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ORIGINAL ARTICLE
MRI evaluation following partial HIFU therapy for localized prostate cancer:
A single-center study
Résultats du traitement par hémi-HIFU Ablatherm ® pour cancer localise de la prostate : étude de la place de l’IRM et implication pour la surveillance après thérapie focale
L. Hoquetis
∗, B. Malavaud , X. Game , J.B. Beauval , D. Portalez , M. Soulie , P. Rischmann
Urologydepartment,Rangueiluniversityhospital,1,avenueduPr-Jean-Poulhes,31059 Toulousecedex,France
Received9April2016;accepted22July2016 Availableonline24August2016
KEYWORDS Magneticresonance imaging;
High-intensity focusedultrasound;
Prostatecancer;
Focaltherapy;
PSAdensity;
Biopsy
Summary
Objective.—Toevaluate thevalue ofMRIfor surveillanceofprimaryhemi-HIFU therapyfor localizedPCainasingle-center.
Patientsandmethods.—Patientswithlocalizedprostatecancerweretreatedwithhemi-HIFU fromOctober2009toMarch2014.AllpatientsperformedMRIbeforefocaltherapy,thereader wasblindedtothetreatment.Oncologicalfailurewasdefinedaspositivebiopsyorbiochemical recurrence(Phoenix).
Results.—Twenty-fivepatientsweretreatedwithhemi-HIFUinonecenter.Themediannadir PSAwas1.45±1.4ng/mL.Prostatevolumedecreasedfrom45ccto25cconMRIfindings.At20 months,noneofthepatientshadhistologicalrecurrence.Biochemical-freesurvivalratewas 88%.MRIevaluationhadanegativepredictivevalueof100%onthetreatedareaand81%on theuntreatedarea.PSAd≥0.1ng/mL2wasapredictivefactor forcanceronuntreated area (P=0.042).
∗Correspondingauthor.
E-mailaddress:lionel.hoquetis@gmail.com(L.Hoquetis).
http://dx.doi.org/10.1016/j.purol.2016.07.006
1166-7087/©2016ElsevierMassonSAS.Allrightsreserved.
Conclusion.—MRIcontrolat6monthsisapotentiallyeffectiveevaluationoftreatedareaafter hemi-HIFUandmayreplacerandomizedbiopsiesifPSAd<0.1ng/mL2duringfollow-up.
Levelofevidence.—4.
©2016ElsevierMassonSAS.Allrightsreserved.
MOTSCLÉS Imageriepar résonance magnétique; High-intensity focusedultrasound; Cancerdela prostate; Thérapiefocale; PSAdensité; Biopsie
Résumé
Objectif.—Étudierlafiabilitédel’IRMdanslasurveillancedutraitementparhémi-HIFUdans lescancerslocalisésdeprostate.
Populationetméthodes.—Étude monocentrique, d’une cohorte de 25 patients consécutifs ayanteuuneséanced’hémi-HIFUpourcancerdelaprostatelocalisé,entreoctobre2009et mars2014.Lescritèresd’évaluationétaient:PBPdecontrôleà6mois,suividuPSAtotalet réalisationd’uneIRMdecontrôle.L’ensembledesIRMpré-etpostopératoiresontétérelues parunseulpraticien,enaveugledutraitementavecrecherchedecible,évaluationduvolume prostatiqueetdescriptiondesmodificationsIRMinduitesparHIFU.
Résultats.—Vingt-cinqpatientsontététraitésparHIFUcentrésurunlobedansnotrecentre.
LevolumeinitialmoyenmesuréparIRMaétéréduitde45mLà25mL.LePSAnadirmédianétait de1,45±1,4ng/mL.Apresunsuivimédiande21,2mois,aucunerécidivesurlazonetraitée n’aétéprouvée.L’évaluation IRMdelazonetraitéeavaitunevaleurprédictivenégativede 100%etde81%surlazonenontraitée.UnPSAd≥0,1ng/mL2étaitunfacteurprédictifde tumeurcontrolatérale(p=0,042).
