University of Groningen Oligometastatic Prostate Cancer Dutch Oligometastatic Prostate Cancer Working Group; Aluwini, Shafak S; Mehra, Niven; Lolkema, Martijn P; Oprea-Lager, Daniela E; Yakar, Derya; Stoevelaar, Herman; van der Poel, Henk

(1)

University of Groningen

Oligometastatic Prostate Cancer

Dutch Oligometastatic Prostate Cancer Working Group; Aluwini, Shafak S; Mehra, Niven;

Lolkema, Martijn P; Oprea-Lager, Daniela E; Yakar, Derya; Stoevelaar, Herman; van der Poel, Henk

Published in:

European urology oncology

DOI:

10.1016/j.euo.2019.07.010

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date:

2020

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Dutch Oligometastatic Prostate Cancer Working Group, Aluwini, S. S., Mehra, N., Lolkema, M. P., Oprea- Lager, D. E., Yakar, D., Stoevelaar, H., & van der Poel, H. (2020). Oligometastatic Prostate Cancer:

Results of a Dutch Multidisciplinary Consensus Meeting. European urology oncology, 3(2), 231-238.

https://doi.org/10.1016/j.euo.2019.07.010

Copyright

Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).

The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.

More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment.

Take-down policy

If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.

(2)

Oligometastatic Prostate Cancer: Results of a Dutch Multidisciplinary Consensus Meeting

Shafak S. Aluwini

^a

, Niven Mehra

^b

, Martijn P. Lolkema

^c

, Daniela E. Oprea-Lager

^d

, Derya Yakar

^e

, Herman Stoevelaar

^f

, Henk van der Poel

^g,

*,

Dutch Oligometastatic Prostate Cancer Working Group

aDepartmentofRadiationOncology,UMCG,Groningen,TheNetherlands;^bDepartmentofMedicalOncology,Radboudumc,Nijmegen,TheNetherlands;

cDepartmentofMedicalOncology,ErasmusMCCancerInstitute,Rotterdam,TheNetherlands;^dDepartmentofRadiology&NuclearMedicine,Amsterdam UniversityMedicalCenters,VUUniversity,Amsterdam,TheNetherlands;^eDepartmentofRadiology,UMCG,Groningen,TheNetherlands;^fCentreforDecision Analysis&Support,IsmarHealthcareNV,Lier,Belgium;^gDepartmentofUrology,AntonivanLeeuwenhoek,Amsterdam,TheNetherlands

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 : e u o n c o l o g y . e u r o p e a n u r o l o g y. c o m

Articleinfo Articlehistory:

Received 28 May 2019Received inrevisedform

20 June 2019Accepted July 12, 2019

AssociateEditor :GianlucaGiannarini

Keywords:

Castration-resistantprostate cancer

Consensus

Hormone-sensitiveprostate cancer

Metastases

Metastasis-directedtherapy Oligometastases

Oligometastaticprostatecancer Prostatecancer

Prostate-specificmembrane antigenpositronemission tomography/computed tomography

Recurrentprostatecancer

Abstract

Background: Oligometastatic prostate cancer (OMPC) is aheterogeneous disease statethatisimperfectlyunderstood,anditsclinicalimplicationsareunclear.

Objective: TodeterminetheconsensusofaDutchmultidisciplinaryexpertpanelon biological aspects, treatment goals, and management of OMPC in daily clinical practice.

Design, setting, and participants: Thestudy comprised amodiﬁedDelphi method includinganexplorativesurveywithvariousstatementsandquestions,followedbya consensusmeetingtodiscussanddeterminetheagreementwithrevisedstatementsand relateditems.Thepanelconsistedof34Dutchrepresentativesfromurology,medicaland radiationoncology,radiology,nuclearmedicine,andbasicresearch.

Outcomemeasurementsandstatisticalanalysis: Agreementwasdeterminedwith statements(ﬁve-pointscale).Consensuswasdeﬁnedas75%panelagreementwitha statement.

Resultsandlimitations: Consensusexistedfor56%ofstatements.Thepanelagreed thatOMPCcomprisesalimitedmetastaticspreadinthehormone-sensitivesetting,in boththesynchronousandthemetachronouspresentation.Limitedmetastaticspread was believed to involvethree toﬁve metastasesand amaximum of two organs.

Prostate-specific membrane antigen positron emission tomography/computed tomography scanwas currently perceived as the most accurate diagnostic imaging modality.Althoughtherewasaconsensusthattargetedtreatmentofallmetastasesin OMPCwilldelayfurtherdisseminationofthedisease,opinionsonspecifictreatment regimensweredivided.Paneloutcomeswerelimitedbythelackofscientificevidence onOMPC.

Conclusions: AmultidisciplinarypanelreachedaconsensusthatOMPCisaspeciﬁc diseasestaterequiringatailoredtreatmentapproach.OMPCregistriesandclinical studiesshouldfocusonboththebiologyandtheclinicalparametersinrelationto optimaltreatmentstrategiesinsynchronousandmetachronousOMPC.

