多倫多病童醫(yī)院腦干膠質(zhì)瘤課件

1、Paediatric Brainstem Tumours 多倫多病童醫(yī)院腦干膠質(zhì)瘤1Paediatric Brainstem Tumours多倫多倫多病童醫(yī)院腦干膠質(zhì)瘤2多倫多病童醫(yī)院腦干膠質(zhì)瘤2among brainstem gliomasAtectal gliomaBfocal midbrain tumorCfocal intrinsic pontine gliomaDdorsal/exophytic gliomaEdiffuse intrinsic pontine glioma*Ffocal medullary gliomaGcervicomedullary gliomaA Few Im

2、portant Distinctions* a form of high grade glioma, akin toanaplastic astrocytoma or glioblastoma multiforme多倫多病童醫(yī)院腦干膠質(zhì)瘤3among brainstem gliomasAtectaBrainstem GliomasLow grade gliomasNot common!Focal exophyticCervicomedullary tumoursDiffuse Intrinsic Brainstem Tumours10-15% of all brain tumours25% o

3、f the mortality by brain tumour in childrenAtypical brainstem tumoursAtypical brainstem lesionsBrainstem tumours in infants多倫多病童醫(yī)院腦干膠質(zhì)瘤4Brainstem Gliomas多倫多病童醫(yī)院腦干膠質(zhì)瘤4Low grade glioma of the brainstemClinical symptomsOften long presenting historyProgressive motor deficit or ataxiaCranial nerve defici

4、ts are infrequentRadiological characteristicsMajority are focal and exophiticEnhancing tumours多倫多病童醫(yī)院腦干膠質(zhì)瘤5Low grade glioma of the brains多倫多病童醫(yī)院腦干膠質(zhì)瘤6多倫多病童醫(yī)院腦干膠質(zhì)瘤6多倫多病童醫(yī)院腦干膠質(zhì)瘤7多倫多病童醫(yī)院腦干膠質(zhì)瘤7Diagnosis and management of LGGNeed a biopsy/resectionOften pilocyticResult needs to be correlated with the cli

5、nical and radiological characteristicsSurgical resection (even incomplete) can lead to sustained remission or cure多倫多病童醫(yī)院腦干膠質(zhì)瘤8Diagnosis and management of LGAugust 2001August 2006October 2014多倫多病童醫(yī)院腦干膠質(zhì)瘤9August 2001August 2006October August 2000December 2001多倫多病童醫(yī)院腦干膠質(zhì)瘤10August 2000December 2001多倫多病

6、童Diagnosis and management of LGGPostoperative managementEither immediately after surgeryOr at the time of progressionRadiation or chemotherapy?No clear answerRadiation still standard treatmentChemotherapy works 多倫多病童醫(yī)院腦干膠質(zhì)瘤11Diagnosis and management of LGDecember 2001December 2002Low grade glioma of

7、 the brainstem: chemotherapy with weekly vincristine and carboplatin多倫多病童醫(yī)院腦干膠質(zhì)瘤12December 2001December 2002Low Diagnosis (11/2013)1/2015 (one year of VBL)BRAF V600 mutated tumour多倫多病童醫(yī)院腦干膠質(zhì)瘤13Diagnosis (11/2013)1/2015 (oneThe diffuse intrinsic brainstem tumours15-20% of all paediatric brain tumours

8、Typical clinical presentationShort history (6 3 1 month)At least 2 of the 3 signs/symptomsCranial nerve deficitLong tracts signsAtaxiaNot often reported, but nearly always present: behavioral changesLaughter (night)School phobiaSadness多倫多病童醫(yī)院腦干膠質(zhì)瘤14The diffuse intrinsic brainsteThe diffuse intrinsic

9、 brainstem tumoursCranial nerve deficitsOcular motor deficits (CN 6 the most common)Facial weaknessUnilateral deafnessSwallowing disordersNystagmus often present多倫多病童醫(yī)院腦干膠質(zhì)瘤15The diffuse intrinsic brainsteThe diffuse intrinsic brainstem tumoursRadiologyMore than 50% of the ponsHypodenseLittle/no enh

