Mortality among men with advanced prostate cancer excluded from the ProtecT Trial

warwick.ac.uk/lib-publications

Original citation:

ProtecT study group (Including: Johnston, Thomas J., Shaw, Greg L., Lamb, Alastair D.,

Parashar, Deepak, Greenberg, David, Xiong, Tengbin, Edwards, Alison L., Gnanapragasam,

Vincent, Holding, Peter, Herbert, Phillipa et al.). (2016) Mortality among men with advanced

prostate cancer excluded from the ProtecT Trial. European Urology.

Permanent WRAP URL:

http://wrap.warwick.ac.uk/82243

Copyright and reuse:

The Warwick Research Archive Portal (WRAP) makes this work by researchers of the

University of Warwick available open access under the following conditions. Copyright ©

and all moral rights to the version of the paper presented here belong to the individual

author(s) and/or other copyright owners. To the extent reasonable and practicable the

material made available in WRAP has been checked for eligibility before being made

available.

Copies of full items can be used for personal research or study, educational, or not-for-profit

purposes without prior permission or charge. Provided that the authors, title and full

bibliographic details are credited, a hyperlink and/or URL is given for the original metadata

page and the content is not changed in any way.

Publisher’s statement:

© 2016, Elsevier. Licensed under the Creative Commons

Attribution-NonCommercial-NoDerivatives 4.0 International

http://creativecommons.org/licenses/by-nc-nd/4.0/

A note on versions:

The version presented here may differ from the published version or, version of record, if

you wish to cite this item you are advised to consult the publisher’s version. Please see the

‘permanent WRAP URL’ above for details on accessing the published version and note that

access may require a subscription.

Platinum

Priority

–

Prostate

Cancer

EditorialbyXXXonpp.x–yofthisissue

Mortality

Among

Men

with

Advanced

Prostate

Cancer

Excluded

from

the

ProtecT

Trial

Thomas

J.

Johnston

*,

Greg

L.

Shaw

,

Alastair

D.

Lamb

,

Deepak

Parashar

,

David

Greenberg

,

Tengbin

Xiong

,

Alison

L.

Edwards

,

Vincent

Gnanapragasam

,

Peter

Holding

_,

_Phillipa

_Herbert

_,

_Michael

_Davis

_,

_Elizabeth

_Mizielinsk

_,

_J.

_Athene

_Lane

_,

Jon

Oxley

,

Mary

Robinson

,

Malcolm

Mason

,

John

Staffurth

,

Prasad

Bollina

,

James

Catto

,

Andrew

Doble

,

Alan

Doherty

,

David

Gillatt

,

Roger

Kockelbergh

,

Howard

Kynaston

,

Steve

Prescott

,

Alan

Paul

,

Philip

Powell

,

Derek

Rosario

,

Edward

Rowe

,

Jenny

L.

Donovan

_,

_Freddie

_C.

_Hamdy

_,

_David

_E.

_Neal

_*,

for

the

ProtecT

study

group

a_{AcademicUrologyGroup,UniversityofCambridge,Cambridge,UK;}b_{CancerResearchUKCambridgeInstitute,LiKaShingCentre,Cambridge,UK;}c_Statistics

andEpidemiologyUnit&CancerResearchCentre,UniversityofWarwick,Coventry,UK;d_{NationalCancerRegistrationService–EasternOffice,PublicHealth} England,Cambridge,UK;e_{NuffieldDepartmentofSurgicalSciences,UniversityofOxford,Oxford,UK;}f_{SchoolofSocialandCommunityMedicine,University} ofBristol,Bristol,UK;g_{DepartmentofCellularPathology,NorthBristolNHSTrust,Bristol,UK;}h_{DepartmentofCellularPathology,RoyalVictoriaInfirmary,} Newcastle-upon-Tyne,UK;i_{DivisionofCancerandGenetics, SchoolofMedicine,CardiffUniversity,Cardiff,UK;}j_{Department ofUrologyandSurgery,} WesternGeneralHospital,UniversityofEdinburgh,Edinburgh,UK;k_{AcademicUrologyUnit,UniversityofSheffield,Sheffield,UK;}l_{DepartmentofUrology,} Addenbrooke’sHospital,Cambridge,UK;m_{DepartmentofUrology,QueenElizabethHospital,Birmingham,UK;}n_{DepartmentofUrology,SouthmeadHospital} andBristolUrologicalInstitute,Bristol,UK;o_{DepartmentofUrology,UniversityHospitalsofLeicester,Leicester,UK;}p_{DepartmentofUrology,Cardiffand} ValeUniversityHealthBoard,Cardiff,UK;q_{DepartmentofUrology,LeedsTeachingHospitalsNHSTrust,Leeds,UK;}r_{DepartmentofUrology,Freeman} Hospital,Newcastle-upon-Tyne,UK

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

Articleinfo

Articlehistory:

AcceptedSeptember26,2016

AssociateEditor:

StephenBoorjian

Keywords: Prostatecancer

Prostate-specificantigen screening

Survival

Abstract

Background: Earlydetectionandtreatmentofasymptomaticmenwithadvancedand high-riskprostatecancer(PCa)mayimprovesurvivalrates.

Objective: To determine outcomesfor mendiagnosedwithadvanced PCa following prostate-specificantigen(PSA)testingwhowereexcludedfromtheProtecTrandomised trial.

