多伦多病童医院脑干胶质瘤课件.ppt

Paediatric Brainstem Tumours,多伦多病童医院脑干胶质瘤,1,Paediatric Brainstem Tumours多伦,多伦多病童医院脑干胶质瘤,2,多伦多病童医院脑干胶质瘤2,among brainstem gliomas,Atectal gliomaBfocal midbrain tumorCfocal intrinsic pontine gliomaDdorsal/exophytic gliomaEdiffuse intrinsic pontine glioma*Ffocal medullary gliomaGcervicomedullary glioma,A Few Important Distinctions,* a form of high grade glioma, akin toanaplastic astrocytoma or glioblastoma multiforme,多伦多病童医院脑干胶质瘤,3,among brainstem gliomasAtecta,Brainstem Gliomas,Low grade gliomasNot common!Focal exophyticCervicomedullary tumoursDiffuse Intrinsic Brainstem Tumours10-15% of all brain tumours25% of the mortality by brain tumour in childrenAtypical brainstem tumoursAtypical brainstem lesionsBrainstem tumours in infants,多伦多病童医院脑干胶质瘤,4,Brainstem Gliomas多伦多病童医院脑干胶质瘤4,Low grade glioma of the brainstem,Clinical symptomsOften long presenting historyProgressive motor deficit or ataxiaCranial nerve deficits are infrequentRadiological characteristicsMajority are focal and exophiticEnhancing tumours,多伦多病童医院脑干胶质瘤,5,Low grade glioma of the brains,多伦多病童医院脑干胶质瘤,6,多伦多病童医院脑干胶质瘤6,多伦多病童医院脑干胶质瘤,7,多伦多病童医院脑干胶质瘤7,Diagnosis and management of LGG,Need a biopsy/resectionOften pilocyticResult needs to be correlated with the clinical and radiological characteristicsSurgical resection (even incomplete) can lead to sustained remission or cure,多伦多病童医院脑干胶质瘤,8,Diagnosis and management of LG,August 2001,August 2006,October 2014,多伦多病童医院脑干胶质瘤,9,August 2001August 2006October,August 2000,December 2001,多伦多病童医院脑干胶质瘤,10,August 2000December 2001多伦多病童,Diagnosis and management of LGG,Postoperative managementEither immediately after surgeryOr at the time of progressionRadiation or chemotherapy?No clear answerRadiation still standard treatmentChemotherapy works,多伦多病童医院脑干胶质瘤,11,Diagnosis and management of LG,December 2001,December 2002,Low grade glioma of the brainstem: chemotherapy with weekly vincristine and carboplatin,多伦多病童医院脑干胶质瘤,12,December 2001December 2002Low,Diagnosis (11/2013),1/2015 (one year of VBL),BRAF V600 mutated tumour,多伦多病童医院脑干胶质瘤,13,Diagnosis (11/2013)1/2015 (one,The diffuse intrinsic brainstem tumours,15-20% of all paediatric brain tumoursTypical 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,多伦多病童医院脑干胶质瘤,14,The diffuse intrinsic brainste,The diffuse intrinsic brainstem tumours,Cranial nerve deficitsOcular motor deficits (CN 6 the most common)Facial weaknessUnilateral deafnessSwallowing disordersNystagmus often present,多伦多病童医院脑干胶质瘤,15,The diffuse intrinsic brainste,The diffuse intrinsic brainstem tumours,RadiologyMore than 50% of the ponsHypodenseLittle/no enhancement,多伦多病童医院脑干胶质瘤,16,The diffuse intrinsic brainste,Typical DPG,多伦多病童医院脑干胶质瘤,17,Typical DPG多伦多病童医院脑干胶质瘤17,Typical BSG,多伦多病童医院脑干胶质瘤,18,Typical BSG 多伦多病童医院脑干胶质瘤18,The atypical brainstem tumours,Atypical by clinical presentationLong history and imaging suggesting diffuse pontine gliomaAtypical by imagingFocal enhancing tumour and short symptomsAtypical by pathologyShort symptoms and low grade pathologyDiscrepancy symptoms/radiology/pathology,多伦多病童医院脑干胶质瘤,19,The atypical brainstem tumours,13 year old10 month history of progressive right sided weakness, (R) CN 7 and 8Grade 2 on histolology,多伦多病童医院脑干胶质瘤,20,13 year old多伦多病童医院脑干胶质瘤20,17 year old12 month history of dizziness when lying downNo CN deficit, no Long tract sign, no ataxia,多伦多病童医院脑干胶质瘤,21,17 year old多伦多病童医院脑干胶质瘤21,多伦多病童医院脑干胶质瘤,22,多伦多病童医院脑干胶质瘤22,The atypical brainstem tumours,Always treat as a diffuse intrinsic glioma with upfront focal