10、ancement多倫多病童醫(yī)院腦干膠質(zhì)瘤16The diffuse intrinsic brainsteTypical DPG多倫多病童醫(yī)院腦干膠質(zhì)瘤17Typical DPG多倫多病童醫(yī)院腦干膠質(zhì)瘤17Typical BSG 多倫多病童醫(yī)院腦干膠質(zhì)瘤18Typical BSG 多倫多病童醫(yī)院腦干膠質(zhì)瘤18The atypical brainstem tumoursAtypical by clinical presentationLong history and imaging suggesting diffuse pontine gliomaAtypical by imagingFocal

11、enhancing tumour and short symptomsAtypical by pathologyShort symptoms and low grade pathologyDiscrepancy symptoms/radiology/pathology多倫多病童醫(yī)院腦干膠質(zhì)瘤19The atypical brainstem tumours13 year old10 month history of progressive right sided weakness, (R) CN 7 and 8Grade 2 on histolology 多倫多病童醫(yī)院腦干膠質(zhì)瘤2013 yea

12、r old多倫多病童醫(yī)院腦干膠質(zhì)瘤2017 year old12 month history of dizziness when lying downNo CN deficit, no Long tract sign, no ataxia多倫多病童醫(yī)院腦干膠質(zhì)瘤2117 year old多倫多病童醫(yī)院腦干膠質(zhì)瘤21多倫多病童醫(yī)院腦干膠質(zhì)瘤22多倫多病童醫(yī)院腦干膠質(zhì)瘤22The atypical brainstem tumoursAlways treat as a diffuse intrinsic glioma with upfront focal radiationChemotherapy

13、to discuss case by case多倫多病童醫(yī)院腦干膠質(zhì)瘤23The atypical brainstem tumoursThe atypical brainstem lesionsNo correlation between clinical and radiological findingDo not treat unless evidence of progression多倫多病童醫(yī)院腦干膠質(zhì)瘤24The atypical brainstem lesions11 year-oldJanuary 20042010 (18 years old)多倫多病童醫(yī)院腦干膠質(zhì)瘤2511 y

14、ear-oldJanuary 20042010 (1January 20042010多倫多病童醫(yī)院腦干膠質(zhì)瘤26January 20042010多倫多病童醫(yī)院腦干膠質(zhì)瘤26多倫多病童醫(yī)院腦干膠質(zhì)瘤27多倫多病童醫(yī)院腦干膠質(zhì)瘤27Brainstem tumours in babiesNot good (except LGG)Not always gliomas多倫多病童醫(yī)院腦干膠質(zhì)瘤28Brainstem tumours in babies多倫多1 day oldPM: PNET1 day oldNo PM多倫多病童醫(yī)院腦干膠質(zhì)瘤291 day old1 day old多倫多病童醫(yī)院腦干膠質(zhì)瘤L

15、GG of infancy4 month oldPilocytic AstrocytomaOn chemo多倫多病童醫(yī)院腦干膠質(zhì)瘤30LGG of infancy4 month old多倫多病童How to distinguish?Clinical contextClinical examRadiologySpectroscopyPathology多倫多病童醫(yī)院腦干膠質(zhì)瘤31How to distinguish?多倫多病童醫(yī)院腦干膠質(zhì)DPGLGG多倫多病童醫(yī)院腦干膠質(zhì)瘤32DPGLGG多倫多病童醫(yī)院腦干膠質(zhì)瘤32Focal HGGDPGLGG多倫多病童醫(yī)院腦干膠質(zhì)瘤33Focal HGGDPG

16、LGG多倫多病童醫(yī)院腦干膠質(zhì)瘤332 year-old, 5 months history of ataxia and gaze palsyBiopsy: low grade astrocytoma多倫多病童醫(yī)院腦干膠質(zhì)瘤342 year-old, 5 months history3 years old, NF110/20127/2013多倫多病童醫(yī)院腦干膠質(zhì)瘤353 years old, NF110/20127/2013多3 years old Mild hemiparesisBiopsy: infiltrative astrocytoma (grade 2)9/201210/2016多倫多