Patientsummary: AgroupofDutchmedicalspecialistsagreedthatprostatecancer patientshavingfewmetastasesmaybeneﬁtfromanewtherapeuticapproach.Clinical studiesneedtodeterminewhichtreatmentisbestforeachspeciﬁcsituation.

*Corresponding author. Department of Urology, Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam1066CX,TheNetherlands.Tel.+3120-5122553;Fax:+3120-5122554.

E-mailaddress:h.vd.poel@nki.nl(H.vanderPoel).

https://doi.org/10.1016/j.euo.2019.07.010

(3)

1. Introduction

Theconceptof“oligometastaticdisease”wasfirstdescribedin 1995byHellmanandWeichselbaum[1]toidentifyasubgroup of metastatic patients with a limited number of clinically detectablemetastases.Ithasbeenproposedasanintermedi- atestagebetweenlocalised andwidespreaddisease,which might be amenable to focal metastasis-directed therapies (MDTs),with theaimofpreventing furtherdiseasespread, delayingsystemictherapy,andpotentiallyimprovingoverall survival[1,2].However,thebiologyofoligometastaticdisease isnotyetwellunderstood,andknowledgeaboutthegenomic andmoleculareventsinvolvedindiseaseprogressionislargely lacking [3,4]. Furthermore, there is no consensus on the definitionofoligometastaticprostatecancer(OMPC)[5].Most commonly,OMPChasbeendefinedbyspecificcut-offsforthe numberofmetastasesandinvolvedsites,buttheremay alsobe other relevant variables such as the time and onset of metastasis(synchronous[denovo,within3moofprimary diagnosis]versusmetachronous[recurrent]),andhormone- sensitive versus castration-resistant disease state [6,7]. In addition,thedetectionofmetastasesishighlydependenton the imaging modality used [8]. Finally, the evidence on treatmentofOMPCisverylimited.Moststudiesinvestigating local therapy and MDT for OMPC are retrospective and intervention focused [9,10]. Only few prospective studies evaluatedtheroleoflocaltreatmenttotheprostateindenovo (lowburden)metastaticpatientsandMDTinpatientswith oligorecurrentdisease[11–15].Todeterminethestateofthe artonOMPCanditsclinicalimplicationsfortheNetherlands,a multidisciplinaryconsensusmeetingwasorganised.

2. Patientsandmethods

2.1. Studydesign

Thestudycomprisedatwo-phasemodifiedDelphiapproach inwhichanexpertpanelwasfirstlyaskedtocompletean explorative survey on various statements and questions related to OMPC. During a subsequent 2-d consensus meeting, surveyoutcomes were discussed in light of the availablescientific evidence, andpanellists wereaskedto indicatetheiragreementwiththe(revised)statements.This approach combines elements from the Delphi method, Nominal Group Technique, and consensus development techniques[16].

2.2. Panelcompositionandselectionofparticipants

Selectioncriteriawereformulatedbytheinitiatingscien- tific committee (N.M., S.A., M.L., and H.P.), and included clinical and scientific expertise in the field of OMPC, representationofprincipaldisciplinesinvolved,geographic spread, and availability to participate in the consensus meeting.Thepanel("DutchOligometastaticProstateCancer WorkingGroup")consistedof11urologists,sevenmedical oncologists,fiveradiationoncologists,fourradiologists,five nuclearmedicinephysicians,andtwobasicscientists.

2.3. Explorativesurvey

Thesurveywaspreparedbythescientificcommitteetogether witharesearcherexperiencedinconsensusmethodology(H.

S.).BasedonkeypublicationsonOMPC[4,5,7,8,10,13,17,18], guideline recommendations [19,20], andclinical expertise, 26statementsandquestionsonkeyareasofOMPC(biology, definition/diagnosis, treatment,and treatmentgoals) were formulated. Panel members were encouraged to provide detailed feedbackandsuggestionsforimprovement ofthe items included. Based on this feedback, statements and questionswererevisedbythescientificcommittee.

2.4. Consensusmeeting

ThemeetingtookplaceinUtrecht(theNetherlands)on22– 23March2019andwasdividedintofourpartsrelatedtothe keyareas.Eachpartwas introducedbyastate-of-the-art lecture presentedby an (inter)national expert, to ensure thatparticipantscouldstartfromthesamelevelofscientific evidence.Thereafter,thesurveyresultswerediscussedand revisedstatementswerepresented.Thediscussionwasled by the scientific committee members and an advising nonvoting methodologist. Where needed, the statements were further adapted. Subsequently, all items were anonymously(re)ratedusinganonlinevotingsystem.For the 18 statements included,afive-point Likertscale (1= strongly disagree,5=stronglyagree)wasused; foreight additional questions an adapted multiple-choice format wasapplied.Allitemsincludedtheoption“can’tjudge”in casetheexpertlackedexperienceforaspecificquestionor feltunabletovoteforanyotherreason.

2.5. Statisticalanalysis

Frequencytableswereusedtodescribetheoutcomesonthe variousstatementsandquestions.Consensus(goodagree- ment) wasdefinedasthesituationinwhich75%ofthe panellists chosethe same option.If 50–74% of panellists chose thesame option,this wasdeemed fairagreement.