radiationChemotherapy to discuss case by case,多伦多病童医院脑干胶质瘤,23,The atypical brainstem tumours,The atypical brainstem lesions,No correlation between clinical and radiological findingDo not treat unless evidence of progression,多伦多病童医院脑干胶质瘤,24,The atypical brainstem lesions,11 year-old,January 2004,2010 (18 years old),多伦多病童医院脑干胶质瘤,25,11 year-oldJanuary 20042010 (1,January 2004,2010,多伦多病童医院脑干胶质瘤,26,January 20042010多伦多病童医院脑干胶质瘤26,多伦多病童医院脑干胶质瘤,27,多伦多病童医院脑干胶质瘤27,Brainstem tumours in babies,Not good (except LGG)Not always gliomas,多伦多病童医院脑干胶质瘤,28,Brainstem tumours in babies多伦多,1 day oldPM: PNET,1 day oldNo PM,多伦多病童医院脑干胶质瘤,29,1 day old1 day old多伦多病童医院脑干胶质瘤,LGG of infancy,4 month oldPilocytic AstrocytomaOn chemo,多伦多病童医院脑干胶质瘤,30,LGG of infancy4 month old多伦多病童,How to distinguish?,Clinical contextClinical examRadiologySpectroscopyPathology,多伦多病童医院脑干胶质瘤,31,How to distinguish?多伦多病童医院脑干胶质,DPG,LGG,多伦多病童医院脑干胶质瘤,32,DPGLGG多伦多病童医院脑干胶质瘤32,Focal HGG,DPG,LGG,多伦多病童医院脑干胶质瘤,33,Focal HGGDPGLGG多伦多病童医院脑干胶质瘤33,2 year-old, 5 months history of ataxia and gaze palsy,Biopsy: low grade astrocytoma,多伦多病童医院脑干胶质瘤,34,2 year-old, 5 months history,3 years old, NF1,10/2012,7/2013,多伦多病童医院脑干胶质瘤,35,3 years old, NF110/20127/2013多,3 years old Mild hemiparesisBiopsy: infiltrative astrocytoma (grade 2),9/2012,10/2016,多伦多病童医院脑干胶质瘤,36,3 years old Mild hemiparesi,MALIGNANT GLIOMA OF PONSCANADIAN CASES BY YEAR,多伦多病童医院脑干胶质瘤,37,MALIGNANT GLIOMA OF PONS多伦多病童医,Management of DIPG,Role of surgeryNo role has been demonstratedDoes not affect treatmentDoes not influence survivalCan be misleadingRisks are significantOngoing discussionsBiology?,多伦多病童医院脑干胶质瘤,38,Management of DIPGRole of surg,Short symptoms ( 1 month)Classical triadCranial nerve deficitsLong tract signsAtaxiaNO NEED FOR BIOPSY!TREATMENT SHOULD BE STARTED ASAP (within 48 hours),多伦多病童医院脑干胶质瘤,39,Short symptoms ( 1 month)多伦多病,Management,RadiationThe standard treatmentAims: to improve symptoms (the best palliative treatment)Timing: ASAP + (within 24-48 hours)Technique: focal, opposed parallel fields, standard fractionationDose: 54 Gy in 30 fractions,多伦多病童医院脑干胶质瘤,40,ManagementRadiation多伦多病童医院脑干胶质,Diffuse Pontine Glioma,Standard RT50-54 Gy in 1.8 GyDaily fractions,Current trend to move to conformal techniques,多伦多病童医院脑干胶质瘤,41,Diffuse Pontine GliomaStandar,Management,RadiationRole 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 toxicity,多伦多病童医院脑干胶质瘤,42,ManagementRadiation多伦多病童医院脑干胶质,Hyperfractionation: results of prospective studies,多伦多病童医院脑干胶质瘤,43,Hyperfractionation: results of,Freeman et al, POG 9239, IJROBP1999,多伦多病童医院脑干胶质瘤,44,Freeman et al, POG 9239, IJROB,Management,RadiationRole of other techniques?Gamma knife: BSG often listed as one of the tumours eligible for gamma knifeNo series reportedNo rational for this technique (would cause brainstem necrosis),多伦多病童医院脑干胶质瘤,45,ManagementRadiation多伦多病童医院脑干胶质,Management,RadiationRole of other techniques?Radiosensitising agentsGadolinium texaphyrin: COG phase I ongoing, should be completed soon 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,多伦多病童医院脑干胶质瘤,46,ManagementRadiation多伦多病童医院脑干胶质,Hypofractionation,Less sessionsHigher dose per fraction (13 or 15 instead 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,多伦多病童医院脑干胶质瘤,47,HypofractionationLess sessions,Hypofractionaltion,54 Gy in 30 fractions versus 39 Gy in 13 fractions,Zhagloul et alRadiotherapy & Oncology 2014,多伦多病童医院脑干胶质瘤,48,Hypofractionaltion 54 Gy in 30,多伦多病童医院脑干胶质瘤,49,多伦多病童医院脑干胶质瘤49,Management,SteroidsA major roleAlways the lowest possible dose to limit