17、病童醫(yī)院腦干膠質(zhì)瘤363 years old Mild hemiparesiMALIGNANT GLIOMA OF PONSCANADIAN CASES BY YEAR多倫多病童醫(yī)院腦干膠質(zhì)瘤37MALIGNANT GLIOMA OF PONS多倫多病童醫(yī)Management of DIPGRole of surgeryNo role has been demonstratedDoes not affect treatmentDoes not influence survivalCan be misleadingRisks are significantOngoing discussionsB

18、iology?多倫多病童醫(yī)院腦干膠質(zhì)瘤38Management of DIPGRole of surgShort symptoms ( 1 month)Classical triadCranial nerve deficitsLong tract signsAtaxiaNO NEED FOR BIOPSY!TREATMENT SHOULD BE STARTED ASAP (within 48 hours)多倫多病童醫(yī)院腦干膠質(zhì)瘤39Short symptoms ( 1 month)多倫多病ManagementRadiationThe standard treatmentAims: to imp

19、rove symptoms (the best palliative treatment)Timing: ASAP + (within 24-48 hours)Technique: focal, opposed parallel fields, standard fractionationDose: 54 Gy in 30 fractions多倫多病童醫(yī)院腦干膠質(zhì)瘤40ManagementRadiation多倫多病童醫(yī)院腦干膠質(zhì)Diffuse Pontine GliomaStandard RT50-54 Gy in 1.8 GyDaily fractionsCurrent trend to m

20、ove to conformal techniques多倫多病童醫(yī)院腦干膠質(zhì)瘤41Diffuse Pontine GliomaStandarManagementRadiationRole of other techniques?Hyperfractionation: POG and CCSG experienceSeveral studies have been conducted in the late 80s/early 90s Doses up to 84 GyNo evidence of survival benefitSome evidence of increased toxici

21、ty多倫多病童醫(yī)院腦干膠質(zhì)瘤42ManagementRadiation多倫多病童醫(yī)院腦干膠質(zhì)Hyperfractionation: results of prospective studies多倫多病童醫(yī)院腦干膠質(zhì)瘤43Hyperfractionation: results ofFreeman et al, POG 9239, IJROBP1999多倫多病童醫(yī)院腦干膠質(zhì)瘤44Freeman et al, POG 9239, IJROBManagementRadiationRole of other techniques?Gamma knife: BSG often listed as one

22、of the tumours eligible for gamma knifeNo series reportedNo rational for this technique (would cause brainstem necrosis)多倫多病童醫(yī)院腦干膠質(zhì)瘤45ManagementRadiation多倫多病童醫(yī)院腦干膠質(zhì)ManagementRadiationRole of other techniques?Radiosensitising agentsGadolinium texaphyrin: COG phase I ongoing, should be completed soon

23、and followed by a phase II studyTopotecan: phase I POG study completed 4 years ago, published in 2003 in Neuro-oncology. Suggest improvement in median survival. Phase II study planned多倫多病童醫(yī)院腦干膠質(zhì)瘤46ManagementRadiation多倫多病童醫(yī)院腦干膠質(zhì)HypofractionationLess sessionsHigher dose per fraction (13 or 15 instead

24、of 30)Usually offered as a palliative option, in particular in elderly patientsHas been suggested and tested in patients with DIPGRandomised study published in 2014 (Cairo)No significant difference with conventional radiation多倫多病童醫(yī)院腦干膠質(zhì)瘤47HypofractionationLess sessionsHypofractionaltion 54 Gy in 30

25、fractions versus 39 Gy in 13 fractionsZhagloul et alRadiotherapy & Oncology 2014多倫多病童醫(yī)院腦干膠質(zhì)瘤48Hypofractionaltion 54 Gy in 30多倫多病童醫(yī)院腦干膠質(zhì)瘤49多倫多病童醫(yī)院腦干膠質(zhì)瘤49ManagementSteroidsA major roleAlways the lowest possible dose to limit the side effects (quality of life)Be careful during the first week (significa