Thosewhoselectedtheoption“can’tjudge”wereexcluded fromtheagreementcalculations.

3. Results

3.1. Biology

Table 1 showsthe panel results regarding thebiology of OMPC. There were a consensus that MDT delays further diseasedissemination(statement3)andafairagreementthat OMPCisadistinctbiologicalstatecomparedwithpolymeta- staticdisease(statement1),isassociatedwithlimitedgenetic intermetastatic heterogeneity (statement 2), and is not limitedtothehormone-sensitivesetting(statement4).

3.2. Definitionanddiagnosis

There was a consensus that OMPC defines a limited metastaticspreadinthehormone-sensitivesetting,inboth

EUROPEAN UROLOGYONCOLOGY3(2020)231–238 232

(4)

the synchronous and the metachronous disease stage (Table 2, statements1 and 2). There was fair agreement thatdifferentcut-off pointsareneededforthenumberof metastaticlesionsinrelationtolocationofOMPC(statement 3)andtheexclusionofvisceralmetastasesinthedefinition ofOMPC(statement4).Separatequestionsonthemaximum numberofmetastasesand locationsthatconstitute OMPC revealedfairtogoodagreement.Allpanellistsfoundthatthe maximum numberof metastases(diagnosed by prostate- specificmembraneantigenpositronemissiontomography/

computed tomography [PSMA-PET/CT], excluding four or

fewer pelviclymphnodes)rangedbetween3and5,more specifically,52%votedforthree,14%forfour,and34%forfive metastases. The maximum number of involved organs (irrespectiveofthenumberofmetastases)wasconsidered tobe2by89%ofthepanellists.Anadditionalquestionon defining lagtimesfor OMPCin themetachronoussetting revealedthat82%foundthatitisnotyetpossibletodefine validtimecut-offpoints.Aminorityvotedforalagtimeof

3 mo (6%), 6 mo (9%), or 1 yr (3%). The perceived accuracy of several diagnostic imaging modalities for diagnosingOMPC(Fig.1)washighestforPSMA-PET/CTscan.

Table1–PanelresultsonstatementsregardingthebiologyofOMPC.

Statement No.ofanswers

(no.ofvalidanswers)^a

Agree^b (%)

Neutral^b (%)

Disagree^b (%)

1. Oligometastaticdiseaseinprostatecancerrepresentsadistinctbiologicalstatein comparisonwithpolymetastaticdisease

33(32) 69 3 28

2. Oligometastaticdiseaseinprostatecancerisassociatedwithlimitedgenetic intermetastaticheterogeneity

34(20) 65 15 20

3. Targetedtreatmentofallmetastasesinoligometastaticdiseasewilldelayfurther disseminationofdisease

32(31) 78 19 3

4. Oligometastaticdiseaseexistsonlyinthehormone-sensitivesetting 34(31) 23 6 71

OMPC=oligometastaticprostatecancer.

Theboldvaluesrepresentstatementsforwhich=75%ofthepanellistschosethesameoption.

a Validanswers:“can’tjudge(unqualifiedtoanswer)”excluded.

b Agree=categories“agree”+“stronglyagree”;disagree=categories“disagree”+“stronglydisagree”.%=percentagesofvalidanswers.

Table2–PanelresultsonstatementsregardingdefinitionsanddiagnosticsofOMPC.

Agree^b (%)

Neutral^b (%)

Disagree^b (%)

1. OMPCdeﬁnesalimitedmetastaticspreadatdiagnosis,inthehormone-sensitive setting

30(30) 100 0 0

2. OMPCdeﬁnesalimitedmetastaticspreadinthehormone-sensitivesetting, followingPSArelapseafterdeﬁnitivetreatmentoftheprostate/regionalnodes

33(32) 94 3 3

3. Thereshouldbedifferentcut-offsinthenumberofmetastasesfordifferent anatomicallocations

33(31) 61 0 39

4. OMPCinthehormone-sensitivesettingexcludesthepresenceofvisceral metastases

33(33) 58 3 39

OMPC=oligometastaticprostatecancer;PSA=prostate-speciﬁcantigen.

Fig.1–Perceivedaccuracyofdifferentdiagnosticmodalitiestoassess(ordiagnose)thepresence(oroccurrence)ofOMPC,plottedagainstpercentage ofrespondents.CT=computedtomography;Good=categories“very”+“extremely”;MRI=magneticresonanceimaging;OMPC=oligometastaticprostate cancer;PET=positronemissiontomography;Poor=categories“notatall”+“slightly”;PSMA=prostate-specificmembraneantigen.