Design,setting,andparticipants: Mortalitywascomparedfor492menfollowedupfora median of 7.4 yrto a contemporaneous cohort ofmen fromtheUK Anglia Cancer Network(ACN)andwithamatchedsubsetfromtheACN.

Outcomemeasurementsandstatisticalanalysis: PCa-specificand all-causemortality werecomparedusingKaplan-MeieranalysisandCox’sproportionalhazardsregression. Resultsandlimitations: Ofthe492menexcludedfromtheProtecTcohort,37(8%)had metastases (N1, M0=5, M1=32) and 305 had locallyadvanced disease (62%). The medianPSAwas17mg/l.Treatmentsincludedradicalprostatectomy(RP;n=54;11%), radiotherapy (RT;n=245; 50%),androgendeprivation therapy (ADT; n=122;25%), othertreatments(n=11;2%),andunknown(n=60;12%).Therewere49PCa-specific

y_{Theseauthorscontributedequallytothiswork.}

§ _{ThemembersoftheProtecTstudygrouparelistedintheSupplementarymaterial.}

* Correspondingauthors.AcademicUrologyGroup,UniversityofCambridge,CambridgeBiomedical Campus,CambridgeCB20QQ,UK.

E-mailaddresses:thomasjohnston1@nhs.net(T.J.Johnston),den22@cam.ac.uk(D.E.Neal).

http://dx.doi.org/10.1016/j.eururo.2016.09.040

1. Introduction

Population-basedprostatespecificantigen(PSA)screening remains controversial [1]. Although screening in the European Randomised Study of Screening for Prostate Cancer(ERSPC)detectedhighnumbersofprostatecancers (PCas)andlowermortalityfromthatdisease,themajority of cancers were indolent, leading to overdetection and overtreatment[2,3].TheProstate,LungandOvariancancer screening study(PCLO) reportednosurvival benefitafter 11.5yroffollow-up,buttherewaswidespread contamina-tioninthecontrolarmwithpreviousPSAtesting(upto90%) [2,3].

There is uncertainty regarding the effectiveness of treatments for PSA-detected clinically localised PCa. The Prostate Cancer Intervention Versus Observation Trial (PIVOT)reportednosurvivalbenefitafter12yrof follow-upamongmenwithmainlylow-riskdiseasetreatedwith surgeryorobservation,althoughtherewashighall-cause mortality in both arms, suggesting that men with major comorbiditieswereincluded[4].Norandomisedtrialshave compared different radical treatments for men with advanced [5,6] or high-risk disease, and retrospective studies have reportedconflictingresults [7–10]. There is uncertaintyregardingoutcomesamongmenwith higher-riskPCa detectedviaPSAscreening, althoughasubgroup analysis of PIVOT suggested benefit in favour of radical treatmentforintermediate-orhigh-riskdisease[4].

Details of the ProtecT trial are reported elsewhere [11–15].Menwithmetastaticorlocallyadvanceddisease (cT3–4)and/orPSA20mg/lwereexcludedfromProtecT, along with men considered by local urologists to be unsuitable for the trial becauseof their clinical features. ThesemenexcludedfromtheProtecTrandomisedtrialbut diagnosedcontemporaneouslyprovide aunique opportu-nity to assess the outcomes of advanced and high-risk diseaseatdiagnosisinapopulationwithverylowratesof opportunisticPSAscreening(8–13%)[12,16].

Here we present survival data for these men in comparison to data for a contemporaneous cohort from theUKAngliaCancerNetwork(ACN),whichhasgenerally lowratesofPSAtesting,andwithamatchedACNcohort withsimilardiseasefeatures.

2. Patientsandmethods

2.1. Casepopulation

TheProtecTtrialcomparesactivemonitoring,conformalexternal-beam radicalradiotherapy(RT)withorwithoutandrogendeprivationtherapy (ADT) and radical prostatectomy (RP) treatments for PSA-detected clinicallylocalisedPCa[12].Between2001and2009therewere82429 asymptomaticmenaged50and69yrwhounderwentPSAtesting,and thosewithPSA3mg/lproceededtobiopsy.ParticipantswithinitialPSA

20mg/lorfoundtohavelocallyadvanced(T3–4)PCaordistantdisease (N1orM1)wereineligibleandreferredforstandardcare.Themajorityhad locallyadvancedPCa;asmallproportion(5%)wereclassedasathighriskof havingnon–organ-confineddiseaseandwerefelttobeunsuitablefor randomisation.Intotal,513men(PSA20mg/l,orlocallyadvancedcT3–4 PCa, orGleason 8, orN1/M1 disease)wereexcluded fromProtecT (Table1). ThesemenformtheProtecTadvancedcasescohortreportedhere. Informationontreatmentandsurvivalwasobtainedduringannual ProtecTfollow-upandcheckedusingtheEnglishNationalCancerOnline RegistrationEnvironmentdatabaseintheEasternOfficeoftheNational Cancer Registration Service (NCRS-E) [15]. Cause of death was determined byreview ofcertificationby twoindependentclinicians blindedtostudygroupandtreatment.

2.2. Comparisonpopulation

Comparison patients (controls) were identified by the NCRS-E by interrogationoftheAngliaCancerNetwork(ACN)[10]fora contempo-rarycohortofmen withcomparableage andyearofdiagnosisand similarly advanced and high-risk disease features: PSA 20 ng/ml, locally advanced disease (cT3–4), Gleason score 8, or N1/M1 disease.TheACNcaseswerejudgedtobeasuitablecomparativecohort becauseoflowratesofPSAtesting (10–13%)intheACNpopulation

[12,17](Supplementarymaterial).

