Salvage Hemiablation High Intensity Focused Ultrasound for unilateral radio-recurrent prostate cancer

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ORIGINAL ARTICLE

Salvage Hemiablation High Intensity Focused Ultrasound for unilateral radio-recurrent prostate cancer

Hémiablation prostatique de sauvetage par des ultrasons focalisés à haute intensité pour des récidives unilatérales après radiothérapie prostatique

Fouad Aoun

^a^,^b^,∗

, Simone Albisinni

^c

, Ibrahim Biaou

^a

, Alexandre Peltier

^a

, Ksenija Limani

^a

,

Thierry Roumeguère

^c

, Roland van Velthoven

^a

aServiced’Urologie,InstitutJules-Bordet,UniversitéLibredeBruxelles,Bruxelles,Belgique

bServiced’Urologie,HôtelDieudeFrance,Facultédemédecine-UniversitéSaint-Joseph, Beyrouth,Liban

cServiced’Urologie,CliniquesUniversitairesdeBruxelles,hôpitalErasme,UniversitéLibre deBruxelles,Bruxelles,Belgique

Received30January2019;receivedinrevisedform16April2019;accepted11June2019 Availableonline7August2019

KEYWORDS Prostatecancer;

Radiotherapy;

Salvagetreatment;

High-intensity focusedultrasound (HIFU);

Hemiablation;

Localrecurrence;

Oncological outcomes;

Functionaloutcomes

Summary

Objective.—Toreporttheoncologicalandfunctionaloutcomesofsalvagehemiablationhigh- intensityfocusedultrasound(HIFU)inpatientswithunilateralradio-recurrentprostatecancer.

Patientsandmethods.—Patientswithbiochemicalrecurrence(BCR)afterprimaryradiation therapy andevidence of unilateral organ conﬁned recurrence based on acomplete match betweenmpMRIandMRItargetedbiopsieswereincluded.Patientswithdistantmetastasiswere excluded.PatientswerefollowedwithserialserumPSAdeterminations.BCRweredeﬁnedusing thePhoenixcriteria.ComplicationsweregradedaccordingtotheClavienscore.IIEF-5question- nairewasusedtoassesserectiledysfunction.Urinaryincontinencewasreportedusingphysician reportedrates.

Results.—Atotalof10consecutivepatients(medianage:71years,IQR:69—76)wereprospec- tivelyenrolled.Themedianpre-treatmentPSAandpost-treatmentPSAnadirwere3.1ng/mL (IQR:1.54—8.59)and1.52ng/mL(IQR:0.76—2.2),respectively.Atamedianfollow-upof41.5

∗Correspondingauthorat:Serviced’urologie,InstitutJules-Bordet,1,rueHégerBordet,Bruxelles,1000,Belgique.

E-mailaddress:fouad.aoun@bordet.be(F.Aoun).

https://doi.org/10.1016/j.purol.2019.06.004

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(IQR:18—58)months, 50%ofpatients experienceBCR.BCR free-survivalratesat24 and36 monthswere75%(CI95%:31—93)and60%(CI95%:20—85),respectively.Urinaryincontinence gradeIIoccurredintwopatientsandtheremainingpatientswerepad-free.Onepatientdevel- opeddenovoerectiledysfunctionrequiringPDE5I.Theerectilefunctionscoresdecreasedfrom ameanof10.1to8.7.

Conclusion.—HemiablationHIFUisanalternativetowholeglandtherapyinpatientswithuni- lateralradio-recurrentprostatecancer,whichofferslimitedurinaryandrectalmorbidity,and preservesfunctionaloutcomes.

Levelofevidence.—3.

MOTSCLÉS Cancerprostate; Radiothérapie; Traitementde sauvetage; HIFU; Hémiablation

Résumé

Objective.—Reporterlesrésultatsoncologiquesetfonctionnelsdel’hémiablationprostatique desauvetagepardesultrasonsfocalisésàhauteintensitéchezdespatientsayantdesrécidives unilatéralesaprèsradiothérapieprostatique.

