Exploring All Avenues for Radiotherapy in Oligorecurrent Prostate Cancer Disease Limited to Lymph Nodes: A Systematic Review of the Role of Stereotactic Body Radiotherapy

Review

–

Prostate

Cancer

Exploring

All

Avenues

for

Radiotherapy

in

Oligorecurrent

Prostate

Cancer

Disease

Limited

to

Lymph

Nodes:

A

Systematic

Review

of

the

Role

of

Stereotactic

Body

Radiotherapy

Elisabetta

Ponti

,

Andrea

Lancia

,

Piet

Ost

,

Fabio

Trippa

,

Luca

Triggiani

,

Beatrice

Detti

,

Gianluca

Ingrosso

*

a_{Departmentof RadiationOncology,PoliclinicoTorVergata,University,Rome, Italy;}b_{DepartmentofRadiotherapy,GhentUniversityHospital,Ghent,} Belgium;c_{DepartmentofRadiationOncology,‘S.Maria’Hospital,Terni,Italy;}d_{DepartmentofRadiationOncology,UniversityandSpedaliCiviliHospital,} Brescia,Italy;e_{DepartmentofRadiationOncology,A.O.UCareggi,UniversityofFlorence,Florence,Italy}

a v a i l ab 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 a l h o m e p a g e : w w w . e u r o p e a n u r o l o g y . c o m / e u fo c u s

Articleinfo

AssociateEditor:JamesCatto

Keywords:

Oligorecurrentprostatecancer Lymphnodemetastasis Stereotacticbodyradiotherapy Localcontrol

Progression-freesurvival Androgen-deprivationfree survival

Abstract

Context: Stereotacticbody radiotherapy(SBRT)isemergingasatreatmentoptionin patientsaffectedbyoligorecurrentprostatecancerdiseaselimitedtolymphnodes,a subgroupofpatientswhowouldotherwisebetreatedonlywithandrogendeprivation therapy(ADT).

Objective: ToperformasystematicreviewofSBRTforoligorecurrentprostatecancer limitedtolymphnodes.

Evidenceacquisition: WeperformedasystematicreviewofPubMed/MedlineinOctober 2016accordingtothePreferredReportingItemsforSystematicReviewandMeta-analysis (PRISMA).Wesearchedforstudiesreportingonbiochemicalorclinicalprogressionand/or toxicityorcomplicationsofSBRT.Reportswereexcludediftheseendpointscouldnotbe ascertainedorseparatelyanalyzed,orifinsufficientdetailswereprovided.

Evidenceofsynthesis: Atotalof363patientsfromninestudieswerecollected.Ofthese patients,211weretreatedwithSBRTforatotalof270lymphnodes.Withanalpha–beta ratioof3Gy,thebiologicallyeffectivedoseinfractionatedSBRTwas>100Gyinall studies(range,88–216Gy).Withamedianfollow-upof19.23mo,localcontrolwas achievedin98.1%ofpatients.Medianprogression-freesurvival(definedasbiochemical and/orradiologicalprogression)was22.5mo(range,11–30mo).InformationaboutADT duringSBRTwasavailablein281patients,ofwhom114(40.5%)wereonADTduring SBRT,andthedurationofhormonetherapyrangedfrom1to17.5mo.MedianADT-free survivalwas32.8mo(range,25–44mo).Abouttoxicity,CommonTerminologyCriteria forAdverseEventstoxicityscalewasmostused.Acuteand/orlategrade2toxicitywas reportedinonly5.6%ofpatients,andnopatientdevelopedgrade4toxicity.

Conclusions: SBRTseemstobepromisinginlymphnodeoligorecurrentprostatecancer, althoughthereisaweaklevelofevidencetosupportsuchinvestigationaltreatment, whichiscurrentlybasedonretrospectivestudiesofsingle-institutionorpooled experi-ences.ADT-freesurvivalisaninterestingendpoint,whichneedstobeinvestigated.

Patientsummary: Weperformedasystematicreviewtoassessoutcomesandtoxicityof stereotacticbodyradiotherapy(SBRT)forpatientsaffectedbyoligorecurrentprostate cancerlimitedtolymphnodes.WeconcludedthatSBRTisapromisingtherapyinthis setting,butitneedstobevalidatedinrandomizedcontrolledtrials.