The ProtecT trial was approved by the East Midlands Ethics Committee(Derby,UK;recordnumber01/4/025).

2.3. Statisticalanalysis

We usedthe x2testforheterogeneityto assessbaseline differences betweencasesandcontrols.Theprimaryanalysiscomparedriskofdeath fromPCaandallcausesbetweenProtecTcasesandACNcontrolswith clinicallydetectedPCa.Casesandcontrolswerematched1:1according toage,yearofdiagnosis,PSA,Gleasonscore,andclinicalstage.Survival estimates werecarriedoutusingKaplan-Meiermethods, withgroup differences(unmatchedandmatched)expressedasthehazardratio(HR) deaths (10%),ofwhom14menhadreceived radicaltreatment(5%);and129all-cause deaths(26%).InmatchedProtecTandACNcohorts,37(9%)and64(16%),respectively,died ofPCa,while89(22%)and103(26%)diedofallcauses.ProtecTmenhada45%lowerriskof death fromPCacomparedtomatchedcases(hazardratio0.55,95%confidenceinterval 0.38–0.83; p=0.0037), but mortality was similar in those treated radically. The non-randomiseddesignisalimitation.

Conclusions: MenwithPSA-detectedadvanced PCaexcluded fromProtecTand treated radically had low ratesof PCadeath at 7.4-yr follow-up.Among menwho underwent nonradicaltreatment,theProtecTgrouphadalowerrateofPCadeath.Earlydetection throughPSAtesting,leadtimebias,andgroupheterogeneityarepossiblefactorsinthis finding.

Patient summary: Prostatecancer that hasspread outside the prostate glandwithout causingsymptomscanbedetectedviaprostate-specificantigentestingandtreated,leading tolowratesofdeathfromthisdisease.

#_{2016PublishedbyElsevierB.V.onbehalfofEuropeanAssociationofUrology.} EUROPEAN UROLOGYXXX(2016)XXX–XXX

with95%confidenceinterval(CI)andcomparedusingthelog-ranktest. Coxproportionalhazardsregressionmodels(univariableand multivari-able)werealsofittedtoestimatesurvivalfortheunmatchedProtecT casesandACNcontrolsadjustedfortheabovevariables,withresults expressed asHR with 95% CI. A sensitivityCox regression survival analysiswasperformedforasubsetoftheunmatchedgroupsseparated forN0M0andN1orM1disease,andwasalsofittedforthematched groupswithfurtheradjustmentfortreatmentallocation.Fisher’sexact test and a two-sample z-test of proportions were used to assess differences between treatments received in the matched groups. A secondaryanalysis assessedbiochemical-free andcastrate-resistant– freesurvivalwithintreatmentgroups.Dataforpatientswhodiedfrom PCaorothercauseswerecensoredatdateofdeath.Alltestswere two-sided, withstatistical significance setatp<0.05.Allanalyseswere performedusingIBMSPSSforWindows,version22.0,GraphPadPrism, version6,andSTATAversion14.

3. Results

3.1. ProtecTcaseandACNcontrolcharacteristics

Theflowofthepatientsthroughthestudyissummarised in Figure 1. There were 513 ProtecT advanced cases, of whom 21 were excluded because of incomplete data at presentation.Fortheremaining492cases,themeanagewas 64 yr(interquartilerange [IQR] 61–68); median PSA was

17ng/ml(mean33,IQR8–32ng/ml);43%hadPSA20ng/ ml;62%hadclinicalstageT3;23%hadaGleasonscore8; and8%hadN1orM1disease.Medianfollow-upwas7.4yr (IQR 5.5–9.7;Table 1). For analysis of biochemical recur-rence,dataonprimarytreatmentwereavailablefor432out of492ProtecTcases(88%),anddataonPSAfollow-upandon neoadjuvant,adjuvant,orsalvagetherapiesfor352outof 492cases(72%).

We identified3978 ACN controls aged 50–72 yr with clinicallydetectedPCa.Medianfollow-upwas5yr(IQR3.1– 7.8).Thereweredifferencesinbaselinecharacteristics:ACN controlswereolder,hadhigherPSAlevels,higherGleason scores,andhigherPCastages(allp< 0.0002).Accordingly, we matched ProtecT cases (n=401) to ACN controls (n=401) across these variables (Table 1). The median follow-upforthematchedcohortswas7.6yr(IQR5.1–9.8). Therewerecompletedataonprimarytreatmentfor352of 401(88%)matchedProtecTcasesand391of401(98%)ACN controls(Table2).

