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