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Definitionand
Managementofoligometastatichormonenaive prostatecancer
Pr.JL Descotes
CHUdeGrenoble
Liensd’intérêts
• Invitationsàdesmanifestationsscientifiques– Allergan– AstraZeneca– Astellas– GSK– Ipsen– Jansen– Novartis– Pfizer– PierreFabre– Sanofi– Takeda
• Boardsscientifiques– Generalelectrics– Ipsen– Jansen
• Relationsaveclesindustrielsdanslecadredelaprésidencedel’AFU
Localized cancerandlocally advanced
70à80%
Biochemical relapseafter treatment
15à70%
5à10%death from disease
Metastatic evolution8+5years
5%denovometastatic disease
Clinicalcasen°1
• 68years old
• FirstpresentationBackpain
• PSA 1023ng/ml
• cT3,Geason 8(4+4)
ClinicalcaseN° 2
• 70yearsold
• Biochemicalrelapse10yearsafterRP
• PSA=14ng/ml
• Nosymptom
Clinicalcasen° 3
• 85yearsold
• PSArelapseafterRTE
• Intermittentbackpain,– Noanalgesic
– ScintigraphyNle
Treatment ofmetastatic disease(lymph nodes,visceral,skeleton)
=Hormonaldeprivation
However heterogeneousdisease
Treatments
• Orchidectomy• Antagonist /Agonist LHRH• Completeandrogen blocage• Intermittenttreatment• Chemo :novantrone
• Bone targeted therapies
• RoleofChemo(Docetaxel)• Morerecently–Microenvironnement?– Immunotherapy?
• KnowledgeofAndrogenReceptorbiology– Newdrugs• Acétated’abitarérone• Enzalutamide
– New« guidelines »:EAUetAUA• Multidisciplinaryapproach
Metastatic disease :recent changes
2013NégativeTrial
LancetOncol2013
Globalsurvival
ClinicalDFS
Biochemicalrelapse
Getug 15
• GETUG15– 202oligometastaticpatients• 102:ADTalone• 100:Chemo+ADT
• Patientsdobetteriflowvolumedisease– 20– 30%diewithin3-4years
• Overallsurvival–Median83monthsinbothgroups
Chaarted• 790metastatic patients« chemo
naive »• Randomisation
– 6cyclesofDocétaxel +ADT– ADT alone
• Globalsurvival– 57,6months Vs44months (HR=0,66)
• Highvolume– 4Osseous lésions(1extraappendicular /orviscéral)
– 49,2months Vs32,2months (HR =0,6)MHussain,CommunicationASCO2015
Globalsurvival
MHussain,CommunicationASCO2015Sweeney,NEnglJMed2015;373:737–46
EtudeChaarted
• Oligometastatic:277patients– 3lesionsorlessevenifonebeyongvertebraeandpelvis• 143:ADTalone• 134:chemo+ADT
• Overallsurvival– ADTalone:4yearsOS– 70%– Chemo+ADT:4yearsOS– 70%
Too shortfollowup ??
Stampede
2292patients
ADT+DOCHR=0,77;CI0,68-0,87;p<0,0001
9%d’améliorationdelasurvieglobaleà4ans
GuidelineEAU
• Firstlinetreatmentofmetastaticcancer– Docetaxel+ADT• OffercastrationcombinedwithchemotoallpatientswhosefistpresentationisM1diseaseandwhoarefitenoughforchemotherapy(LE:1A;GRA)
– Castrationalone• Offercastrationalonewithorwithoutanantiandrogentopatientsunfitfororunwillingtoconsidercastration+chemo
– Castrationcombinedwithanylocaltreatment(RT/Surgery)• inaninvestigationalsettingonly(LE3GRA)
Norecommandationforoligometastatic patients
Necessity ofrevisiting our visionofmetastatic disease
• Resultsoftheserecentstudies– Subclassification
• Bettersurvivaliflowmetastaticvolume
• Bettercomprehensionofbiology
• Newtoolsforimaging
BiologyNewconceptofmetastatic disease
Nature,2015,520,(7547),353-357
These datasleadtoidentifietheconceptof
Oligometastatic disease
Oligometastatic disease2 mainquestions
1. Definition
2. Management
Definition
• Basedonthenumberofmetastaticlesion?
• Basedonthesitesofmetastaticlesions?
• Orisitaquestionof:– naturalhistory• survivaldifferences
– abilitytotreatallvisiblelesions?
Definition ofoligometastatic disease
• Notauniqueentity– Prostateglandtreated– Prostateglandintact
• Nocleardefinition– Tumorburden:hugevariability
• Nocleartreatment– Isitreallyasystemicdisease?