3.2. Survivalanalysis

3.2.1. ProtecTadvancedcases

Ofthe492ProtecTmen,54(11%)hadradicalprostatectomy (RP);245(50%)hadRT,ofwhom93%hadneoadjuvantand Table1–Demographicandclinicopathologicdataforthestudycohort

Variable Unmatched Matched

ProtecT ACN pvaluea _{ProtecT ACN pvalue}a

Patients(n) 492 3978 401 401

Yearofdiagnosis,n(%) <0.0001 1

1999–2003 178(36) 1109(28) 151(38) 151(38)

2004–2006 191(39) 1117(28) 157(39) 157(39)

2007–2010 123(25) 1752(44) 93(23) 93(23)

Ageband,n(%) <0.0002 0.86

50–59yr 102(21) 567(14) 83(21) 81(20)

60–72yr 390(79) 3411(86) 318(79) 320(80)

SerumPSA,n(%) <0.0001 0.48

<10ng/ml 160(33) 728(18) 149(37) 144(36)

10–20ng/ml 116(24) 752(19) 112(28) 117(29)

20–50ng/ml 141(28) 1086(27) 90(22) 75(19)

50–100ng/ml 49(10) 462(12) 24(6) 30(7)

>100ng/ml 26(5) 769(19) 26(6) 35(9)

Unknown 0(0) 181(5) 0(0) 0(0)

MeanPSA,ng/ml(median) 32.6(16.7) 201.1(26.5) 31.7(14) 217.2(13)

Gleasonscore,n(%) <0.0001 1

<7 112(23) 473(12) 93(23) 92(23)

7 259(53) 1300(33) 222(55) 223(55)

>7 115(23) 1654(42) 86(21)) 86(21)

Unknown 6(10 551(14) 0(0) 0(0)

MeanGleasonscore(median) 7.1(7) 7.6(7) 7.1(7) 7.0(7)

Clinicalstage,n(%) <0.0001 0.18

T1 17(4) 989(25) 16(4) 29(7)

T2 42(8) 750(19) 42(10) 29(7)

T3 305(62) 1063(27) 301(75) 298(74)

T4 5(10 44(1) 4(1) 5(1)

M1orN1 37(8) 1132(28) 37(9) 40(10)

Tstageunknown 86(18) 0(0) 1(1) 0(0)

Follow-up(yr)

Mean 7.5 5.5 7.7 7.5

Median 7.4 5 7.6 7.6

Interquartilerange 5.5–9.7 3.1–7.8 5.5–9.8 5.1–9.8

ACN=AngliaCancerNetwork;PSA=prostate-specificantigen. a

adjuvant ADT; 122 (25%) had ADT alone; five (1%) had primarychemotherapy;six(1%)hadothertreatment (high-intensity focused ultrasound or monitoring); and for 60 (12%) the treatment was unknown. We were unable to demonstrate a difference in PCa-specific (HR 0.95, 95% CI0.22–4.12;p=0.94)orall-causemortality(HR0.69,95% CI 0.29–1.67; p=0.41) between the RP and RT groups

(Fig.2A,2B).MenwhoreceivedRPwereyounger(p< 0.01) andhadlowerPSA(p<0.0001)comparedtotheRTgroup, butnosignificantdifferencewasobservedinGleasonscore (p=0.84)orstage(p=0.19;SupplementaryTable1).

All-cause mortality was 7% (4/54) among men who underwentRP(2diedofPCa;4%)and15%(37/245)among those who received RT (12 died of PCa; 5%). All-cause

Fig.1–Diagramofpatientflowthroughstudy.KM=Kaplan-Meier;PSA=prostate-specificantigen.

Table2–PrimarytreatmentsanddeathratesamongmatchedProtecTcasesandAngliaCancerNetwork(ACN)controls

Treatment MatchedProtecTcases MatchedACNcontrols

N Deaths,n(%) n Deaths,n(%)

PCS AC PCS AC

RP 47 1(4) 2(4) 150 5(3) 12(8)

RT+ADTa

200 11(6) 31(16) 127 6(5) 20(16)

Nonradicalb

105 19(18) 37(35) 114 51(45) 68(60)

Unknown 49 6(12) 19(38) 10 1(10) 3(3)

Total 401 37(9) 89(22) 401 63(16) 103(26)

RP=radicalprostatectomy;ADT=androgendeprivationtherapy;PCS=prostatecancer–specific;AC=allcauses. a

AdjuvantADTwasgivenincombinationwithradicalradiotherapyin93%ofProtecTcasesand88%ofACNcontrols. b

NonradicaltreatmentincludesprimaryADT,palliativechemotherapy,palliativeradiotherapy,andmonitoring. EUROPEAN UROLOGYXXX(2016)XXX–XXX

mortality was higher among men who underwent non-radicaltreatment(51/133;38%)andmenwhosetreatments were unknown (25/60; 42%; all p< 0.0001; Fig. 2A,2B). MentreatedusingADTwereolder(p=0.01)andhadhigher PSA (p<0.0001), Gleason score (p=0.05), and stage (p< 0.0001) compared to men who received radical treatment(SupplementaryTable1).

3.2.2. ComparisonwithACNcontrols:Kaplan-Meiersurvival analysis

Wefoundlowerrisks ofdeathfromPCa(HR0.29,95%CI 0.38–0.53;p<0.0001)andfromallcauses(HR0.45,95%CI 0.48–0.63;p< 0.0001)amongProtecTcasescomparedto unmatchedACNcontrols(SupplementaryFig.1A,1B).After matching(Table1)weobserveda45%lowerrateofdeath fromPCa(HR0.55,95%CI0.38–0.83;p=0.0037),butwere unabletodemonstrateadifferenceinall-causedeaths(HR 0.83;95%CI0.63–1.1;p=0.19)betweenmatchedProtecT casesandACNcontrolsat7.6yr(Fig.3A,3B).