Conclusion.—L’IRMdecontrôleà6moisaprèstraitementparhémi-HIFUamontrésonefficacité danslasurveillancedelaglandetraitéeetpourraitsesubstituerauxbiopsiesrandomiséesen casdePSAd≥0,1ng/mL2aucoursdusuivi.
Niveaudepreuve.— 4.
©2016ElsevierMassonSAS.Tousdroitsr´eserv´es.
Introduction
ThegoaloffocalPCatherapyisthemaintenanceofpatient QoLwithoutcompromisinglifeexpectancy,byindextumor destructionandpreservationofnon-malignantprostaticand normaladjacenttissueinordertolimiterectiledysfunction andurinaryincontinence[1].
European guidelines recommend TRUS biopsies after focal therapy [2] but it is not realized in all studies as revealed in the latest systematic review of focal therapy [3].
While randomized biopsies may miss any tumor resur- gence,targetedbiopsieshavegoodsensitivity[4—6].
Theprimaryobjectiveofthisstudywastoevaluatethe utilityofMRIincancercontrolmonitoringfollowing hemi- HIFUtherapyoflocalizedPCa.Secondaryobjectiveswereto studychangesinprostatemorphologyinducedbyHIFU,and toevaluatethesafetyandefficacyofhemi-HIFUtherapyin localizedPCa.
Materials and methods Population
Patientsweretreatedintothecurrent studyfromOctober 2009toMarch2014inanacademichospital.
Theymustmeetthefollowinginclusioncriteria:age<80 years old; unifocal or multifocal localized PCa (clinical stage≤T2N0M0);PSA<15ng/mL;Gleasonscore≤7andno grade4predominant;nopriorlocalorsystemictreatment ofprostatecancer;andnocontraindicationstoMRI.
Theclinicalstagewasassignedaccordingtothe2002TNM stagingsystem,prostatebiopsycoreswereobtainedunder transrectalultrasoundguidance,usinga12-corebiopsypro- tocol, and pretreatment PSAwasmeasured before digital rectal examination. Dedicated genitourinary pathologists assessedbiopsygradingaccordingtothemodifiedISUPGlea- sonscore.
Systematic TURP before HIFU was realized except if patienthad prostate volumelessthan 40mL andnoLUTS (definedbyIPSS<7).
MRI localization and definition of target tumor volume
Data obtained by baseline MRI included prostate volume, lesioncharacteristics,ESURscore,anddetectionofinciden- tallesion.
Unilateraldominanttumor,definedbytheindexlesion, was measured by length and width, and volume esti- matedusingtheellipsoidformula(L×l2×0.53).Accessories lesions were measured by the same way. The Dickinson 27 Sectors definition was applied to determine spatial
characteristicsofthelesion[7].Thetherapeuticindexwas defined as the ratio of MRI-measured treated volume to tumorvolume(mL).AllMRIimageswereanalyzedbyasingle uroradiologistwithexpertiseinprostateMRIinterpretation.
Partial HIFU
WeusedthedefinitionofAhmedetal.[1]tocharacterize partialprostatetreatmentastreatmentofone-halfortwo- thirdsof the gland. Ablatherm(EDAP-TMS, Vaux-en-Velin, France)techniquewasused.Treatment wasrealizedwith totalanesthesia,andasecuritylimitdefinedby1mmabove theprostaticapex.
Peri- and postoperative data were obtained from the surgeryreportandthehospitaldischarge.
Post-HIFU evaluation
Patients were evaluated during post-HIFU follow-up with digitalrectalexamination(DRE)andPSAmeasurementevery 3months,andcontrolmpMRIat6months.
Randomizedcontrolbiopsiesweredoneexceptifatarget wasseen.Ifso,targetedbiopsieswereperformed.
Biochemical assessment
SerumPSAlevelswereobtained atbaseline,andthrough- outpatientfollow-up. ThefollowingPSAparameterswere evaluated.