Méthodes.—Lespatientsayantuncancerdelaprostatelocalisétraitésparradiothérapiepri- maireetprésentantunerécidiveprostatiqueunilatéralesanslésionssuspectesàdistanceont étéinclus. Cetterécidiveestdocumentée paruneconcordance entrela résonancemagné- tiquemultiparamétriqueetunebiopsieciblée.LespatientssontsuivispardesmesuresdePSA jusqu’àprogressionbiologiqueselonlescritèresdePhoenix.Lescomplicationssontenregistrées prospectivementselonlescoredeClavien.LequestionnaireIIEF5aétéutilisépourdéterminer lafonctionérectileetlacontinenceaétéreportéeparlescliniciens.

Résultats.—Dixpatientsontétéinclusavecunemédianed’âgede71ans(IQR:69—76).La médianeduPSAavantletraitementétaitde3,1ng/ml(IQR:1,54—8,59).LamédianeduPSA aprèsletraitementétaitde1,52ng/ml(IQR:0,76—2,2).Aprèsunsuivimédiande41,5mois (IQR:18—58),lamoitiédespatientsontprésentéuneaugmentationduPSAaunadir+2.Letaux desurviesansrécidiveétaitde60%(IC95%:20—85)à3ans.Huitpatientsétaientparfaitement secsetneufpatientsn’avaientaucunchangementsurlequestionnaireIIEF5.

Conclusion.—L’hémiablation est unealternativethérapeutique chez lespatients ayantune récidiveunilatéraleaprèsradiothérapieprostatique.Elleoffredesrésultatsoncologiquessat- isfaisantsetaltèrepeulesrésultatsfonctionnels.

Niveaudepreuve.— 3.

Introduction

Radiationtherapy(RT)isastandardoptionfortheprimary managementof menwithlocalized prostate cancer (PCa) [1].Arecentanalysisfromanationalcommunity-basedPCa registryrevealed that approximately 25% of PCa patients inthe36clinicalsitesthatcontributeddatatotheCancer oftheProstateStrategicUrologicResearchEndeavor(CaP- SURE)registryunderwentRTastheprimarytreatment for PCa[2]. Despite improvement in long term survival rates incontemporaryseriesusingnovelradiotherapytechniques thatprovidemoretargetedandescalateddosesofradiation totheprostate,uptoonethirdofpatientswillexperience biochemical recurrence (BCR) [3]. The majority of these patients are treated with palliative androgen deprivation therapy(ADT)thatcanadverselyimpactthequalityoflife andincreasetheriskofcardiovascularevents[4].However, a non-negligible subset of these patients had recurrence limited to the prostate and can be offered salvage local procedureswithcurativeintent[5].

Atpresent,thereisnolevel1evidenceaboutthebest post-RT salvage procedure and salvage radical prostatectomy (SRP), although challenging, is the recommended standard [1]. However, most urologists are reluctant to offersurgeryandprefertoimplementlessinvasivealterna- tivessuchasCryotherapy,Brachytherapyor HighIntensity Focused ultrasound(HIFU) [6].However, by extrapolating fromclinical studies involving primarymanagement,each post-radiation salvage whole gland therapy carries higher risks of genitourinary and bowel complications compared to its implementation in the initial management of PCa patients[6].

Recently,focaltherapy hasbeenproposedasan effec- tivetherapyinpatientswithclinicallysigniﬁcantunilateral PCa that offers limited morbidities and promising func- tionaloutcomesandpreserveshealth-relatedqualityoflife [7].Ofnote,localradio-recurrentPCaisunilateralintwo- third of cases [8]. This means that focal salvage therapy couldalsobeinvestigatedinpatientswithunilaterallocal radio-recurrent disease. Some researchers had examined

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suchanapproachusingCryotherapyandHIFU[9—15].They demonstratedthatfocalsalvagetherapyisfeasibleandsafe withacceptableshort-termoncologicaloutcomesandgood functional results. However,all theseauthors stressed on carefully selecting patients before offering focal salvage therapy.Theselectionprocessshouldincorporatethemost effectivemethodtoexcludedistantmetastasisatthetime oftreatmentandthemostaccuratediagnosticstrategyto identifylocal recurrence.In thepresent study,we report ourexperiencewithsalvagehemiablationHIFUincarefully selectedpatients withunilateral radio-recurrentPCawith anemphasisonourstrategyofcombinedlocalizationwith mpMRIoftheprostateandMRItargetedbiopsy.

