaccordingtonomograms-derivedprobabil- itiesoftreatmentfailure.Inthepast,patientswithlocally advancedorhigh-riskprostatecancerweremostfrequently managedwithExternalBeamRadiotherapy(EBRT)combined withlong-term Androgen DeprivationTherapy (ADT).This default strategy stems from the lack of level I evidence comparingradiationtherapy tosurgeryandfromhistorical concernsaboutthemorbidityofradicalprostatectomy(RP)

(3)

Prostatectomyinlocallyadvancedorhigh-riskcancer:Reviewoftheliterature 877

Figure1. Studyﬂowchart.

inthelocallyadvancedsetting,alongwithalimitedappre- ciationofthecumulativebeneﬁtofmultimodalitytherapy.

Retrospectivelong-termcancercontroldatahowever,sup- port the role of RP alone or in combination with other therapeuticmodalitiesinthemanagementofhigh-riskand locallyadvancedPCa[1].

Theaimofthissystematicreviewwastoassesstherole ofRPinthemanagementofhigh-riskandlocallyadvanced PCapatientsbyevaluatingoncological,peri-operativeand functionaloutcomesofthissurgicalapproach.

Materials and methods

MEDLINE,EmbaseandtheCochraneCentralRegisterofCon- trolled Trials were searched from January 2000 through May 2016 according to the PRISMA (Preferred Reporting ItemsforSystematicReviewsandMeta-analysis)statement guidelines. The systematic review used both subject and text-word terms for ‘‘radical prostatectomy’’, ‘‘prostate cancer’’,‘‘surgery’’,‘‘outcome’’,‘‘high risk’’and‘‘high- grade’’incombination withkeywordsearchingtoidentify articles describing oncological and functional outcomes of RP among patients withhigh-risk and locally-advanced prostate cancer. Search resultswere restricted to English language.Referencesofallselectedarticleswerechecked foradditionalcross-references.Giventhelowlevelofstan- dardizationinthedeﬁnitionofhigh-riskorlocallyadvanced diseaseandtheuseofadjuvanttherapy,noexclusionregard- ingthesetwoparameterswasperformed.Twoauthors(FH andGD) independentlyselected studiesanddiscrepancies between the two investigators were resolved via consen- susamongparticipatingauthors.Fig.1presentsthesearch strategyﬂowchart.

Results

Studies characteristics

Ourliteraturesearchidentified42original articlesreport- ing results for 52,546 patients (Table 1). Studies were heterogeneousespeciallyregardingthedefinitionusedfor high-risk disease. Seventeen used the D’Amico definition [2—18], 9 used the National comprehensive cancer net- work(NCCN)definition[19—27],16usedadefinitionbased on the presence of at least 1 or 2 criteria of high-risk disease [28—43]. Three studies included 2 subgroups for analysis: Bastian et al. [29] reported results of patients from2 centers,Pierorazio et al. [10] reported results of 2 different eras (before and after 2000), Chulkoo et al.

[26]reported2groupsofpatients:high-riskprostatecancer group(PSA≥20ng/mLor Gleason 8—10or cT3a)andvery high-riskprostatecancergroup(≥cT3band/orcN1).

Patient characteristics and perioperative outcomes

PatientcharacteristicsaresummarizedinTable1.Thenum- berof patients included in each study ranged from 41 to 30,379.Medianageofpatientsrangedfrom56to73.5years.

Thepre-operativePSAlevelwas≥20ng/mLin7.9%to100%

ofpatients.Clinicalstageofincludedpatientswas≥T2cin 3%to76% and≥T3cin3.8% to100% ofcases.Therewere nodataregardingclinicalstagein4studies.BiopsyGleason score≥8rangedfrom9to100%.

Perioperativedata arepresentedin Table 2.Regarding thesurgical approach, 14studies showedresults for open retropubicRP,4studies forlaparoscopicRP (withor with- outroboticassistance)and4studiesreportedresultsusing both modalities. There were missing data for 20 studies

(4)

878G.Delporteetal.

Table1 Studiescharacteristics.

Author(yr) Deﬁnitionof high-riskdisease

Number of patients

Age (median)

Preoperatory PSA≥20ng/mL n(%)

ClinicalTstagen(%) BiopsyGleason score≥8n(%)

Preoperatory medianor/and meanPSA(ng/mL)

Yossepowitch(2007) D’Amico 957 61 275(28.7%) ≥T3:144(15%) 274(28.6%) 6.19(median)

Yossepowitch(2008) D’Amico 1359 61 441(32.5%) ≥T3:243(17.8%) 401(29.5%) NA

Lodde(2008) D’Amico 290 NA 152(52.4%) ≥T3:45(15.5%) 99(34.1%) NA

Loeb(2010) D’Amico 175 59 58(33%) ≥T2c:66(38%) 63(36%) NA

Spahn(2010) D’Amico 372 67 NA ≥T2c:282(76%) 92(28%) 34.1(median)

Walz(2010) D’Amico 887 62.8 NA ≥T3:293(33%) 269(30.3%) 17.9(median)

Ploussard(2009) D’Amico 110 61.6 NA ≥T3:8(7%) 40(36%) 23.2(median)

Ploussard(2011) D’Amico 813 63.6 389(47.8%) ≥T2c:274(33.7%) 283(34.6%) 17.6(median)

21.7(mean) Pierorazo(2011)

Before2000area

D’Amico 667 59 NA ≥T2c:260(39%) 214(32.2%) NA

Pierorazo(2011) After2000area

D’Amico 764 59.5 NA ≥T2c:108(14.6%) 535(70%) NA

Masson-Lecompte (2010)

D’Amico 138 63.4 50(36%) ≥T3:90(66%) 19(14%) 15.5(mean)

Roder(2013) D’Amico 231 63 112(48.5%) ≥T2c:108(46.7%) 61(26.4%) 20(median)

Abdollah(2015) D’Amico 1100 63 187(16.9%) ≥T2c:437(39.8%) 635(57.7%) 6.5(median)

DiBenedetto(2015) D’Amico 446 64 NA ≥T2c:335(75.1%) 223(50%) 8.1(median)