(5)

3.3. Treatment

Panel results on treatment ofOMPC (Table 3)revealed a consensusthatwhenconsideringMDTforOMPC,allvisible metastasesshouldbetreated(statement6).Whenconsider- ingMDTfor OMPC,thepanel disagreedthatcombination withandrogen-deprivationtherapy(ADT)isalwaysrequired (statements2and5).Thepanelagreedthatchemotherapyis notindicatedinOMPC(statement7),andthattreatmentof

nodalOMPC shouldbebasedon thelevelandnumberof metastases (statement 4). Other aspects showed more diverse answers.Panelresults per discipline areavailable intheSupplementarytables.Theimportanceofdiagnostic measuresfortreatmentchoice(Fig.2)washighest forthe numberandlocationofmetastases.Prostate-specificantigen (PSA) kinetics wasfound to beespecially relevant inthe metachronous setting, while molecular or pathological characteristicswereconsideredtobeoflessvalue.

Table3–PanelresultsonstatementsregardingtreatmentofOMPC.

Agree^b (%)

Neutral^b (%)

Disagree^b (%)

1. Patientswithsynchronous(denovo;pelviclymphnodes

4excluded)oligometastasesshouldalwaysbeoffered MDTwhentreatmenttothelocaltumourisgiven

32(32) 25 6 69

2. Patientswithmetachronous(recurrent)asymptomatic oligometastasesshouldalwaysreceiveADTwith orwithoutMDT

33(29) 7 7 86

3. OMPC,inthehormone-sensitivesettingfollowing deﬁnitivetherapytotheprostate,shouldbe treatedonlybyMDT(withoutADT)toall oligometastaticsites

30(26) 42 4 54

4. Inpatientswithmetachronous(recurrent)OMPC withexclusivenodalinvolvement,treatmentchoice isdependentonthelevelandnumberoflymph nodemetastases

29(28) 100 0 0

5. Inpatientswithmetachronous(recurrent)OMPC andexclusivelynodalinvolvementafterlocal treatmentoftheprostatewithcurativeintent, lymphnode–targetedtreatmentshouldbe combinedwithADT

31(28) 7 7 86

6. Whenoligometastasis-targetedtherapyis considered,allvisiblemetastaticlesions shouldbetreated

31(31) 81 0 19

7. Chemotherapyhasnoroleinthemanagement ofpatientswitholigometastases

30(27) 85 0 15

8. Oligometastasis-targetedtherapyshouldbeconsidered onlyformetastatichormone-sensitiveprostatecancer

29(28) 57 4 39

9. OMPCfollowingfailuretoADT(incastrate-resistant state)shouldpreferablybetreatedbyradicalMDT

31(29) 10 0 90

ADT=androgen-deprivationtherapy;MDT=metastasis-directedtherapy;OMPC=oligometastaticprostatecancer.

Fig.2–Perceivedimportanceofdifferentdiagnosticmeasuresfortreatmentdecisionsinpatientswitholigometastaticdisease,plottedagainst percentageofrespondents.Not=categories“notatall”+“slightly”;PSA=prostate-specificantigen;Very=categories:“very”+“extremely”.

(6)

3.4. Treatmentgoals

OpinionsontheprimarytreatmentgoalofOMPCshowed considerablevariation.Forthehormone-sensitivesynchro- noussetting,prolongedmetastasis-freesurvival,improved qualityoflife,anddelayedorreduceddurationofsystemic therapies each accounted for 25% of the voting. For the hormone-sensitive metachronous setting, delayed or re- ducedduration ofsystemictherapies(40%)andimproved qualityoflife(32%)weremostfrequentlymentionedasthe primarytreatment goal.Improved overallsurvival scored relatively low in both the synchronous (8%) and the metachronous (8%) setting. There was a consensus that toxicityshould beweightedheavilyagainstthe potential benefitoftargetedtherapy(100%).

4. Discussion

This work aimedto determine the consensus ofa Dutch multidisciplinaryexpertpanelonbiologicalaspects,treatment goals, and management of OMPC in daily clinical practice.

4.1. Biology

About two-thirds of the experts agreed that OMPC represents a distinct biological state compared with polymetastaticdisease.Understandingthebiologybehind oligometastaticdiseasemayhelpidentify patientspoten- tially benefitting from ablative treatment of limited metastases[4].

Severalstudies have attemptedto unravel thegenetic and molecular landscape of (oligo)metastatic disease [4].Thelack ofresearchconcerningthegenetic signature ofOMPCisreflectedinthe largenumberofexperts who optedfor “can’t judge”when asked aboutthis aspect.In metastaticprostatecancer,metastasis-to-metastasisspread isfoundtobecommon,througheitherdenovomonoclonal seeding of daughter metastases or polyclonal seeding betweenmetastaticsites[17,21].Thiscross-metastaticsite seeding is often associated with heterogeneous tumour cloneswith varyingdegrees of aggressivenessand resis- tancetotherapy[22].Therefore,limitedmetastaticdisease maybeeligibleforMDT,withtheaimofreducingfurther seedingofmetastases.Indeed,aboutthree-quartersofthe expertsagreedthattargetedtreatmentofallmetastasesin oligometastaticdiseasewoulddelayfurtherdissemination of disease. In addition to cross-metastatic site seeding, metachronousmetastaticprostatecancercouldarisefrom anycloneintheheterogeneousprimarydisease,notjustthe dominant one [18].In other cancers,including colorectal cancer,heterogeneityoftheprimarytumourwasfoundto bepredictiveforthemetastaticpotentialandconsequently clinicaloutcomeofthepatients[4,23].Limitedmolecular datahavebeenobtainedfrompatientswitholigometastatic cancer, but available data support differential genomic, transcriptomic, or regulatory networks, with heterogeneous outcomes within aggressive and nonaggressive

oligometastatic cancer, or between oligo- and polymetastaticdisease[4,24–26].

Duringthemeeting,itwasdiscussedthatdiseasespread occursonacontinuousscalesimilartopopulationgrowth [4]. Therefore, it seems important to also invest in understandingwhetherbiologicalprocessessuchasgrowth speedandextentofspreadareimportantdeterminantsof patients’outcome.

4.2. Definitionanddiagnosis

Opinionsonthemaximumnumberofmetastasestodefine OMPC(diagnosedbyPSMA-PET/CT,excludingfourorfewer synchronous pelvic lymph nodes) varied between 3 and 5. In the Netherlands, four or fewer synchronous pelvic lymph nodes are still considered curative by combined hormonal therapyand pelvic radiotherapy, including the prostate[20],andarethereforeexcludedfromthedefini- tion of OMPC. In addition, PSMA-PET/CT is commonly performedindailyclinicalpractice intheNetherlandsfor earlyscreeningofmetastasesandwasthereforechosento define a clinically relevant cut-off. During the Advanced ProstateCancerConsensusConference(APCCC)2017meet- ing,66%ofpanellistsoptedforthreeorfewermetastasesto beconsideredasacut-offforthedefinitionofoligometas- taseswhenusingCTandbonescans,while20%votedfor fiveorfewermetastases[27].Moststudiesuse(d)threeor five metastases as the cut-off. However, the imaging modality used differs between studies. In our panel, a consensuswasreachedonthenumberofinvolvedorgans, with 89% of the experts defining two organs as the maximum.

PSMA-PET/CT scan was considered the most accurate diagnostic tool to assess the presence or occurrence of oligometastaticdiseasebythepanellists.Indeed,datashow thatPSMA-PET/CTissensitivefordetectingsmallmetasta- ses[28].However,PSMA-PET/CTiscurrentlyrecommended by theEuropean AssociationofUrology (EAU)guidelines only for patients with biochemical recurrence following radicalprostatectomyif thePSAlevelis>0.2ng/mlandif theresultswill influence subsequenttreatment decisions [19]. Although often routinely used for the detection of metastases, bone and CT scans have poor diagnostic accuracy for low-burden disease [29,30]. The value of whole-bodymagneticresonanceimaginginthesettingof OMPCwasscoredaslimitedbythepanellists.

4.3. Treatment

For thesynchronous oligometastatic setting,only 25%of experts agreed thatMDTshould alwaysbeoffered when treatment to the local tumour is given. In the APCCC 2017 consensus meeting, >60% of panellists voted for a treatmentstrategyincludinglocalablativetreatmentofthe primary tumour site and allmetastases inpatients with newly diagnosedOMPC [27].The differencein consensus mightbeexplainedbythephrasingofourstatement,asthe majorityofpanellistshesitatedon “always”andtherefore disagreed.However,MDTofnon-nodaland/ornodaldisease

(7)

outsidethepelvisisnotthestandardofcareandshouldbe considered experimental [19]. A recent meta-analysis of twoprospectivephase III trials inpatients with de novo metastatic disease showed a 7% improvement in 3-yr overallsurvivalwhenlocalradiotherapytotheprostatewas addedtoADTincaseofalowdiseaseburden[31].Currently, no prospective randomised data are available showing a benefitof MDT inaddition to localtherapyin “de novo” oligometastatic setting.STAMPEDE is planningon anew armrandomisingpatientswithlow-volumediseasetolocal therapy versus local therapy combined with MDT, with overallsurvivalastheprimaryendpoint.

Forthemetachronoussetting,only7%ofexpertsagreed thatasymptomaticpatientsshouldalwaysreceiveADTwith orwithout MDT, and 42% agreedthatpatients shouldbe treatedwithMDT(withoutADT)atallmetastaticsites.Inthe APCCC2017meeting,12%ofpanellistsoptedforradicallocal treatment ofalllesionswithout ADT[27]. Thisdifference mightbeexplainedbyrecentlypublisheddata,notavailable atthetimeoftheAPCCC2017meeting,showingadelayof androgen ablation when patients receive MDT [13]. EAU guidelines recommend immediate systemic treatment in asymptomaticandsymptomaticmetastaticpatients[19].De- ferred castration can be discussed with well-informed asymptomaticmetastatic patients providedthe patient is closelymonitored[19].Theevidencefortreatmentofmen witholigorecurrentprostatecancerisscarce.Recently,two small prospective phase II studies evaluated MDT versus observationinasymptomaticpatientsintheoligorecurrent setting, with ADT-free survival as the primary endpoint [13,14].Bothtrials,notpoweredforoverallsurvival,founda modestdelayinprogressionwithlimitedtoxicity[13,14].A prospective phase I trial showed that stereotactic body radiotherapywasfeasibleandsafeinagroupof33oligor- ecurrentprostatecancerpatients[15].However,MDTinthis settingshouldstillbeconsideredinvestigational[19].Incase ofexclusivelynodalinvolvement,only7%ofexpertsagreed thatlymphnode–targetedtreatment shouldbecombined withADT,andallexpertsagreedthattreatment choiceis dependent on the level and number of lymph node metastases.

Forboththesynchronousandthemetachronoussetting, thenumberandlocationofmetastaseswereconsideredthe mostimportantdiagnosticmeasurestodecideontreatment bytheexperts.Althoughclearevidenceislacking,thepanel agreedthatPSAkinetics,numberandlocationofmetastases (byimaging),andmolecularorpathologicalcharacteristics should be taken into account during multidisciplinary meetingsonmanagementofapatientwithOMPC,bothin thehormone-sensitiveandthecastration-resistantsetting.

Only10%ofexpertsagreedthatOMPCshouldpreferably betreatedwithradicalMDTinthecastrate-resistantstate, suggestingthatOMPCincastrate-resistantdiseaseisofless valuethaninhormone-sensitivedisease.However,sinceno consensuswasobtainedonthestatementthatMDTshould only be considered for metastatic hormone-sensitive prostate cancer (57% agree, 39% disagree), its use in the castration-resistant setting remains an experimental option.Guidelinesrecommendlife-prolongingsystemicther-

apy combined with ADT as the standard of care, and symptomaticbone lesionsshouldbetreatedbypalliative radiotherapy[19].RadicalMDTisexperimentalandshould beofferedonlyinthecontextofclinicaltrials.

Finally,intheabsenceofprospectiverandomisedtrials, thepanelbelievedthatalargenationalregistryisneededto prospectively collect data of patients treated for OMPC.

Prospectiveinitiatives,suchastheregistrytrialOligo-Care initiatedbyEORTC-ESTRO,willevaluatechangingpatterns ofcareofoligometastaticdisease[32].

4.4. Treatmentgoals

Therewasnoconsensusontheprimarytreatmentgoalof MDTinclinicalpractice.Thismay(partly)beexplainedby thefactthatcurrentandon-goingclinicaltrialsonOMPC use differentendpoints [3]. The panellists discussedthat surrogateendpointsofoverallsurvivalareneededandare morerelevantintheshortterm.

4.5. Limitations

Theprincipallimitationofthisstudyisrelatedtothelackof scientific evidence, whichnecessitated relying on expert opinionsformostofthetopicsdiscussed.Owingtoasmall numberofpanellists,analysisofagreementamongdifferent specialtieswasnotfeasible.Thecompositionofthepanel withthemajoritybeingurologistsmayhaveinfluencedthe consensusoncombiningMDT(suchasradiotherapy)with ADT.Forfullresultsperdiscipline,seetheSupplementary tables.

5. Conclusions

OMPC was considered an important clinical concept, particularly in the hormone-sensitive disease state, but theconsensusonitsmanagementindailyclinicalpractice was limitedbyscarcity ofevidence from clinical studies.

Further basic research is needed to establish oligometastatic disease as a distinct biological entity. In addition, PSMA-PET/CT was consideredthebest imaging modality.

ManagementofOMPCshouldbestandardisedsothatfuture clinicaltrialscanbedesignedandcomparedproperly.Inthe absence of clinical prospective studies, a large national registry is recommended to prospectivelycollect data of patientstreatedforOMPC.

Authorcontributions:HenkvanderPoelhadfullaccesstoallthedatain thestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Aluwini,Mehra,Lolkema,Oprea-Lager,Yakar, Stoevelaar,vanderPoel.

Acquisition of data: Aluwini, Mehra, Lolkema, Oprea-Lager, Yakar, Stoevelaar,vanderPoel.

Analysis and interpretationof data:Aluwini, Mehra,Lolkema, Oprea- Lager,Yakar,Stoevelaar,vanderPoel.

Draftingofthemanuscript:Aluwini,vanderPoel,Stoevelaar.

Critical revision of the manuscript for important intellectual content:

Aluwini,Mehra,Lolkema,Oprea-Lager,Yakar,vanderPoel.

(8)

Statisticalanalysis:Stoevelaar.

Obtainingfunding:Aluwini,Mehra,Lolkema,vanderPoel.

Administrative,technical,ormaterialsupport:Stoevelaar.

Supervision:Stoevelaar,vanderPoel.

Other:None.

Financialdisclosures:HenkvanderPoelcertifiesthatallconflictsof interest, including specific financial interests and relationships and affiliationsrelevanttothesubjectmatterormaterialsdiscussedinthe manuscript(eg,employment/affiliation,grantsorfunding,consultan- cies,honoraria,stockownershiporoptions,experttestimony,royalties, orpatents filed, received,or pending),are the following: Shafak S.