©2017EuropeanAssociationofUrology.PublishedbyElsevierB.V.Allrightsreserved.

*Correspondingauthor.DepartmentofRadiationOncology,PoliclinicoTorVergata,University,Rome, Italy.Tel.+390620904300;Fax:+390620904332.

E-mailaddress:ingrosso.gianluca@gmail.com(G.Ingrosso). http://dx.doi.org/10.1016/j.euf.2017.07.006

1. Introduction

Stereotactic body radiotherapy (SBRT) is emerging as an appropriatetreatmentoptioninpatientsaffectedbylimited metastatic disease, defined as “oligometastatic state,” whichisconsideredasanintermediatestatebetween local-izedandwidespreadcancer,andseemstobecharacterized byaunique biologicalprofile[1].Insuch patientswith a limitednumberofmetastases(<3or<5)fromavarietyof primarysites,itseemsthatlocaltherapy(surgeryor abla-tiveradiotherapy)mightimproveoverallsurvivaland dis-easeprogression-freesurvival(PFS),anddelaytheneedfor systemictherapy[2–6].Inthistherapeuticscenario,SBRT seemstobeasafetreatmentoptionwithaverylowtoxicity profile,andwithoutthemorbidityandriskassociatedwith surgicalprocedures[7].

Inoligorecurrentprostatecancerpatients,who eventu-allydevelopalowburdenofdisease aftercurative treat-ment,SBRTcouldmeananappropriatetherapeuticstrategy withcurativeintent.SBRTcouldalsodeferpalliative andro-gendeprivationtherapy(ADT),whichiscurrentlythe stan-dardofcareforsuchpatients,despite thefact thatitcan haveadetrimentaleffectontheirqualityoflife.Thesubset ofprostatecancerpatientswitholigorecurrenceconfinedto lymphnodesrepresentsaveryearlymetastaticsettingin which local treatment such as SBRT might have a great impactondiseasecontrol[8–10].

Theaimofourstudywastoreviewtheavailable liter-ature on SBRT for lymph node recurrent prostate cancer patients, inorderto evaluate efficacyandtoxicityof this high-precision noninvasiveablative treatmentin such an earlymetastaticsetting.IntheDiscussionsection,wealso provideananalysisofthemajorstudiesinvestigatingthe roleofprophylacticirradiationofregionallymphnodesin thesamesettingofpatients.

2. Evidenceacquisition

Wesearchedforarticlesreportingononcologicaloutcome (biochemicalresponseand/orPFS)andtoxicityofprostate cancerpatients, affectedbyoligorecurrentdiseaselimited tolymphnodesandtreatedwithSBRT.SBRTwasdefinedas a radiotherapy dose of at least 5 Gy per fraction to a biologicallyeffectivedoseof80Gywithanalpha–betaratio of3Gy.APubMedliteraturesearchwasconductedusingthe Preferred Reporting Items and Meta-Analyses (PRISMA)

[11].Weidentifiedarticlespublishedwithinthelast10yr upto September30,2016, usingMedlinesearchwith the followingselection criteria:English language,fullpapers, oligorecurrentprostatecancerlimitedtolymphnodes trea-tedwithSBRT,andoncologicalandtoxicitydataavailable. ThefollowingMedline termswere used: prostatecancer, lymphnodemetastasis,lymphnoderecurrence, oligometa-staticprostatecancer, oligorecurrentprostatecancer, ste-reotactic radiotherapy, stereotactic body radiotherapy, radiosurgery,andstereotacticablativeradiotherapy.If mul-tiplepublicationsfromthesamecenterwereavailable,the mostrecentonewasselected.Wereviewedthefullversion ofeach article.The followinginformationwasabstracted

fromallprimaryreports:primaryauthor,reference,yearof publication, number of patients, patientpopulation, age, numberofpatientstreatedwithSBRTfornodemetastasis, numberofirradiatedmetastases,studydesign,treatmentof theprimaryprostatecancer,doseandfractionationofSBRT, oncologicaloutcome (PFSandoverallsurvival),local con-trol, prognosticfactors (univariate andmultivariate),and toxicity.