Briganti(2014) D’Amico 2065 64.5 NA ≥T2c:853(41.3%) 956(46.3%) 16.3(mean)

Busch(2014) D’Amico 330 65 NA ≥T2c:24(7.3%) 286(86.6%) 8.4(median)

Park(2013) D’Amico 55 68.1 NA ≥T3:11(20%) 37(67.3%) 10.6(median)

Kulkarni(2015) D’Amico 208 63 97(46.4%) ≥T3:10(4.8%) 60(28.2%) NA

Arcangeli(2009) NCCN 122 65.5 58(47%) ≥T2c:12(10%) 11(9%) NA

Kawamorita(2009) NCCN 46 65.5 9(19.6%) ≥T3:8(17.4%) 9(19.6%) 8.1(median)

Briganti(2012) NCCN 1366 66 745(54.6%) ≥T3:779(57%) 347(25.4%) 21.3(median)

24.9(mean)

Castelli(2014) NCCN 244 68 122(50%) ≥T3:22(9%) 153(52.7%) 20(median)

Lee(2014) NCCN 251 67.5 NA ≥T3:157(62.5%) 107(42.6%) 12.3(median)

Briganti(2013) NCCN 3828 65 NA ≥T3:1362(35.6%) 1537(40.2%) 18.2(median)

Boorjian(2011) NCCN 1238 66 NA ≥T3:411(33.2%) 464(37.5%) NA

ChulKoo(2014) Highriskdisease

NCCN—Highrisk disease

(PSA≥20ng/mLor Gleason8—10or cT3a)

101 73.2 NA NA 55(55%) 16.8(median)

ChulKoo(2014) Veryhighrisk disease

NCCN—Veryhigh riskdisease(≥cT3b orcN1)

53 73.5 NA NA 31(60%) 26.3(median)

(5)

Prostatectomyinlocallyadvancedorhigh-riskcancer:Reviewoftheliterature879

Table1(Continued)

Author(yr) Deﬁnitionof high-riskdisease

Number of patients

Age (median)

Preoperatory PSA≥20ng/mL n(%)

ClinicalTstagen(%) BiopsyGleason score≥8n(%)

Preoperatory medianor/and meanPSA(ng/mL)

Dell’Oglio(2016) NCCN 600 56 NA ≥T3:375(62.5%) 258(43%) 9.8(median)

Manoharan(2003) BiopsyGleason score≥8

79 63 13(16.5%) ≥T3:3(3.8%) 79(100%) 12.7(mean)

Bastian(2006) BiopsyGleason score≥8

369 61.8 NA ≥T2c:50(13.5%) 369(100%) 9(median)13

(mean) Westover(2011) BiopsyGleason

score≥8

285 65 42(15%) ≥T2c:9(3%) 285(100%) 7.9(median)

Pokala(2013) BiopsyGleason score≥8

30379 62.5 NA ≥T3:8422(27.7%) 30379(100%) NA

Carver(2006) cT3 176 61 NA ≥T3:176(100%) 26(15%) 12.7(median)

Freedland(2007) cT3a 58 55.9 NA T3a:58(100%) 13(22%) 9.5(median)14

(mean)

Moltzahn(2014) cT3bandcT4 266 65 NA T3b:241(90.6%)T4:

25(9.4%)

68(25.6%) NA

Joniau(2012) cT3bandcT4 51 64.2 NA T3b:41(80.4%)T4:

10(19.6%)

NA 16.9(median)

Brandli(2003) PSA≥20ng/mL 50 63 50(100%) T1—T2:50(100%) 13(26%) 37.9(mean)

Zwergel(2007) PSA≥20ng/mL 275 64 275(100%) NA NA NA

Nguyen(2009) PSA≥20ng/mL 41 62 41(100%) ≥T2c:19(46%) 2(5%) 24(median)27.4

(mean)

Spahn(2010) PSA≥20ng/mL 712 65.6 712(100%) ≥T3:315(44.2%) 140(19.7%) 46.6(mean)

Berglund(2006) ≥cT2b—Biopsy Gleasonscore≥8 PSA≥15ng/mL

281 61 NA NA NA 22.7(mean)

Loeb(2007) ≥cT2b—Biopsy Gleasonscore≥8 PSA≥15ng/mL

288 63 NA NA NA 17.5(median)19.8

(mean) Miocinovic(2011) ≥cT2b—Biopsy

Gleasonscore≥8 PSA≥15ng/mL

267 62 64(24%) ≥cT2b:129(48%) 94(36%) NA

Savdie(2012) ≥cT2b—Biopsy Gleasonscore≥8 PSA≥20ng/mL

153 62.2 12(7.9%) ≥T3:10(6.7%) 45(29.4%) 8.1(median)

NA:notavailable;NCCN:nationalcomprehensivecancernetwork.

(6)

880G.Delporteetal.

Table2 Perioperativeoutcomes.

Author(yr) Surgery

modality

Bilateral standard PLND

≥pT3n(%) Gleason score≥8n (%)

pN+n(%) Positivesurgical marginsn(%)

Complications n(%)

Yossepowitch(2007) NA Yes 550(57%) 200(21%) 111(12%) 275(29%) NA

Yossepowitch(2008) NA Yes NA NA NA NA NA

Lodde(2008) NA Yes 215(74.2%) 73(25.1%) 96(33%) NA NA

Loeb(2010) ORP Yes 87(50%) NA 25(14%) 32(18%) NA

Spahn(2010) ORP Yes 318(85.5%) NA 139(37.4%) 178(57.2%) NA

Walz(2010) NA Yes 468(52.8%) 186(21%) 104(11.7%) 343(38.7%) NA

Ploussard(2009) LRP Yes 72(65.5%) 36(33%) 4(3.6%) 43(39%) NA

Ploussard(2011) NA Yes 516(63.5%) 290(35.6%) 84(10.3%) 371(45.6%) NA

Pierorazo(2011) Before2000area

NA Yes 412(61.8%) 173(26.1%) 69(10.4%) NA NA

NA Yes 395(51.7%) 379(50.3%) 65(8.7%) NA NA

ORP(80%)

—LRP(20%)

