Mortalidad en cancer de prostata

15/9/2015 www.medscape.com/viewarticle/835767_print

http://www.medscape.com/viewarticle/835767_print 1/11

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AbstractandIntroductionAbstract

BackgroundDuringthelast30years,therehasbeenamajorshiftininitialstaginginprostatecancer(CaP)inWesterncountries,withtheincidenceofmetastasesatdiagnosisdecreasingfromover50%inthe1970stocurrentlylessthan10%.Yet,CaPisstillthesecondcauseofcancerdeathinmen.Weusedtwomonthlycurateddatabasesofpatientswithcastrationresistantprostatecancer(CRPC)todescribethenaturalhistoryofpatientsdyingofCaPinthemodernera.

MethodsTheoutcomeof190menwithmetastaticCRPCtreatedfrom2008to2011wasstudied.ThecharacteristicsofthepatientswhodiedfromCaP(n=113patients,61%)wereanalyzed.

ResultsAll113patientswhodiedofCaPwereassessableforthepresenceofmetastasesatdiagnosis.Sixtythreepatients(56%)haddetectablemetastasesatdiagnosis:67%,11%and43%hadbone,visceralandlymphnodemetastases,respectively.ThemediantimetoCRPCwas16monthsandmedianoverallsurvival(OS)was5.2years.AmongthepatientswithlocalizedCaPatdiagnosis(n=50,44%),46%hadTstage3and38%hadaGleasonscore8.Overall,64%ofpatientswereclassifiedashavingahighriskCaP.Only26%whodiedfromCaPhadaGleasonscore6.MedianOSwas8.8years.

ConclusionsInthemodernera,approximatelyhalfofthepatientswhodiefromCaPhavemetastasesatdiagnosis.Theparadigmofprogressionfromlocalizeddiseasetometastasisandeventuallydeathisonlyrepresentedintheotherhalf,althoughpossibleinitialscreeningandstagingerrorsoughttobetakenintoconsideration.MoreeffortsareneededtoconducttrialsinpatientswithnewlydiagnosedmetastaticCaP.

Introduction

TheintroductionofsystematicPSAscreeningresultedinasignificantriseintheincidenceofprostatecancer(CaP)inWesternsocieties.Itpeakedintheearly2000s,thendeclinedaftertheinitialenthusiasmgiventhesideeffectsofoverdiagnosisandovertreatment,andiscurrentlyrelativelystablewithmoderatefluctuation.[1]Asaresult,therehasbeenamajorshiftininitialstagingformenwithCaPinWesterncountries,withtheincidenceofdetectablemetastasesatdiagnosisdecreasingfrommorethan50%ofthecasesinthe1970stocurrentlylessthan10%.[24]

DespitethechangesintheepidemiologicalprofileofCaPinWesterncountrieswithanincreasedpercentageofearlystage,lowriskdiseaseatdiagnosis,thesurvivalbenefitofPSAbasedscreeningremainscontroversial,becausethisearlydetectionandtreatmentofCaPs,whichdonotthreatenlifeexpectancy,leadstounnecessarysideeffects,impairedqualityoflifeandhealthexpenses.UpdatedsurvivaldatafromthelargestEuropeanPSAscreeningrandomizedtrialsuggestarelativereductionof21%intheriskofdeathfromCaP,increasingto29%afteradjustmentforselectionbiasandnoncompliance(butwithoutabenefitinoverallsurvival(OS))ontheotherhand,screeningofover1000menisnecessarytodetect37cancersandpreventonedeathfromCaP.[3]

Accountingforapproximately9%oftotalestimatedcancerdeaths,CaPremainsthesecondcauseofcancerrelatedmortalityinmenintheUS,[1]andthethirdcauseinEurope.[5]CaPspecificmortalityisapproximately12%intheUS[1]and17%inEurope,[5]althoughpercentagesashighas35%areobservedinspecificpopulationssuchasSweden.[6,7]Itisthereforeimportanttobettercharacterizetheprofileofpatientswhowilleventuallydieofthedisease,andaccuratelydistinguishthemfromthemajorityofpatientswithindolent,slowgrowingdiseaseforwhomdeathwillmostlikelybeattributedtocomorbidities.

ThisstudyaimedtodescribethecharacteristicsandnaturalhistoryofpatientsdyingofCaPinthemodernera.

