多伦多病童医院脑干胶质瘤

PaediatricBrainstemTumours

..amongbrainstemgliomasA tectalgliomaB focalmidbraintumorC focalintrinsicpontinegliomaD dorsal/exophyticgliomaE diffuseintrinsicpontineglioma*F focalmedullarygliomaG cervicomedullarygliomaAFewImportantDistinctions*aformofhighgradeglioma,akintoanaplasticastrocytomaorglioblastomamultiforme.BrainstemGliomasLowgradegliomasNotcommon!FocalexophyticCervicomedullarytumoursDiffuseIntrinsicBrainstemTumours10-15%ofallbraintumours25%ofthemortalitybybraintumourinchildrenAtypicalbrainstemtumoursAtypicalbrainstemlesionsBrainstemtumoursininfants.LowgradegliomaofthebrainstemClinicalsymptomsOftenlongpresentinghistoryProgressivemotordeficitorataxiaCranialnervedeficitsareinfrequentRadiologicalcharacteristicsMajorityarefocalandexophiticEnhancingtumours...DiagnosisandmanagementofLGGNeedabiopsy/resectionOftenpilocyticResultneedstobecorrelatedwiththeclinicalandradiologicalcharacteristicsSurgicalresection(evenincomplete)canleadtosustainedremissionorcure.August2001August2006October2014.August2000December2001.DiagnosisandmanagementofLGGPostoperativemanagementEitherimmediatelyaftersurgeryOratthetimeofprogressionRadiationorchemotherapy?NoclearanswerRadiationstillstandardtreatmentChemotherapyworks.December2001December2002Lowgradegliomaofthebrainstem:chemotherapywithweeklyvincristineandcarboplatin.Diagnosis(11/2013)1/2015(oneyearofVBL))BRAFV600mutatedtumour.Thediffuseintrinsicbrainstemtumours15-20%ofallpaediatricbraintumoursTypicalclinicalpresentationShorthistory(631month)Atleast2ofthe3signs/symptomsCranialnervedeficitLongtractssignsAtaxiaNotoftenreported,butnearlyalwayspresent:behavioralchangesLaughter(night)SchoolphobiaSadness.ThediffuseintrinsicbrainstemtumoursCranialnervedeficitsOcularmotordeficits(CN6themostcommon)FacialweaknessUnilateraldeafnessSwallowingdisordersNystagmusoftenpresent.ThediffuseintrinsicbrainstemtumoursRadiologyMorethan50%oftheponsHypodenseLittle/noenhancement.TypicalDPG.TypicalBSG.TheatypicalbrainstemtumoursAtypicalbyclinicalpresentationLonghistoryandimagingsuggestingdiffusepontinegliomaAtypicalbyimagingFocalenhancingtumourandshortsymptomsAtypicalbypathologyShortsymptomsandlowgradepathologyDiscrepancysymptoms/radiology/pathology.13yearold10monthhistoryofprogressiverightsidedweakness,(R)CN7and8Grade2onhistolology.17yearold12monthhistoryofdizzinesswhenlyingdownNoCNdeficit,noLongtractsign,noataxia..TheatypicalbrainstemtumoursAlwaystreatasadiffuseintrinsicgliomawithupfrontfocalradiationChemotherapytodiscusscasebycase.TheatypicalbrainstemlesionsNocorrelationbetweenclinicalandradiologicalfindingDonottreatunlessevidenceofprogression.11year-oldJanuary20042010(18yearsold).January20042010..BrainstemtumoursinbabiesNotgood(exceptLGG)Notalwaysgliomas.1dayoldPM:PNET1dayoldNoPM.LGGofinfancy4montholdPilocyticAstrocytomaOnchemo.Howtodistinguish?ClinicalcontextClinicalexamRadiologySpectroscopyPathology.DPGLGG.FocalHGGDPGLGG.2½year-old,5monthshistoryofataxiaandgazepalsyBiopsy:lowgradeastrocytoma.3yearsold,NF110/20127/2013.3yearsold–MildhemiparesisBiopsy:infiltrativeastrocytoma(grade2)9/201210/2016.MALIGNANTGLIOMAOFPONSCANADIANCASESBYYEAR.ManagementofDIPGRoleofsurgeryNorolehasbeendemonstratedDoesnotaffecttreatmentDoesnotinfluencesurvivalCanbemisleadingRisksaresignificantOngoingdiscussionsBiology?.Shortsymptoms(<1month)ClassicaltriadCranialnervedeficitsLongtractsignsAtaxiaNONEEDFORBIOPSY!TREATMENTSHOULDBESTARTEDASAP(within48hours).ManagementRadiationThestandardtreatmentAims:toimprovesymptoms(thebestpalliativetreatment)Timing:ASAP+++(within24-48hours)Technique:focal,opposedparallelfields,standardfractionationDose:54Gyin30fractions.DiffusePontineGlioma‘Standard’RT50-54Gyin1.8GyDailyfractionsCurrenttrendtomovetoconformaltechniques.ManagementRadiationRoleofothertechniques?Hyperfractionation:POGandCCSGexperienceSeveralstudieshavebeenconductedinthelate80s/early90sDosesupto84GyNoevidenceofsurvivalbenefitSomeevidenceofincreasedtoxicity.Hyperfractionation:resultsofprospectivestudies.Freemanetal,POG9239,IJROBP1999.ManagementRadiationRoleofothertechniques?Gammaknife:BSGoftenlistedasoneofthetumourseligibleforgammaknifeNoseriesreportedNorationalforthistechnique(wouldcausebrainstemnecrosis).ManagementRadiationRoleofothertechniques?RadiosensitisingagentsGadoliniumtexaphyrin:COGphaseIongoing,shouldbecompletedsoonandfollowedbyaphaseIIstudyTopotecan:phaseIPOGstudycompleted4yearsago,publishedin2003inNeuro-oncology.Suggestimprovementinmediansurvival.PhaseIIstudyplanned.HypofractionationLesssessionsHigherdoseperfraction(13or15insteadof30)Usuallyofferedasapalliativeoption,inparticularinelderlypatientsHasbeensuggestedandtestedinpatientswithDIPGRandomisedstudypublishedin2014(Cairo)Nosignificantdifferencewithconventionalradiation.Hypofractionaltion54Gyin30fractionsversus39Gyin13fractionsZhaglouletalRadiotherapy&Oncology2014..ManagementSteroidsAmajorroleAlwaysthelowestpossibledosetolimitthesideeffects(qualityoflife)Becarefulduringthefirstweek(significantreactionstothefirstsessionsofradiation)Withcautionatthetimeofprogression.DiffusebrainstemGliomas

