What risk of prostate cancer led urologist to recommend prostate biopsies?

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ORIGINAL ARTICLE

What risk of prostate cancer led urologist to recommend prostate biopsies?

Quel niveau de risque de cancer incite l’urologue à réaliser des biopsies de la prostate ?

M. Roumiguié

^a^,∗

, J.-B. Beauval

^a

, B. Bordier

^g

, T. Filleron

^b

, F. Rozet

^d

, A. Rufﬁon

^e

, N. Mottet

^f

, O. Cussenot

^c

, B. Malavaud

^a^,^b

aDépartementd’urologie,CHURangueil,1,avenueJean-Poulhès,TSA50032,31059Toulouse cedexFrance

bDépartementdebiostatistiques,IUCToncopôle,Toulouse,France

cDépartementd’urologie,hôpitalTenon,CHU,AP—HP,4,ruedelaChine,75970Pariscedex 20,France

dInstitutMontsouris,départementd’urologie,42,boulevardJourdan,75014Pariscedex, France

eDépartementd’urologie,centrehospitalierLyonSud,Pierre-Bénite,France

fDépartementd’urologie,hôpitalNord,42055Saint-Étiennecedex2,France

gCliniquePasteur,serviced’urologie,5,avenuedeLombez,31300Toulouse,France

Received7July2015;accepted4August2015 Availableonline1October2015

KEYWORDS Prostatecancer;

Diagnosis;

Nomogram;

Biopsy;

Risk

Summary

Objective.—Theaimofthisstudywastoestimatetheriskofprostatecancerthatledurologists toperformprostatebiopsies.

Patientsandmethods.—Eighthundredandeightpatientshadprostatebiopsiesin5tertiary centresin2010.Followingdatawerecollected:age,PSA,DRE,prostatevolume,negativeprior prostatebiopsyandestimatedlifeexpectancy(>or<10years).Theriskofprostatecancerwas calculatedbyvalidatednomogramofPCPT-CRCandSWOP-PRIandcorrelatedwithpathological biopsyresults.

Results.—In ﬁnal analysis, 625 patients were included, 568 (90.9%) had alife expectancy greaterthan10years.Prostatecancerwasfoundin291(46.6%)cases.Thesepatientswereolder (66.7±6.8vs64.3±5.6years,P<0.001),hadhigherPSAvalues(10±7.9vs7.7±4.3ng/mL, P<0.0001) and the prostate volume decreased (43.8±19.8 vs 51.3±20.7mL, P<0.0001)

∗Correspondingauthor.

E-mailaddress:roumiguiemathieu@yahoo.fr(M.Roumiguié).

http://dx.doi.org/10.1016/j.purol.2015.08.007

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comparedwithhealthysubjects.DigitalRectalExaminationwasmorefrequentlysuspiciousin thegroupofpatientswithprostatecancer(43.6%vs18.9%,P<0.0001).Riskofprostatecancer estimatedwas50.6±14%forPCPT-CRCwithoutATCD,56.2±12.8%withPCPT-CRCATCDand 31.2±17.3%forSWOP-PRI.Thelikelihoodofhigh-riskprostatecancerwas22.4±16.9%with thePCPT-CRC,and14.8±18.2%withSWOP-PRI.

Conclusion.—Thisstudyshowedthaturologistsperformedprostatebiopsieswhentheriskof cancerwashigh.

Levelofevidence.— 5.

MOTSCLÉS Cancerdeprostate; Diagnostic;

Nomogramme; Biopsies; Risques

Résumé

Objectif.—Déterminerquelniveauderisquedecancerconduitlesurologuesfranc¸aisàréaliser desbiopsiesdelaprostate.

Matérieletméthodes.—Ils’agissaitd’uneétudeportantsur808patientsayanteudesbiopsies delaprostatedans5 centresuniversitairesfranc¸aisen2010.Lesdonnéessuivantesétaient colligées :l’âge,lePSA, letoucherrectal, levolume prostatiqueetlenombredesériede biopsiespréalables.L’espérancedevieétaitestimée(supérieureouinférieure à10ans)par l’urologue.Lesrésultatsanatomopathologiquesdesbiopsiesétaientrenseignés.Àpartirdeces données,lerisquedecancerétait calculéparlesnomogrammesvalidés duPCPT-CRCetdu SWOP-PRI.