MaterialsandMethodsTheoutcomeofpatientswithmetastaticcastrationresistantCaP(CRPC)treatedinclinicaltrialsfrom2008to2011intwoinstitutionsinFrance(InstitutGustaveRoussy,Villejuif,andInstitutJeanGodinot,Reims)wasstudiedinaretrospectivepooledanalysis.Patientsweredefinedasmetastaticiftheyhadradiologicallyand/orhistologicallydetectedregionallymphnodemetastasis(N+)and/ordistantmetastasis(M+).Atotalof190patientswithmetastaticCRPCwereidentified.Afteramedianfollowupof6.8yearsfrominitialdiagnosis,113patientshaddiedofCaPandwereassessableforthepresenceofmetastasisatdiagnosis(Figure1).

WhoDiesFromProstateCancer?APatrikidouYLoriotJCEymardLAlbigesCMassardEIleanaMDiPalmaBEscudierKFizaziProstateCancerProstaticDis.201417(4):348352.



Figure1.

CONSORTdiagramofthestudy.

ThecharacteristicsofpatientswhodiedfromCaPwereanalyzed.Patientrecordswereaccessedthroughhospitalelectronicdatabases.Datacollectionpertainedtodemographics,initialPSAvalues,Gleasonscoreandstagingdata,riskgroups,primarytreatmentmodalities,durationofresponsetoandrogendeprivationtherapy(ADT),metastaticsites,docetaxeltreatment(duration,bestresponse,clinicalbenefit,timetoprogression(TTP)),preandpostdocetaxeltreatmentlines,terminalPSAvalues(lastavailablePSApriortodeath)andOS.CRPCwasdefinedasaprogressiveCaPdespitecastratelevelsoftestosterone.ProgressionwasdefinedaccordingtothePCWG2criteria.[8]RiskgroupsforpatientswithlocalizeddiseaseweredefinedaccordingtotheD'Amicoclassification.[9]ObjectiveresponsesweremeasuredaccordingtoRECISTcriteria.Clinicalbenefitwasdefinedasadecreaseintheuseofanalgesicsandimprovementoftheperformancestatus.TheintervalfromthediagnosistothelastavailablefollowupordeathwasusedtocalculateOS.Informationonthecompletenessofdataisprovidedinand.

Table1.Cohortcharacteristics:metastaticatdiagnosisCaPpatients

Characteristics Metastaticpatients(n=63)

Age(years)

Median(range) 63(4781)

Unknown(n,%) 1(1.6)

Metastaticsites(n,%)

Bone 42(66.7)

Lymphnode 27(42.8)

N1 25(39.7)

M1a 2(3.2)

Visceral 7(11.1)

Multiplesites 9(14.3)

Unknown 0(0.0)

Gleasonscore(%)



6 5(7.9)

=7 22(34.9)

8 34(54.0)

Unknown 2(3.2)

Localtreatment(%)

Surgery 5(8.0)

Radiotherapy 9(14.3)

Brachytherapy 0(0.0)

None 37(58.7)

Unknown 12(19.0)

PSA(ngml1)


Unknown(n,%) 6(9.5)

PSA(ngml1,%)

04 0(0.0)

410 1(1.6)

1020 8(12.7)

>20 48(76.2)

Unknown 6(9.5)

TimetoADT(fromdiagnosis)(months)

Median(range) 0.6(0146)

Unknown(n,%) 0(0.0)

TimetoCRPC(months)


Unknown(n,%) 0(0.0)

Timetodocetaxelstart(fromdiagnosis)(months) 30.7(3.3152.2)

Median(range)

Unknown(n,%)

Overallsurvival(months)

Median(95%CI) 62(3878)

Unknown(n,%) 0(0.0)

Abbreviations:ADT,androgendeprivationtherapyCaP,prostatecancerCI,confidenceintervalCRPCcastrationresistantprostatecancer.