Yes 92(67%) 39(28%) 21(15%) 67(49%) NA

Roder(2013) ORP Yes 129(66%) 57(24.7%) 10(4.3%) 115(49.8%) NA

Abdollah(2015) RARP Yes

(93.6%)

NA 402(36.5%) 127(11.5%) 383(34.8%) NA

DiBenedetto(2015) LRP Yes 394(88.3%) NA 72(16.2%) 116(26%) 7.6%—

Clavien>2:29 (6.5%)

Briganti(2014) NA Yes 1148(55.6%) 400(19.4%) 207(10%) 1129(54.7%) NA

Busch(2014) ORP—LRP

—RARP

Yes (94.2%)

159(48.2%) 151(45.8%) 37(11.2%) 134(40.6%) NA

Park(2013) ORP Yes 37(67.3%) 39(70.9%) 3(5.4%) 19(34.5%) 1.8%—Clavien

3

Kulkarni(2015) ORP Yes NA 68(32.7%) 56(26.9%) 65(31.2%) NA

Arcangeli(2009) NA Yes NA NA NA NA NA

Kawamorita(2009) NA Yes 27(58.7%) 26(56.5%) 1(2.2%) NA NA

Briganti(2012) ORP Yes 1025(75%) 397(29.1%) 313(22.9%) 613(44.9%) NA

Castelli(2014) NA Yes 164(67.2%) 109(44.7%) 0%(excluded) 86(35.2%) NA

Lee(2014) ORP(24%)

—RARP (76%)

Yes NA NA NA NA NA

(7)

Table2(Continued)

Author(yr) Surgery

modality

Bilateral standard PLND

≥pT3n(%) Gleason score≥8n (%)

pN+n(%) Positivesurgical marginsn(%)

Complications n(%)

Briganti(2013) NA Yes 1834(47.9%) 931(24.3%) 745(19.5%) 2242(58.6%) NA

Boorjian(2011) ORP NA NA NA NA NA NA

RARP Yes NA 38(38%) 7(7%) 47(47%) Clavien1:4%;

Clavien2:1%

Clavien3:8%

ChulKoo(2014) Veryhighriskdisease

RARP Yes NA 29(54%) 13(25%) 43(60%) Clavien1:4%;

Clavien2:2%

Clavien3:12%

Dell’Oglio(2016) ORP Yes NA 257(42.8%) 174(29%) 259(43.2%) NA

Manoharan(2003) ORP Yes 34(43%) 54(68%) 2(2.5%) 32(40.5%) NA

Bastian(2006) NA Yes 235(63.7%) 211(57.2%) 46(12.5%) 131(35.5%) NA

Westover(2011) ORP Yes NA NA NA NA NA

Pokala(2013) NA Yes

(80.2%)

NA NA 2228(7.3%) NA NA

Carver(2006) ORP Yes 107(61%) 27(15%) 33(19%) 47(27%) NA

Freedland(2007) NA Yes 53(91%) 24(41%) 18(31%) 13(22%) NA

Moltzahn(2014) NA Yes 186(69.9%) 82(30.8%) 30(12.2%) 152(57.1%) NA

Joniau(2012) ORP Yes 47(92.2%) NA 11(21.6%) 32(62.7%) NA

Brandli(2003) NA Yes 14(28%) 48(96%) 2(4%) 23(46%) NA

Zwergel(2007) NA Yes 216(78%) 77(28%) 78(28.4%) NA Mortality(1

month):4 (1.4%)

Nguyen(2009) ORP—LRP Yes 20(48%) 3(7.5%) 5(12%) 15(36%) NA

Spahn(2010) NA Yes 561(78.7%) 183(25.7%) 175(25.6%) 392(55.1%) NA

Berglund(2006) NA Yes 225(80%) NA 23(8.9%) 52(18.5%) 9.7%;

mortality0%

Loeb(2007) ORP Yes 165(57%) 102(36%) 17(6%) 118(41%) 11%;mortality

0%

Miocinovic(2011) NA Yes NA NA NA NA NA

Savdie(2012) ORP Yes 74(51.6%) 35(22.9%) 3(1.9%) 75(49%) NA

NA:notavailable;PLND:pelviclymphnodedissection;ORP:openradicalprostatectomy;RARP:robot-assistedradicalprostatectomy;LRP:laparoscopicradicalprostatectomy.

(8)

882 G.Delporteetal.

regardingthesurgical approachused.Allstudies reported data on lymphadenectomy except one. Regarding pathological features, the proportion of Gleason score≥8, pathologicalstage≥T3,positive surgicalmargins andpN+

rangedfrom7.5%to96.0%,28.0%to92.2%,18.0%to62.7%

and1.9%to37.4%,respectively.

Postoperative complication rates were rarely reported (Table 2). Mortality within 30 days postoperatively was 0—1%andClavien≥3complicationsrangedfrom1.8%to12%.

Although,manyseriesdidnotusestandardizedclassiﬁcation for complication reporting, thus events may be underre- ported.

Adjuvant and salvage therapy

Adjuvanttherapywasadministratedin1.9%to100%ofcases in23studiesandconsistedofADT,EBRTorcombinationof both(Table3).Noadjuvanttherapywasusedin9studiesand datawasmissingin8studies.Salvagetherapywasdelivered in19studiesincaseofbiochemicalorclinicalrecurrencein 0.7%to87%ofcases.Nosalvagetherapywasdeliveredin4 studiesandtherewerenodataregardingsalvagetherapyin 17studies.

Oncological outcomes

The follow-up duration ranged from 25 to 186 months, and was not reported in 4 studies (Table 4). Biochemi- cal recurrence (BCR) was most often defined by a PSA concentration≥0.2ng/mL. Two studies took as threshold an elevation greater than 0.4ng/mL and a threshold of 0.1ng/mLwasreportedfor onestudy.Some authorshave reportedtheclinicalrecurrencethattheydefinedaseither localrecurrencedocumentedbyhistologyordistantmetas- tasis confirmed by imaging. Carver et al. [32] included hormonerefractorydiseasestatus.Mostofthestudieshave reportedonlymetastasisrecurrence.BCR-freesurvivaland clinicalrecurrence-freesurvivalrangedfrom32to94%and 78to94.2%at5yearsandfrom27to68%and72.5to87.4%at 10years,respectively.Metastasis-freesurvival(MFS)ranged from 90 to 96.1% at 5 years and from 64.4 to 85.1% at 10years.Overallsurvival(OS)andCancerspecificsurvival (CSS)rangedfrom73.6to98.6%and89.8to100%at5years andfrom58to84%and65to96.2%at10years,respectively.