26、nt reactions to the first sessions of radiation)With caution at the time of progression多倫多病童醫(yī)院腦干膠質(zhì)瘤50ManagementSteroids多倫多病童醫(yī)院腦干膠質(zhì)瘤Diffuse brainstem GliomasRole of chemotherapyNumerous studies Upfront or at the time of progressionSingle agent or combinationsResponse rate low0 to 20%No drug or combin

27、ation seems to have a significant activity多倫多病童醫(yī)院腦干膠質(zhì)瘤51Diffuse brainstem GliomasRoleDiffuse brainstem GliomasRole of chemotherapyOne randomised study CCG 943Conducted in the pre-MRI era (all BSG)Radiation + Chemotherapy (vincristine-CCNU)Overall survival 22% at 2 yearsNo evidence of benefit with ch

28、emotherapy多倫多病童醫(yī)院腦干膠質(zhì)瘤52Diffuse brainstem GliomasRoleDiffuse brainstem GliomasRole of chemotherapyOther studiesConventional chemotherapyCisplatinCarboplatin before and/or during radiationEtoposide oralHigh dose chemotherapySFOP experience with high dose busulfan and thiotepa 多倫多病童醫(yī)院腦干膠質(zhì)瘤53Diffuse br

29、ainstem GliomasRoleDiffuse brainstem Gliomas:Other agentsOther studiesInterferon (CCG study)Tamoxifen (Brazilian study)Thalidomide (Boston)Small molecules (PBTC)Imatinib (TK inhibitor)Gefitinib (EGFR inhibitor)Vandetanib (inhibitor of VEGFR2 & EGFR)多倫多病童醫(yī)院腦干膠質(zhì)瘤54Diffuse brainstem Gliomas:OthCorrelat

30、ive studiesUK/French study of erlotinib (EGFR inhibitor)Biopsy driven多倫多病童醫(yī)院腦干膠質(zhì)瘤55Correlative studiesUK/French sDiffuse brainstem GliomasResultsMedian survival8-11 monthsSurvival at one year 30-40%Survival at 2 years 10%Progression-free survival6-8 months多倫多病童醫(yī)院腦干膠質(zhì)瘤56Diffuse brainstem GliomasResuE

31、xamplesExcellent Response to Radiotherapy?PATIENT DIED AT 11 MONTHS POST DIAGNOSIS多倫多病童醫(yī)院腦干膠質(zhì)瘤57ExamplesExcellent Response to LONG TERM SURVIVORSClinical HistoryFemale 3.5 yrs3 week Hx headache right sided VI N palsyMRI - T2 hyperdense intrinsic pontine gliomaNo biopsyRadiotherapy 54GyReceived ICE c

32、hemotherapy x 5MRI post radiotherapy showed some improvement6 months post diagnosis recurrence of symptomsNo further conventional therapy/ -alternative healerNo further MRI- refused, but clinical follow upAlive age 18 yrsNormal stature 50th centile, premature pubertyNeuro-psychometric testing. Diffi

33、culties in:Verbal processing, language acquisition Attention poor多倫多病童醫(yī)院腦干膠質(zhì)瘤58LONG TERM SURVIVORSClinical HiAge at Diagnosis(MONTHS)SexNeurological Signs at PresentationInterval Between Onset of Symptoms and Diagnosis(Weeks)Initial TreatmentSurvival (Years)Cranial Nerve PalsyPyramidal DeficitsCereb

34、ellar Signs20MaleYesYesYes24 RT +Temozolomide+522MaleYesYesNo12-24 RT+4CLINICAL CHARACTERISTICS, TREATMENT AND OUTCOME OF SURVIVING PATIENTS多倫多病童醫(yī)院腦干膠質(zhì)瘤59Age at SexNeurological Signs aMRI IMAGING OF LONG TERM SURVIVORS多倫多病童醫(yī)院腦干膠質(zhì)瘤60MRI IMAGING OF LONG TERM SURVIAre they true DIPG?多倫多病童醫(yī)院腦干膠質(zhì)瘤61Are t