3. Evidencesynthesis

The flowchart of the systematic review is reported in

Fig.1.Intotal,363patientsfromninestudies[12–20]were collected(Table1).Ofthesepatients,211weretreatedwith SBRTforatotalof270lymphnodes(Table2).InTable3,we reportedthesite(pelvicorextrapelvic)ofnodesirradiated with SBRT: 162 (76.7%) patients were affected by pelvic oligorecurrence.Informationabouttheprimarytreatment wasavailablein334(92%)patients:250(75%)underwent radical prostatectomyradiotherapyADT, 78 (23.3%) underwentradiotherapyADT,andsix(1.7%)received che-motherapyasprimarytreatment.

Mediantimefromprimarytreatmenttooligorecurrent diseasewasavailableonlyinsevenstudies(Table1),withan overall median valueof 37.45 mo (range,11.5–75.6 mo). Choline-positron emission tomography (PET)/computed tomography(CT) wasusedinalmost allstudies todetect disease inpatients withbiochemicalrecurrence after pri-marytreatment.Themedianprostate-specificantigen(PSA) valueatoligorecurrentdisease,availableinsixstudies,was 4.2ng/ml (range, 1.77–16ng/ml). Median follow up was 21.9mo(range,4.4–36mo).

SBRTwasdeliveredwithalinearacceleratorinalmostall studies(Table2).Severalradiotherapyscheduleswereused, varyingfrom5to11Gyperfraction,toatotaldoseof25–50 Gy,whereasfourmetastaticnodeswereirradiatedusinga singlefraction(range,12–24Gy).Withanalpha–betaratio of3Gy,thebiologicallyeffectivedoseinfractionatedSBRT was>100Gyinallstudies(range,88–216Gy).Themedian gross tumorvolume–planning targetvolumemarginwas 5mm. In all studies, image guidance was used prior to radiotherapydelivery.

Betweenstudies,biochemicalrecurrenceafterSBRTwas definedindifferentways:someauthorsconsidereditasa

Table1–Patientcharacteristics. Study No. of pts (total) Age (median) No. of ptstreated for nodes Median time tometastatic recurrence (mo) Median PSA attimeofnode metastasis (ng/ml)

Staging method Median

FU(mo) ADT No. of ptsin ADT Median durationof ADT (mo) Casamassima et al (2011)[12] 25 66a _{25 11.8} –36.7 5.65 Choline-PET (100%) 29 No – – Jereczek-Fossa et al (2012)[13]

34 68.3 18 66 (mean) 1.77; 10.7b _{Choline-PET (100%) 21.9; 13.7}b _{Yes 14 (78%) 17.5; 12}b

Ahmedetal(2013) [14] 17 65 1 50.4 NR Choline-PET(53%), MRI (47%) 4.4 Yes 1(100%) NR Decaesteckeretal (2014)[15] 50 59a _{27 57.6 5.1 Choline-PET(36%),} FDG-PET (64%) 24 Yes 35(70%) 1 Dettietal(2015) [16] 30 64a _{30 75.6 16 Choline-PET(100%) 12 Yes 14(46%) NR} Muldermans et al (2016)[17] 66 61.4a _{5 NR NR Choline-PET (70%),} MRI (12%), CT (3%) 16 NR NR NR Pasqualetti et al (2016)[18] 29 71.2 17 11.5 3.43 (mean) Choline-PET (100%) 11.5 No – – Ingrosso et al (2016)[19] 40 74 40 37.4 4.2 Choline-PET (100%) 23.8 Yes 19 (47%) NR Ost et al (2016) [20] 72 60a _{72 44.4 3.4 Choline-PET (75%),} FDG-PET(24%), MRI (1%) 36 Yes 31 (43%) 1

ADT=androgendeprivationtherapy;FDG=fludeoxyglucose;FU=follow-up;MRI=magneticresonanceimaging;NR=notreported;PET=positronemission

tomography;PSA=prostate-specificantigen;pts=patients.

a

Meanvalue.

b _{Twopatientswithretroperitonealnodemetastasis.}

Table2–Treatmentcharacteristics.