Résultats.—Six cent vingt-cinq patients étaient inclus pour l’analyse ﬁnale, 568 (90,9 %) avaientuneespérancedeviesupérieureà10ans.Uncancerdelaprostateétaitretrouvésur lesbiopsiessystématiséeschez291 patients(46,6%).Cespatientsétaientplusâgés(66,7±6,8 vs64,3±5,6ans,p<0,001),avaientunPSAplusélevé(10±7,9vs7,7±4,3ng/mL,p<0,0001) etunvolumeprostatiquediminué(43,8±19,8 vs51,3±20,7mL,p<0,0001)parcomparaison auxsujetssains.Letoucherrectalétaitplusfréquemmentanormaldanslapopulationmalade (43,6%vs18,9%,p<0,0001).Lesniveauxderisqueincitantlesurologuesàbiopsierétaienten moyennepourlesnomogrammesPCPT-CRCsansATCDde50,6±14 %,PCPT-CRCavecATCDde 56,2±12,8 %etpourleSWOP-PRIde31,2±17,3 %.Laprobabilitéquelesbiopsiesdétectent uncancerdehautgradeétaitaveclePCPT-CRCde22,4±16,9 %etde14,8±18,2 %avecle SWOP-PRI.Lesniveauxderisqueaugmentaientavecl’âge,étaientdifférentsentrelespatients déjàbiopsiésetindemnesdebiopsiespourlesdeuxcalculateursderisque.

Conclusion.—Silesurdiagnosticestunepréoccupationactuelledeshautesautoritésdesanté, cetravailmontrequelesurologuestolèrentunniveauderisquedecancerprostatiqueélevé avantdefairedesbiopsies.

Niveaudepreuve.— 5.

Introduction

ProstatecanceristhemostcommonsolidcancerinFrance (71,500 patients/year) andthe second cause of deathby cancer(8791 patients/years)inmales[1].TheFrenchAsso- ciationofUrologysupportsindividualscreeningbyProstatic SpeciﬁcAntigen(PSA)testingandDigitalRectalExamination (DRE)[2].

In a recent report, PSA with a threshold of 4ng/mL exhibited excellent sensitivity (93%) but mediocre speci- ﬁcity (24%) [3]. In the PCPT study, random systematic sextant biopsies demonstrated cancer in 15.2% patients with PSA values <4ng/mL and unsuspicious DRE while in the Catalona report the rate of positive biopsies in the so-called ‘‘grey zone’’ (PSA: 4—10ng/mL) was in

the range of 25% [4,5]. Thus, the large majority of prostate biopsies do not show cancer [6]. According to the French Parliamentary Ofﬁce for the evaluation of Health Care Policies (OPEPS), up to 250,000 biopsies are taken every year in France suggesting that a large num- berof patientsaresubjected tobiopsy witha littleorno beneﬁt. (http://www.senat.fr/rap/r08-318/r08-3181.pdf).

Pre-biopsyevaluationoftheindividualriskofpositivebiop- sies would help control the negative aspects of prostate biopsy(morbidity,negativeresults)withminimalimpacton thebeneﬁtsofearlyprostatecancerdiagnosis(Schroeder).

Manypredictiveinstruments suchasPCPT-CRCandSWOP- PRI were designed and validated to estimate the risk of positivebiopsy[7,8].Theywereusedinthepresentpaper to estimate in a cohort of patients submitted toprimary

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andrepeatbiopsiestherisksofshowingcancerthatledthe referringurologiststorecommendbiopsies.