Patients and methods

Between2013and2016,10consecutivepatientswithaBCR deﬁned using Phoenix criteria (nadir+2ng/mL) [16] after primaryRTunderwentmpMRIoftheprostate,bonescanand pelviccomputedtomography.Patientswithorganconﬁned unilateralrecurrencebasedonacompletematchbetween mpMRIandMRItargetedbiopsyandnoevidenceofregional ordistantmetastaseswereincluded.Allpatientsincluded hadalifeexpectancy>5years.Ourstudywasapprovedby thelocalethicsreviewcommitteeandallpatientsgavepre- operativeconsent.

Multiparametric MRI and biopsies

Patientsunderwent ampMRI of the prostate ona 3 Tesla magnet Verio system (Siemens A.G., Erlangen, Germany) using an external multichannel phased array coil and an endorectal coil (Medrad Inc.).The conduct and reporting ofmpMRIwereconformedtoEuropeanSociety ofUrogen- ital Radiology recommendations in the Prostate Imaging Reporting and Data System version 1 document [17]. Of note,examinationswereinterpretedbyatrainedradiologist with20 years’experience.Patientswithsuspected radio- recurrentdiseaseonmpMRIunderwentMRI-targetedbiopsy.

Thedetailsofourbiopsyplatform(Medison/koelis^®Urosta- tion)andthedescriptionofourbiopsytechniquehavebeen previouslydescribed[18].

HIFU hemiablation

Alltheprocedureswereperformedunderspinalanesthesia byasinglehighvolumesurgeonusingtheAblatherm^®Inte- gratedImagingdevice(EDAPTMS,Vaulx-en-Velin,France).

ThedetailsofourHIFUplatformanddescriptionofourhemi- ablationtechniqueshavebeenpreviouslydescribed[19].It isnoteworthytorecallthathemiablationreferstoablation of one lobeof the prostate and notjust the indexlesion becauseof devicetechnicallimitations. Safetymarginsin patientswitharadio-recurrentdiseaseweredeﬁnedasfol- lows:≥4mmbetweentheanatomicalapexandthelowest sectionofthetreatedlobe.Ifbiopsieswerepositiveatthe apex,theﬁringlesionswereheldclosetothesphincter.A limitedtransurethralresectionwasperformedattheendof theHIFUsession[20].

Follow-up

Patientswere followed withserial serum PSA determina- tionsat 1,3,6,and12 monthsandthen every6months.

Patients experiencing BCR according to Phoenix criteria were offered bone scan, pelvic CT and mpMRI of the prostate.Patients withnoevidenceof regionalor distant metastasesunderwent68Ga-PSMApositronemissiontomog- raphy(PET)hybridimaging.Onlypatientssuspectedtohave localrecurrenceunderwentsubsequentMRItargetedbiopsy.

Patientswithhistologicallyconﬁrmedlocalrecurrencewere offered a redo-HIFU particularly when the recurrence is in the untreated contralateral lobe. Complications were gradedaccordingtoClavienscore[21].IIEF-5questionnaire wasusedtoassesserectiledysfunction[22].Urinaryincon- tinence was reported using physician reported rates and gradedaccordingtoStameyintothreegrades[23].