Study No. of nodes (total) No. of pts treated with SBRT for node metastases No. of nodes treated with SBRT Median GTV (cc) Median GTV–PTV margin (mm) Linac/Cyber knife SBRT schedule Dose prescription BED (a/b= 3) Casamassima et al (2011)[12]

25 18 18 NR 5 Linac 3 10 Gy To the isodose

covering95%of the PTV 130 Jereczek-Fossa et al (2012)[13] 18 18 18 NR 2 Cyber 3 11 Gy; 3 12 Gy (in 2 pts M1) To the mean 80% isodose 154–165 Ahmedetal(2013) [14] 1 1 1 NR 5 Linac 510Gy NR 130 Decaesteckeretal (2014)[15] 27 27 27 NR 3 Linac 310Gy; 5 10 Gy 80%ofthe prescribed dose covering90%of the PTV 130–133 Detti et al (2015) [16] 39 30 39 NR 2 Cyber 1 24 Gy; 5 6 Gy; 3 9 Gy; 3 10 Gy; 3 12 Gy NR 180–216 Muldermansetal (2016)[17] 6 5 6 NR 5 Linac 124Gy; 1  16 Gy; 510Gy; 3 10 Gy AAPM101 101–133 Pasqualetti et al (2016)[18]

25 NR 25 2.9 (mean) 3 Linac 1 24 Gy;

3 9 Gy To the periphery of the target 64.8–129.6 Ingrosso et al (2016)[19] 47 40 47 3 5–8 Linac 1  12 Gy; 5 10 Gy; 5 8 Gy; 48Gy; 5 7 Gy; 56Gy; 5 5 Gy 95% of the dose to the 95% of the PTV 36–130 Ostetal(2016) [20] 89 72 89 NR 2–7 Linac/Cyber 310Gy; 3 8 Gy; 5 6 Gy; 10 5 Gy NR 88–140

single PSA increase without a cutoff value, while others defineditastwoconsecutiveincreases of20–25% com-paredwiththepre-SBRTvalue,orsimplytwoconsecutive increases.RadiologicalPFSwasdefinedasthepresenceof new metastases after SBRT, or the presence of in-field recurrence and/or new metastases. Follow-up evaluation consisted in PSAevery 2–3 moand choline-PET 3–6 mo afterSBRT.

Localcontrolwasachievedin98.1%ofpatients,andPFS (defined as biochemical and/or radiological progression) ranged between 11 and 30 mo with a median value of 22.5mo (Table4). Onlyintwo studies,therewas an in-fieldrecurrence(foratotaloffourpatients).

Data on concomitantADT (Table 1) were available in eightstudies(intwoofthemno ADTwascombinedwith SBRT),foratotalof281patients.Ofthe114(40.5%)patients whowere onADTduring SBRT,theduration ofhormone therapy ranged from 1 to 17.5 mo (Table 1). ADT-free survival,rangingfrom 25 to 44mowith a medianvalue

of 32.8 mo (Table 4), was available only in four studies (including 191 patients), and thismeans that in106/191 (55.5%)patientstherecouldbeapotentialimportantdelay inthestartofADT.

About toxicity, the Common Terminology Criteria for AdverseEventstoxicityscalewasthemostused,whereas RadiationTherapyOncologyGroupscalewasusedinthree studies (Table4).Acuteand/orlategrade2toxicitywas reportedinonly5.6%ofpatients,andnopatientdeveloped grade4toxicity.Morespecifically,twopatientsexperienced acutetoxicity2[13,19]andlatetoxicitywasreportedin fivepatients(threepatientswithgrade2andtwopatients withgrade3)[13,15,19,20].