There was a similar proportion of men who received radicalandnonradicaltreatmentsinthe matchedgroups

(p=0.87),butmoremenintheProtecTgroupreceivedRT compared to the matched ACN controls (p<0.0001; Table2).

Among the ProtecTmatched cases,247 men received radicaltreatment(RPn=47;RTn=200)ofwhom12died fromPCa(RPn=1[4%];RTn=11[6%])and33diedofall causes[RPn=2[4%];RTn=31[16%]).

Among the ACN matched controls, 277 men received radicaltreatment(RPn=150;RTn=127)ofwhom11died ofPCa(RPn=5[3%];RTn=6[5%])and32diedofallcauses (RPn=12[8%];RTn=20[16%]).

Among the matched men who received nonradical treatment, a significantly greater proportion died in the ACNcontrolgroup(n=114;51PCadeathsand68all-cause deaths)thanintheProtecTgroup(n=105;19PCadeaths and37all-causedeaths;p< 0.0002;Table2).

3.2.3. ComparisonwithACNcontrols:Coxproportionalhazards survivalanalysis

Multivariableanalysisfortheunmatchedgroupsrevealed thatProtecTcases(n=404)hada53%lowerriskofdeath fromPCa(HR0.47,95%CI0.34–0.66;p<0.0001)anda30% lowerriskofdeathfromallcauses(HR0.70,95%CI0.56– 0.88; p<0.0001) compared to unmatched ACN controls (n=3335;Table3).HigherPSA,higherGleasonscore,and higherstageallindicatedagreaterriskofdeath,whereas lateryearsofdiagnosisloweredtherisk.Therewasalsoa higherriskofdeathfromallcausesintheoldestagegroup

Fig.3–Kaplan-Meierplotsof(A)prostatecancer–specificsurvivaland

(B)overallsurvivalamongmatchedProtecTcasesandAngliaCancer

Network(ACN)controls.Bytheendofthestudy,37matchedcases(9%)

and64controls(16%)diedfromprostatecancer.Deathfromallcauses

occurredin89cases(22%)and103controls(26%).HR=hazardratio;

CI=confidenceinterval.

Fig.2–(A)Prostatecancer–specificsurvivaland(B)overallsurvival

accordingtoprimarytreatmentgroupsamongProtecTcases.Death

fromprostatecanceroccurredintwo(4%)oftheRPand12(5%)ofthe

RTgroup(HR0.95,CI95%0.22–4.12;p=0.94).Deathfromallcauses

occurredinfour(7%)oftheRPand37(15%)oftheRTgroup(HR0.69,

95%CI0.29–1.67;p=0.41).AsignificantlygreaterproportionoftheADT

groupdiedfromprostatecancer(n=27,22%)andallcauses(n=49,

40%)comparedtomentreatedwithradicaltherapy(p<0.0001).

RP=radicalprostatectomy;RT=radicalradiotherapy;ADT=androgen

(67–72yr).AsubsetanalysisformenwithN0,M0disease didnotdemonstrateadifferenceintheriskofdeathfrom PCa(HR0.69,95%CI0.45–1.06;p=0.09)orallcauses(HR 0.94,95%CI0.73–1.22;p=0.65)betweentheunmatched groups.However,menwithN1orM1diseasehadamuch lowerriskofdeathfromPCa (HR0.33,95%CI0.18–0.59;

p<0.0001)andallcauses(HR0.38;0.22-0.63;P<0.0001) intheProtecTgroupthanintheACNgroup(Supplementary Table2).

Multivariableanalysiswas performedforthematched groupsafterfurtheradjustingfortreatmentreceived. We didnotfindevidenceofadifferenceintheriskofdeathfrom PCaamongmenwhoreceivedradicaltreatment(HR1.91, 95% CI 0.73–5.02; p=0.19). Men treated with RT had a higher riskof deathfrom all causes comparedto the RP group(HR 2.02, 95%CI 1.08–3.77, p=0.03). Therewas a muchhigherriskofdeathfromPCa(HR6.70,95%CI2.64– 16.9;p<0.0001)andallcauses(HR4.55,95%CI2.42–8.52;

p<0.0001)amongmenwhoreceivednonradicaltreatment compared to those who underwent radical treatment (SupplementaryTable3).

3.2.4. Kaplan-Meieranalysisofbiochemicalrecurrencebyprimary treatmentgroupintheProtecTgroup

PSA follow-up was available for ProtecT cases and is reportedinmoredetailintheSupplementarymaterial.Ata medianof7.4yr,PCa-specificsurvivalwas 96%intheRP groupand96%intheRTgroup.Therewerenopredictorsof biochemical failure, PCa-specific mortality, or overall mortalityamongmentreatedwithRPorRTonunivariable or multivariable analysis, except for high Gleason score, whichincreasedtheriskofdeathfromallcausesintheRT group(HR6.48,95%CI1.48–28.4;p=0.01;Supplementary Table4andSupplementaryFig.2).

4. Discussion

This study reports on asymptomatic men who were excludedfromProtecTbecauseofadvancedandhigh-risk PCa;theiroutcomesform animportantcomponentofthe overallcontextoftheProtecTstudyanditsgeneralisability withrespecttotreatmentofPSA-detectedPCa.Inmenwho wereexcludedfromProtecT,butweretreatedradically,we foundlowratesofall-cause andPCa specificdeaths (14% and 5%),with nodifferences betweensurgeryand radio-therapy at a median of 7.4 years. Most deaths occurred among men receiving nonradical treatments, probably becausetheyhadmoreadvanceddiseaseand/orwerenot fit for radical treatment, although very unfit men were screenedoutfromProtecTbythegeneralpractitioner.