Biochemicaldisease-freesurvivalusedthePhoenixdef- inition of biochemical failure [8]. PSA density (PSAd) measuredthepersistenceofuntreatedprostatictissue,cal- culated by the ratio of post-HIFU (±TURP) PSA level to residualtissuevolumemeasuredbycontrolMRI.
Morphology assessment
Control MRI was used for assessing changes in prostate morphology following HIFU, and were assessed by pre- and post-HIFU prostate volume; evaluation of capsular retraction or development of peri-prostatic fibrosis; and determinationofapexsparing.
Theradiologistreviewingallpost-treatmentMRIimages wasblindedtotheoperativereport.
Table1 Clinicalcharacteristicsofthepopulation.
Mean(min—max) Median±SD Age(years) 66.0(52—80) 66.4±7.3 PSA(ng/mL) 6.13(3.1—13) 5.7±2.5 Prostaticvolume
(mL)
46(20—109) 40±22 PSAd(ng/mL2) 0.15(0.05—0.38) 0.14±0.05 Lengthof
hospitalization (days)
3.0(1—5) 3±0.9
Timeforurethral catheter(days)
4.7(2—10) 3±3.07 Follow-up(months) 25.1(6—73) 21.2±16
Table2 Tumorcharacteristics.
Population(%) TNM
T1c 17(68)
T2a 8(32)
Localization(cores)
Apex 7
Middle 14
Base 9
Unifocaltumor 16(72)
Multifocaltumor 7(28)
Gleasonscore
6(3+3) 19(76)
7(3+4) 6(24)
Totaltumorlength
<3mm 11
Between3mmet10mm 9
>10mm 4
NC 1
Side effects
Erectile function and continency were evaluated every 3 monthsduringfollow-up.
Statistical analysis
Conventional descriptive statistics were used to summa- rizedemographicandclinicaldata.Groupcomparisonswere analyzed usingthe PearsonChi2 test, and comparisons of qualitativevariableswereperformedusingtheFisherexact test.
TheSpearmanranktestwasusedtoassessthecorrelation StatisticalanalysiswasperformedusingDM90® software.
Patients’informedconsentwasnotobtained.
Results
Baseline measurements
Clinical characteristics
Twenty-fivepatientswereevaluatedinthisstudy.Atbase- line,patients hada meanage of66.6±7.2 yearsoldand PSA:6.1±2.0ng/mL.Tumorcharacteristicsincluded clini- calstageT1cin68%(n=17)andT2ain32%(n=8);Gleason scorewas6(3+3)in76%(n=19)and7(3+4)in24%(n=6).
Multifocaltumorwasfoundin28%ofpatients.
Patientswerefollowedamedian21.2±16.8months,and 18patientsmetPRIAScriteriaforAS[9].Summariesofthe studypopulationclinicalcharacteristicsareshowninTable1 andtumorcharacteristicsinTable2.
MRI characteristics
InitialdiagnosticMRIwasperformedinallpatients.Asingle targetwasfoundin20patients,2targetswerefoundin5 patients.Theindexlesionwasdetectedinonesectorin19 cases,and2sectorsin6cases.Thetotalnumberofsectors withMRI-visiblelesionwas30.
Targeted tumor volume
MRI pre-HIFU tumor volumes ranged from 0.004mL to 0.9mL.Tumorvolume<0.5mLwasfoundin20patients.
ThetargetedtumorvolumeoninitialMRIwascorrelated withtumoraggressiveness,Gleasonscore(P<0.01).
The relative risk of Gleason score 7 (3+4) tumor with MRI-measuredtumorvolume>0.5mLwas4.38.
HIFU treatment
Fourteen patients had a half-gland treatment and 11 patientstwothirdofthegland.