Patients and methods

Eight hundred and eight patients biopsied in ﬁve French universitycentreswererecruitedinthisretrospectivemul- ticenterstudy[9].Age,digitalrectalexamination,prostate volumemeasuredwithtransrectalultrasonography(TRUS), biopsyhistory,andserumPSAvalueswereobtainedfor all patientsandusedtoestimatetheindividualriskofcancer using two validated instruments of prediction: PCPT-CRC (http://deb.uthscsa.edu/URORiskCalc/Pages/calcs.jsp) and SWOP-PRI (http://www.prostatecancer-riskcalculator.

com/seven-prostate-cancer-risk-calculators). For each patient,life expectancy(less or morethan 10 years)was estimatedbythereferringurologistbasedonpatient’sage, personalhistoryandconcurrentmorbidity.

PCPT-CRC nomogram wasdeveloped from the placebo arm (5519 patients) of Prostate Cancer Prevention Trial where sixrandomcores weretakenfor PSA valueshigher than4ng/mLorsuspiciousDRE.Patientsnotfoundpositive forprostatecancer atinitiationofthestudy orduringthe seven-yearfollow-upwerealsoofferedend-of-studyrandom systematiccores(6cores)[10].Thisnomogramwaslaterval- idatedwith12-corebiopsyprotocol[11].Ofnote,asfamily historyofprostatecancerwasnotavailableinourdatabase, theweightofthisinformationwasmodeledbythebootstrap technique.

The SWOP-PRI‘‘riskcalculator 4+ DRE’’ wasdeveloped from the data obtained within the Rotterdam arm (6288 men)oftheEuropeanRandomizedStudyofscreeningofthe ProstateCancer(ERSPC)[12,13].

Thesenomogramsalsoprovidedtheestimateoftherisk ofhigh-gradeprostatecancer(Gleasonscore≥7forPCPT- CRC;Gleasonscore≥7and/or>T2bforSWOP-PRI).

Statistical analysis

Meanandstandarddeviationarepresentedforquantitative variables,percentageand95%conﬁdenceintervalforqual- itative variables. Statistical analysis wasperformed using GraphPad Prism^® version 5.0 (GraphPad Software,Inc, La Jolla,CA,USA).Differencesbetweenthequantitativeand qualitative variables were sought by Mann-Whitney test, Chi² test and Fisher’s exact test, respectively. P values

<0.05 were considered signiﬁcant. Receiver Operating Characteristic (ROC)curves wereplotted toillustrate the performance of PSA, PCPT-CRC and SWOP-PRI and AUCs of the ROC curves compared by the C-statistics. Finally, calibrationcurveswereplottedtoillustratetherelationship existingbetweentheestimatedrisksandtheactualresults.

Results

Thefilesof808consecutivepatientssubmittedtoprostate biopsiescentresin2010,werecollectedin5academies.One hundredandeighty-threefilesdidnotfittherequisitesof thepredictivemodels(PSA>50ng/mL,age<55years)ordid

notcover somekey information(TRUS-measured prostate volume)andwereexcludedfromtheanalysis.

Characteristicsofthe625patientsincludedintheﬁnal analysisarepresented in Table1.Fivehundredandsixty- eight (90.8%) patients had a life expectancy>10 years.

PCa was diagnosed in 291 patients (46.6%) who were older(66.7±6.8vs64.3±5.6years,P<0,001)andshowed higherPSAvalues(10±7.9 vs7.7±4.3ng/mL,P<0.0001) andlowerprostatevolumes(43.8±19.8vs51.3±20.7mL, P<0.0001)thanhealthysubjects.Gleasonscorewasrespec- tively≤6,7,and>7in47.1%,41.6%and11.3%ofthecases.

PCPT-CRC risk estimates were 56.2±12.8% and 50.6±14% in patients with and without family history ofprostatecancer,respectively.SWOP-PRIshowedalower ﬁgure (31.2±17.3%). The estimates todetect high-grade cancer were 22.4±16.9% for PCPT-CRC and 14.8±18.2%

for SWOP-PRI (Table 2). Forthe two risk calculators, the calculatedestimates increased withage andprior history ofnegativebiopsy(Table3).AUCsoftheROCcurveswere 0.58±0.02,0.67±0.02and0.72±0.02forPSA,PCPT-CRC andSWOP-PRI,respectively.Nosigniﬁcantdifferenceswere demonstrated in the diagnostic performances of the two nomograms(P=0.09).