Aluwini: none.Niven Mehra: none.Martijn P.Lolkema: fundingfor researchtoinstitutefromAstellas,Johnson&Johnson,MSD,andSanoﬁ;

advisoryroleforAstellas,Bayer,Johnson&Johnson,andSanoﬁ.Daniela E.Oprea-Lager:none.DeryaYakar:none.HermanStoevelaar:partner Ismar Healthcare NV.Henk vander Poel:research grants from 3D- Simbionix,Astellas,Intuitive,Ipsen,Mimic,andStorz.

Funding/Supportandroleofthesponsor:Thisworkwassupportedby AstellasPharmaB.V.

Acknowledgements:TheauthorsaregratefultoIsmarHealthcareNVfor theirassistanceindevelopmentofthepremeetingsurveyandanalysis, dataanalysisofthe onlinevotingduringthe meeting,andeditorial assistance,whichwerefundedbyAstellasPharmaB.V.AstellasPharma B.V.hadnoinﬂuenceonthecontentinanystageoftheprocess.The survey andonlinevoting were completedexclusively by the Dutch experts. Panel members (in alphabetic order by specialty) were as follows: urology: Martijn Busstra (Erasmus MC), Igle-Jan de Jong (UMCG),TheodeReijke(AMC),SjoerdKlaver(Maasstad),GisèleLeyten (AVL),MichielSedelaar(Radboudumc),DiederikSomford(CWZNijme- gen),Henk vanderPoel (AVL),Pim van Leeuwen(AVL),Jeroen van Moorselaar(VUMC),IngevanOort(Radboudumc);medicaloncology:

MartijnLolkema(ErasmusMC),NivenMehra(Radboudumc),Susanne Osanto (LUMC), Irma Oving (ZGT), Franchette van den Berkmortel (Zuyderland),TomvanderHulle(LUMC),HansWestgeest(Amphia);

nuclearmedicine:JulesLavalaye(St.Antonius),JamesNagaraj(Radbou- dumc), Walter Noordzij (UMCG), Daniela Oprea-Lager (Amsterdam UMC),WouterVogel(AVL);radiationoncology:ShafakAluwini(UMCG), Kim deVries(ErasmusMC), Luc Moonen (AVL),Eva Schaake(AVL), JochemvanderVoortvanZyp(UMCU);radiology:StijnHeijmink(AVL), TomScheenen(Radboudumc),IvoSchoots(ErasmusMC),DeryaYakar (UMCG);basicresearch:GuidoJenster(ErasmusMC),JeroenKneppers (NKI).Speakers:G.StevenBova(TampereUniversity,Finland),Markus Graefen (University Medical Center Hamburg-Eppendorf, Germany), JulesLavalaye, Niven Mehra,Jeroen vanMoorselaar, TomScheenen.

Scientiﬁccommittee:ShafakAluwini,MartijnLolkema,NivenMehra, HenkvanderPoel.

AppendixA. Supplementarydata

Supplementary material related to this article can be found,intheonlineversion,atdoi:https://doi.org/10.1016/j.

euo.2019.07.010.

References

[1] Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol 1995;13:8–10.

[2] WeichselbaumRR,HellmanS.Oligometastasesrevisited.NatRev ClinOncol2011;8:378–82.

[3]LanciaA,ZilliT,AchardV,etal.Oligometastaticprostatecancer:the gameisafoot.CancerTreatRev2019;73:84–90.

[4]ReyesDK,PientaKJ.Thebiologyandtreatmentofoligometastatic cancer.Oncotarget2015;6:8491–524.

[5]TosoianJJ, GorinMA,RossAE,PientaKJ,TranPT,SchaefferEM.

Oligometastaticprostatecancer:deﬁnitions,clinicaloutcomes,and treatmentconsiderations.NatRevUrol2017;14:15–25.

[6]FosterCC,WeichselbaumRR,PitrodaSP.Oligometastaticprostate cancer:realityorﬁgmentofimagination?Cancer2019;125:340–52.

[7]SlaouiA,AlbisinniS,AounF,etal.Asystematicreviewofcontem- porarymanagementofoligometastaticprostatecancer:ﬁghtinga challengeortiltingatwindmills?WorldJUrol.Inpress.https://doi.

org/10.1007/s00345-019-02652-7.

[8]LecouvetFE,Oprea-LagerDE,LiuY,etal.Useofmodernimaging methodstofacilitatetrialsofmetastasis-directedtherapyforoligo- metastaticdiseaseinprostatecancer:aconsensusrecommendation fromtheEORTCImagingGroup.LancetOncol2018;19:e534–45.

[9]YuanY,KishanAU,NickolsNG.Treatmentoftheprimarytumorin metastaticprostatecancer.WorldJUrol.Inpress.https://doi.org/10.

1007/s00345-018-2552-8.

[10] OstP,BossiA,DecaesteckerK,etal.Metastasis-directedtherapyof regionalanddistantrecurrencesaftercurativetreatmentofpros- tate cancer: a systematic review of the literature. Eur Urol 2015;67:852–63.