Functional outcomes: continence and potency

Definitions used and technique of nerve sparing varied widely among studies, contributing to the heterogeneity of reportedoutcomes. Only 7 studies reportedfunctional outcomes(Table 4). Continence was definedby the free- domfromurineleakage(nopaduse)but2studiesdidnot provideanydefinition[18,19].The12-mocontinencerates rangedfrom32%to96.2%.Potencywasdefinedbytheability toachievevaginalpenetrationwithor withoutphosphodi- esterasetype-5inhibitorsdependingoftheseries.Erectile functionrecoveryafterRP,calculatedforpatientswhowere potentpreoperatively,rangedfrom60%to64%.

Discussion

Historically, RP has focused on the treatment of low and intermediate-risk, organ conﬁned PCa. Converseley, patientswithlocally advancedor high-gradediseasewere less likelytoreceive surgicalmanagementbecauseof the high-risk of treatment failure and positive surgical margins. These patients were mainly treated by ERBT. Such a paradigm was reinforced by the positive ﬁndings from a phase III randomized trial sponsored by the European Organization for the Research and Treatment of Cancer (EORTC)comparingEBRTalonetoEBRTplusimmediateADT in patients with high risk clinical T1c-T2 and clinical T3- 4, without regional lymph nodes involvement. This trial showed that the combination EBRT plus ADT was associ- ated withimproved 5-year diseasefree survivalfrom 40%

to73%andimproved5-yearOSfrom62%to78%[44].Sub- sequentlyit hasbeenextrapolatedthatthetreatmentfor high-riskandlocallyadvancedPCawasthecombinedmodal- ityADTplusEBRT.However,surgeryhasneverbeen tested to either ADT or EBRT+ADT in this patient group in any randomizedtrial anditremainedlargelyunstudiedin this patient population. Nevertheless, several studies showed theexcellentpost-operativeoutcomesofRPinhigh-riskPCa patients. In this review, we found that for high-risk men treatedwithRPeither aloneor incombinationwithadju- vant treatment(s),OSand CSSranged from73.6 to98.6%

and89.8to100%at5yearsandfrom58 to84%and65to 96.2%at10years,respectively.Althoughliteratureevidence highlightspromisingoutcomesafterRP,theresultsarevery heterogeneous and all studies are retrospective. Further- more,heterogeneityofhigh-riskandlocallyadvancedPCa definitions usedin publishedseriesmakes outcomescom- parisoninappropriate.Riskheterogeneitywasdemonstrated within risk groups, when risk was assessed by predictive models.Indeed,arecentstudyshowedthatamongpatients definedashigh-riskbasedonlyonaPSAlevel>20ng/mL,a significant proportionofthese menhadfavourable profile at final pathology. Thus, 33% had pT2 disease, 57.9% had pathological Gleason score<7, 54% had negative surgical margins, and 85% were lymph node negative [39]. Simi- lar studiesof patientsundergoingRP for locally advanced diseasehavefoundthatupto17%—30%hadapathologically- confirmedorganconfineddisease.Moreover,biopsyGleason scoreorclinicalstagealonehasnotalwaysproventobeuse- fulinpredictingdiseaseextentandoutcomeforindividual patients,sinceclinicalstagingbydigitalrectalexamination may underestimatethe presenceof extracapsular disease extentin30%to50%ofpatientsandtheincidenceofGlea- sonupgradingbetweenbiopsyandRPspecimenmayreach 45%insomeseries[45].

However,whethersurgeryaloneorincombinationwith adjuvanttreatment(s)isequallyormoreeffectivethanEBRT associatedwithlong-termADTiscurrentlyunknown.Previ- ousretrospectiveevidencehasshownpossibleadvantagesof RPoverEBRTwithregardstooncologicaloutcomes.Zelef- skyetal.comparedtheriskofmetastasisbetweensurgery and radiation therapy.This retrospective study comprised 2380mentreatedatMemorialSloanKetteringCancerCen- ter.Thosetreatedwithsurgeryhadasigniﬁcantlylowerrisk ofmetastasisat 8yearsthanpatientswhoreceivedradia- tiontherapy.The scopeof theriskreductionincreasedas

(9)

Prostatectomyinlocallyadvancedorhigh-riskcancer:Reviewoftheliterature883 Table3 Adjuvantorsalvagetreatmentmodalities.

Author(yr) Adjuvanttherapy Salvagetherapy

aRT aHT aRT+aHT sRT sHT sRT+sHT

Yossepowitch(2007) 0 0 0 NA NA NA

Yossepowitch(2008) NA NA NA 272(20%) 204(15%) NA

Lodde(2008) NA NA NA NA NA NA

Loeb(2010) 3(1.9%) 0 0 13(7.4%) 51(29%) NA

Spahn(2010) 0 299(80%) 0 NA NA NA

Walz(2010) NA NA NA NA NA NA

Ploussard(2009) 0 4(3.6%) 0 14(12.7%) 6(5.6%) 0

Ploussard(2011) 289(35.5%) 289(35.5%) 289(35.5%) 195(24%) 92(11.3%) 73(9%)

Pierorazo(2011)Before2000Area NA NA NA NA NA NA

Pierorazo(2011)After2000Area NA NA NA NA NA NA

Masson-Lecompte(2010) 0 21(15%) 0 31(22.5%) 4(3%) 10(7.2%)

Roder(2013) 0 10(4.3%) 0 32(13.8%) 51(22.1%) NA

Abdollah(2015) 53(4.81%) 12(1.11%) 0 177(16.1%) 109(9.9%) 185(16.8%)