Results

Baselineandtumorcharacteristicsofthestudypopulation aresummarized in Table1.Mediantimebetween primary radiationtherapyandfocalsalvageHIFUwas4.2years(IQR 2.8—6.1). ADT was usedconcomitantly toradiation ther- apyin3patients. Atthetimeofsalvage therapy,noneof ourpatientwasonADTandtotaltestosterone wasinthe normal range. All patients had a histologically confirmed organconfined unilateral radio-recurrent clinicallysignifi- cantPCawithoutevidenceofregionalordistantmetastases onconventionalimaging.OnlyonepatienthadaGleason6 cancer,but cancerlength was>5mm andthe patientwas treated,accordingly.Theoncologicoutcomesaftersalvage hemiablationHIFU aresummarizedin Table2.Allpatients experiencedaPSAnadirinthepostoperativesetting.Ata medianfollow-upof41.5(IQR:18—58)months,5/10(50%) ofpatientsexperiencedBCRaccordingtoPhoenixcriteria.

LocalrecurrencewasidentifiedintwopatientsatMRI.One ofthesehadasuspiciousbilateralrecurrencewithdistant metastasisidentified onbonescanand theother onehad ipsilateraldiseasewithnoevidenceofmetastasison68Ga- PSMA.ThelatterpatientunderwentanMRItargetedbiopsy andwassubsequently treatedbySRP.The operativespec- imenshoweda clinicallysignificant cancer locatedat the ipsilateralapex. The procedure was challenging but with noperioperativecomplications.PSAwasundetectableafter the operation but the patient developed urinary incontinence.Twopatientsdevelopedonlydistantmetastasesand onepatienthadaBCR without evidenceof clinicalrecur- renceon68Ga-PSMA.Allpatients withdistantmetastases wereofferedADT.The onlypatientwithrisingPSAandno evidenceofrecurrencewasofferedsurveillance.BCRfree- survivalratesat24and36monthswere75%(CI95%:31—93) and60% (CI95%: 20—85),respectively. The procedure was welltoleratedintheurinaryandgastro-intestinaldomains.

At the end of the follow-up, two patients presented uri- naryincontinencegradeIIandtheremainingpatientswere pad-freeandleak-free.Onepatientdevelopeddenovoerec- tiledysfunctionrequiringPDE5I.Theerectilefunctionscores decreasedfromameanof10.1to8.7.Therewerenorectal toxicitiesattotalcohortfollow-up.

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Table1 Baselineandtumorcharacteristicsof10patientswithorganconﬁnedunilateralradio-recurrentprostatecancer beforetreatmentbyhemiablationHIFU.

Radiationtherapy SalvagefocalHIFU

Medianage(IQR),years 68(65—73) 71(69—76)

PSApre-treatment,ng/mL 7.2(5—11) 3.1(1.54—8.59)

Gleasonscore

≤6 2 1

3+4 5 4

4+3 1 2

4+4 1 2

4+5 1 1

D’Amicoriskgroup

Low 2 1

Intermediate 3 4

High 3 4

Unknown 2 1

Medianprostatevolume(IQR),mL 37(21—47) 20(8—22)

Table2 Oncologicoutcomesof10patientswithorganconﬁnedunilateralradio-recurrentprostatecanceraftertreat- mentbyhemiablationHIFU.

Median±SDPSAnadir,ng/ml(IQR) 1.52±2.1(0.52—2.07)

Mediantime±SDtoachievePSAnadir,months(IQR) 1±1.9(1—3)

Phoenixcriteria(PSAnadir+2ng/ml),patients(%) 5(50%)

MultiparametricprostateMRI(n=5)

Positive 2

Negative 3

Metastasesonbonescanand/orpelvicCT 3

68Ga-PSMAPETimaging(n=2)

Positive(site) 1(prostate,Fig.1)

Negative 1

Biopsyresults(n=1)

Clinicallysigniﬁcantdisease 1

Clinicallyinsigniﬁcantdisease 0

Nocancer 0

24monthsactuarialPhoenixrecurrencefreesurvivalrates 75%(CI95%:31—93) 36monthsactuarialPhoenixrecurrencefreesurvivalrates 60%(CI95%:20—85)

Discussion

LocalrecurrencesafterprimaryPCatherapyleadtodisease progressionandat timedeath. Therefore,complete local tumoreradicationismandatorytoimprovelong-termcan- cercontrol.SRPisthemoststudiedprocedurewithreported 10-yearBCRfreesurvivalratesrangingfrom28%to53%[24].