Anheterogeneousdisease
• Define clearly theburden oftheextensionofthedisease– Lymph nodes– Bones– Visceral
• Biology :– PSA;Phosphatasesalcalines..–Waiting forother markers
• Histologic evaluation– Gleason,Neuroendocrinedifferenciation– Fortheprimitivelesion and/ormetastatic lesions
Variationsarefunction of
imaging modalities
Anheterogeneousdisease
• Define clearly theburden oftheextensionofthedisease– Lymph nodes– Bones– Visceral
• Biology– PSA;Phosphatasesalcalines..–Waiting forother markers
• Histologic evaluation– Gleason,Neuroendocrinedifferenciation– Fortheprimitivelesion and/ormetastatic lesions
Anheterogeneousdisease
• Define clearly theburden oftheextensionofthedisease– Lymph nodes– Bones– Visceral
• Biology :– PSA;Phosphatasesalcalines..–Waiting forother markers
• Histologic evaluation– Gleason,Neuroendocrinedifferenciation– Fortheprimitivelesion and/ormetastatic lesions
Oligometastatic disease :which imaging tool ?
• Based onclinical trials?– SWOG;Chaarted;GETUG 15
• Based onconventional imaging ?– CT/IRM– TcScintigraphy
• Based ofnewmodalities ofimaging– PETCT– Whole MRI
• Yes
• Yes
• Unknown
ConsensusfordefinitionStGallens (Gillessen ann oncol 2015)
• Novisceraldisease(lungorliver)• Nodiseasebeyongtheappendicularskeletal(SWOGdefinition)
• Lymphnodediseaseisfrequent
• 2or3axialosseouslesions– Vertebreae– Pelvis
Definition oftumor burden willprobably movequickly
• TcBoneScintigraphy+CTscan• Novelimaging–WholebodyMRI–CholinePET–PET/MRI–PSMA–NaFPET
• Morelesions:micrometastaticlesions–Newentity?Stagemigration?
Imaging:alotofworkStrenghts Weakness
CTScan WidelyavailableEasilystandardisedLowcostTrialguidelines
RadiationexposureLimitedlocaldiseaseevaluationsSubcentimetrenodalcharacterisationCTflare
Bonescan WidelyavailableEasilystandardisedLowcostTrialguidelines
NoabilitytoassesssofttissuediseaseLowersensibility/specificitythanCT/MRIDoesnotdirectlyevaluatemalignatbonedisease:osteoblasticuptake
PetCTCholine
HighsensitivityrelativelygoodspecificityObjectiveresponseparameters(SUV)
LimitedtraceravailabilityExpensiveRadiationexposureNonaccurateforliverandurinarylesions
WholebodyMRI
Flexible;adaptableimagingObjectiveresponseparameters
longeracquisitiontimeCostExpertiseandcompetingdemands
Other tracers
• 18F– FACBC PET/CT
• 68Ga-PSMAPET/CT– Salvagetreatments
• 18FDCFPylis PET/CT– Salvagetreatments
• 18FBombesin PET/CT– Activesurveillance
• Lack ofstudies
Imagingandevaluation oftherapeutic response (HT)
3.Dowe need tomanagedifferently
• Localtreatment?–WithorwithoutADT
• Treatmentofallmetastaticlesions?– Surgery/RT
• ADTalone– +HT2eme
• Chemo+ADT
Missinglongterm studiesATM
Treatment choice
• Age,globalstatus,voidingandsexualfunction
• Symptômesinducedbymetastaticdiffusion• Cardiovascularevaluation– « RègleABCDE »
• Metabolicsyndrom• Skeletonrelatedevents– Ostéoporosis?
Managementofoligométastatic disease
1. Isthere arole for:1. Lymph node surgery2. Prostatectomy surgery
2. Isthere aplaceforRT
Rationalforlocaltreatment ..
• 369ptsT1-T3aN0M0,RTE65Gysuivis10ansdont74(20%)devenusM+encoursdesuivi
• Survieselonnbmétaos:– ≤5:73%et36%à5et10ans
– >5:45%et18%
• Délaide4,9ansvs3,3ansaudiagnosticdeM+osseusesi+/-5M+
Singhetal.Isthereafavorablesubsetofpatientswithprostatecancerwhodevelopoligometastases?.IJROBP(2004)vol.58 (1)pp.3-10
A:pasdemétaB:populationglobaleC:oligométastase≤5D:>5méta
Localtreatment inpN+
RP inpN+disease
• 30– 45%improvedoverallsurvivalinpatientstreatedwithRP(Verhagenetal,EurUrol,2010)
• Cadedduetal,1997• Ghavamianetal,JUrol,1999
– CSS40vs80%;OS:30vs65%at10years
• Engeletal,EurUrol,2010,……
• Improvesriskstratification• Moschini,JUrol,2016
• Differhormonaltherapy(pN+<=2)• Toujier,EurUrol2014
Lymph node microinvasion:RéductiondurisquelocalOccult Node Positive and Local
Symptoms
Study Year nLocal Symptomatic Progression
ADT CombinedFrazier (N+) 1994 156 24.6% 9.5%
Wiegand (N+) 2010 192 44.6 6.5%
Frazier et al. World J Urol. 1994;12(6):308-12.Wiegand. BJUI 107 (2010) 1238-1242
- Improvement in symptomatic progression may be reason alone for providing local treatment
Occult Node Positive and Local Symptoms
Study Year nLocal Symptomatic Progression
ADT CombinedFrazier (N+) 1994 156 24.6% 9.5%
Wiegand (N+) 2010 192 44.6 6.5%
Frazier et al. World J Urol. 1994;12(6):308-12.Wiegand. BJUI 107 (2010) 1238-1242
- Improvement in symptomatic progression may be reason alone for providing local treatment
Arealbenefice
Salvagelymphadenectomy
• Athirdofradicalprostatectomyexperiencebiochemicalrecurrence
• 11C– Choline–Morefavorablepronosticafterexerese• 50%DFPat5years
– Acceptablemorbidity• Abdollah,EurUrol2014
Oligometastatic patientsIsthere arole ofprostatesurgery
• Allseries:Selectedpatients– Numberofbiais
• Howeversurgerymayimprove– localcontrol– survival(kidney,colon)– responsetoADT(N+)• Messing…
Radicalprostatectomy inmetastaticpatients:survival
Control of the Primary Tumor is Linked to Longer Survival in Men with Metastatic Prostate Cancer
¹ Culp et al Eur. Urol, 2014 Jun;65 (6):1058²Engel et al Eur Urol, 2014 Sep;66(3):602
1 2
5%
95%
1538pts
• 11Patients• Followup 7years– N+10patients;Positivemargins 8patients– Multimodalapproach (RT +HT)
• 2died at7years (20%cancerspecificmortality
Radiotherapy foroligometastatic patients
N=25patients• Contrôlelocalà3ans:90%
• ToxicitéG2+=0• Pelvic,paraaorticMediastinal LN
Casamassimaetal.Tumori2011
Concept:• Curativeintent ofallmetastases• Localcontrol• Immunological effect (effetabscopal)
Conditionforlocalradiationtherapy
• Traitementofallmetastaticlesions• Stereotacticradiotherapyismandatory– Highdoseperfraction– Bettertargeting– Safer(preventlesionadjacentorganatrisk)– Feasible
• Multileafcollimator• Cyberknife• Imagefusion;immobilisationofpatients
Stereotaxy
• Tolimitmorbidity
• Tracking
• Highdose
• Focusedtreatment
• 119patientswith163metastases– One:72,3%;Two18,5%;Three:9,2%
– Lymphnode:60%;Bone36%• Irradiationofmetastaticsites– 80gyto140gy
• Distantprogressionfreesurvival– 30%at3years– 15%at5years
• Overallsurvival:88%at5years
Median timetoprogression21Months
Potential Indications
• Oligometastaticdisease– Fewlesions:2?3?4?5?(Moreno2014)– Smalllesions
• Whom?– Oligometastatic≠oligorecurrence≠oligoprogressive– Goodperformancestatus– SymptomaticlesionswithnoresponsetoADT?
• ≠Palliativerole
• Why:– Delaydiseaseprogressionandtimetopalliativettt:noanswer– Limithormondeprivation(sideeffects)
Ost2016Berkovic2012
Fewresults inthelitterature
• Muracevic,2013– 40patients• 75:singlelocation• Meanfolow-upshort:14months
• Brignanti:2011– Solitarymet:betterprogressionfreesurvival
• ProspectiveTrials++
SalvageTreatmentorActiveClinicalSurveillanceforOligometastatic ProstateCancer:a
RandomizedPhaseIITrial(NCT01558427)
Activeclinical surveillance§ Activemonitoringofpatients
with low volumemetastaseswith PSAandsequentialimaging.
§ Procedure:Surveillance§ Activeclinical surveillance
Salvagetreatment ofmetastases§ Surgical orradiotherapy
treatment ofmetastases.
§ Procedure:Surgical removalofmetastases,orstereotacticbodyradiotherapy ofmetastases.
PrimaryEndpoint: ADTfree-survivalSecondaryEndpoint: QOL
PietOst – GhentUniversityhospital
Summary
• Dogmahaschanged• Multidisciplinaryapproach• Betteridentifycandidates:Trials+++• Genenicsandmolecularimaging
Summary
• Somepatientswith« conventionalhighriskdisease »wereprobablyoligometastatic– (ifweconsidernewimaging)andcured
• IfmicrometareveryADTdependant,localtherapy+ADT+/- nonARtherapycouldimprovesurvival
• Understandbiologyiswaranted• Roleofdocetaxelforthesepatients:unknown– Thinkqualityoflife