DiBenedetto(2015) 8(1.8%) 10(2.2%) 0 34(7.6%) 37(8.3%) NA

Briganti(2014) 0 0 0 NA NA NA

Busch(2014) NA NA NA NA NA NA

Park(2013) 20(36.4%) 28(50.9%) 0 NA NA NA

Kulkarni(2015) 65(31.2%) NA NA NA NA NA

Arcangeli(2009) 83(68%) NA NA 0 0 0

Kawamorita(2009) 0 0 0 NA NA NA

Briganti(2012) 112(8.2%) 406(29.7%) 139(10.2%) NA NA NA

Castelli(2014) 0 0 74(30.4%) 0 0 34(13.9%)

Lee(2014) 0 0 0 26(10.4%) 0 0

Briganti(2013) 226(5.9%) 863(22.5%) 2739(71.6%) 0 0 0

Boorjian(2011) 85(6.9%) 367(29.6%) 51(4.1%) 253(20.4%) 415(33.5%) NA

ChulKoo(2014)HighRiskdisease 2(2%) 11(11%) 2(2%) 0 0 0

ChulKoo(2014)VeryHighRiskdisease 2(4%) 14(26%) 2(4%) 0 0 0

Dell’Oglio(2016) 157(26.2%) 202(33.7%) NA NA NA NA

Manoharan(2003) 0 0 0 0 0 0

Bastian(2006) 0 0 0 NA NA NA

Westover(2011) NA NA NA 13(4.6%) NA NA

Pokala(2013) 3915(12.9%) NA NA NA NA NA

Carver(2006) 0 0 0 17(10%) 65(77%) NA

Freedland(2007) 2(3.4%) 0 0 5(8.6%) 7(12.1%) 1(1.7%)

Moltzahn(2014) 45(16.9%) 106(39.8%) 21(7.9%) NA NA NA

Joniau(2012) 27(52.9%) 27(52.9%) 27(52.9%) 18(35.3%) 18(35.3%) 18(35.3%)

Brandli(2003) NA NA NA NA NA NA

Zwergel(2007) 2(0.7%) 129(46.9%) NA 0 36(13.1%) 0

Nguyen(2009) 0 0 0 6(14.6%) 18(43.9%) NA

Spahn(2010) 109(15.3%) 356(50%) NA 67(9.4%) 111(15.6%) NA

Berglund(2006) 0 0 0 0 2(0.7%) 0

Loeb(2007) 24(8.3%) 31(11%) 20(6.9%) 34(11.8%) 0 47(16.3%)

Miocinovic(2011) 8(3%) 8(3%) 0 32(12%) 46(17.2%) 17(6.4%)

Savdie(2012) NA NA NA NA NA NA

NA:notavailable;aRT:adjuvantradiotherapy;aHT:adjuvanthormonaltherapy;sRT:salvageradiotherapy;sHT:salvagehormonaltherapy.

(10)

884G.Delporteetal.

Table4 Oncologicalandfunctionaloutcomes.

Author(yr) Follow- upin month (median)

Biochemical recurrencefree survival

Clinical recurrencefree survival

Metastasis- free survival

Cancer-speciﬁc survival

Overallsurvival Functionaloutcomes

Yossepowitch(2007) 51.6 5years:68%;

10years:59%

NA NA NA NA NA

Yossepowitch(2008) 66 NA NA 5years:92%;

10years:85%

5years:97.7%;

10years:93%

NA NA

Lodde(2008) 98.2 10years:45% NA NA 10years:89.7% NA NA

Loeb(2010) 96 10years:68% NA 10years:84% 10years:92% NA NA

Spahn(2010) 60 5years:76.6%;

10years:56.2%

5years:

86.2%;

10years:

79.9%

NA 5years:91.3%;

10years:87.2%

5years:84.3%;

10years:72.1%

NA

Walz(2010) 28.8 5years:47.4%;

10years:35.7%

NA NA NA NA NA

Ploussard(2009) 37.6 1year:79.4%;

3years:69.8%

NA NA NA NA NA

Ploussard(2011) 63.7 5years:74.1% NA 5years:96.1% NA 5years:98.6% NA

Pierorazo(2011) Before2000area

NA 10years:44.1% NA 10years:

77.1%

10years:83.3% NA NA

NA 10years:36.4% NA 10years:

85.1%

10years:96.2% NA NA

53 5years:40% NA NA NA NA NA

Roder(2013) 52.8 10years:49% NA 10years:81% 10years:90% 10years:84% NA

Abdollah(2015) 49 5years:62.3%;

10years:50.4%

5years:

94.2%;

10years:

87.4%

NA NA NA NA

DiBenedetto(2015) 24.9 2years:79.2% NA NA 2years:79.2% 2years:100% 2years:91.8%

continent(PADFree) 64.4%potent (previouslypotent non-diabeticmen aged<70yearsafter bilateralnerve preservation)

Briganti(2014) 70 5years:55.2% NA NA 5years:93.7%;

10years:85.2%

NA NA

Busch(2014) 34.7 3years:57.8% NA NA NA 3years:97.8% NA

(11)

Table4(Continued)

Park(2013) 31 3years:82.6% NA NA NA NA 3month:69.1%

continent

(<1pad/day)61.8%

potent(previously potent)

Kulkarni(2015) NA 7years:42.4%;

10years:36.7%

NA 7years:

71.1%;

10years:

64.4%

7years:79.7%;

10years:65%

NA 1year:96.2%

continent

Arcangeli(2009) 33.7 3years:69.8% NA NA NA NA 81%continent

Kawamorita(2009) 39 3years:64.5% NA NA NA NA NA

Briganti(2012) 186 5years:69.4%;

10years:53.8%

NA NA 5years:96.3%;

10years:91.1%

NA NA

Castelli(2014) 54.17 5years:94% 5years:85% NA 5years:95% 5years:87% NA

Lee(2014) 71 NA NA NA 5years:96.5% NA NA

Briganti(2013) 72 NA NA NA 10years:94.1% 10years:79.7% NA

Boorjian(2011) 122.4 NA NA 5years:93%;

10years:85%

15years:79%

5years:97%;

10years:92%

15years:85%

5years:92%;

10years:77%

15years:56%

NA

31.1 3years:77% NA NA NA NA 1year:56%

continent ChulKoo(2014)

Veryhighrisk disease

36.1 3years:58% NA NA NA NA 1year:32%

continent

Dell’Oglio(2016) 116 NA NA NA 10years:88.4%;

15years:84.5%

20years:81.6%

10years:82.9%;

15years:71%

20years:62.3%

NA

Manoharan(2003) 54.7 4years:62% NA NA NA NA NA

Bastian(2006) NA JohnsHopkins cohort:5years:

40%10years:27%

SEARCHcohort:

5years:32%

10years:28%

NA NA NA NA NA

Westover(2011) 91.2 NA NA NA 5years:100% NA NA

(12)

886G.Delporteetal.