Conversely, for the high-grade cancer risk estimation (PCPT-CRC)andforthehigh-riskcancerprediction(SWOP- PRI),theAUCwas0.72±0.03(CI95%0.67—0.78;P<0.0001) and 0.73±0.03 (0.68—0.79; P<0.0001) respectively. The calibration graphs demonstrated that the SWOP-PRI was closer to the ideal prediction model than the PCPT-CRC (Fig.1).

Discussion

Currently, overdiagnosis of PCa is a major concern for health high authorities. This study shows that the urolo- gistsoftertiarycentresrecommendedprostatebiopsyonly in high risk of PCa(50.1% PCPT-CRC withnegative family history, 55.8% PCPT-CRC with positive family history and 31.2±17.3%SWOP-PRI).

Before,toperformbiopsy,urologistsconsideredthelife expectancyandthe morbidities.Over90% ofpatientshad lifeexpectancyhigherthan10years.Fortheother10%,the riskestimatedofPCawasveryhigh(PCPT-CRC65.6%;SWOP- PRI 45.1%). Indeed, the Farmington group study reported thattheriskofdeathincreasesinallclinicalsituationsalong withtimeandcomorbidities.Forexample,theoverallmor- talityat5-yearsfollow-upofamanwithcomorbiditiesand awell-differentiatedPCawas10timesupperthanPCamor- tality(42.5%and4.3%)[14].

Theriskestimatedifferenceinpatientswithorwithout negativeprevious biopsy (49% vs 58.2%, P<0.0001, PCPT- CRCand14.8vs35.8%,P<0.0001,SWOP-PRI)showedthata priornegativebiopsydisturbedthestrategyofPCadiagno- sis.Indeed,negativebiopsiescreateuncertaintyamongthe urologistsbecauseoffalsenegativerateof40—25%,leading themtorepeatbiopsieseveniftheestimatedriskofcancer is.Ploussard etal.reported 25to 35%of re-biopsiesin 5 yearsafteraﬁrstnegativebiopsywitharateofcancerat 17%intheﬁrsttwore-biopsies,then between12and14%

forthenextseries[15].Thisuncertaintyrelatedtothefalse negativenumbersofprostatebiopsiescanbeovercomeby

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Table1 Characteristicsoftheoverallpopulationandofthebothsubgroupsofpatientswithandwithoutprostatecancer (Mann-Withneytest,Fisherexacttestor²).

Overall population

Prostate cancer

Noprostate cancer

Pvalue

n(%) 625(100) 291(46.6) 334(53.4)

Age(years) 65.4±6.3

(55—86)

66.7±6.8 (55—86)

64.3±5.6 (55—85)

P<0.0001 Lifeexpectancy

>10years(%) 568(90.9) 249(85.6) 319(95.5) P<0.0001

<10years(%) 57(9.1) 42(14.4) 15(4.5)

TotalPSA(ng/mL) 8.8±6.3 (0.7—46)

10.0±7.9 (2—46)

7.7±4.3 (0.7—30)

P=0.001 DRE

Normal(%) 435(69.6) 164(56.4) 271(81.1) P<0.0001

Suspicious(%) 190(30.4) 127(43.6) 63(18.9)

Prostatevolume(mL) 47.8±20.6 (10—120)

43.8±19.8 (10—116)

51.3±20.7 (15—120)

P<0.0001 Priornegativebiopsy

0 486(77.8) 253(86.9) 233(69.8) P<0.0001

>1 139(22.2) 38(13.1) 101(30.2)

DRE:DigitalRectalExamination.

Table2 EstimatedriskofprostatecancerwithPCPT-CRCandSWOP-PRI(Mann-Whitneytest).

Overallpopulation Prostatecancer Noprostatecancer Pvalue Riskofpositivebiopsy(%)

PCPT-CRC

Nofamilyhistory 50.6±14(14.9—75) 55.2±14.9(17.7—75) 46.5±11.8(14.9—75) P<0.0001 Familyhistory 56.2±12.8(18.6—75) 60.3±13.2(24—75) 52.6±11.2(18.6—75) P<0.0001 SWOP-PRI 31.2±17.3(7—88) 38.4±18.8(7—88) 24.9±12.9(7—70) P<0.0001 Riskofhighriskprostate

cancer(%)

PCPT-CRC 22.4±16.9(2—75) 28.2±19.9(2.6—75) 17.3±11.6(2—75) P<0.0001 SWOP-PRI 14.8±18.2(0.37±93) 22±22.7(0.37—93) 8.4±9.3(1—61) P<0.0001

providing newbiopsy techniques (MRI-guided) and witha betterselectionofpatients[6].