35、hey true DIPG?多倫多病童醫(yī)院腦干膠質(zhì)多倫多病童醫(yī)院腦干膠質(zhì)瘤62多倫多病童醫(yī)院腦干膠質(zhì)瘤62Are they true DIPG?多倫多病童醫(yī)院腦干膠質(zhì)瘤63Are they true DIPG?多倫多病童醫(yī)院腦干膠質(zhì)October 2011January 2012January 2017Long term survivor多倫多病童醫(yī)院腦干膠質(zhì)瘤64October 2011January 2012JanuarDiffuse brainstem GliomasNorth American studiesFew studies openFuture studies多倫多病童醫(yī)院腦干

36、膠質(zhì)瘤65Diffuse brainstem GliomasNortBrainstem GliomasRecently closed ACNS 0927: phase II study of SAHA (vorinostat) during and after radiationOpenADVL 1217 (A phase I study of MK-1775 concurrent with local radiation therapy for the treatment of newly diagnosed children with diffuse intrinsic pontine g

37、liomas (DIPG)Soon?Arsenic trioxyde (antivascular effect, radiosensitizer)多倫多病童醫(yī)院腦干膠質(zhì)瘤66Brainstem GliomasRecently closBrainstem Gliomas PBTC studies: PARP inhibitor + Temozolomide + radiation (closed for futility)Pembrolizumab (closed for toxicity)Panabinostat (HDAC inhibitor) currently recruiting多倫多

38、病童醫(yī)院腦干膠質(zhì)瘤67Brainstem Gliomas PBTC studiesBiospy for DIPG: Why? How?Frame-basedFrame lessNo indication for DIPG多倫多病童醫(yī)院腦干膠質(zhì)瘤68Biospy for DIPG: Why? How?多倫多病How is it done?多倫多病童醫(yī)院腦干膠質(zhì)瘤69How is it done?多倫多病童醫(yī)院腦干膠質(zhì)瘤69多倫多病童醫(yī)院腦干膠質(zhì)瘤70多倫多病童醫(yī)院腦干膠質(zhì)瘤70多倫多病童醫(yī)院腦干膠質(zhì)瘤71多倫多病童醫(yī)院腦干膠質(zhì)瘤71多倫多病童醫(yī)院腦干膠質(zhì)瘤72多倫多病童醫(yī)院腦干膠質(zhì)瘤72多倫多病

39、童醫(yī)院腦干膠質(zhì)瘤73多倫多病童醫(yī)院腦干膠質(zhì)瘤73LimitationsNo direct benefit for the patient yetClear explanation & Parents informed consentRisk of neurological deteriorationSmall & few samples多倫多病童醫(yī)院腦干膠質(zhì)瘤74LimitationsNo direct benefit fNecker series65 stereotactic biopsies of DIPG4 patients refused Number of samples incre

40、ased with time (up to 8)Histological diagFrozen samplesStem cell culturesNo mortalityNo permanent morbidity3 transient morbidity (facial nerve palsy associated with increased motor deficit in 1 case)2 tumoral dissemination along the trajectory多倫多病童醫(yī)院腦干膠質(zhì)瘤75Necker series65 stereotactic bBiopsyCohort

41、1 MGMT- EGFR-Cohort 2 MGMT- EGFR+Cohort 3 MGMT+ EGFR-Cohort 4 MGMT+EGFR+RT BevacizumabRTBevacizumab ErlotinibRTBevacizumabTemozolomideRTBevacizumab ErlotinibTemozolomide4 Weeks Bevacizumab4 Weeks Bevacizumab Erlotinib4 Weeks Bevacizumab4 Weeks Bevacizumab ErlotinibMaintenance BevacizumabMaintenance

42、Bevacizumab ErlotinibMaintenanceBevacizumab TemozolomideMaintenance Bevacizumab ErlotinibTemozolomideMRI Diagnosis DIPGTREATMENT SCHEMAEnrollmentTissue AnalysesBoston/UCSF protocol多倫多病童醫(yī)院腦干膠質(zhì)瘤76BiopsyCohort 1 Cohort 2 CohorConvection delivery (Lonser J Child Neurol 2008) Brainstem gliomaPatient 3-ye