3.1. Discussion

Oligorecurrentprostatecancerlimitedtolymphnodesmay be a very favorable clinical condition. The present work underlinestheroleofablativeSBRTinthemanagementof

Table4_–Results. Study Median PFS(mo) b-RFS (mo) Toxicity scale

FUevaluation In-field

recurrence ADT-FS (mo) RECIST criteria No.ofptswith acuteand/orlate toxicity(grade2)

Casamassimaetal

(2011)[12]

24 NR RTOG PSAevery3mo,choline-PETat2mo No NR NR 0

Jereczek-Fossaetal

(2012)[13]

>30;11a _{NR RTOG PSAevery3moandcholine-PET}

(timingnotreported)

No NR Yes 1(acute);2(late)

Ahmedetal(2013)[14] NR NR CTCAE3.0 PSAevery3moandimagingat3mo No NR Yes 0

Decaesteckeretal

(2014)[15]

19 NR CTCAE3.0 PSAevery3moandcholine-PET

atPSAprogression

No 25 Yes 3(late)

Dettietal(2015)[16] NR 8.1 CTCAE4.0 PSAevery3moandimaging

atPSAprogression

No NR Yes 1(acute)

Muldermansetal

(2016)[17]

NR NR CTCAE4.0 PSAevery3moandcholine-PET

at3–6mo

No NR Yes 0

Pasqualettietal

(2016)[18]

NR NR CTCAE4.0 PSAevery3moandcholine-PET

at3–6mo

No 39.7 Yes 0

Ingrossoetal

(2016)[19]

15.5 24 RTOG PSAevery3moandcholine-PET

atPSAprogression

Yes(1pt) 26(mean) Yes 1(acute);1(late)

Ostetal(2016)[20] 21 NR CTCAE4.0 PSAevery3moandcholine-PET

at3–6mo

Yes(3pts) 44 Yes 3(late)

ADT-FS=androgendeprivationtherapy-freesurvival;b-RFS=biochemicalrelapse-freesurvival;FU=follow-up;NR=notreported;PET=positronemission

tomography; PFS=progression-free survival; PSA=prostate-specific antigen; pts=patients; RECIST=response evaluation criteria in solid tumors;

RTOG=RadiationTherapyOncologyGroup.

a

Twopatientswithretroperitonealnodemetastasis.

Table3_–Site(pelvicorextrapelvic)ofnodestreatedwithSBRT. Totalno.ofpatients

treatedwith SBRT

Totalno.ofnodes treatedwith

SBRT

Pelvic (no.ofpts/no.ofnodes)

Extrapelvic(no.of pts/no.ofnodes)

Casamassimaetal(2011)[12] 18 18 15(pelvicand/orextrapelvic)/NR 3(mediastinal)/NR

Jereczek-Fossaetal(2012)[13] 18 18 16/16 2/2 Ahmedetal(2013)[14] 1 1 0 1/1 Decaesteckeretal(2014)[15] 27 27 25/25 2/2 Dettietal(2015)[16] 30 39 NR/27 NR/12 Muldermansetal(2016)[17] 5 6 NR NR Pasqualettietal(2016)[18] NR 25 NR/18 NR/7 Ingrossoetal(2016)[19] 40 47 35/40 5/7 Ostetal(2016)[20] 72 89 53/NR 19/NR

patientsaffectedbylymphnodeoligorecurrentdisease, a subgroupofpatientswhowouldotherwisebetreatedonly withdelayedorimmediateADT[21],whichaffectspatients’ qualityoflifeinmultiplespheres.

Choline-PET was the most used staging modality at diagnosis of oligorecurrence. In fact,it was employed in 100%ofcasesinfive studies andfrom36%to 75%in the remainingfour(Table1);however,thisimagingtechnique, witheither18F-fluoromethylcholineor11C-choline,hasa lowdetection rate[22,23] at lowPSAlevels, asetting in which a targeted salvage therapy might result in better outcome.Currently,manypatientsbeingtreatedwith abla-tivetherapyforoligometastaticdiseaseactuallyhave unde-tectablemicrometastasesthatwillcausemainly oligopro-gressionrather thanwidespread disease[20]. Inarecent retrospectiveanalysis,Ostetal[20]foundthatafterSBRT for nodal prostate canceroligometastases,the pattern of relapsewasmainlynodalandoligometastatic.This modal-ityofprogression mightgivethepossibilityofarepeated SBRTstrategy,similarlytowhathasbeendescribedforbrain metastasisstereotacticradiotherapy[24].Inthesepatients, alsothecombinationofprophylacticregionalnodal irradi-ation and ablative boost to the nodal lesion could be a treatmentoption.Forinstance,Rischkeetal[25]reported thatprophylacticnodalirradiationaddedtosalvagelymph nodedissectionresultsinasignificantdelayofnoderelapse withinthetreatedregioncomparedwithsurgeryonly(5-yr relapse-freerate70.7%vs26.3%,p<0.0001).Otherstudies onprophylacticirradiationonlymphnodechainsadjacent toPET-positivenodesreportedagoodoutcome with gra-detoxicityratesrangingfrom15%to25%[26,27].