Table2.Cohortcharacteristics:nonmetastaticatdiagnosisCaPpatients

Characteristics Nonmetastaticpatients(n=50)

Age(years)


Unknown(n,%) 1(2.0)

Tstage(n,%)

T2 9(18)



T3 22(44)

T4 1(2)

Unknown 18(36)

Gleasonscore(n,%)

6 13(26)

=7 13(26)

8 19(38)

Unknown 5(10)

Prognosisgroup(n,%)

Lowrisk 4(8)

Intermediaterisk 11(22)

Highrisk 32(64)

Unknown 3(6)

Localtreatment(n,%)

Surgery 20(40)

Radiotherapy 30(60)

Brachytherapy 1(2)

None 3(6)

Unknown 2(4)

PSA(ngml1)


PSA(ngml1,%)

04 2(4.0)

410 12(24.0)

1020 13(26.0)

>20 15(30.0)

Unknown 8(16.0)



Unknown(n,%) 3(6.0)

TimetoCRPC(months)


Unknown(n,%) 0(0.0)

Timetodocetaxelstart(fromdiagnosis)(months)


Unknown(n,%) 0(0.0)


Median(95%CI) 106(96120)

Unknown(n,%) 0(0.0)




StatisticalanalysiswascarriedoutusingthePrismstatisticalsoftware,version6(GraphPadSoftware).Descriptivestatisticalmethodswereused.OSandTTPpostdocetaxelwerecalculatedusingKaplanMeierestimatesandcomparedusingalogranktest.

ResultsOfthe113patientswhodiedofCaP,63patients(55.7%)haddetectablemetastasesatdiagnosis:42(67%),27(43%)and7patients(11%)hadbone,lymphnodeandvisceralmetastases,respectively.Overall,ninepatients(14%)hadmultiplemetastaticsites.Themajorityoftumors(89%)hadaGleasonscoreof7orabove.ThemedianPSAatdiagnosiswas81ngmll(95%confidenceinterval(CI)45150ngml1),withthevastmajorityofpatientsdiagnosedwithaPSAover20ngml1.Nolocoregionaltreatmentwasperformedin59%ofthepatientswithdenovometastaticCaP,whereasdatawerenotavailablefor19%ofpatients.Only8%and14%hadsurgeryandradiotherapy,respectively(fivepatientsunderwentradicalprostatectomy,combinedwithapelviclymphnodedissectionintwocases).Onepatienthadbothsurgeryandradiotherapy.ThemediantimetoADTinitiationwas0.6months.ThemediantimetoCRPCwas16months(95%CI1319months).Themediannumberofdocetaxelcycleswas8,andthemedianTTPpostdocetaxelwas7months.MedianPSAatdocetaxelinitiationwas145ngml1

andmediannadirPSApostdocetaxelwas27.35ngml1.APSAreductionof>50%wasseenin77.5%ofpatients,whilea>30%reductionwasseenin84.5%.AnadirPSAof



Unknown(n,%) 6(9.5)

PSA(ngml1,%)

04 0(0.0)

410 1(1.6)

1020 8(12.7)

>20 48(76.2)

Unknown 6(9.5)



Unknown(n,%) 0(0.0)

TimetoCRPC(months)


Unknown(n,%) 0(0.0)

Timetodocetaxelstart(fromdiagnosis)(months) 30.7(3.3152.2)

Median(range)

Unknown(n,%)


Median(95%CI) 62(3878)

Unknown(n,%) 0(0.0)


AmongpatientswithlocalizedCaPatdiagnosis(n=5045%),23patients(46%)hadaTstage3and9patients(18%)hadaTstage2,whereaspreciseTstagingdatawerenotavailableforasignificantproportionofpatients(36%).ThiscanbeattributedtothefactthattheinitialdiagnosisandmanagementhadnotbeenperformedinthestudycentersforalargenumberofthelocalizedCaPcohortthesepatientswereinfactreferredtoourcentersafterenteringtheCRPCstage.Nevertheless,specificMstaginginformationwasavailableforallthepatientsforwhomtheTstagewasnotavailable,andspecificNstaginginformationwasavailableforallbuttwoofthem.Approximatelytwothirdsofthepatients(32patients,64%)hadaGleasonscore7,while13patients(26%)hadaGleasonscore6,andfor5patients(10%),theGleasonscorewasnotavailable.ThemedianPSAatdiagnosiswas16ngml1(95%CI10.924ngml1).Overall,32patients(64%)hadhighriskCaP,and8%ofpatientshadalowrisktumoratdiagnosis.Only4%ofthepatientsdidnotreceiveanylocoregionaltreatment,while40%,60%and2%underwentsurgery,radiotherapyandbrachytherapy,respectively.ThemediantimetoADTinitiationwas23.1months.ThemediantimetoCRPCwas19months(95%CI:1232months).Themediannumberofdocetaxelcycleswas7,andthemedianpostdocetaxelTTPwas7months(95%CI:5.98months).ThemedianPSAatdocetaxelinitiationwas78ngml1,andthemedianpostdocetaxelPSAnadirwas14.4ngml1.APSAreductionof>50%wasseenin65.7%oftheinformativepatients,whilea>30%reductionwasobservedin74.3%ofpatients.AnadirPSAof