43、ar, 10-month-old femaleHistoryDiagnosed (May 2005) Headaches and fallingRadiation therapy (June 2005)Chemotherapy (January 2006)MR-imaging evidence of progression (January 2006)ExaminationLeft facial nerve weaknessDisconjugate gazeWeakness bilateral 6th nerves (left greater than right)Gait discoordi

44、nation多倫多病童醫(yī)院腦干膠質(zhì)瘤77Convection delivery (Lonser JConvective deliveryBrainstem gliomaPerfuse the hypointense region of tumorIL13-PE (0.125 mcg/ml)Gadolinium-DTPA (1 mM)Intraoperative MR-imagingT1 and FLAIR-imaging多倫多病童醫(yī)院腦干膠質(zhì)瘤78Convective deliveryBrainstem gConvective deliveryBrainstem gliomaResultsIn

45、traoperative MR-imagingRate of infusion of 0.5 to 5 microliters/minutePerfusion of 1.4 ml多倫多病童醫(yī)院腦干膠質(zhì)瘤79Convective deliveryBrainstem gConvective deliveryBrainstem gliomaResults多倫多病童醫(yī)院腦干膠質(zhì)瘤80Convective deliveryBrainstem g多倫多病童醫(yī)院腦干膠質(zhì)瘤81多倫多病童醫(yī)院腦干膠質(zhì)瘤81多倫多病童醫(yī)院腦干膠質(zhì)瘤82多倫多病童醫(yī)院腦干膠質(zhì)瘤82Dec 2013Oct 201330 Gy in

46、17 sessions Oct 2012: 54 Gy in 30 sessions 多倫多病童醫(yī)院腦干膠質(zhì)瘤83Dec 2013Oct 201330 Gy in 17 se多倫多病童醫(yī)院腦干膠質(zhì)瘤84多倫多病童醫(yī)院腦干膠質(zhì)瘤84DIPG STUDYCollecting post-mortem tumor and matched normal brain samples from DIPG patientsLinked to DIPG clinical trial at SickKids Drs. Bouffet and BartelsPerforming high-resolution DN

47、A microarray analysis (whole-genome single nucleotide polymorphism arrays (Affymetrix 500K and 6.0)多倫多病童醫(yī)院腦干膠質(zhì)瘤85DIPG STUDYCollecting post-mort多倫多病童醫(yī)院腦干膠質(zhì)瘤86多倫多病童醫(yī)院腦干膠質(zhì)瘤86DIPGsHGAs13579112468101315171921X12141618202213579111315171921X246810121416182022DIPGs are genetically distinct from supratentori

48、al high grade astrocytomas多倫多病童醫(yī)院腦干膠質(zhì)瘤87DIPGsHGAs135791124681013151719DIPGHGA12345678910111234567891011Chromosome 14Chromosome 17p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24

49、.1q24.2q24.3q25.1q25.3p13p12p11.2q11.1q11.2q12q13.1q21.1q21.2q21.3q23.1q22.1q23.2q23.3q24.1q24.2q24.3q31.1q31.3q32.13q32.2q32.33p13.3p13.2p13.1p11.2p12q11.2q12q21.2q21.31q21.32q21.33q22q23.2q24.1q24.2q24.3q25.1q25.3DIPGs are genetically distinct from supratentorial high grade astrocytomas多倫多病童醫(yī)院腦干膠質(zhì)

50、瘤88DIPGHGA12345678910111234567891RESULTSSpecific GenesTP53One copy deleted in 7 of 11 DIPGs TP53 mutations present in 6/6 DIPGs testedEGFRNot amplified in any case, gained in one Protein strongly expressed in 3 tumors, weak in a further 4? therapeutic target多倫多病童醫(yī)院腦干膠質(zhì)瘤89RESULTSSpecific GenesTP53多倫多病RESULTSSpecific GenesMGMTOne copy deleted in 2 tumorsProtein not expressed in any case?Methylation status PTENHemizygous loss of 10q, including PTEN, in 2 tumors多倫多病童醫(yī)院腦干膠質(zhì)瘤90RESULTSSpecific GenesMGMT多倫多病RESULTSSpecific GenesPDGFRAGained in 4/11 DIPGs FISHQ-PCR多倫多病童醫(yī)院