In the recent past, regionallymph node dissection in oligorecurrent prostate cancer limited to lymph nodes has been proposed to reduce disease burden, improve the efficacy of ADT, and delay clinical progression

[28,29].Inthesameway,regionallymphnodeirradiation, suchaswhole-pelvisradiotherapy(wpRT),hasbeen evalu-ated [26,30,31]. The series bySchick et al [30] analyzed 43patients affectedby4metachronous prostatecancer metastatic nodes. More specifically, 21 patients received radiotherapyforpelviclymphnodemetastasesandfivefor bothpelvicandextrapelvicnodemetastases.Thissubsetof 26patientsreceivedwpRT(totalmediandose50.4Gy)with a boost (total median dose 65 Gy) to the choline-PET– positive nodes, in addition to limited ADT (median 12mo).At3yr,biochemicalrelapse-freesurvival(b-RFS) was54.5%,clinicalfailure–freesurvival(definedasthetime fromradiotherapytothedevelopmentofnewmetastases) 58.6%,andoverallsurvival91.7%.Fodoretal[26]published theresultsofaphaseIItrialoncholine-PET–guided radio-therapyanalyzing3yrtoxicityandoutcomein83patients affectedby lymph node relapseafter primarytreatment. Fifty-eight(71.6%)patientsreceivedconcomitant/adjuvant ADTforamediantimeof12mo.Regardingradiotherapy, theareasofmicroscopicinvolvementincludedinthe clini-caltargetvolumeweretheregionallymphnodechainsor only the lymphatic chain including choline-PET–positive nodes, depending on overlap with previously irradiated volumesforprimarytreatment.Seventy-twopatientswere

irradiatedatthepelvicand/orlumbar-aorticlymphnodes. The totaldosefor prophylacticirradiationwas51.8Gyin 28fractions.Thetotaldoseinthesimultaneousintegrated boostofthecholine-PET–positivenodeswas65.5Gy. Three-yearactuarialoverall,localrelapse-freesurvival,and clini-calrelapse-freesurvival(definedasnewmetastases)were 80%, 89.8%, and 61.8%, respectively. The 3-yr b-RFS was 42.2%. The presence of extrapelvic lymph node disease andthenumberofPET-positivenodesnegativelyinfluenced clinicalrelapse.Regardingtoxicity,the3-yractuarialgrade 2rectalandgenitourinarytoxicitieswere6.6%and26.3%, respectively.Würschmidtetal[27]reporteda3-yrb-RFSof 49%andamediansurvivalof28.3moin19patientswho receivedwpRT(totaldose45 Gyin3Dconformal irradia-tion, 50.4 Gy in intensity-modulated radiation therapy) with aboost (mediantotaldose 66.6Gy) to the choline-PET–positivenodes. At 28 mo,75% ofpatients were free from new metastases. In thetotal cohort,acute and late grade2toxicitieswere15%and16%,respectively.