Table4(Continued)

Pokala(2013) NA NA NA NA 5years:96.4%;

10years:89.5%;

15years:82%;

20years:72.9%

5years:92.8%;

10years:78.6%;

15years:59.5%;

20years:38.6%

NA

Carver(2006) 76.8 5years:48%;

10years:44%

5years:86%;

10years:76%

NA 5years:94%;

10years:85%

NA NA

Freedland(2007) 156 5years:62%;

10years:49%

15years:49%

NA 5years:90%;

10years:80%

15years:73%

5years:98%;

10years:91%

15years:84%

NA NA

Moltzahn(2014) 111 NA NA NA 10years:87.9% 10years:76.6% NA

Joniau(2012) 108 5years:52.7%;

10years:45.8%

5years:78%;

10years:

72.5%

NA 5years:91.9%;

10years:91.9%

5years:88%;

10years:70.7%

NA

Brandli(2003) 54 3years:60%;

5years:48%

NA NA NA NA NA

Zwergel(2007) 42 NA NA NA 5years:93%;

10years:83%

15years:71%

5years:87%;

10years:70%

15years:58%

NA

Nguyen(2009) 94 5years:53% NA NA 8years:92.7% 8years:82.9% NA

Spahn(2010) 77 5years:64.8%;

10years:51.9%

5years:

82.3%;

10years:

73.3%

NA 5years:89.8%;

10years:84.5%

5years:73.6%;

10years:58%

NA

Berglund(2006) 34 3years:70.4% NA 5years:96.1% 5years:98.9% 5years:97.2% 1year:90%

continent

Loeb(2007) 88 7years:39%;

10years:35%

NA NA 7years:92%;

10years:88%

7years:91%;

10years:74%

92%continent;60%

potent(previously potentandno adjuvanttreatment)

Miocinovic(2011) 80.4 8years:46% NA 8years:87% 8years:93% NA NA

Savdie(2012) 95 5year:65.5%;

10years:55.4%

NA NA NA NA NA

NA:notavailable.

(13)

Prostatectomyinlocallyadvancedorhigh-riskcancer:Reviewoftheliterature 887 theriskofthediseaseincreased.Therewas7.8%riskreduc-

tioninthehigh-riskgroupvs.3.3%intheintermediateand 1.8%inthelow-riskgroup[46].Recently,Wallisetal.pub- lishedameta-analysisof19studiescomparingRPandEBRT for clinically-localised prostate cancer including 118 830 patients.Theyfoundthattheriskofoverallmortality(aHR 1.63,95%CI1.54—1.73,P<0.00001)andPCaspecificmortal- ity(aHR2.08,95%CI1.76—2.47,P<0.00001)werehigherfor patienttreatedwithEBRTcomparedwiththosetreatedwith surgery[47].Subgroupanalysisforhigh-riskPCadidnotalter the direction of results regarding overall mortality (aHR 1.88, 95% CI 1.64—2.16, P<0.00001) and cancer specific mortality(aHR1.83,95%CI1.51—2.22,P<0.0001).Another recentstudyincluding9362high-riskoftheProstateCancer dataBaseSweden3.0whohadundergoneRTorRPbetween 1998 and 2012 showed a higher risk of prostate cancer deathwhenEBRTwasperformed(HR1.5795%CI1.33—1.85) butnodifferencesafterfulladjustement(HR1.03,95%CI 0.81—1.31)[48].However,theseresultscannotsupportthe superiorityofsurgeryover EBRTgiventheintrinsiclimita- tionsofthestudiesincludedinthismeta-analysis,including theirretrospective design,thelack ofrandomization, and potential selection bias(the majority of large T3 cancers mayhavebeenprecludedfromRPandofferedEBRT).Only a randomizedtrial (currently ongoing) can answer to this clinicallyrelevantquestion(http://www.spcginfo.org/).As amatteroffact,the2016EuropeanAssociationofUrology (EAU)guidelinesonPCasuggestbothtreatmentmodalities as possible options for men with high-risk disease. What is certainly true isthat recent advancesin RP techniques during the last two decades have led to improved out- comessuchaslowerpositivesurgicalmarginsrates,lower bloodloss,reducedlengthofstayandbetterfunctionalout- comes, sparkinga renewed interest in the use of surgery inmenwithadvancedPCa[32,33,41].Predictivefactorsof biochemicalrecurrenceafterRParewellknownandpreop- erativeevaluationofriskhasbeenimprovedbytheuseof MRI,targetedbiopsyandcholinepositronemissiontomog- raphy. Furthermore, accurately staging the lymph nodes offer the opportunity for those with nodal metastases to beconsidered candidates for adensified treatment based onimmediatehormonaltherapyand/oradjuvantradiother- apy. On the other hand, long-term data on patients with smallburdennodalmetastasessuggeststhatupto20%can remainfreeof diseasewithsurgeryasthesoletreatment making and selected patients with N+ disease eventually candidateforawait-and-seeapproachafterRP[49].

Conclusions

Evidence suggests that surgical management, integrated or not in a multimodality approach, appears to be safe and reasonable therapeutic option in patients with high- riskandlocally advancedPCa.Despitesomeretrospective and population-based studies have suggested improved outcomes after RP compared with RT, randomized trials assessingbothoncologicandfunctionalresultsareneeded toconﬁrm theimportantroleofRPinthemanagementof thispopulation.Inaddition,thewidevariabilityofthemost commonlyuseddeﬁnitionofhigh-risk prostatecancer will

affecttheeligibilityandsamplesizewhendesigningsurgical clinicaltrials.

Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

References

[1]GrubbRL, KibelAS.High-risklocalizedprostatecancer:role of radical prostatectomy. Curr Opin Urol 2010;20:204—10, http://dx.doi.org/10.1097/MOU.0b013e3283384101.

[2]YossepowitchO, EggenerSE,Bianco FJ, CarverBS, SerioA, ScardinoPT,etal.Radicalprostatectomyforclinicallylocal- ized,highriskprostatecancer:criticalanalysisofriskassess- ment methods. J Urol 2007;178:493—9, http://dx.doi.org/

10.1016/j.juro.2007.03.105[discussion499].

[3]Yossepowitch O, Eggener SE, Serio AM, Carver BS, Bianco FJJ, Scardino PT, et al. Secondary therapy, metastatic progression, and cancer-speciﬁc mortality in men with clinically high-risk prostate cancer treated with radical prostatectomy. Eur Urol 2008;53:950—9, http://dx.doi.org/

10.1016/j.eururo.2007.10.008.

[4]Lodde M, Harel F, Lacombe L, Fradet Y. Substratiﬁca- tion of high-risk localised prostate cancer treated by radical prostatectomy. World J Urol 2008;26:225—9, http://dx.doi.org/10.1007/s00345-008-0252-5.

[5]Loeb S,Schaeffer EM, Trock BJ,Epstein JI, Humphreys EB, Walsh PC. What are the outcomes of radical prostatectomy for high-risk prostatecancer? Urology 2010;76:710—4, http://dx.doi.org/10.1016/j.urology.2009.09.014.

[6]SpahnM,WeissC,BaderP,StröbelP,GerharzEW,KneitzB, etal.Long-termoutcomeofpatientswithhigh-riskprostate cancerfollowingradicalprostatectomyandstage-dependent adjuvant androgen deprivation. Urol Int 2010;84:164—73, http://dx.doi.org/10.1159/000277593.

[7]Walz J, Joniau S, Chun FK,Isbarn H, Jeldres C, Yossepow- itch O, et al. Pathological results and rates of treatment failure in high-risk prostate cancer patients after radical prostatectomy.BJUInt2011;107:765—70,http://dx.doi.org/

10.1111/j.1464-410X.2010.09594.x.

[8]Ploussard G, Salomon L, Allory Y, Terry S, Vordos D, Hoznek A, et al. Pathological ﬁndings and prostate-speciﬁc antigen outcomes after laparoscopic radical prostatectomy for high-risk prostate cancer. BJU Int 2010;106:86—90, http://dx.doi.org/10.1111/j.1464-410X.2009.09080.x.

[9]Ploussard G, Masson-Lecomte A, Beauval J-B, Ouzzane A, Bonniol R, Buge F, et al. Radical prostatectomy for high-risk prostate cancer deﬁned by preoperative criteria: oncologic follow-up in national multicenter study in 813 patientsand assessmentof easy-to-use prognostic sub- stratiﬁcation. Urology 2011;78:607—13, http://dx.doi.org/

10.1016/j.urology.2011.05.021.

[10]PierorazioPM,RossAE,HanM,Epstein JI,PartinAW, Scha- effer EM. Evolution of the clinical presentation of men undergoing radical prostatectomy for high-risk prostate cancer. BJU Int 2012;109:988—93, http://dx.doi.org/

10.1111/j.1464-410X.2011.10514.x.

[11]Masson-Lecomte A, Hupertan V, Comperat E, Vaessen C, Chartier-Kastler E, Cussenot O, et al. Pathologi- cal ﬁndings and oncological control afforded by radical prostatectomy in men with high-risk prostate cancer:

a single-centre study. World J Urol 2011;29:665—70, http://dx.doi.org/10.1007/s00345-010-0608-5.

(14)

888 G.Delporteetal.

[12]Røder MA, Berg KD, Christensen IJ, Gruschy L, Brasso K, Iversen P. Radical prostatectomy in clinically localized high-risk prostate cancer: outcome of 231 consecutive patients. Scand J Urol 2013;47:19—25, http://dx.doi.org/10.3109/00365599.2012.698304.

[13]Abdollah F, Sood A, Sammon JD, Hsu L, Beyer B, Mos- chini M, et al. Long-term cancer control outcomes in patientswithclinicallyhigh-riskprostatecancertreatedwith robot-assisted radical prostatectomy: results from a multi- institutionalstudyof1100patients.EurUrol2015;68:497—505, http://dx.doi.org/10.1016/j.eururo.2015.06.020.

[14]Di Benedetto A, Soares R, Dovey Z, Bott S, McGre- gor RG, Eden CG. Laparoscopic radical prostatectomy for high-risk prostate cancer. BJU Int 2015;115:780—6, http://dx.doi.org/10.1111/bju.12797.

[15]Briganti A, Karnes RJ, Gandaglia G, Spahn M, Gontero P, Tosco L, et al. Natural history of surgically treated high-risk prostate cancer. Urol Oncol 2015;33:163, http://dx.doi.org/10.1016/j.urolonc.2014.11.018[e7—13].

[16]Busch J, Magheli A, Leva N, Hinz S, Ferrari M, Frieder- sdorff F, et al. Matched comparison of outcomes following open and minimally invasive radical prostatectomy for high-risk patients. World J Urol 2014;32:1411—6, http://dx.doi.org/10.1007/s00345-014-1270-0.

[17]Park DS, Gong IH, Choi DK, Hwang JH, Shin HS, Oh JJ. Radical prostatectomy versus high dose per- manent prostate brachytherapy using iodine-125 seeds for patients with high risk prostate cancer: a matched cohort analysis. World J Urol 2013;31:1511—7, http://dx.doi.org/10.1007/s00345-013-1086-3.

[18]Kulkarni JN, Gunavanthe VS, Dhale A. Outcome of radical prostatectomy as primary treatment for high-risk prostate cancer patients. Indian J Cancer 2015;52:646—52, http://dx.doi.org/10.4103/0019-509X.178446.

[19]Arcangeli G, Strigari L, Arcangeli S, Petrongari MG, Saracino B, Gomellini S, et al. Retrospective comparison of external beam radiotherapy and radical prostatectomy in high-risk, clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2009;75:975—82, http://dx.doi.org/10.1016/j.ijrobp.2008.12.045.