Post-HIFU outcomes
Histological results
Controlbiopsieswereperformedinallpatientsatamedian timeof 7.44±6.6months.Nomalignancieswerefoundin treatedprostateareas,andcontralateraltumorwasfound infourpatients, forapositivecontralateraltumorrateat follow-upof16%.AllcontralateraltumorswereGS6,showed onepositivebiopsycore,andatumorlengthfrom2to5mm.
Managementofcontralateraltumorsconsistedofasecond HIFUsession(n=2)andAS(n=2).FinalPSAlevelsinthese patientsrangedfrom0.1to1.0ng/mL.
Biochemical results
Medianvaluesfound theinitial PSA6.13±2.5ng/mL,PSA nadir1.45±1.4ng/mL,andfinalPSA1.8±1.9ng/mL.
Meanvaluesfound theinitial PSA6.1ng/mL,PSAnadir 1.72ng/mLandfinalPSA2.36ng/mL.
Post-treatment PSA evolution decreased until reaching nadirPSA,themeanevolutionofPSAcorrespondedtoinitial PSAdividedby3.54.
Biochemical failure occurred in three patients by last follow-up. PSA values in these patients were 4.55, 5.35, and6.5ng/mL;andPSAnadirwas1.5,3.3,and4.1ng/mL, respectively.ResultsfrombiopsyandMRIimagingfollowing biochemicalfailurewerenegativefor tumorsorlesionsin all3patients.
At last follow-up, twelve patients had PSA density (PSAd)≥0.1ng/mL2.
PSAd wasa significantpredictorof contralateraltumor (Fisher’sexact test; P=0.042);allfour patientswithcon- tralateraltumorhadPSAd≥0.1ng/mL2.
Control MRI
ControlmpMRIimageswereobtainedat amediantimeof 15.4±17.2(range:1.2—48)monthsfollowingHIFU.
WithMRI-targetedbiopsyusingtheKoelissystem,anMRI targetwith ESUR score 10/15 wasbiopsied and notumor wasfound. Inanother patient,an MRI targetwitha 5/15 ESURscorewasfoundinatreatedarea,butthepatienthad alreadyundergonecontrolrandomizedbiopsieswithnega- tiveresultsandnoguidedbiopsywasthereforeperformed.
Morphologic changes
Asmeasured byinitial andcontrolMRI,the medianinitial andpost-HIFUprostatevolumeswere45.0mL(20—100)and
25.3mL(5—52),respectively,indicatingthepost-treatment volumewas56%oftheinitialvolumeafterTURPandHIFU.
Evaluationforeachpatientofindexandassociatedtumor localizationandestimatedvolumebyinitialMRI;percentage of treatedgland,andthepresence andvolumeoftargets with≥9ESURscorebycontrolMRIareshowninTable3.
Side effects
ThemostfrequentHIFU-relatedmorbiditiesweremilduri- naryincontinencepersistinglessthan6months(n=2),and erectiledysfunctionrequiringPDE-5inhibitortherapy(n=4) (Claviengrade2).Throughoutfollow-up, nopatientexpe- rienced urinary retention, urinarytract infection, serious adverseevents,orrecto-urethralfistula.
Discussion
Over the past decade, the potential of focal therapy to providecancercontrolandlimitmorbidityhasbeenrecog- nized.Theinabilitytoaccuratelylocalizeandcharacterize tumorshasimposedbarrierstoclinicaluse.Withavailability ofmultiparametricMRI(mpMRI)methodsanddirectionfor itsoptimalapplication,focaltherapyhasrecentlybecome afeasiblealternativetoradicaltherapyandASforlocalized PCa.
Study population
We found pre-HIFU tumor volume significantly correlated withtumoraggressiveness(reflectedbyGleasonscore).Sev- eralpreviousstudies havereportedacorrelation between tumoraggressiveness andvolume≥0.5mL.In131patients imagedwithmpMRIpriortoRP,tumorvolume>0.5mLwas significantly associatedwithGleason score≥7 (P=0.0033) [10]. Similarly, Styles et al. [11] and Karademir et al.