Cancerspeciﬁcsurvivalandoverallsurvivalratesashighas 80% were also reported[25]. However, morbidity of such anapproachcouldbequitehighwithupto1/3ofpatients experiencinggrade3and4complications[26].Additionally, the surgical technique is challenging and functional out- comesarepoor[27].Thus,themajorityofsurgeonsprefer tomanagethesepatientsexpectantlyandtoofferADTfor metastasis[28].Bydoingso,mostofthesepatientswilllive morethan10yearsbutsomeofthemwillalsoprogressand succumbtotheir disease.That’swhy somesurgeons have usedenergy-basedmodalitiesbutretrospectivecaseseries reporting on salvage Cryotherapy, HIFU or brachytherapy for radio-recurrentPCayielded loweroncologic outcomes

compared to SRP [6]. Therefore, the need for a minimal invasiveapproachthatexhibitafavorablebalanceofharms andbeneﬁtsopenedthedoortoapplyfocaltherapyasan alternativesalvagetreatmentofrecurrentdiseaseafterRT.

EisenbergandShinoharawerethefirsttoreportresultsof focalCryotherapyinproperlyselectedpatientswithauni- lateralfocusofdiseaserecurrenceafterradiotherapy[12].A recentobservationalstudyoftheCryoOn-LineData(COLD) Registrysuggestedthatpatientstreatedwithfocalcryother- apy were at lower risk of urinary incontinence, erectile dysfunction, urinary retention, and recto-urethral fistula comparedtotheirpeerstreatedwithwholeglandCryother- apy [13]. Oncologic outcomes appeared also comparable to whole gland cryotherapy with BCR free survival rates varying between 47%and 54% at5 years[9,14]. Recently, a pilot study examined 39 patients with organ confined radio-recurrentPCatreatedbyfocalHIFU[10].Theauthors reported at a median follow-up of 17 monthsa BCR free survivalratesof69%and49%at12and24months,respectively. The procedure was well tolerated with only one

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Figure1. A68Ga-PSMAPET/CTobtainedina56yearsoldpatientpresentingwithaBCR(PSA=3,8ng/ml)13yearsafterexternalbeam radiationtherapy. Coronalviewsdemonstratea suspicioushypermetaboliclesionintheapicalright prostaticlobe andnoevidenceof regionalordistantmetastases.

patientdeveloping arecto-urethralﬁstulathatwasman- agedconservatively.Inaprospectivetwo-centerstudythat examined48patients,Bacoetal.demonstratedlocalrecur- rencein17%oftheirpatients[11].Thepatientandcancer characteristicsaswellasthemorbidity,thefunctionaland oncologic results of these different studies are summa- rized in Table 3. In the present study, local recurrence wasdocumentedin one patientandsuspected in another one. Three patients presented metastasis in the relative short follow-up period. Of note, these patients had not been primarily investigatedby68Ga-PSMAandcouldhave presentedmicrometastaticdiseaseat thetimeofstaging.

Despite a decrease in their PSA, these patients probably didnotbenefitfromsalvagetreatment.Therefore,abetter selection of patientsbased onthemost effective method formetastaticevaluationismandatoryinfuturestudies.In total, 5 patients were free of BCR at the end of follow- up. Another point is the early achievement of PSA nadir that provides immediate feedback on treatment efficacy and allowsidentification of patients withresidualcancer.

Thesepatientscouldbeofferedanothercurativetreatment eveninthesalvagesetting.Intotal,ADTwasavoidedin70%

ofpatients. Additionally, 60%of patientshad aneffective PSAnadirandcouldbeconsideredcured.However,alonger

follow-upisnecessarytoascertainthishypothesis.Further- more,thetreatmentwassafeandrelativelywell-tolerated.

Ourfunctionaloutcomeswereinlinewiththosereportedin contemporaryseries[10,11] withonlytwopatients devel- opingmoderateurinaryincontinence.