RoleofchemotherapyNumerousstudiesUpfrontoratthetimeofprogressionSingleagentorcombinationsResponseratelow0to20%Nodrugorcombinationseemstohaveasignificantactivity.DiffusebrainstemGliomas

RoleofchemotherapyOnerandomisedstudyCCG943Conductedinthepre-MRIera(allBSG)Radiation+Chemotherapy(vincristine-CCNU)Overallsurvival22%at2yearsNoevidenceofbenefitwithchemotherapy.DiffusebrainstemGliomas

RoleofchemotherapyOtherstudiesConventionalchemotherapyCisplatinCarboplatinbeforeand/orduringradiationEtoposideoralHighdosechemotherapySFOPexperiencewithhighdosebusulfanandthiotepa.DiffusebrainstemGliomas:

OtheragentsOtherstudiesInterferon(CCGstudy)Tamoxifen(Brazilianstudy)Thalidomide(Boston)Smallmolecules(PBTC)Imatinib(TKinhibitor)Gefitinib(EGFRinhibitor)Vandetanib(inhibitorofVEGFR2&EGFR).CorrelativestudiesUK/Frenchstudyoferlotinib(EGFRinhibitor)Biopsydriven.DiffusebrainstemGliomas

ResultsMediansurvival8-11monthsSurvivalatoneyear~30-40%Survivalat2years~10%Progression-freesurvival6-8months.ExamplesExcellentResponsetoRadiotherapy?PATIENTDIEDAT11MONTHSPOSTDIAGNOSIS.LONGTERMSURVIVORSClinicalHistoryFemale3.5yrs3weekHx↑headacherightsidedVINpalsyMRI-T2hyperdenseintrinsicpontinegliomaNobiopsyRadiotherapy54GyReceivedICEchemotherapyx5MRIpostradiotherapyshowedsomeimprovement6monthspostdiagnosisrecurrenceofsymptomsNofurtherconventionaltherapy/-alternativehealerNofurtherMRI-refused,butclinicalfollowupAliveage18yrsNormalstature50thcentile,prematurepubertyNeuro-psychometrictesting.Difficultiesin:Verbalprocessing,languageacquisitionAttentionpoor.AgeatDiagnosis(MONTHS)SexNeurologicalSignsatPresentationIntervalBetweenOnsetofSymptomsandDiagnosis(Weeks)InitialTreatmentSurvival(Years)CranialNervePalsyPyramidalDeficitsCerebellarSigns20MaleYesYesYes<6RT+99703+866FemaleYesNoYes>24RT+Temozolomide+522MaleYesYesNo>12-24RT+4CLINICALCHARACTERISTICS,TREATMENTANDOUTCOMEOFSURVIVINGPATIENTS.MRIIMAGINGOFLONGTERMSURVIVORS.AretheytrueDIPG?..AretheytrueDIPG?.October2011January2012January2017Longtermsurvivor.DiffusebrainstemGliomas