Withrespect tothemain clinicaloutcome paperfrom ProtecT,all-causemortality(10%atamedianof10yr)[13] waslowerthanthatnotedhereintheRTgroup(15%).This suggests thatProtecTmenwith advancedPCatreatedby RT in the present study were less fit than those in the randomised group. Moreover, the group who received nonradical treatment and those whose treatment was unknownhadsignificantlygreaterall-causemortality(38% and 42%, respectively) compared with those undergoing radical treatment. The PCa-specific mortality among the ProtecTgroupreceivingradicaltreatment(5%)wasgreater than that found in the randomised group (1%), but neverthelessindicatesverygoodcancersurvival.

ThereductioninriskofdeathfromPCaamongadvanced ProtecT cases (45%) compared to ACN controls persisted aftercarefulcase-controlmatchingtoattemptto compen-sate for leadtime bias and differences in baseline char-acteristics. However, other biases cannot be ruled out, includingthegreaternumberofmenundergoingsurgeryin Table3–Coxproportionalhazardssurvivalanalysis

Variable Reference Univariateanalysis Multivariateanalysis

category Prostatecancer–specific survival

Overallsurvival Prostatecancer–specific survival

Overallsurvival

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

ProtecTcases ACNcontrols 0.29(0.21–0.38) <0.0001 0.45(0.38–0.55) <0.0001 0.47(0.34–0.66) <0.0001 0.70(0.56–0.88) <0.002 Yearofdiagnosis 1999–2009

2004–2006 0.63(0.55–0.72) <0.0001 0.71(0.63–0.79) <0.0001 0.55(0.46–0.65) <0.0001 0.69(0.60–0.79) <0.0001 2007–2010 0.48(0.41–0.58) <0.0001 0.55(0.48–0.64) <0.0001 0.48(0.38–0.60) <0.0001 0.59(0.50–0.71) <0.0001 Ageband 50–59yr

60–66yr 0.90(0.75–1.07) 0.24 1.09(0.93–1.28) 0.29 0.89(0.71–1.10) 0.28 1.06(0.88–1.29) 0.52 67–72yr 1.12(0.94–1.33) 0.20 1.56(1.34–1.81) <0.0001 0.97(0.79–1.19) 0.75 1.43(1.19–1.71) <0.0001

PSA 0–10ng/ml

10–20ng/ml 1.23(0.93–1.62) 0.14 1.37(1.12–1.67) 0.002 1.05(0.78–1.40) 0.76 1.22(0.99–1.50) 0.065 20–50ng/ml 1.58(1.23–2.01) <0.0001 1.57(1.31–1.89) <0.0001 1.48(1.14–1.93) <0.003 1.52(1.25–1.85) <0.0001 50–100ng/ml 2.57(1.97–3.36) <0.0001 2.20(1.80–2.71) <0.0001 1.80(1.35–2.43) <0.0001 1.66(1.32–2.08) <0.0001

>100ng/ml 8.38(6.70–10.5) <0.0001 5.87(4.93–6.98) <0.0001 2.65(2.02–3.45) <0.0001 2.43(1.96–2.98) <0.0001 CombinedGleason <7

7 1.39(1.05–1.84) 0.02 1.04(0.86–1.26) 0.68 1.66(1.22–2.26) <0.001 1.18(0.96–1.44) 0.12

>7 4.13(3.18–5.36) <0.0001 2.47(2.08–2.93) <0.0001 4.01(3.0–5.37) <0.0001 2.45(2.01–2.96) <0.0001 Clinicalstage T1/T2

T3 0.71(0.57–0.88) <0.002 0.70(0.60–0.81) <0.0001 1.21(0.96–1.53) 0.11 1.08(0.92–1.29) 0.32 T4 2.10(1.18–3.76) 0.01 1.51(0.95–2.43) 0.08 2.74(1.52–4.92) <0.001 1.96(1.22–3.15) <0.005 M1orN1 8.22(7.08–9.55) <0.0001 4.88(4.36–5.47) <0.0001 5.79(4.82–6.95) <0.0001 3.53(3.07–4.10) <0.0001

HR=hazardratio;CI=confidenceinterval;ACN=AngliaCancerNetwork;PSA=prostate-specificantigen. EUROPEAN UROLOGYXXX(2016)XXX–XXX

theACNgroupthanintheProtecTgroupwhencomparing thosewhoreceivedradicaltreatment,andthefactthatthe ACNgroupweregenerallylessfit.However,therewereno differencesinPCa-specificorall-causemortalitybetween thematchedcasesandcontrolswhencomparingthosewho receivedradicaltreatment.Thehigherdeathratesobserved amongACNcontrolsoccurredmainlyinmenwhoreceived nonradical treatments, suggesting early detection may improve the life expectancy of this subgroup, although otherexplanationssuch asgroupheterogeneity,leadtime bias,andselectionbiascannotberuledout.

Coxregressionresultsforsurvival analysis(53%lower riskof death from PCa anda 30% reductionin all-cause mortalityintheProtecTgroup)canprobablybeexplainedin partbyleadtimebiasintheProtecTcohort[18,19].

WefoundnodifferenceinPCa-specificoroverallsurvival between the RP and RT ProtecT groups. Only a small proportionofmenwhoreceivedradicaltreatment(RP4%,RT 5%)diedfromPCa,whichaddstoincreasingevidencethat radicaltreatment oflocallyadvanced orhigh-risk disease delivers good oncologic outcomes[8,9]. The all-cause and PCasurvivaloutcomesfortheProtecTgrouparebetterthan inmoststudiesonmenclinicallypresentingwithadvanced disease[20],supportingthehypothesisthatearlydetection ofadvancedandhigh-riskPCamaybeofbenefit.Thewider contextoftheimpactofPSAtestingon community-based menwillbepresentedinthefindingsoftheCAP(Cluster randomisedtrialofprostatecancer)trialin2017[21].

ThequalityofdatafortheACNgroupislikelytobegood [15,21].Weminimisedmisattributionofdeathbyusingtwo independent clinicians blinded to the study group and treatment,andbycheckingwith theProtecTrecruitment centreoforigin.Matchingreducedthenumberofmenfor thematchedanalysis(n=401)andtheremaybeadditional biasesthatourmatching processwas unabletotakeinto account.Multidisciplinaryteamsreviewedthe histopathol-ogyforACNcontrols,whereasProtecTcaseswerereviewed by the expert ProtecT histopathology group [22]. For surgically treated ACN cases, however, histology was reviewedcentrally.Potentialdifferencesingradeandstage allocationmayhavehadsomeimpactonapparentsurvival benefitsamongtheProtecTcases.Therewasnoinformation availableonthecomorbidityburdenfortheACNcontrols, andtherefore we were unable to match the two groups accordingto thesefactors. ProtecTparticipantswere 98% Caucasianandpatientswithapriorhistoryofcancerwere excluded,whichmayhaveinfluencedoverallsurvival.The naturalhistoryofPCacanbelongandfurtherfollow-upis required,butsuchleadtimefactorsarelikelytobeoflesser magnitudeamongmenwithadvanceddisease[23–25].

5. Conclusions

PSA testing identifies asymptomatic men with advanced and high-risk PCa whose early treatment leads to good survival rates. We observed improved survival in the ProtecTmenwhoreceivednonradicaltreatmentcompared tomenpresentingclinicallywithoutPSAtesting,although leadtimeandselectionbiasaredifficulttoexclude.Itwillbe

importanttoassesslonger-termsurvivalandadd patient-reportedoutcomesamongthesementoassessthebalance betweentreatmentimpactandsurvival.

Authorcontributions:AlastairD.Lambhadfullaccesstoallthedatain thestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Neal,Hamdy,Donovan,Lane.

Acquisitionofdata:Xiong,Johnston,Shaw,Lamb,Neal,Hamdy,Donovan, Davis.

Analysis and interpretationof data:Johnston, Parashar, Shaw, Lamb, Xiong.

Draftingofthemanuscript:Johnston,Lamb,Neal.

Critical revision of the manuscript for important intellectual content:

Johnston,Lamb,Neal,Hamdy,Donovan.

Statisticalanalysis:Johnston,Parashar.

Obtainingfunding:Neal,Hamdy,Donovan.

Administrative,technical,ormaterialsupport:None.

Supervision:Neal,Hamdy,Donovan.

Other(reviewofmanuscript):Allauthors.

Financial disclosures: Alastair D. Lamb 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:None.

Funding/Supportandroleofthesponsor:TheProtecTtrialisfundedby theUKNationalInstituteforHealthResearch(NIHR)HealthTechnology AssessmentProgramme(projects96/20/06,96/20/99)withthe Univer-sity ofOxfordassponsor(www.nets.nihr.ac.uk/projects/hta/962099). Thesponsorplayedaroleinthedesignandconductofthestudy.JennyL. Donovan is supported by the NIHR Collaboration for Leadership in AppliedHealthResearchandCareWest,hostedbyUniversityHospitals BristolNHSFoundationTrust.FreddieC.Hamdyissupportedbythe Oxford NIHR Biomedical Research Centre Surgical Innovation and EvaluationTheme,andtheCancerResearchUKOxfordCentre.

Acknowledgments:Theauthorswishtoacknowledgethetremendous contribution of all the ProtecT study participants,researchers, data monitoringcommittee(Chairs:ProfessorsAdrianGrantandIanRoberts; Prof.DeborahAshby,Dr.RichardCowan,Prof.PeterFayers,Prof.Killian Mellon,Prof.JamesN’Dow,Mr.TimO’Brien,Dr.MichaelSokal),andtrial steeringcommittee(Chair:Prof.MichaelBaum;Prof.AnthonyZietman, Prof.DavidDearnaley,Dr.JanAdolfsson,Prof.PeterAlbertsen,Prof.Fritz Schro¨der,Prof.TracyRoberts).

Department ofHealthdisclaimer: Theviews andopinions expressed hereinarethoseoftheauthorsanddonotnecessarilyreflectthoseofthe DepartmentofHealth.

AppendixA. Supplementarydata

Supplementary data associated with this article can be found,intheonlineversion,athttp://dx.doi.org/10.1016/j. eururo.2016.09.040.

References

[2] AndrioleGL,CrawfordED, Grubb RL3rd,etal.Prostate cancer screeningintherandomizedProstate,Lung,Colorectal,andOvarian CancerScreeningTrial:mortalityresultsafter13yearsoffollow-up. JNatlCancerInst2012;104:125–32.