[20]KawamoritaN,SaitoS,IshidoyaS,ItoA,SaitoH,KatoM,etal.

Radicalprostatectomyforhigh-riskprostatecancer:biochem- icaloutcome.IntJUrolOffJJpnUrolAssoc2009;16:733—8, http://dx.doi.org/10.1111/j.1442-2042.2009.02352.x.

[21]Briganti A, Joniau S, Gontero P, Abdollah F, Passoni NM, Tombal B, et al. Identifying the best candi- date for radical prostatectomy among patients with high-risk prostate cancer. Eur Urol 2012;61:584—92, http://dx.doi.org/10.1016/j.eururo.2011.11.043.

[22]Castelli T, Russo GI, Favilla V, Urzi D, Spitaleri F, Reale G, et al. Tailored treatment including radical prostatectomy and radiation therapy+androgen deprivation therapy versus exclusive radical prostatectomy in high- risk prostate cancer patients: results from a prospective study. Int Braz J Urol Off J Braz Soc Urol 2014;40:

322—9.

[23]Lee JY, Cho KS, Kwon JK, Jeh SU, Kang HW, Diaz RR, et al. A competing risk analysis of cancer-speciﬁc mortality of initial treatment with radical prostatectomy versus radiation therapy in clinically localized high- risk prostate cancer. Ann Surg Oncol 2014;21:4026—33, http://dx.doi.org/10.1245/s10434-014-3780-9.

[24]Briganti A, Spahn M, Joniau S, Gontero P, Bianchi M, Kneitz B, et al. Impact of age and comorbidities on long- term survival of patients with high-risk prostate cancer treated with radical prostatectomy: a multi-institutional

competing-risks analysis. Eur Urol 2013;63:693—701, http://dx.doi.org/10.1016/j.eururo.2012.08.054.

[25]Boorjian SA, Karnes RJ, Viterbo R, Rangel LJ, Bergstralh EJ, Horwitz EM, et al. Long-term survival after radical prostatectomyversusexternal-beamradiotherapyforpatients with high-risk prostate cancer. Cancer 2011;117:2883—91, http://dx.doi.org/10.1002/cncr.25900.

[26]Koo KC, Jung DC, Lee SH, Choi YD, Chung BH, Hong SJ, etal. Feasibilityofrobot-assistedradicalprostatectomyfor very-highriskprostatecancer:surgical andoncological out- comesin menaged≥70years.Prostate Int2014;2:127—32, http://dx.doi.org/10.12954/PI.14050.

[27]Dell’Oglio P, Karnes RJ, Joniau S, Spahn M, Gontero P, Tosco L, et al. Very long-term survival patterns of young patients treated with radical prostatectomy for high-risk prostate cancer. Urol Oncol 2016;34:234, http://dx.doi.org/10.1016/j.urolonc.2015.11.018

[e13—234.e19].

[28]ManoharanM,BirdVG,KimSS,CivantosF,SolowayMS.Out- comeafterradicalprostatectomywithapretreatmentprostate biopsyGleasonscoreof>=8.BJUInt2003;92:539—44.

[29]Bastian PJ,Gonzalgo ML, Aronson WJ, Terris MK,Kane CJ, AmlingCL,etal.Clinicalandpathologicoutcomeafterradical prostatectomyfor prostate cancerpatientswitha preoperative Gleason sum of 8 to 10. Cancer 2006;107:1265—72, http://dx.doi.org/10.1002/cncr.22116.

[30]Westover K, Chen M-H, Moul J, Robertson C, Polascik T, Dosoretz D, et al. Radical prostatectomy vs. radiation therapy and androgen-suppression therapy in high-risk prostate cancer. BJU Int 2012;110:1116—21, http://dx.doi.org/10.1111/j.1464-410X.2012.11012.x.

[31]Pokala N, Trulson JJ, Islam M. Long-term outcome following radical prostatectomy for Gleason 8-10 prostatic adenocarcinoma. World J Urol 2014;32:1385—92, http://dx.doi.org/10.1007/s00345-014-1253-1.

[32]Carver BS, Bianco FJ, Scardino PT, Eastham JA. Long- termoutcome following radicalprostatectomy inmen with clinical stage T3 prostate cancer. J Urol 2006;176:564—8, http://dx.doi.org/10.1016/j.juro.2006.03.093.

[33]FreedlandSJ,PartinAW,HumphreysEB,MangoldLA,WalshPC.

Radicalprostatectomyfor clinicalstageT3adisease. Cancer 2007;109:1273—8,http://dx.doi.org/10.1002/cncr.22544.

[34]Moltzahn F, Karnes J, Gontero P, Kneitz B, Tombal B, Bader P,et al. Predicting prostate cancer-speciﬁc outcome after radical prostatectomy among men with very high- risk cT3b/4 PCa: a multi-institutional outcome study of 266 patients. Prostate Cancer Prostatic Dis 2015;18:31—7, http://dx.doi.org/10.1038/pcan.2014.41.

[35]Joniau S, Hsu C-Y, Gontero P, Spahn M, Van Poppel H. Radical prostatectomy in very high-risk localized prostate cancer: long-term outcomes and outcome predictors. Scand J Urol Nephrol 2012;46:164—71, http://dx.doi.org/10.3109/00365599.2011.637956.

[36]Brandli DW, Koch MO, Foster RS, Bihrle R, Gardner TA.

Biochemical disease-free survival in patients with a high prostate-speciﬁcantigenlevel(20—100ng/mL)and clinically localizedprostatecancerafterradicalprostatectomy.BJUInt 2003;92[19—22—23].

[37]Zwergel U, Suttmann H, Schroeder T, Siemer S, Wul- lich B, Kamradt J, et al. Outcome of prostate cancer patients with initial PSA>or=20ng/mL undergoing radical prostatectomy. Eur Urol 2007;52:1058—65, http://dx.doi.org/10.1016/j.eururo.2007.03.056.

[38]Nguyen K, Eltz S, Drouin SJ, Comperat E, Audenet F, Renard-Penna R, et al. Oncologic outcome after radical prostatectomy in men with PSA values above 20ng/mL: