多倫多病童醫(yī)院腦干膠質(zhì)瘤課件

PaediatricBrainstemTumours

PaediatricBrainstemTumours多倫多病童醫(yī)院腦干膠質(zhì)瘤課件amongbrainstemgliomasA tectalgliomaB focalmidbraintumorC focalintrinsicpontinegliomaD dorsal/exophyticgliomaE diffuseintrinsicpontineglioma*F focalmedullarygliomaG cervicomedullarygliomaAFewImportantDistinctions*aformofhighgradeglioma,akintoanaplasticastrocytomaorglioblastomamultiformeamongbrainstemgliomasA tectaBrainstemGliomasLowgradegliomasNotcommon!FocalexophyticCervicomedullarytumoursDiffuseIntrinsicBrainstemTumours10-15%ofallbraintumours25%ofthemortalitybybraintumourinchildrenAtypicalbrainstemtumoursAtypicalbrainstemlesionsBrainstemtumoursininfantsBrainstemGliomasLowgradegliomaofthebrainstemClinicalsymptomsOftenlongpresentinghistoryProgressivemotordeficitorataxiaCranialnervedeficitsareinfrequentRadiologicalcharacteristicsMajorityarefocalandexophiticEnhancingtumoursLowgradegliomaofthebrains多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件DiagnosisandmanagementofLGGNeedabiopsy/resectionOftenpilocyticResultneedstobecorrelatedwiththeclinicalandradiologicalcharacteristicsSurgicalresection(evenincomplete)canleadtosustainedremissionorcureDiagnosisandmanagementofLGAugust2001August2006October2014August2001August2006OctoberAugust2000December2001August2000December2001DiagnosisandmanagementofLGGPostoperativemanagementEitherimmediatelyaftersurgeryOratthetimeofprogressionRadiationorchemotherapy?NoclearanswerRadiationstillstandardtreatmentChemotherapyworksDiagnosisandmanagementofLGDecember2001December2002Lowgradegliomaofthebrainstem:chemotherapywithweeklyvincristineandcarboplatinDecember2001December2002LowDiagnosis(11/2013)1/2015(oneyearofVBL))BRAFV600mutatedtumourDiagnosis(11/2013)1/2015(oneThediffuseintrinsicbrainstemtumours15-20%ofallpaediatricbraintumoursTypicalclinicalpresentationShorthistory(631month)Atleast2ofthe3signs/symptomsCranialnervedeficitLongtractssignsAtaxiaNotoftenreported,butnearlyalwayspresent:behavioralchangesLaughter(night)SchoolphobiaSadnessThediffuseintrinsicbrainsteThediffuseintrinsicbrainstemtumoursCranialnervedeficitsOcularmotordeficits(CN6themostcommon)FacialweaknessUnilateraldeafnessSwallowingdisordersNystagmusoftenpresentThediffuseintrinsicbrainsteThediffuseintrinsicbrainstemtumoursRadiologyMorethan50%oftheponsHypodenseLittle/noenhancementThediffuseintrinsicbrainsteTypicalDPGTypicalDPGTypicalBSGTypicalBSGTheatypicalbrainstemtumoursAtypicalbyclinicalpresentationLonghistoryandimagingsuggestingdiffusepontinegliomaAtypicalbyimagingFocalenhancingtumourandshortsymptomsAtypicalbypathologyShortsymptomsandlowgradepathologyDiscrepancysymptoms/radiology/pathologyTheatypicalbrainstemtumours13yearold10monthhistoryofprogressiverightsidedweakness,(R)CN7and8Grade2onhistolology13yearold17yearold12monthhistoryofdizzinesswhenlyingdownNoCNdeficit,noLongtractsign,noataxia17yearold多倫多病童醫(yī)院腦干膠質(zhì)瘤課件TheatypicalbrainstemtumoursAlwaystreatasadiffuseintrinsicgliomawithupfrontfocalradiationChemotherapytodiscusscasebycaseTheatypicalbrainstemtumoursTheatypicalbrainstemlesionsNocorrelationbetweenclinicalandradiologicalfindingDonottreatunlessevidenceofprogressionTheatypicalbrainstemlesions11year-oldJanuary20042010(18yearsold)11year-oldJanuary20042010(1January20042010January20042010多倫多病童醫(yī)院腦干膠質(zhì)瘤課件BrainstemtumoursinbabiesNotgood(exceptLGG)NotalwaysgliomasBrainstemtumoursinbabies1dayoldPM:PNET1dayoldNoPM1dayold1dayoldLGGofinfancy4montholdPilocyticAstrocytomaOnchemoLGGofinfancy4montholdHowtodistinguish?ClinicalcontextClinicalexamRadiologySpectroscopyPathologyHowtodistinguish?DPGLGGDPGLGGFocalHGGDPGLGGFocalHGGDPGLGG2?year-old,5monthshistoryofataxiaandgazepalsyBiopsy:lowgradeastrocytoma2?year-old,5monthshistory3yearsold,NF110/20127/20133yearsold,NF110/20127/20133yearsold–MildhemiparesisBiopsy:infiltrativeastrocytoma(grade2)9/201210/20163yearsold–MildhemiparesiMALIGNANTGLIOMAOFPONSCANADIANCASESBYYEARMALIGNANTGLIOMAOFPONSManagementofDIPGRoleofsurgeryNorolehasbeendemonstratedDoesnotaffecttreatmentDoesnotinfluencesurvivalCanbemisleadingRisksaresignificantOngoingdiscussionsBiology?ManagementofDIPGRoleofsurgShortsymptoms(<1month)ClassicaltriadCranialnervedeficitsLongtractsignsAtaxiaNONEEDFORBIOPSY!TREATMENTSHOULDBESTARTEDASAP(within48hours)Shortsymptoms(<1month)ManagementRadiationThestandardtreatmentAims:toimprovesymptoms(thebestpalliativetreatment)Timing:ASAP+++(within24-48hours)Technique:focal,opposedparallelfields,standardfractionationDose:54Gyin30fractionsManagementRadiationDiffusePontineGlioma‘Standard’RT50-54Gyin1.8GyDailyfractionsCurrenttrendtomovetoconformaltechniquesDiffusePontineGlioma‘StandarManagementRadiationRoleofothertechniques?Hyperfractionation:POGandCCSGexperienceSeveralstudieshavebeenconductedinthelate80s/early90sDosesupto84GyNoevidenceofsurvivalbenefitSomeevidenceofincreasedtoxicityManagementRadiationHyperfractionation:resultsofprospectivestudiesHyperfractionation:resultsofFreemanetal,POG9239,IJROBP1999Freemanetal,POG9239,IJROBManagementRadiationRoleofothertechniques?Gammaknife:BSGoftenlistedasoneofthetumourseligibleforgammaknifeNoseriesreportedNorationalforthistechnique(wouldcausebrainstemnecrosis)ManagementRadiationManagementRadiationRoleofothertechniques?RadiosensitisingagentsGadoliniumtexaphyrin:COGphaseIongoing,shouldbecompletedsoonandfollowedbyaphaseIIstudyTopotecan:phaseIPOGstudycompleted4yearsago,publishedin2003inNeuro-oncology.Suggestimprovementinmediansurvival.PhaseIIstudyplannedManagementRadiationHypofractionationLesssessionsHigherdoseperfraction(13or15insteadof30)Usuallyofferedasapalliativeoption,inparticularinelderlypatientsHasbeensuggestedandtestedinpatientswithDIPGRandomisedstudypublishedin2014(Cairo)NosignificantdifferencewithconventionalradiationHypofractionationLesssessionsHypofractionaltion54Gyin30fractionsversus39Gyin13fractionsZhaglouletalRadiotherapy&Oncology2014Hypofractionaltion54Gyin30多倫多病童醫(yī)院腦干膠質(zhì)瘤課件ManagementSteroidsAmajorroleAlwaysthelowestpossibledosetolimitthesideeffects(qualityoflife)Becarefulduringthefirstweek(significantreactionstothefirstsessionsofradiation)WithcautionatthetimeofprogressionManagementSteroidsDiffusebrainstemGliomas

RoleofchemotherapyNumerousstudiesUpfrontoratthetimeofprogressionSingleagentorcombinationsResponseratelow0to20%NodrugorcombinationseemstohaveasignificantactivityDiffusebrainstemGliomas

RoleDiffusebrainstemGliomas

RoleofchemotherapyOnerandomisedstudyCCG943Conductedinthepre-MRIera(allBSG)Radiation+Chemotherapy(vincristine-CCNU)Overallsurvival22%at2yearsNoevidenceofbenefitwithchemotherapyDiffusebrainstemGliomas

RoleDiffusebrainstemGliomas

RoleofchemotherapyOtherstudiesConventionalchemotherapyCisplatinCarboplatinbeforeand/orduringradiationEtoposideoralHighdosechemotherapySFOPexperiencewithhighdosebusulfanandthiotepaDiffusebrainstemGliomas

RoleDiffusebrainstemGliomas:

OtheragentsOtherstudiesInterferon(CCGstudy)Tamoxifen(Brazilianstudy)Thalidomide(Boston)Smallmolecules(PBTC)Imatinib(TKinhibitor)Gefitinib(EGFRinhibitor)Vandetanib(inhibitorofVEGFR2&EGFR)DiffusebrainstemGliomas:

OthCorrelativestudiesUK/Frenchstudyoferlotinib(EGFRinhibitor)BiopsydrivenCorrelativestudiesUK/FrenchsDiffusebrainstemGliomas

ResultsMediansurvival8-11monthsSurvivalatoneyear~30-40%Survivalat2years~10%Progression-freesurvival6-8monthsDiffusebrainstemGliomas

ResuExamplesExcellentResponsetoRadiotherapy?PATIENTDIEDAT11MONTHSPOSTDIAGNOSISExamplesExcellentResponsetoLONGTERMSURVIVORSClinicalHistoryFemale3.5yrs3weekHx↑headacherightsidedVINpalsyMRI-T2hyperdenseintrinsicpontinegliomaNobiopsyRadiotherapy54GyReceivedICEchemotherapyx5MRIpostradiotherapyshowedsomeimprovement6monthspostdiagnosisrecurrenceofsymptomsNofurtherconventionaltherapy/-alternativehealerNofurtherMRI-refused,butclinicalfollowupAliveage18yrsNormalstature50thcentile,prematurepubertyNeuro-psychometrictesting.Difficultiesin:Verbalprocessing,languageacquisitionAttentionpoorLONGTERMSURVIVORSClinicalHiAgeatDiagnosis(MONTHS)SexNeurologicalSignsatPresentationIntervalBetweenOnsetofSymptomsandDiagnosis(Weeks)InitialTreatmentSurvival(Years)CranialNervePalsyPyramidalDeficitsCerebellarSigns20MaleYesYesYes<6RT+99703+866FemaleYesNoYes>24RT+Temozolomide+522MaleYesYesNo>12-24RT+4CLINICALCHARACTERISTICS,TREATMENTANDOUTCOMEOFSURVIVINGPATIENTSAgeatSexNeurologicalSignsaMRIIMAGINGOFLONGTERMSURVIVORSMRIIMAGINGOFLONGTERMSURVIAretheytrueDIPG?AretheytrueDIPG?多倫多病童醫(yī)院腦干膠質(zhì)瘤課件AretheytrueDIPG?AretheytrueDIPG?October2011January2012January2017LongtermsurvivorOctober2011January2012JanuarDiffusebrainstemGliomas

NorthAmericanstudiesFewstudiesopenFuturestudiesDiffusebrainstemGliomas

NortBrainstemGliomasRecentlyclosed

ACNS0927:

phaseIIstudyofSAHA(vorinostat)duringandafterradiationOpenADVL1217(AphaseIstudyofMK-1775concurrentwithlocalradiationtherapyforthetreatmentofnewlydiagnosedchildrenwithdiffuseintrinsicpontinegliomas(DIPG))Soon?Arsenictrioxyde(antivasculareffect,radiosensitizer)BrainstemGliomasRecentlyclosBrainstemGliomasPBTCstudies:PARPinhibitor+Temozolomide+radiation(closedforfutility)Pembrolizumab(closedfortoxicity)Panabinostat(HDACinhibitor)currentlyrecruitingBrainstemGliomasPBTCstudiesBiospyforDIPG:Why?How?Frame-basedFramelessNoindicationforDIPGBiospyforDIPG:Why?How?Howisitdone?Howisitdone?多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件LimitationsNodirectbenefitforthepatientyetClearexplanation&ParentsinformedconsentRiskofneurologicaldeteriorationSmall&fewsamplesLimitationsNodirectbenefitfNeckerseries65stereotacticbiopsiesofDIPG4patientsrefusedNumberofsamplesincreasedwithtime(upto8)HistologicaldiagFrozensamplesStemcellculturesNomortalityNopermanentmorbidity3transientmorbidity(facialnervepalsyassociatedwithincreasedmotordeficitin1case)2tumoraldisseminationalongthetrajectoryNeckerseries65stereotacticbBiopsyCohort1MGMT-

EGFR-Cohort2MGMT-

EGFR+Cohort3MGMT+

EGFR-Cohort4MGMT+EGFR+RTBevacizumabRTBevacizumab

ErlotinibRTBevacizumabTemozolomideRTBevacizumab

ErlotinibTemozolomide4WeeksBevacizumab4WeeksBevacizumab

Erlotinib4WeeksBevacizumab4WeeksBevacizumab

ErlotinibMaintenanceBevacizumabMaintenanceBevacizumab

ErlotinibMaintenanceBevacizumab

TemozolomideMaintenanceBevacizumab

ErlotinibTemozolomideMRIDiagnosisDIPGTREATMENTSCHEMAEnrollmentTissueAnalysesBoston/UCSFprotocolBiopsyCohort1Cohort2CohorConvectiondelivery

(LonserJChildNeurol2008)

BrainstemgliomaPatient3-year,10-month-oldfemaleHistoryDiagnosed(May2005)HeadachesandfallingRadiationtherapy(June2005)Chemotherapy(January2006)MR-imagingevidenceofprogression(January2006)ExaminationLeftfacialnerveweaknessDisconjugategazeWeaknessbilateral6thnerves(leftgreaterthanright)GaitdiscoordinationConvectiondelivery

(LonserJConvectivedeliveryBrainstemgliomaPerfusethehypointenseregionoftumorIL13-PE(0.125mcg/ml)Gadolinium-DTPA(1mM)IntraoperativeMR-imagingT1andFLAIR-imagingConvectivedeliveryBrainstemgConvectivedeliveryBrainstemgliomaResultsIntraoperativeMR-imagingRateofinfusionof0.5to5microliters/minutePerfusionof1.4mlConvectivedeliveryBrainstemgConvectivedeliveryBrainstemglioma ResultsConvectivedeliveryBrainstemg多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件Dec2013Oct201330Gyin17sessionsOct2012:54Gyin30sessionsDec2013Oct201330Gyin17se多倫多病童醫(yī)院腦干膠質(zhì)瘤課件DIPGSTUDYCollectingpost-mortemtumorandmatchednormalbrainsamplesfromDIPGpatientsLinkedtoDIPGclinicaltrialatSickKids–Drs.BouffetandBartelsPerforminghigh-resolutionDNAmicroarrayanalysis(whole-genomesinglenucleotidepolymorphismarrays(Affymetrix500Kand6.0))DIPGSTUDYCollectingpost-mort多倫多病童醫(yī)院腦干膠質(zhì)瘤課件DIPGsHGAs13579112468101315171921X12141618202213579111315171921X246810121416182022DIPGsaregeneticallydistinctfromsupratentorialhighgradeastrocytomasDIPGsHGAs135791124681013151719DIPGHGA12345678910111234567891011Chromosome14Chromosome17p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24.1q24.2q24.3q25.1q25.3p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24.1q24.2q24.3q25.1q25.3DIPGsaregeneticallydistinctfromsupratentorialhighgradeastrocytomasDIPGHGA12345678910111234567891RESULTS

SpecificGenesTP53Onecopydeletedin7of11DIPGsTP53mutationspresentin6/6DIPGstestedEGFRNotamplifiedinanycase,gainedinoneProteinstronglyexpressedin3tumors,weakinafurther4?therapeutictargetRESULTS

SpecificGenesTP53RESULTS

SpecificGenesMGMTOnecopydeletedin2tumorsProteinnotexpressedinanycase?MethylationstatusPTENHemizygouslossof10q,includingPTEN,in2tumorsRESULTS

SpecificGenesMGMTRESULTS

SpecificGenesPDGFRAGainedin4/11DIPGsFISHQ-PCRRESULTS

SpecificGenesPDGFRAFIRESULTS

SpecificGenes–PARP-1Gainedin3casesProteinexpressedin6casesPARPRESULTS

SpecificGenes–PARP-RESULTS

SpecificGenes–PARP-1PARP-1

encodesachromatin-associatedenzymewhichmodifiesnuclearproteinsandisinvolvedintheregulationofdifferentiation,proliferation,tumortransformationandrecoveryofcellsfromDNAdamagePARPinhibitorshavebeenshowntoinducegrowthinhibitioninmalignantgliomacellsRESULTS

SpecificGenes–PARP-RESULTS

SpecificGenes–PARP-1PARPpossibletherapeutictargetforasubsetofpediatricDIPGs?AuroraKinaseACVR1(FOP:fibrodysplasiaossifiansprogressive)OtherGenesRESULTS

SpecificGenes–PARP-PediatricHighGradeAstrocytomaandHistoneMutationsMeH3F3A

replication-independenthistone3variant3.3twocriticalpositionswithinthehistonetail-K27M,G34RHIST1H3B/CReplication-dependenthistone3variant3.1K27MonlyPediatricHighGradeAstrocytoLocationandfrequencyofHistone3mutationsinpediatricHGGH3K27MisamidlinediseaseH3G34R/VisahemisphericdiseaseHemisphericThalamicPontine(DIPG)20%H3.3K27MH3.3G34R/V65%50%15%H3.1K27M50%SpinalcordLocationandfrequencyofHistCONCLUSIONSPediatricDIPGsareoneofthemaincausesofbraintumordeathinchildrenAfterdecadesofclinicaltrials,largelybasedonprotocolsforadultbraintumors,noeffectivetreatmenthasyetbeenfoundOngoingstudiesarenowbasedontheresultsofgenomicstudiesthathaveidentifiedpotentialtarget.Stillradiationisthemainstayoftreatmentandre-irradiationsofferbenefitinsomechildrenCONCLUSIONSPediatricDIPGsarePaediatricBrainstemTumours

PaediatricBrainstemTumours多倫多病童醫(yī)院腦干膠質(zhì)瘤課件amongbrainstemgliomasA tectalgliomaB focalmidbraintumorC focalintrinsicpontinegliomaD dorsal/exophyticgliomaE diffuseintrinsicpontineglioma*F focalmedullarygliomaG cervicomedullarygliomaAFewImportantDistinctions*aformofhighgradeglioma,akintoanaplasticastrocytomaorglioblastomamultiformeamongbrainstemgliomasA tectaBrainstemGliomasLowgradegliomasNotcommon!FocalexophyticCervicomedullarytumoursDiffuseIntrinsicBrainstemTumours10-15%ofallbraintumours25%ofthemortalitybybraintumourinchildrenAtypicalbrainstemtumoursAtypicalbrainstemlesionsBrainstemtumoursininfantsBrainstemGliomasLowgradegliomaofthebrainstemClinicalsymptomsOftenlongpresentinghistoryProgressivemotordeficitorataxiaCranialnervedeficitsareinfrequentRadiologicalcharacteristicsMajorityarefocalandexophiticEnhancingtumoursLowgradegliomaofthebrains多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件DiagnosisandmanagementofLGGNeedabiopsy/resectionOftenpilocyticResultneedstobecorrelatedwiththeclinicalandradiologicalcharacteristicsSurgicalresection(evenincomplete)canleadtosustainedremissionorcureDiagnosisandmanagementofLGAugust2001August2006October2014August2001August2006OctoberAugust2000December2001August2000December2001DiagnosisandmanagementofLGGPostoperativemanagementEitherimmediatelyaftersurgeryOratthetimeofprogressionRadiationorchemotherapy?NoclearanswerRadiationstillstandardtreatmentChemotherapyworksDiagnosisandmanagementofLGDecember2001December2002Lowgradegliomaofthebrainstem:chemotherapywithweeklyvincristineandcarboplatinDecember2001December2002LowDiagnosis(11/2013)1/2015(oneyearofVBL))BRAFV600mutatedtumourDiagnosis(11/2013)1/2015(oneThediffuseintrinsicbrainstemtumours15-20%ofallpaediatricbraintumoursTypicalclinicalpresentationShorthistory(631month)Atleast2ofthe3signs/symptomsCranialnervedeficitLongtractssignsAtaxiaNotoftenreported,butnearlyalwayspresent:behavioralchangesLaughter(night)SchoolphobiaSadnessThediffuseintrinsicbrainsteThediffuseintrinsicbrainstemtumoursCranialnervedeficitsOcularmotordeficits(CN6themostcommon)FacialweaknessUnilateraldeafnessSwallowingdisordersNystagmusoftenpresentThediffuseintrinsicbrainsteThediffuseintrinsicbrainstemtumoursRadiologyMorethan50%oftheponsHypodenseLittle/noenhancementThediffuseintrinsicbrainsteTypicalDPGTypicalDPGTypicalBSGTypicalBSGTheatypicalbrainstemtumoursAtypicalbyclinicalpresentationLonghistoryandimagingsuggestingdiffusepontinegliomaAtypicalbyimagingFocalenhancingtumourandshortsymptomsAtypicalbypathologyShortsymptomsandlowgradepathologyDiscrepancysymptoms/radiology/pathologyTheatypicalbrainstemtumours13yearold10monthhistoryofprogressiverightsidedweakness,(R)CN7and8Grade2onhistolology13yearold17yearold12monthhistoryofdizzinesswhenlyingdownNoCNdeficit,noLongtractsign,noataxia17yearold多倫多病童醫(yī)院腦干膠質(zhì)瘤課件TheatypicalbrainstemtumoursAlwaystreatasadiffuseintrinsicgliomawithupfrontfocalradiationChemotherapytodiscusscasebycaseTheatypicalbrainstemtumoursTheatypicalbrainstemlesionsNocorrelationbetweenclinicalandradiologicalfindingDonottreatunlessevidenceofprogressionTheatypicalbrainstemlesions11year-oldJanuary20042010(18yearsold)11year-oldJanuary20042010(1January20042010January20042010多倫多病童醫(yī)院腦干膠質(zhì)瘤課件BrainstemtumoursinbabiesNotgood(exceptLGG)NotalwaysgliomasBrainstemtumoursinbabies1dayoldPM:PNET1dayoldNoPM1dayold1dayoldLGGofinfancy4montholdPilocyticAstrocytomaOnchemoLGGofinfancy4montholdHowtodistinguish?ClinicalcontextClinicalexamRadiologySpectroscopyPathologyHowtodistinguish?DPGLGGDPGLGGFocalHGGDPGLGGFocalHGGDPGLGG2?year-old,5monthshistoryofataxiaandgazepalsyBiopsy:lowgradeastrocytoma2?year-old,5monthshistory3yearsold,NF110/20127/20133yearsold,NF110/20127/20133yearsold–MildhemiparesisBiopsy:infiltrativeastrocytoma(grade2)9/201210/20163yearsold–MildhemiparesiMALIGNANTGLIOMAOFPONSCANADIANCASESBYYEARMALIGNANTGLIOMAOFPONSManagementofDIPGRoleofsurgeryNorolehasbeendemonstratedDoesnotaffecttreatmentDoesnotinfluencesurvivalCanbemisleadingRisksaresignificantOngoingdiscussionsBiology?ManagementofDIPGRoleofsurgShortsymptoms(<1month)ClassicaltriadCranialnervedeficitsLongtractsignsAtaxiaNONEEDFORBIOPSY!TREATMENTSHOULDBESTARTEDASAP(within48hours)Shortsymptoms(<1month)ManagementRadiationThestandardtreatmentAims:toimprovesymptoms(thebestpalliativetreatment)Timing:ASAP+++(within24-48hours)Technique:focal,opposedparallelfields,standardfractionationDose:54Gyin30fractionsManagementRadiationDiffusePontineGlioma‘Standard’RT50-54Gyin1.8GyDailyfractionsCurrenttrendtomovetoconformaltechniquesDiffusePontineGlioma‘StandarManagementRadiationRoleofothertechniques?Hyperfractionation:POGandCCSGexperienceSeveralstudieshavebeenconductedinthelate80s/early90sDosesupto84GyNoevidenceofsurvivalbenefitSomeevidenceofincreasedtoxicityManagementRadiationHyperfractionation:resultsofprospectivestudiesHyperfractionation:resultsofFreemanetal,POG9239,IJROBP1999Freemanetal,POG9239,IJROBManagementRadiationRoleofothertechniques?Gammaknife:BSGoftenlistedasoneofthetumourseligibleforgammaknifeNoseriesreportedNorationalforthistechnique(wouldcausebrainstemnecrosis)ManagementRadiationManagementRadiationRoleofothertechniques?RadiosensitisingagentsGadoliniumtexaphyrin:COGphaseIongoing,shouldbecompletedsoonandfollowedbyaphaseIIstudyTopotecan:phaseIPOGstudycompleted4yearsago,publishedin2003inNeuro-oncology.Suggestimprovementinmediansurvival.PhaseIIstudyplannedManagementRadiationHypofractionationLesssessionsHigherdoseperfraction(13or15insteadof30)Usuallyofferedasapalliativeoption,inparticularinelderlypatientsHasbeensuggestedandtestedinpatientswithDIPGRandomisedstudypublishedin2014(Cairo)NosignificantdifferencewithconventionalradiationHypofractionationLesssessionsHypofractionaltion54Gyin30fractionsversus39Gyin13fractionsZhaglouletalRadiotherapy&Oncology2014Hypofractionaltion54Gyin30多倫多病童醫(yī)院腦干膠質(zhì)瘤課件ManagementSteroidsAmajorroleAlwaysthelowestpossibledosetolimitthesideeffects(qualityoflife)Becarefulduringthefirstweek(significantreactionstothefirstsessionsofradiation)WithcautionatthetimeofprogressionManagementSteroidsDiffusebrainstemGliomas

RoleofchemotherapyNumerousstudiesUpfrontoratthetimeofprogressionSingleagentorcombinationsResponseratelow0to20%NodrugorcombinationseemstohaveasignificantactivityDiffusebrainstemGliomas

RoleDiffusebrainstemGliomas

RoleofchemotherapyOnerandomisedstudyCCG943Conductedinthepre-MRIera(allBSG)Radiation+Chemotherapy(vincristine-CCNU)Overallsurvival22%at2yearsNoevidenceofbenefitwithchemotherapyDiffusebrainstemGliomas

RoleDiffusebrainstemGliomas

RoleofchemotherapyOtherstudiesConventionalchemotherapyCisplatinCarboplatinbeforeand/orduringradiationEtoposideoralHighdosechemotherapySFOPexperiencewithhighdosebusulfanandthiotepaDiffusebrainstemGliomas

RoleDiffusebrainstemGliomas:

OtheragentsOtherstudiesInterferon(CCGstudy)Tamoxifen(Brazilianstudy)Thalidomide(Boston)Smallmolecules(PBTC)Imatinib(TKinhibitor)Gefitinib(EGFRinhibitor)Vandetanib(inhibitorofVEGFR2&EGFR)DiffusebrainstemGliomas:

OthCorrelativestudiesUK/Frenchstudyoferlotinib(EGFRinhibitor)BiopsydrivenCorrelativestudiesUK/FrenchsDiffusebrainstemGliomas

ResultsMediansurvival8-11monthsSurvivalatoneyear~30-40%Survivalat2years~10%Progression-freesurvival6-8monthsDiffusebrainstemGliomas

ResuExamplesExcellentResponsetoRadiotherapy?PATIENTDIEDAT11MONTHSPOSTDIAGNOSISExamplesExcellentResponsetoLONGTERMSURVIVORSClinicalHistoryFemale3.5yrs3weekHx↑headacherightsidedVINpalsyMRI-T2hyperdenseintrinsicpontinegliomaNobiopsyRadiotherapy54GyReceivedICEchemotherapyx5MRIpostradiotherapyshowedsomeimprovement6monthspostdiagnosisrecurrenceofsymptomsNofurtherconventionaltherapy/-alternativehealerNofurtherMRI-refused,butclinicalfollowupAliveage18yrsNormalstature50thcentile,prematurepubertyNeuro-psychometrictesting.Difficultiesin:Verbalprocessing,languageacquisitionAttentionpoorLONGTERMSURVIVORSClinicalHiAgeatDiagnosis(MONTHS)SexNeurologicalSignsatPresentationIntervalBetweenOnsetofSymptomsandDiagnosis(Weeks)InitialTreatmentSurvival(Years)CranialNervePalsyPyramidalDeficitsCerebellarSigns20MaleYesYesYes<6RT+99703+866FemaleYesNoYes>24RT+Temozolomide+522MaleYesYesNo>12-24RT+4CLINICALCHARACTERISTICS,TREATMENTANDOUTCOMEOFSURVIVINGPATIENTSAgeatSexNeurologicalSignsaMRIIMAGINGOFLONGTERMSURVIVORSMRIIMAGINGOFLONGTERMSURVIAretheytrueDIPG?AretheytrueDIPG?多倫多病童醫(yī)院腦干膠質(zhì)瘤課件AretheytrueDIPG?AretheytrueDIPG?October2011January2012January2017LongtermsurvivorOctober2011January2012JanuarDiffusebrainstemGliomas

NorthAmericanstudiesFewstudiesopenFuturestudiesDiffusebrainstemGliomas

NortBrainstemGliomasRecentlyclosed

ACNS0927:

phaseIIstudyofSAHA(vorinostat)duringandafterradiationOpenADVL1217(AphaseIstudyofMK-1775concurrentwithlocalradiationtherapyforthetreatmentofnewlydiagnosedchildrenwithdiffuseintrinsicpontinegliomas(DIPG))Soon?Arsenictrioxyde(antivasculareffect,radiosensitizer)BrainstemGliomasRecentlyclosBrainstemGliomasPBTCstudies:PARPinhibitor+Temozolomide+radiation(closedforfutility)Pembrolizumab(closedfortoxicity)Panabinostat(HDACinhibitor)currentlyrecruitingBrainstemGliomasPBTCstudiesBiospyforDIPG:Why?How?Frame-basedFramelessNoindicationforDIPGBiospyforDIPG:Why?How?Howisitdone?Howisitdone?多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件多倫多病童醫(yī)院腦干膠質(zhì)瘤課件LimitationsNodirectbenefitforthepatientyetClear