[12]reportedidenticalcorrelationsintworetrospectiveRP serieswithsmallersamples(n=38andn=61,respectively).
Cancer control outcomes
Biochemical
In the present study, the mean PSA nadir of initial PSA divided by 3.54 was in line with post-treatment PSA decreases reported in other recent focaltherapy studies.
Mean PSA nadir values from two focal cryotherapy stud- ies were initial PSA divided by 2.6 and 2.3, respectively [13,14].AfocalHIFUtherapytrial of42patientsreported a nadir PSA value of median initial PSA divided by 3.5 [1],while arecentlypublishedfocal HIFUtherapy trial of 56 patients withsoleablation of the indexlesion showed medianPSAvaluesof7.4ng/mLatbaselineanda2.4ng/mL nadir[15].
ThepredictivevalueofnadirPSAhasbeendemonstrated inradicalHIFUtherapystudies,withtwotrialsfindingPSA nadirsignificantlypredictiveofPSAfailureonmultivariate analysis [16,17]. Data analysis froma larger radical HIFU study[18]foundPSAnadir≤1.0ng/mLasignificantpredic- tivefactorforfreedomfromdiseaseprogression(P<0.001).
Table3 ResultsofMRIevaluationbeforeandafterHIFU.
InitialMRI ControlMRI
Indextarget Associatedtarget Atrophic volume(%)
Therapeutic Index
Target
Sector Volume(mL) Sector Volume(mL) Sector Volume(mL)
Patient1 4p 0.172 88.98 181 — 0
Patient2 10p 0.21 4p 0.119 10.24 25 — 0
Patient3 10p9p 0.159 26.48 98 — 0
Patient4 4p 0.153 7.35 26 — 0
Patient5 4p 0.076 10p 0.033 76.78 513 — 0
Patient6 4p 0.373 28.54 50 — 0
Patient7 7p9p 0.901 44.49 20 — 0
Patient8 10p 0.898 28.84 26 — 0
Patient9 4p 0.373 44.49 119 — 0
Patient10 9p10p 0.312 3p 0.339 44.49 50 — 0
Patient11 9p10p 0.954 69.19 26 — 0
Patient12 6a 0.386 32.3 33 — 0
Patient13 7p8p 0.364 44.49 32 — 0
Patient14 10p 0.795 44.49 21 — 0
Patient15 7p 0.407 20.18 23 — 0
Patient16 3a14as 0.127 5p 0.08 75.13 213 — 0
Patient17 10p 0.305 44.49 52 — 0
Patient18 3p 0.441 44.49 44 — 0
Patient19 8p 0.042 34.03 193 — 0
Patient20 3p 0.019 26.07 273 — 0
Patient21 10p 0.004 10.24 603 — 0
Patient22 3a 0.687 88.98 26 — 0
Patient23 9p 0.153 30.49 110 — 0
Patient24 2p 0.373 20.18 17 — 0
Patient25 3p 0.47 12p 0.08 20.93 287 3p4p 2.078
Histological
Wefoundapositivecontralateraltumorrateof16%.Focal PCa therapy is based on the principle of preserving non- cancerousprostaticandsurroundingtissue,tomaintaintheir respectivefunctionallevels.Radicalprostatectomystudies have found multifocalPCa rates of 50—76% [19,20].More recentlyintroducedhavebeentheconceptsof‘‘index’’and
‘‘secondary’’ tumor [21,22], and differentiating features suchasindexlesionsaccountingfor80%oftotaltumorvol- umeand90%ofextra-prostaticextensions.Secondarytumor presenceandvolumearebelievedbysomeresearchersto havenegligibleimpactonbiochemicalrecurrenceafterRP [23].
