TLD-1433 Photodynamic Therapy for BCG Unresponsive NMIBC ...
BCG Failure or BCG Unresponsive: Defining and Managing ......BCG Failure or BCG Unresponsive:...
Transcript of BCG Failure or BCG Unresponsive: Defining and Managing ......BCG Failure or BCG Unresponsive:...
BCG Failure orBCGUnresponsive:DefiningandManagingDifficultPatients
MichaelS.Cookson,MD,ProfessorandChairDepartmentofUrologyUniversityofOklahoma
Non-muscleInvasiveBladderCancer
BladderCancer:Facts
§ 80%presentwith NMIBC:§ 70%Ta(papillary)
§ 20%T1(laminapropria)
§ 10%CIS(highgrade,flat)
NaturalHistory
• Difficulttopredict(tumorheterogeneity)• Twocharacteristicfeatures:
1. Recurrence:- 70%recurrencewithTURalone
2. Tumorprogression:- 30%tumorprogressionw/TURalone
Treated Natural History of NMIBC 15YearFollow-up
• 86high-riskpatientwithNMIBC• TreatedwithTURaloneorTUR+BCG• Progressionin53%,18%UTT• 36%underwentcystectomy• 15-yrDSSwas63%,34%deadofdisease• Life-longbladderandUTTsurveillance
CooksonMS,HerrHW,etal:J.Urol.1997;158:62–67.
BCGIsStandardofCare
• MostintermediateandallhighriskNMIBC• Superiortointravesical chemotherapy• Supportedbymeta-analysis(9RCTs)
– 68%initialCR– 47%durableCR(3.6yrmedianf/u)
• EndorsedbyAUA,EAUNCCNGuidelines• Bestresultswithmaintenance
SylvesterRJ.JUrol 174:86-92,2005
HasBecomeU.S.StandardofCareSWOG8507- BCGMaintenance
Lamm,DLetal,JUrol 163:1124,2000
p<0.0001
5-yearRFS60%vs.41%with/withoutmaintenance
2-yearRFS82%vs.62%with/withoutmaintenance
TheProblem:SomeWillFailBCG
• DespitethebenefitsofBCG,long-termdisease-freeandprogression-freesurvivalmaybedifficulttoachieve
• 50%willrecurafter induction BCG, and ≅30%salvagedwithadditionalBCG
• But,BCGfailuremaybelethalifuntreated• Key:identifyearlythosefailures
LoganCetal.BJUInt.2012;110:12-21
PotentialCausesofBCGFailure
• Hostimmuneincompetence• Inadequatelyresectedoroccultinvasive• Resistantornon-antigenictumor• Inadequatetreatmentschedule• Inadequatedose:toofewCFU• InadequatecontactofBCGandUCC• ExcessBCGinducingimmunosuppression
DefinitionsofBCGFailure
§ Intolerant: recurrentdiseaseinsettingofinadequateBCGtreatmentduetosideeffects
§ Resistant: recurrenceoflesserorimprovingdiseasethatresolveswithfurtherBCG
§ Relapsing: recurrenceafterachieving6monthCR,i.e.diseaseresolvesafterBCGthenreturns
§ Refractory:NoCRby6monthsafterBCG...notimprovingorworseningdiseasedespitetwocoursesofBCGormaintenance
Nieder AM, et al. Urology 66:108-125, 2005
Determining BCG Resistance:BCGResponseoverTime
HerrHWandDalbagni G.JUrol 169:1706-08,2003
§ 6monthsisthetreatmentperiodtoidentifyhigh-risktumorsastrulyrefractory
BCGRefractory
Time0BCG
Induction
Time:3monthsTumor+
Time:6monthsTumor+
Re-inductionorMaintenance
§ Failuretoachieveadiseasefreestate6monthsafterinitialBCGtherapywitheithermaintenanceorretreatmentat3monthsduetoeitherrapidlyrecurrentorpersistenthighgradedisease
HerrHW.JUrol 169:1706-1708,2003Nieder AM,etal.Urology66(S6A):108-125,2005
Ultimately,determiningwhenapatienthas“failed”BCGisashareddecision
betweenurologistandpatient
Novel Definition: MolecularFailure
• Goal:IncorporateFISHtestingtopredictBCGfailurebeforeitbecomesclinicallyapparent
• 143patientstreatedwithBCGIve therapyfollowedprospectivelyfor2years
• FISHassayscollectedat6weeksand3months• ResultsoftheFISHassayswerecorrelatedwithclinicaloutcomes
Kamat AM,etal.BJUInt.2016;117:754-760
RecurrenceandProgression-FreeSurvivalbasedonFISH
Kamat AM,etal.BJUInt.2016;117:754-760
Novel Definition: MolecularFailure
• Result:FISHresultscorrelatedwithrecurrence
• Conclusion:PatientswithanearlypositiveFISHandanegativecystoscopyat3monthsshouldbeconsidered“molecularBCGfailures”andcouldenrollinprospectiveRCT’s
Kamat AM,etal.BJUInt.2016;117:754-760
TreatmentDilemma
• CystectomyrecommendedasastandardofcareafterBCGfailure
• Cystectomyhashighrateofcureifbeforeprogressiontomuscleinvasion
• Unfortunately,morbidityremainshigh• And,manywithhighriskNMIBCwhofailBCGarenot
candidatesforcystectomy
StrategiestoReducePersistenceandRecurrenceofBCGRefractoryCIS
• BetterSurgeryèEnhanceddetectionandmorecompletefulguration
• BetterAgentsè EnhancedIVe chemotherapyandimmunotherapy
• BetterDeliverySystemè EnhancedBladderPenetration
• BetterDiagnosticsè EnhancedPredictiveandPrognosticTools
PhotodynamicDiagnosticCystoscopy
PDDexploitsthephotoactivepropertiesofcompoundssuchashexaminolevulinate (HAL)(HexvixTM,CysviewTM).Followinginstillation,HALaccumulatesinneoplastictissue.Illuminationwithblue-violetlightproducesaclearlydemarcatedredfluorescencefrommalignanttissue.
BurgerMetal.EurUrol2013
§ Prospectivestudies:1345patients§ FCcystoscopyusedasanadjuncttowhitelight(WL)cystoscopy§ Outcome:DetectionofNMIBCupto1year§ FCcystoscopydetectedsignificantlymoretumorsthanWL
§ Tatumors(14.7%;p<0.001)§ CISlesions(40.8%;p<0.001)
§ In26.7%,CISwasdetectedonlybyFC(p<0.001)§ RecurrencesweresignificantlylowerwithFC
§ 34.5%vs.45.4%(p=0.006)
NarrowBandImagingTM (NBI)
Cauberg ECetal.Urol 76:658,2010
• OlympusOpticalimagingtechnologyenhancesvisibilityofvesselsonmucosalsurfaces
• FiltersWLintospecificlightwavelengthsthatpenetrateonlysurfaceofhumantissueandareabsorbedbyHgB
• Bluishlightenhancessuperficialcapillarynetwork(brown)
• Greenishlightenhancesdeepervesselvisibility:vesselsaregreenish-blue(cyan)
DetectionofCISbyCystoscopyWLandNBI
HerrHW.CurrUrolRep2014
§ Collectively, these studies show superior sensitivity and negative predictive value >90% for NBI over WL
Series No. Cysto Sens. Spec. PPV NPV
Herr&Donat 67 WL/NBI 83/100 72/76 36/36 97/100
Tatsugami 30 WL/NBI 50/90 83/75 76/78 61/87
Cauberg 14 WL/NBI 55/69
Shen 11 WL/NBI 68/77 82/77 75/83
StrategiestoReducePersistenceandRecurrenceofBCGRefractoryCIS
§ BetterAgentsè EnhancedIVechemotherapyandimmunotherapy
Valrubicin:PivotalStudy
§ Open-label,phaseIIItrial§ 90patientswithCISafterpriorIVe therapy§ 21%CRat6months§ 32%CRat6monthsifyouconsider thatwithlowgraderecurrences(10pts)
§ Overallprogressionwaslow§ But,only8%remainedNEDat30months
SteinbergGetal.JUrol.2000;163:761-7.
Valrubicin:TakeHomeMessage
• FDA-approvedforpatientswithCISwhofailBCGandareunfitorunwillingtoundergoaradicalcystectomy
• DespiteFDAapproval,long-termDFSremainspoorandhighlightstheneedforadditionalbladder-conservingtherapies
Gemcitabine Trials• InhibitsDNAsynthesis• IntroducedbyDalbagni (2002)assafe• EfficacydemonstratedinmultiplePhaseIItrialswithBCGnaïveandsomefailurepatients
BrooksNA&O’DonnellMA:IndianJUrol.2015;31:312-319
Gemcitabine:SWOGS0353• U.S.Phase2Trial• 47patientswithHGTa,T1and/orCISwhohasreceivedat
least2priorcoursesofBCG• Received2gramsin100ccNSqweekx6weeksandtheq
monthx10months• Results:Recurrence-free
– 3months:47%CR– 12months:28%CR– 24months:21%CR
SkinnerECetal,JU2013
Taxane Trials• Inhibitsmicrotubuledepolymerization• IntroducedinBCGfailuresbyMcKiernan(2006)withnodose-
limitingtoxicityat75mg• EfficacydemonstratedinseveralPhaseI/IIstudies,mostwith
someformofmaintenance
BrooksNA&O’DonnellMA:IndianJUrol.2015;31:312-319
Docetaxel
Barlow et al, J Urol 189:834, 2013
§ 54 patients§ All failed prior BCG – 22 had only one prior course§ 83% high grade, 53% with CIS
Recurrence-free SurvivalDFSat12months=40%DFSat36months=25%
Paclitaxel
McKiernan et al, J Urol. 2014; 192:1633-8,
§ PhaseIIstudyof28patientsrecurrentTis,T1andTawhofailedatleast1cycleofBCG
§ 6weeklynab-paclitaxel500mg/100ml,andmonthlymaintenancefor6months
CR35%and8of10completed6months,7of8CRat21months
BCG+IFNinBCGFailures• Luciani,Urol.2001:
– 9/15(60%)CR(NED)withmedianF/U18months• Lam,Urol Oncol,2003:
– 12/20(60%)NEDwithmedianF/U22months• Punnen,CanJUrol,2003:
– 6/12(50%)NEDat12months• O’Donnell,2004:
– 231pts:42%remainingdisease-freeat24months
BCG+IFN• Multicenter Phase II: 1,007 pts BCG naïve and failure• At 24 months, 45% of BCG failure were disease-free• Those with >/=2 prior courses of BCG or BCG-refractory had worse
outcomes
Rosevear, J Urol 2011; 186:817
ForCertainHighRisk,NMIBC: TheMostDefinitiveTherapy
StrategiestoReducePersistenceandRecurrenceofBCGRefractoryCIS
§ BetterDeliverySystemè EnhancedBladderPenetration
HyperthermiaSynergy§ Deliveryof
hyperthermicchemotherapywithtemp41°- 44°C
§ Mechanism:-Directcytotoxiceffects-Enhancedpenetrationofchemoagent
CancercellwithMitomycin C deliveredat43°C
Hyperthermia IncreasedIntracellularConcentrationofChemotherapyAgent
Vasodilation
Denatured UnfoldedProtein
Activated Heated ChemotherapyAgent
Increased Permeability of CellMembrane
Heat Shock ProteinsSignaltoNaturalKillerCells
Damaged ImpairedDNA
MMCandHyperthermia• 160patients:129(80.6%)BCGfailuresfromacombined“10-
yearsinglecenterexperience”• MMCinductionplusmaintenance• MedianF/U75months• RFS:60%(1year)• RFS:47%(2years)• ProgressiontoMIBC:4.3%• 6.3%discontinuedduetoside-effects
ArendsTJH etal.JUrol2014
HyperthermiaSystems
§ Synergo§ Intravesicalmicrowaveapplicator§ 5thermocouplers deliver
hyperthermiatothebladderviadirectcontact
§ CombatBRS§ BladderRecirculationSystem§ Externalwarmer
vanderHeijdenAGetal.EurUrol2004Souas Aetal.Int JHyperthermia2014
• Photosensitizingagentwithactivationbylight• Initialreportw/BCGfailureswith5-ALAbyWaidelich (2001)with60%CRinCis
and21%papillarytumors• ALAmaycausehypotensionrequiringintervention• PilotstudieswithHALandRadachlorin showpromise
PhotodynamicTherapy(PDT)
BrooksNA&O’DonnellMA:IndianJUrol.2015;31:312-19
LotsofMedicationsInTrials
BCGUnresponsiveClinicalTrialsBCGUnresponsiveTrials
StrategiestoReducePersistenceandRecurrenceofBCGRefractoryCIS
§ BetterDiagnosticsè EnhancedPredictiveandPrognosticTools
OptimizingBCGTherapy
• BCGreducesrecurrence andprogression
• ~30%patientsfailBCGtherapy– Innon-responders,diseaseoftenprogressesbeforecurativecystectomy
– Decreasedsurvival
• Ifwecanidentifynonrespondersearly,offeralternatetherapyatearliertimepoint
Jinesh G & Kamat A, Oncoimmunology, 2012
• Cytokine responsetoBCGdoesdifferentiaterespondersfromnon-responders
• RespondershavehigherlevelsofBCGinducedcytokinesatBCG– 6
• Magnitudeofinductionofcytokinescorrelateswithrecurrencerateandtimetorecurrence
• Complexinterplayofcytokines
CytokinesandBCGResponse
0%
20%
40%
60%
80%
100%
0 10 20 30 40 50 60
%Rec
urrenc
e-Free
Months
Change 3-2: IL-8 < 1500 Change 3-2: IL-8 ≥ 1500
ΔIL-8with6th BCG
p=0.041
CourtesyofDr.Ashish Kamat,MDACC
CytokineNomogramPoints 0 10 20 30 40 50 60 70 80 90 100
IL-2 >=200<200
IL-6 >=425<425
IL-8 >=1500<1500
IL-18 >=40<40
IL-1ra -2000 -1500 -1000 -500 0 500 1000 1500 2000 2500 3000TRAIL -400 0 400 800 1200 1600 2000IFN-γ
8000 7000 6000 5000 4000 3000 2000 1000 0 -1000IL-12(p70) -5 0 5 10 15 20 25 30TNF-α 0 100 300 500 700 900Total Points 0 20 40 60 80 100 120 140 160 180 200 220 240Probability of Recurrence
0.01 0.5 0.95
Courtesy of Dr. Ashish Kamat, MDACC
Recommendations• RepeatTURBTwithPPDorNBItechnology• Fulgurateallabnormalappearingareas• If>1yearfromBCG,attemptBCGagain• Ifithasbeen<1yearsinceBCG:ConsiderRC• Ifunwillingorunfitforcystectomy
– Clinicaltrialpreferred– IfHGTa,IVe chemogemcitabine,taxotere– ForCIS,IVe valrubicin
Conclusions:BCGFailure
§ BCGfailuregroupremainspoorlydefined§ Bestsalvagetherapytobedetermined,modestdurableresponseratesmodest
§ Riskofprogressionissignificant,increasingwitheachroundoffailedtherapy
§ Cystectomyremainsthemostdurableoptionforappropriatesurgicalcandidates
Forecast for the Future:We need to develop…
• Markersthatpredictresponseorfailure• BettersurgicalstrategiestoeradicateCIS• Moreeffective,lesstoxicsalvageregimens• Enhanceddeliveryforsalvagetherapy• Personalizedtherapytailoredtoindividualpatientandtumorriskprofiles
Stephenson Cancer at OU Health Sciences Center