NorthAmericanstudiesFewstudiesopenFuturestudies.BrainstemGliomasRecentlyclosed

ACNS0927:

phaseIIstudyofSAHA(vorinostat)duringandafterradiationOpenADVL1217(AphaseIstudyofMK-1775concurrentwithlocalradiationtherapyforthetreatmentofnewlydiagnosedchildrenwithdiffuseintrinsicpontinegliomas(DIPG))Soon?Arsenictrioxyde(antivasculareffect,radiosensitizer).BrainstemGliomasPBTCstudies:PARPinhibitor+Temozolomide+radiation(closedforfutility)Pembrolizumab(closedfortoxicity)Panabinostat(HDACinhibitor)currentlyrecruiting.BiospyforDIPG:Why?How?Frame-basedFramelessNoindicationforDIPG.Howisitdone?.....LimitationsNodirectbenefitforthepatientyetClearexplanation&ParentsinformedconsentRiskofneurologicaldeteriorationSmall&fewsamples.Neckerseries65stereotacticbiopsiesofDIPG4patientsrefusedNumberofsamplesincreasedwithtime(upto8)HistologicaldiagFrozensamplesStemcellculturesNomortalityNopermanentmorbidity3transientmorbidity(facialnervepalsyassociatedwithincreasedmotordeficitin1case)2tumoraldisseminationalongthetrajectory.BiopsyCohort1MGMT-

EGFR-Cohort2MGMT-

EGFR+Cohort3MGMT+

EGFR-Cohort4MGMT+EGFR+RTBevacizumabRTBevacizumab

ErlotinibRTBevacizumabTemozolomideRTBevacizumab

ErlotinibTemozolomide4WeeksBevacizumab4WeeksBevacizumab

Erlotinib4WeeksBevacizumab4WeeksBevacizumab

ErlotinibMaintenanceBevacizumabMaintenanceBevacizumab

ErlotinibMaintenanceBevacizumab

TemozolomideMaintenanceBevacizumab

ErlotinibTemozolomideMRIDiagnosisDIPGTREATMENTSCHEMAEnrollmentTissueAnalysesBoston/UCSFprotocol.Convectiondelivery

(LonserJChildNeurol2008)

BrainstemgliomaPatient3-year,10-month-oldfemaleHistoryDiagnosed(May2005)HeadachesandfallingRadiationtherapy(June2005)Chemotherapy(January2006)MR-imagingevidenceofprogression(January2006)ExaminationLeftfacialnerveweaknessDisconjugategazeWeaknessbilateral6thnerves(leftgreaterthanright)Gaitdiscoordination.ConvectivedeliveryBrainstemgliomaPerfusethehypointenseregionoftumorIL13-PE(0.125mcg/ml)Gadolinium-DTPA(1mM)IntraoperativeMR-imagingT1andFLAIR-imaging.ConvectivedeliveryBrainstemgliomaResultsIntraoperativeMR-imagingRateofinfusionof0.5to5microliters/minutePerfusionof1.4ml.ConvectivedeliveryBrainstemglioma Results...Dec2013Oct201330Gyin17sessionsOct2012:54Gyin30sessions..DIPGSTUDYCollectingpost-mortemtumorandmatchednormalbrainsamplesfromDIPGpatientsLinkedtoDIPGclinicaltrialatSickKids–Drs.BouffetandBartelsPerforminghigh-resolutionDNAmicroarrayanalysis(whole-genomesinglenucleotidepolymorphismarrays(Affymetrix500Kand6.0))..DIPGsHGAs13579112468101315171921X12141618202213579111315171921X246810121416182022DIPGsaregeneticallydistinctfromsupratentorialhighgradeastrocytomas.DIPGHGA12345678910111234567891011Chromosome14Chromosome17p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24.1q24.2q24.3q25.1q25.3p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24.1q24.2q24.3q25.1q25.3DIPGsaregeneticallydistinctfromsupratentorialhighgradeastrocytomas.RESULTS

SpecificGenesTP53Onecopydeletedin7of11DIPGsTP53mutationspresentin6/6DIPGstestedEGFRNotamplifiedinanycase,gainedinoneProteinstronglyexpressedin3tumors,weakinafurther4?therapeutictarget.RESULTS

SpecificGenesMGMTOnecopydeletedin2tumorsProteinnotexpressedinanycase?MethylationstatusPTENHemizygouslossof10q,includingPTEN,in2tumors.RESULTS

SpecificGenesPDGFRAGainedin4/11DIPGsFISHQ-PCR.RESULTS

SpecificGenes–PARP-1Gainedin3casesProteinexpressedin6