[3] ShoagJE,MittalS,HuJC.ReevaluatingPSAtestingratesinthePLCO trial.NEnglJMed2016;374:1795–6.

[4] WiltTJ,BrawerMK,JonesKM,etal.Radicalprostatectomyversus observationforlocalizedprostatecancer.NEnglJMed2012;367: 203–13.

[5] WidmarkA,KleppO,SolbergA,etal.Endocrinetreatment,withor withoutradiotherapy,inlocallyadvancedprostatecancer(SPCG-7/ SFUO-3): an openrandomisedphase III trial.Lancet 2009;373: 301–8.

[6] WardeP,MasonM,DingK,etal.Combinedandrogendeprivation therapyandradiationtherapyforlocallyadvancedprostatecancer: arandomised,phase3trial.Lancet2011;378:2104–11.

[7] AbdollahF,SunM,ThuretR,etal.Acompeting-risksanalysisof survivalafteralternativetreatmentmodalitiesforprostatecancer patients:1988-2006.EurUrol2011;59:88–95.

[8] BoorjianSA,KarnesRJ,ViterboR,etal.Long-termsurvivalafter radical prostatectomy versus external-beam radiotherapy for patientswithhigh-riskprostatecancer.Cancer2011;117:2883–91.

[9] SooriakumaranP,NybergT,AkreO,etal.Comparativeeffectiveness of radical prostatectomy and radiotherapy in prostate cancer: observationalstudyofmortalityoutcomes. BrMedJ2014;348: 1502–15.

[10] GreenbergDC,LophatananonA,WrightKA,MuirKR, Gnanapraga-samVJ.Trendsandoutcomefromradicaltherapyforprimary non-metastaticprostatecancerinaUKpopulation.PLoSOne2015;10: e0119494.

[11]DonovanJ,HamdyF,NealD,PetersT,OliverS.ProstateTestingfor CancerandTreatment(ProtecT)feasibilitystudy.HealthTechnol Assess2003;7:42.

[12]Lane JA,DonovanJL, DavisM,etal.Active monitoring, radical prostatectomy,orradiotherapyforlocalisedprostatecancer:study designanddiagnosticandbaselineresultsoftheProtecT random-isedphase3trial.LancetOncol2014;15:1109–18.

[13]HamdyFCDonovanJL,AtheneJL,etal.Prostatecancermortality andoutcomesat10yearfollow-upintheProtecTtrial.NEnglJMed.

http://dx.doi.org/10.1056/NEJMoa1606220

[14] DonovanJL,HamdyFC,LaneAJ,etal.Patientreportedoutcomes oversixyearsintheProtecTprostatecancertrial.NEnglJMed.

http://dx.doi.org/10.1056/NEJMoa1696221

[15] GreenbergDC,WrightKA,LophathanonA,MuirKR, Gnanapraga-samVJ.ChangingpresentationofprostatecancerinaUK popula-tion—10yeartrendsinprostatecancerriskprofilesintheEastof England.BrJCancer2013;109:2115–20.

[16] MeliaJ,MossS,JohnsL.Ratesofprostate-specificantigentestingin generalpracticeinEnglandandWalesinasymptomaticand symp-tomaticpatients:across-sectionalstudy.BJUInt2004;94:51–6.

[17] WilliamsN,HughesLJ,TurnerEL,etal.Prostate-specificantigen testingratesremainlowinUKgeneralpractice:across-sectional studyinsixEnglishcities.BJUInt2011;108:1402–8.

[18] MooreAL,DimitropoulouP,LaneA,etal.Population-based pros-tate-specificantigentestingintheUKleadstoastagemigrationof prostatecancer.BJUInt2009;104:1592–8.

[19] CollinSM,MartinRM,MetcalfeC,etal.Prostate-cancermortalityin theUSAandUKin1975to2004:anecologicalstudy.LancetOncol 2008;9:445–52.

[20] Mason MD, ParulekarWR, SydesMR, etal.Final report ofthe intergrouprandomizedstudyofcombinedandrogen-deprivation therapy plusradiotherapyversus androgen-deprivationtherapy alone in locally advanced prostate cancer. J Clin Oncol 2015; 33:2143–50.

[21] UKDepartmentofHealth.Deliveringthecancerreformstrategy. ReportbytheControllerandAuditorGeneral.London,UK:National Audit Office; 2010. www.nao.org.uk/wp-content/uploads/2010/ 11/1011568.pdf.

[22] OxleyJ,SimpkinA,GoepelJ,etal.GleasondriftintheNIHRProtecT study.Histopathology2015;66:438–46.

[23] AlbertsenPC,HanleyJA,FineJ.20-yearoutcomesfollowing con-servativemanagementofclinicallylocalizedprostatecancer.JAMA 2005;293:2095–101.

[24] Bill-AxelsonA,HolmbergL,RuutuM,etal.Radicalprostatectomy versuswatchfulwaitinginearlyprostate cancer.NEnglJ Med 2005;352:1977–84.

[25] Bill-AxelsonA,HolmbergL,FilenF,etal.Radicalprostatectomy versuswatchfulwaitinginlocalizedprostatecancer:the Scandi-navianprostatecancergroup-4randomizedtrial.JNatlCancerInst 2008;100:1144–54.

EUROPEAN UROLOGYXXX(2016)XXX–XXX