T3 22(44)

T4 1(2)

Unknown 18(36)

Gleasonscore(n,%)

6 13(26)

=7 13(26)

8 19(38)

Unknown 5(10)

Prognosisgroup(n,%)

Lowrisk 4(8)

Intermediaterisk 11(22)

Highrisk 32(64)

Unknown 3(6)

Localtreatment(n,%)

Surgery 20(40)

Radiotherapy 30(60)

Brachytherapy 1(2)

None 3(6)

Unknown 2(4)

PSA(ngml1)


PSA(ngml1,%)

04 2(4.0)

410 12(24.0)

1020 13(26.0)

>20 15(30.0)

Unknown 8(16.0)



Unknown(n,%) 3(6.0)

TimetoCRPC(months)


Unknown(n,%) 0(0.0)

Timetodocetaxelstart(fromdiagnosis)(months)


Unknown(n,%) 0(0.0)


Median(95%CI) 106(96120)

Unknown(n,%) 0(0.0)

Abbreviations:ADT,androgendeprivationtherapyCaP,prostatecancerCI,confidenceintervalCRPCcastrationresistant



prostatecancer.

Asexpected,patientswithlocalizeddiseaseatdiagnosishadabetterOSthanthosewithdenovometastaticcancer(P=0.0001)(Figure2).Therewasnodifferenceintheageatdiagnosis,buttherewereexpecteddifferencesintheinitialPSAlevel(P=0.03)andthepercentageoftumorswithalowGleasonscore,reflectingamoreaggressivebiologyandheavierassociatedtumorburden.AborderlinedifferencewasfoundintimetoCRPCbetweenthetwogroups(P=0.06).TherewasnosignificantdifferenceinthepostdocetaxelTTP(P=0.695)orthepostdocetaxelnadirPSA(P=0.3679),despiteasignificantlylowerpredocetaxelPSAlevelinthenonmetastatictumors.

Figure2.

KaplanMeiercurvesofoverallsurvivalinpatientcohortswithlocalizedanddenovometastaticprostatecancer.

DiscussionDespiteeffectiveinitialmanagementandimprovedtherapeuticoptionsoverrecentyears,patientswithrelapsedCaPundertolongtermcastrationwillinevitablyreachthecastrationresistancephase,developmetastaticdiseaseandeventuallydieofcancerprogression,unlessdeathduetoanunrelatedcauseoccurs.Theneedtoidentifythesepatientsearly,ifpossibleatdiagnosis,isunderlinedbythefindingofoneofthelargestscreeningtrials,whereinthemajority(74%)ofdeathsfromCaPdetectedbyscreeningoccurredinmenwhosecancerwasdiagnosedattheirfirstPSAscreening.[3]Thisindicatesthatthediseasethatwilleventuallybelethalisaggressivefromtheverybeginning.Italsopossiblyexplainswhytheeffectofscreeningdoesnotfurtherincreaseduringextendedfollowupbutthat,conversely,therateofCaPdeathsevenfrominitiallylocalizedcancersmayincreaseduringafollowupperiodof1520years.[3,10]

Oneoftheinterestingfeaturesofouranalysisisthehighpercentage(50%)ofpatientswithdenovometastaticCaPinthiscohortofpatientswhodiedofthedisease.DatafromalargeUKCaPregistryalsoevidencedthat44.5%ofCaPspecificdeathswerepatientswithupfrontmetastaticdisease,despitethefactthatthelattercorrespondedtoonly14%oftheoverallregistry.[4]

Itisnoteworthy,however,thatinformationforstageatdiagnosiswasnotavailablefor23%ofCaPdeathsintheUKstudy.Asimilarcaveatcouldbeputforwardregardingourstudy:menwhopresentwithdenovometastaticdiseasemayhavebeenineffectivelyscreened,andmighthavepresentedwithcurablediseasehadtheybeendiagnosedearlier.Conversely,itcouldbearguedthatourcohortoflocalizedCaPmight,owingtoinefficientscreening,harborpatientswithunderstaged,undetecteddenovometastaticcancer.Indeed,thefactthattherewasnosignificantdifferenceinthetimetoCRPCbetweenthetwocohortsfurtherraisesthisquestion.However,themedianageatdiagnosisdidnotdifferbetweenthetwocohorts,whicharethereforelikelytohavebeenstochasticallysubmittedtothesamelevelofineffectivescreening.Furthermore,thedifferencesinthePSAlevelatdiagnosis,timetoADTinitiationandtimetodocetaxeluse(whichisusuallyahallmarkofsymptomaticmetastaticCRPC)reflectthedifferenceintheinitialtumorburdenandmetastaticstatusofthetwocohorts.

Theanalysisperiodofthisstudyendedjustpriortothewidelyavailableapplicationsofnewertreatmentoptions,notably



abirateroneandenzalutamide.Conversely,however,allstudypatientshadparticipatedinclinicaltrials,thesignificantmajorityinvolvingthesetwodrugs.Thefactthattheseareclinicaltrialpopulationpatientscouldalsobeinterpretedasastudylimitation,inthesensethatitmaynotberepresentativeofthecommunitynontrialsetting(atleastnotforthetimeperiodtheanalysispertainsto)orthedevelopingworldsetting.Onanotherissue,theGleasongradingsystemwasmodifiedin2005and2010,andthisfactoughttobetakeninconsiderationintheinterpretationofourresults,especiallyinregardwithGleason6tumors.

TheoverallpercentageofpatientswithdenovometastaticCaPintheliteraturerangesfromlessthan10%toalittleover20%inscreeningstudiesandpopulationbasedregistries.[24]Inthepoolofpatientswhoeventuallydieofthedisease,thispercentageseemstoincreasetwofoldoreventhreefold.WhatourresultsthereforeindicateisthatthestandardnotionofaninitiallyindolentdiseaseslowlyprogressingtothemetastaticphaseanddeathmightbetrueonlyforhalfofthepatientswhodieofCaP.

Itisobviousthatagreatereffortisneededforthissubsetofpatientswithupfrontmetastaticdisease,whoprobablymeritdifferentmanagementstrategies.Onesuchdirectioncouldbetoadministerchemotherapyearlier,notablybeforereachingtheCRPCstage.TheearlyuseofregimensotherthandocetaxelhasasyetnotbeenprovenofbenefitindenovometastaticpatientsintermsoftimetoCRPCprogressionorinsurvival.[11,12]

Theonlyrandomizedphase3studywithavailableresultsonearlydocetaxeltherapyformetastaticnoncastrateCaPistheGETUG15trial.[13]Overtwothirdsofthepatientsinbotharmsweremetastaticatdiagnosis.Althoughclinical(23.5vs15.4months,P=0.015)andbiochemicalprogressionfreesurvival(22.9vs12.9months,P=0.005)weresignificantlylongerwithdocetaxel,thecombinationofADT/docetaxeldidnotsignificantlyincreaseOScomparedwithADTalone(58.9vs54.2months,P=0.955).Similartrialstestingdocetaxel(STAMPEDEandCHAARTEDECOGE3805trials)[14,15]areconductedintheUSandtheUK.Theresultsofthephase3CHAARTEDtrialwereveryrecentlyreported:withamedianfollowupof29months,docetaxelimprovedOScomparedwithADTalone(52.7vs42.3months,P=0.0006,hazardratio0.63(95%CI:0.48,0.82)).[15]

Thisbenefitwasmainlyseeninthehighvolumediseasegroup,astherewasnosurvivaldifferenceinthelowvolumediseasepatients.Indeed,thefactthatthiswasalargerstudyandincludedmorehighvolumediseasepatients,combinedwiththefactthatlesspatients(31%)intheADTalonegroupreceiveddocetaxeluponprogressioncomparedwiththeGETUG15trial(62%)mightbeaccountableforthedifferenceinOSoutcomebetweenthetwostudies

Anintriguingoptionthatemergedistheearlyadditionofnovelendocrinetherapies.AnongoingphaseIIIEuropeantrial(PEACE1)[16]isdesignedtoaddressthisissueinmetastatichormonenavepatients,bytestingcombinationsofADT,localradiotherapyandabirateroneacetateinfourarms.TheSTAMPEDEtrialalsoincludedanadditionalabirateronearmtoitscomplexdesign,[14]whilethepivotalLatitudephaseIIItrialistestingtheadditionofabirateronetoADTinpatientswithdenovometastaticCaPandadversefeatures.[17]Aphase2trialissimilarlyevaluatingneoadjuvantenzalutamidewithADTinintermediateandhighriskpatients.[18]

Perhapsthemostcontroversialapproachforupfrontmetastaticpatientswouldbetotreattheprimarytumoritself.Currently,locoregionalapproachesareignoredinCaPinthepresenceofmetastaticdisease.Thisattitudeisbasedonthecommonlyheldnotionthattheprognosisisinfluencedbythepresenceofmetastasis,andassuchemployinglocaltreatmentisdeemeduselessorfutileinthiscontext.Asignificanttumorburdenisthusleftinplacethatsystemictreatmentsarecalledupontoaddress.Locoregionaltreatment,however,especiallysurgery,wouldserveasanimportantimmediatecytoreductiveapproach,notallowingtumorcellsthetimetoacquireoractivateadaptivemechanisms.Inaddition,primarytumorsareknowntoberesponsibleforsheddingdisseminatedcancercellsevenatveryearlystages,associatedwithpoorprognosisandlaterdevelopmentofmetastasis,[1921]evenafterlongperiodsoftumordormancy.[22]Thiseffectisamplifiedinthemajorityofmetastaticpatientswhocurrentlydonotreceiveanylocoregionaltreatmentatall,butareinsteadsubmittedtolongtermADT,which,despiteaninitialresponse,willinevitablyleadtocastrationresistanceandprogression.

Evidencefromothersolidtumors,suchasbreast,colorectalandrenalcancerhaveeducatedusontheimportanceoftreatingtheprimarytumorandevenofresectingcarefullyselectedmetastasesinthecontextofmultimodalitytreatment.InCaP,althoughthebenefitofadministeringADTtopatientswithpN1diseasehasbeenclearlysuggested,[23]studiesonclinicallyN+diseasetreatedwithacombinationofsurgeryandADTarelimitedandretrospectivetheydo,however,pointinthesamedirectionintermsofsurvivalbenefit.[24,25]Regardinglocoregionaltreatmentinpatientswithdistantmetastasisatdiagnosis,norealevidenceexists.

Inparallel,effortsareneededtoreinforceourabilitytoappropriatelytreatthosepatientswithlocalizedCaPwhoarelikelytodieofthedisease,possiblyusingmodalitiesotherthanextendedsurgeryandconventionaladjuvantmodalities.TheGETUG12trialaddressedtheimpactofneoadjuvantdocetaxelinadditiontoADTinlocalizedhighriskpatientsincluding25%withnodepositivedisease.Thereportedresultsonresponse,toleranceandqualityoflifeareencouraging,[26]whileprogressionfreesurvivaldataarepending.TheongoingEuropeanPEACE2phaseIIItrialisinvestigatingtheadditionofcabazitaxeltopelvicradiotherapyandhormonotherapyinthesamepopulation.[27]

NewerendocrinetherapieshavealsoenteredthearenaoflocalizedhighriskCaP.Recentstudiesonneoadjuvantabirateroneacetatereportedpromisingbiochemicalandpathologicalresponserates.[28,29]Suchresultsargueinfavoroftesting



combinationsofneoadjuvantabirateroneinphaseIIItrials.

ConclusionOurresultsindicatethatapproximatelyhalfofthepatientswhodieofCaPhavedetectablemetastasesatdiagnosis,althoughinitialscreeningandstagingerrorsoughttobetakenintoconsideration.Furtherevidenceisclearlyneededtoconfirmtheseresults.Similarly,largerandomizedtrialsarewarrantedtodeterminetheappropriatemanagementofpatientswithdenovometastaticCaP,includingtheevaluationofcombinedofsystemicandlocoregionalmodalities.

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Mortalidad en cancer de prostata