MRI outcomes
Consistentwithourcontrolbiopsyfindings,controlMRIdid notidentifytumorrecurrenceintreatedareas,givingcon- trolmpMRIanegativepredictivevalueof100%fordetecting residualtumor intreated areasfollowing focalHIFUther- apy. Four tumorsin untreatedareas confirmed by control biopsywerenotdetected,givingcontrolmpMRIanegative predictivevalue of 81%for detectionof residualtumorin untreatedareas.Inastudyof15patientsreceivingMRIat 1and6 monthsfollowingradical HIFUtherapy,MRItumor visualizationwasnotpossiblein4of5patientswithbiopsy- confirmedrecurrence[24].Thisstudyused1.5TMRIwithT2
sequencesand DCE. Technological refinementsand strong directionfor optimal useof mpMRI[7,25]after thisstudy waspublishedmayexplainthebetterresultsofourstudy.
Thereductionofprostatevolumeaftertreatment,which ismeasuredat56%ofpretreatmentvolumemaybemainly distortedbyTURPbutreflectstheobjectiveofprovidinga hemitreatment.
In our analysis of PSAd kinetics, all 4 patients with contralateral tumor detected by control biopsy showed PSAd≥0.1ng/mL2,andPSAd≥0.1ng/mL2wassignificantly predictive of contralateral tumor (P=0.042). PSA density was suggested as a predictor of localized tumor recur- renceasearly as1994 [21]and confirmed in 2005by the ERSPC trial [26], showing that PSAd cut-off≤0.1ng/mL2 predictedorgan-confinedtumor<0.5mLin94%ofpatients (P<0001).
We demonstrated a significant relationship between PSAd≥0.1ng/mL2 and contralateral tumor recurrence despite our small sample size, and encourage others to assessfor PSAdincrease≥0.1ng/mL2 following focalHIFU therapy.A studyof 26patientswhoreceivedradical HIFU therapy compared dynamic contrast-enhanced (DCE) MRI with serial PSA for detecting post-HIFU residual disease.
Three radiologists interpreted the MRI images. The sen- sitivity and specificity for MRI was 73—87% and 73—82%, respectively;andforPSAnadir>0.2ng/mL,73%and100%, respectively[27].
WefoundnegativeMRIat6-monthfollow-upconfirmatory ofcancercontrol.
Biopsy should be performed of any lesion identified by control MRI, optimally using an MRI-ultrasound fusion device. Patientswith apparent absence of lesion on con- trol MRI can be monitored for cancer control by serial PSA levels to avoid systematic biopsies, with biopsy reservedforpatientsshowingPSAd≥0.1ng/mL2.Ourresults indicate that limiting control biopsy to patients with PSAd≥0.1ng/mL2wouldhavesparedourpatients13control biopsiesandreducedoverallbiopsiesby44%.
Ourresultsshouldbeinterpretedwithconsiderationof several limitations. These include the small sample size, brieffollow-upperiod,retrospectivestudy.
Furtherstudiesshouldbeperformedinordertoconfirm ourresults.
Conclusion
Focaltherapyisnowanalternativemanagementoptionfor patientswithlocalizedPCa.Theeffectofhemi-HIFUther- apyonprostatemorphologywascharacterizedusingmpMRI, whichshoweddevascularizationandatrophywithincreasing intensityovertimeuntilroughly6monthspost-treatment;
andalsoshowedanaverage61%decreaseinprostatevolume after treatment. We found the negative predictive value ofmpMRIfor tumorrecurrencewas100%in treatedareas and84%inuntreatedareas,andthatapost-treatmentPSAd value≥0.1ng/mL2wasapredictorofcontralateraltumor (P=0.042).
These results suggest that mpMRI could, in the near future, replace control biopsies for cancer control moni- toring after hemi-HIFU therapy. Control biopsy would be indicated if PSAd ≥0.1ng/mL2, or MRI-guided biopsy if a target was identified by control mpMRI. Longer patient follow-upisneededtoevaluatethedurabilityresultswith hemi-HIFU as first-line therapy in patients with low- and intermediate-risklocalizedPCa.
Disclosure of interest
Theauthorsdeclarethattheyhavenocompetinginterest.
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