New imaging tools such as 68Ga-PSMA-11 PET could improve the treatmentselection bydetecting oligorecur-rentdiseaseinanearlystageorbyupstaginganapparent oligorecurrent disease.Whencompared with11C-choline PET, 68Ga-PSMA-11 PET demonstrated a significantly higher detection rate of lymph node metastasis (71% vs 94%,p<0.001)[32].Inparticular,itshigherdetectionrate for local relapse, lymph nodes, and bone lesions with respect to 18F-fluoromethylcholine or11C-choline PET is moreevidentatalowPSAvalue(<1ng/ml)[32–34].Finally, thecomparisonwithhistologydatarevealedhigh diagnos-ticaccuracyofPSMA-PET(perlesionspecificityof97%and sensitivity of 80%; per patient specificity and sensitivity bothof86%) [35].Otherimagingoptionsarewhole-body magnetic resonance,which isuseful for the detection of bone metastases [36,37] but less suited for lymph node recurrence [38], and magnetic resonance lymphography with ironoxide nanoparticles,whichhas highsensitivity (65–92%)andspecificity(93–98%)[39]butiscurrentlynot commerciallyavailable.

Advances in diagnostic imaging as well as novel bio-markers willleadto abetterselection ofpatients witha low burden of disease, who could be treated only with localized ablative radiotherapy, obviating the need of regionalprophylacticnodalirradiationandpostponing sys-temictherapy.

Although SBRT seems to bepromising in lymph node oligorecurrent prostate cancer, whichis usually a slowly growingtumor,thereisaweaklevelofevidencetosupport suchtreatment.Infact,themainlimitationofthereported studiesinourreviewistheirretrospectivenature,basedon single-institutionorpooledexperiences.Theother limita-tionisthesmallnumberofpatientsincludedineachseries. No data on tumor volume were reported in almost all studies.

Ongoingrandomizedphase2clinicaltrials,suchasthe STOMP [40] and ORIOLE [41], will assess the impact of ablative radiotherapy in terms of overall survival, PFS, ADT-free survival, andquality oflife inpatients with 3 metastases, comparedwiththestandardofcare.Another

phase2trial[42]willaddresstheroleofwpRTinpatients affectedby5pelvicoligometastasesversusADT. 4. Conclusions

Thestandardtreatmentoptioninlymphnode oligorecur-rentprostatecancerpatients ispalliative ADTuntil resis-tance,butmetastasis-directedtherapyseemstobe prom-isinginthissetting,althoughtheoptimalsalvagetreatment needsto beidentified byprospective trials.A lowerPSA doublingtimeandasmallernumberofmetastases could helpidentifythebestcandidatesforSBRT.

Accordingtoretrospectivelycollecteddata,SBRTissafe (withtoxicityratesrangingfrom0%to15%),achieveshigh localcontrolrate(nearto100%),andhasapositiveimpact onPFS.AninterestingendpointisADT-freesurvival,based onpatient-reportedcomplianceto suchatruly impactful treatment.Hence,furtherinvestigationonthisendpointis needed.

In the near future, clinical, biological, and genomic featureswillbetterdefineoligorecurrentdisease,andthis willleadtothestratificationofdifferentprognosticclasses. ItislikelythatinselectedpatientsSBRTalonewillbethe treatmentofchoice,whereasinothercasestherewouldbe aneedfortreatmentintensification.

Authorcontributions:GianlucaIngrossohadfullaccesstoallthedatain thestudyandtakesresponsibilityfortheintegrityofthedataandthe accuracyofthedataanalysis.

Studyconceptanddesign:Ponti,Lancia,Ingrosso. Acquisitionofdata:Ponti,Lancia,Ingrosso,Detti.

Analysisandinterpretationofdata:Ponti,Lancia,Ingrosso,Ost. Draftingofthemanuscript:Ponti,Lancia,Ingrosso,Trippa,Triggiani. Criticalrevisionofthemanuscriptforimportantintellectualcontent:Ost, Detti.

Statisticalanalysis:Ponti,Lancia,Ingrosso,Detti. Obtainingfunding:None.

Administrative,technical,ormaterialsupport:None. Supervision:None.

Other:None.

Financialdisclosures: GianlucaIngrosso certifies thatall conflicts of interest, including specific financial interests and relationships and affiliationsrelevanttothesubjectmatterormaterialsdiscussedinthe manuscript(eg,employment/af_filiation,grantsorfunding, consultan-cies,honoraria,stockownershiporoptions,experttestimony,royalties, orpatentsfiled,received,orpending),arethefollowing:None. Funding/Supportandroleofthesponsor:None.

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