Inourstudy,therewasnodifferencebetweenpatients witheitheroneorseveralseriesofnegativebiopsies.How- ever, the incidence of PCa decreases as the number of previousnegativehistologyincreases.Moreover,thethresh- oldtore-biopsyshouldincreaseinproportiontothenumber

of previous biopsies. In addition, the cancer detection decreases with the increasing number of biopsies. Gann etal.showedthattherateofpositivebiopsydecreasedto 46%attheﬁrstre-biopsy,to64%atthesecondandto88%

after3series.Thus,theyconcludedthatthereisalackof beneﬁtobtainingmorethantwobiopsieswhentheclinical andbiologicalcriteriaarestable[16].

Table3 Meanestimatedriskaccordingtoageandnegativepriorbiopsies (testOneWayANOVA,Mann-Withneytest).

n PCPT-CRC P SWOP-PRI P

Age(years)

<65 n=314 54.1±12.0 P<0.0001 28.9±15.9 P<0.0001

65≤age<75 n=255 56.7±12.8 30.9±16.3

≥75 n=56 65.6±12.4 45.1±22.1

Previousnegativebiopsies(n)

No n=486 58.2±12.3 P<0.0001 35.8±16.4 P<0.0001

Yes

Total n=139 49.0±11.6 14.8±7.6

1 n=87 41.3±12.9 P=0.01 15.5±7.6 P=0.3

>1 n=52 45.6±10.2 13.9±7.6

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100- Specificity %

Sensibility %

0 20 40 60 80 100

10 20 30 40 50 60 70

0.0 0.2 0.4 0.6 0.8 1.0

predicted probability

observed probability

0 10 20 30 40 50 60 70

predicted probability

Figure1. a:ROCcurvesPSA(black),PCPT-CRC(blue)andSWOP-PRI(red);b:calibrationofPCPT-CRC;c:calibrationofSWOP-PRI.

The risk calculators were based on pertinent clinical andbiologicaldatasettospecifythebeneﬁtofundergoing orrepeatingsystematicbiopsiesintheoverallpopulation.

However, the threshold of PCa risk that should lead the urologisttoperformaprostatebiopsywasnotyetdeﬁned.

Intheirstudy,Rooboletal.showedthatbiopsiescouldbe avoided if estimated risk with SWOP-PRI nomogram was lessthan12.5%.Inourstudy,withthisthresholdvalue,66 biopsies (10.6%)wereavoided with15PCa (5.2%)missed.

AccordingtoRooboletal.study,whentheriskwasbetween 12.5and20%,theauthorsrecommendedbiopsyonlyifthe high-grade cancer risk was>3%. Thus, in our cohort, 45 biopsieswouldhavebeenavoidedforonly8missedcancers amongwhichonlyonehadaGleasonscore≥7[17].Steyer- bergandVickers.haddeterminedtworiskthresholds,10and 40%[18].Inourstudy,theSWOP-PRImodel,theuseofthe lowerthreshold(10%)wouldhaveavoided46biopsies(7.4%) andneglected 8(2.7%) cancers. The latter value (40%) is

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Table4 EstimatedriskofprostatecancerwithPCPT-CRCandSWOP-PRIinseveralclinicalstudies.

Authors Population

(n)

Prostate cancer(%)

PCPT-CRC risk(%)

AUC SWOP-PRI risk(%)

AUC

Parekhetal.,2006[22] 446 33.2 30.4 0.66 — —

Kaplanetal.,2009[23] 624 10.2 22.8 — — —

Hernandezetal.,2009[21] 1280 35.6 43.6 0.67 — —

Cavadasetal.,2010[25] 545 35.2 51 0.74 22 0.80

Trottieretal.,2011[24] 982 46.2 45 0.63 26 0.71

Ourseries,2013 625 46.6 50.6 0.67 31.2 0.72

alsocontroversialsince17.5%and58.4%ofcancerwouldn’t havebeendiagnosedamong24.2%and72.5%avoidedbiop- siesaccordingtothePCPT-CRCandSWOP-PRIrespectively.