Meanwhile we acknowledge several limitations to our study.First, control biopsy wasnot performed systemati- callyinaprotocolbasedscenariobutofferedonlyinpatients whoexperienced BCR withnodocumenteddistantmetas- tases.This could have overestimated local control but it would be difﬁcult to convince our ethical board to sub- jectallpatientstoaninvasive diagnosticprocedurewhen itsresultswould notalterthetreatmentdecision-making.

Second,anotherlimitationistheabsenceofavalidateddef- initionof failurefor HIFUingeneralandfor focaltherapy in particular. While we did use Phoenix criteriato define athresholdtoofferbiopsy, thisdefinitionwasnotusedto definefailureinourstudy.Third,despitethefactthatallour patientswereselectedbasedonacompletematchbetween mpMRIand MRI targetedbiopsy, 68Ga-PSMA wasnot used toruleoutmetastaticspreadbeforeinclusion.Inourcase series,patientswhodevelopedmetastasisshortlyafterthe treatmentwereconsideredasclinical failuresbuttherel- ative short duration between treatment and diagnosis of

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F.Aounetal.

Table3 Publishedseriesoffocalsalvagetreatmentforunilateralradio-recurrentprostatecancer.

Firstauthor (year)

Number of patients

Design ofthe study

Follow-up (range), months

Median age

PSAbefore salvage treatment (range), ng/mL

Proofof local recurrence

Metastatic Evaluation

BCRcriteria aftersalvage treatment

BCR-Free Survival Rates

Continence rate

Potency rate

Recto- urethral Fistularate

Yong-Hong (2013)

91 R 15(1—97) 71.7 4.8(0—926) NA NA Phoenix

criteria

1-year:

95.3%

3-year:

72.4%

5-year:

46.5%

94.5% 50% 3.3%

Bomers (2013)

10 P NA 67 NA MRI

targeted biopsy

WholebodyMRI NA NA NA NA 0%

Wenske (2013)

55 R 47.8

(1.6—203.5)

66 7.0

(1.2—185.8)

TRUS guided biopsy

Bonescan+ abdominopelvic CTscan

Phoenix criteria

5-year:47%

10-year:

42%

NA NA 5.5%

DeCastro Abreu(2013)

25 R 31(4—90) 71 2.8(0.1—8.2) TRUS

guided biopsy

Bonescan+ abdominopelvic CTscanorMRI

Phoenix criteria

5-year:

54.4%

100% 28.6% 0%

Eisenberg (2008)

19 R 18(6—33) 70.6 3.3

(0.28—8.96)

TRUS guided biopsy

Phoenix criteria

1-year:89%

2-year:79%

94.7% 40% 0%

Ahmed (2012)

39 R 17(10—29) 70.5 4.6

(0.02—27.9) MRI targeted biopsy

Bonescan Phoenix criteria

1-year:69%

2-year:49%

87% NA 0.03%

Baco(2013) 48 P 16.3

(10.5—24.5)

68.8 14.2(2.9—70) MRI targeted biopsy

Bonescan+ abdominopelvic CTscanorMRI

Phoenix criteria

1-year:83%

2-year:52%

75% NA 0%

Present study

10 P 21.5(8—28) 71 3.1

(1.54—8.59) MRI targeted biopsy

Phoenix criteria

1-year:75%

2-year:60%

80% NA 0%

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metastaseswould ratherbeinfavor of amicrometastatic diseasepresentatthemomentofstaging.Fourth,thecohort wassmallwith ashortfollow up and nocontrolgroup to assesscollateraldamageandfunctionalandoncologicout- comes.

Conclusion

OurstudysuggeststhathemiablationHIFUcanbeanalter- nativestrategyforpatientswithradio-recurrentunilateral PCa.Appropriatepatientselectionbasedonastrategycom- biningmpMRIandMRItargetedbiopsyaswellas68Ga-PSMA andalargescale prospectivetrial withat least5yearsof follow-upisneededtoobtainaclearideaofhowmeaningful hemiablationtherapywillbeforfunctionalandoncological outcomesinthesalvagesetting.

Disclosure of interest

Theauthorsdeclarethattheyhavenocompetinginterest.

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