[11] Boevé LMS,Hulshof MCCM,Vis AN,etal. Effect onsurvival of androgendeprivationtherapyalonecomparedtoandrogendepri- vationtherapycombinedwithconcurrentradiationtherapytothe prostateinpatientswithprimarybonemetastaticprostatecancer inaprospectiverandomisedclinicaltrial:datafromtheHORRAD trial.EurUrol2019;75:410–8.

[12] ParkerCC,JamesND,BrawleyCD,etal.Radiotherapytotheprimary tumourfornewlydiagnosed,metastaticprostatecancer(STAM- PEDE): a randomised controlled phase 3 trial. Lancet 2018;392:2353–66.

[13] OstP,ReyndersD,DecaesteckerK,etal.Surveillanceormetastasis- directedtherapyforoligometastaticprostatecancerrecurrence:a prospective,randomized,multicenterphaseIItrial.JClinOncol 2018;36:446–53.

[14] PhillipsR,RadwanN,RossAE,etal.Interimresultsofarandomized trialofobservationversusSABRforcastration-sensitiveoligometa- staticprostatecancer.IntJRadiatOncolBiolPhys2018;102:e134–5 (abstractSU_32_2314).

[15] SivaS, Bressel M,MurphyDG, etal. Stereotacticablativebody radiotherapy(SABR)foroligometastaticprostatecancer:aprospec- tiveclinicaltrial.EurUrol2018;74:455–62.

[16] BlackN,MurphyM,Lamping D, et al. Consensusdevelopment methods:areviewofbestpracticeincreatingclinicalguidelines.

JHealthServResPolicy1999;4:236–48.

[17] GundemG,VanLooP,KremeyerB,etal.Theevolutionaryhistoryof lethalmetastaticprostatecancer.Nature2015;520:353–7.

[18]HongJC,Ayala-PeacockDN,LeeJ,etal.Classiﬁcationforlong-term survivalinoligometastaticpatientstreatedwithablativeradiothera- py:a multi-institutional pooled analysis. PLoSOne 2018;13:e0195149.

[19] MottetN,vandenBerghRCN,BriersE,etal.EAU–EANM–ESTRO– ESUR– SIOGguidelinesonprostate cancer.https://uroweb.org/

guideline/prostate-cancer/.

[20] ConsensusLandelijkPlatformUro-oncologyoftheDutchAssocia- tionofRadiotherapyandOncology(NVRO).www.nvro.nl.

[21] HongMKH,MacintyreG,WedgeDC,etal.Trackingtheoriginsand driversofsubclonalmetastaticexpansioninprostatecancer.Nat Commun2015;6:6605.

[22] JadvarH.Oligometastaticprostatecancer:molecularimagingand clinicalmanagementimplicationsintheeraofprecisiononcology.J NuclMed2018;59:1338–9.

(9)

[23] JoungJG,Oh BY,HongHK,etal. Tumorheterogeneitypredicts metastatic potential in colorectal cancer. Clin Cancer Res 2017;23:7209–16.

[24] LussierYA,KhodarevNN,ReganK,etal.Oligo-andpolymetastatic progressioninlungmetastasis(es)patientsisassociatedwithspe- ciﬁcmicroRNAs.PLoSOne2012;7:e50141.

[25] LussierYA,XingHR,SalamaJK,etal.MicroRNAexpressionchar- acterizesoligometastasis(es).PLoSOne2011;6:e28650.

[26] Pitroda SP,Khodarev NN,Huang L, etal. Integratedmolecular subtypingdeﬁnesacurableoligometastaticstateincolorectalliver metastasis.NatCommun2018;9:1793.

[27] GillessenS,AttardG,BeerTM,etal.Managementofpatientswith advancedprostate cancer:the report ofthe Advanced Prostate CancerconsensusConferenceAPCCC2017.EurUrol2018;73:178– 211.

[28] PereraM,PapaN,RobertsM,etal.Gallium-68prostate-speciﬁc membraneantigen positron emissiontomography in advanced

prostatecancer-updateddiagnosticutility,sensitivity,speciﬁcity, and distribution of prostate-speciﬁc membrane antigen-avid lesions:asystematicreviewandmeta-analysis.EurUrol.Inpress.

https://doi.org/10.1016/j.eururo.2019.01.049.

[29] deSouzaNM,LiuY,ChitiA,etal.Strategiesandtechnicalchallenges forimagingoligometastaticdisease:recommendationsfromthe EuropeanOrganisationforResearchandTreatmentofCancerim- agingGroup.EurJCancer2018;91:153–63.

[30] FantiS,MinozziS,AntochG,etal.Consensusonmolecularimaging andtheranosticsinprostatecancer.LancetOncol2018;19:e696– 708.

[31] BurdettS,BoevéLM,InglebyFC,etal.Prostateradiotherapyfor metastatichormone-sensitiveprostatecancer:aSTOPCAPsystem- aticreviewandmeta-analysis.EurUrol2019;76:115–24.

[32] OstP.OLIGOCARE,theEORTCESTROinitiativeforoligometastasis:a pragmaticplatform. Radiother Oncol2018;127:S340–1(abstract SP-0642).