Finally,VanVugtetal.deﬁnedaSWOP-PRIthresholdvalue of20%inacohortof320patientswithoutpreviousnegative biopsy.Theyreported11over63(17%)missedcancerswith onlytwohavingaGleasonscore≥7[19].Inourpopulation, this threshold would avoid 27.8% of biopsies but 14.1%

of cancer would not detect 14.1% of which 29.3% witha Gleason score≥7. The threshold concept is a matter of choiceandsomehave suggestedvaluesbetween12.5and 25%. We believe that the risk must be integrated into a generalapproachofthepatientincludinghiscomorbidities, hischoice andhistolerance to therisk, which is an indi- vidualcharacteristic.However,accordingtotheYouden’sJ statistic,wecouldsetathresholdwiththegreater match betweensensitivityandspeciﬁcity.Inourstudy,thereason- ablethresholdrisktoperformbiopsywas49.6%(sensitivity:

60.1%; speciﬁcity: 68.6%) for PCPT and 30% (sensitivity:

61.7%;speciﬁcity70.4%)forthenomogramERSPC.

Severalstudiesassessedthediagnosticaccuracy ofrisk calculatorsinPCa.Areviewof23studieswhichevaluated 36predictivemodelsdeterminedthatnomogramwere2to 26%moreaccuratethanPSAindiagnosisofprostatecancer [20]. In these papers, the risk of PCa for patients varied between22.8and51%forthePCPTand22to26%forthe SWOP-PRIandwaslowerthanthoseobservedinourstudy [21—25](Table4).Cussenotetal.characterizedtheoverall populationenrolledin thisstudy ashighrisk for PCawith ahighnumberofsuspiciousDREandahighrateofpositive biopsies. They concluded that the increasing reluctance of French general practitioners toward screening could explain this population at high risk of PCa [9]. Finally, our population was into the real life of clinical practice whereaspatients enrolled in the clinical trials originated fromtwo main populations, screening for the ERSPC and chemopreventionforthePCPT.

Ontheotherhand,thisstudyhaslimitations.Firstofall, thelackofdataaboutfamilyhistoryofprostatecancerhad ledtotheuseofrandomsamplingtests(bootstrap).Inaddi- tion,allthepatientsenrolledinourstudyareCaucasians.

Moreover, the risk calculators were based on protocol at 6prostate-cores whereasour average biopsy number was higher (12.4 [3—42]). This represents an additional bias becausethemethodofriskveriﬁcationchangesthediscrim- inant function of the nomogram. For instance, Ploussard etal. reportedthe increase of prostate cancer detection rate,whichdependsonthenumberofcores:from32.5%to 40.4%and43.3%if6,12or21coresweretaken[26].

Finally,theriskcalculatorsaimtohelpthephysicianin thebiopsydecision.Recently,theintegrationofbiomarkers (PHI index,PCA3score)in theseprogramsimproved their accuracy[27].Rooboletal.reportedthattheurologistsmay beabletoselecttheindividualscreeningschedulebasedon theriskthresholdcalculatedinthelastvisit[28].

Conclusion

Iftheprostatecanceroverdiagnosisandtheincreasednum- berofprostatebiopsiesinFrancearedebatableissues,the patientsbiopsiedinthisstudyhadahigherriskofprostate cancer,calculatedbythenomogram,thanotherstudies.In this study,urologiststake intoconsideration the patient’s age and his life expectancy before performing prostate biopsy.Contrariwise,negativepreviousbiopsydidn’tchange the threshold risk value prompting to perform biopsy, as thoughnegativeresultdidn’treassureurologists.

Disclosure of interest

Theauthorsdeclarethattheyhavenoconﬂictsofinterest concerningthisarticle.

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