the side effects (quality of life)Be careful during the first week (significant reactions to the first sessions of radiation)With caution at the time of progression,多伦多病童医院脑干胶质瘤,50,ManagementSteroids多伦多病童医院脑干胶质瘤,Diffuse brainstem GliomasRole of chemotherapy,Numerous studies Upfront or at the time of progressionSingle agent or combinationsResponse rate low0 to 20%No drug or combination seems to have a significant activity,多伦多病童医院脑干胶质瘤,51,Diffuse brainstem GliomasRole,Diffuse brainstem GliomasRole of chemotherapy,One 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 chemotherapy,多伦多病童医院脑干胶质瘤,52,Diffuse brainstem GliomasRole,Diffuse brainstem GliomasRole of chemotherapy,Other studiesConventional chemotherapyCisplatinCarboplatin before and/or during radiationEtoposide oralHigh dose chemotherapySFOP experience with high dose busulfan and thiotepa,多伦多病童医院脑干胶质瘤,53,Diffuse brainstem GliomasRole,Diffuse brainstem Gliomas:Other agents,Other studiesInterferon (CCG study)Tamoxifen (Brazilian study)Thalidomide (Boston)Small molecules (PBTC)Imatinib (TK inhibitor)Gefitinib (EGFR inhibitor)Vandetanib (inhibitor of VEGFR2 & EGFR),多伦多病童医院脑干胶质瘤,54,Diffuse brainstem Gliomas:Oth,Correlative studies,UK/French study of erlotinib (EGFR inhibitor)Biopsy driven,多伦多病童医院脑干胶质瘤,55,Correlative studiesUK/French s,Diffuse brainstem GliomasResults,Median survival8-11 monthsSurvival at one year 30-40%Survival at 2 years 10%Progression-free survival6-8 months,多伦多病童医院脑干胶质瘤,56,Diffuse brainstem GliomasResu,Examples,Excellent Response to Radiotherapy?,PATIENT DIED AT 11 MONTHS POST DIAGNOSIS,多伦多病童医院脑干胶质瘤,57,ExamplesExcellent Response to,LONG TERM SURVIVORS,Clinical HistoryFemale 3.5 yrs3 week Hx headache right sided VI N palsyMRI - T2 hyperdense intrinsic pontine gliomaNo biopsyRadiotherapy 54GyReceived ICE chemotherapy x 5MRI post radiotherapy showed some improvement,6 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. Difficulties in:Verbal processing, language acquisition Attention poor,多伦多病童医院脑干胶质瘤,58,LONG TERM SURVIVORSClinical Hi,CLINICAL CHARACTERISTICS, TREATMENT AND OUTCOME OF SURVIVING PATIENTS,多伦多病童医院脑干胶质瘤,59,Age at SexNeurological Signs a,MRI IMAGING OF LONG TERM SURVIVORS,多伦多病童医院脑干胶质瘤,60,MRI IMAGING OF LONG TERM SURVI,Are they true DIPG?,多伦多病童医院脑干胶质瘤,61,Are they true DIPG?多伦多病童医院脑干胶质,多伦多病童医院脑干胶质瘤,62,多伦多病童医院脑干胶质瘤62,Are they true DIPG?,多伦多病童医院脑干胶质瘤,63,Are they true DIPG?多伦多病童医院脑干胶质,October 2011,January 2012,January 2017,Long term survivor,多伦多病童医院脑干胶质瘤,64,October 2011January 2012Januar,Diffuse brainstem GliomasNorth American studies,Few studies openFuture studies,多伦多病童医院脑干胶质瘤,65,Diffuse brainstem GliomasNort,Brainstem Gliomas,Recently 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 gliomas (DIPG)Soon?Arsenic trioxyde (antivascular effect, radiosensitizer),多伦多病童医院脑干胶质瘤,66,Brainstem GliomasRecently clos,Brainstem Gliomas,PBTC studies: PARP inhibitor + Temozolomide + radiation (closed for futility)Pembrolizumab (closed for toxicity)Panabinostat (HDAC inhibitor) currently recruiting,多伦多病童医院脑干胶质瘤,67,Brainstem Gliomas PBTC studies,Biospy for DIPG: Why? How?,Frame-basedFrame lessNo indication for DIPG,多伦多病童医院脑干胶质瘤,68,Biospy for DIPG: Why? How?多伦多病,How is it done?,多伦多病童医院脑干胶质瘤,69,How is it done?多伦多病童医院脑干胶质瘤69,多伦多病童医院脑干胶质瘤,70,多伦多病童医院脑干胶质瘤70,多伦多病童医院脑干胶质瘤,71,多伦多病童医院脑干胶质瘤71,多伦多病童医院脑干胶质瘤,72,多伦多病童医院脑干胶质瘤72,多伦多病童医院脑干胶质瘤,73,多伦多病童医院脑干胶质瘤73,Limitations,No direct benefit for the patient yetClear explanation & Parents informed consentRisk of neurological deteriorationSmall & few samples,多伦多病童医院脑干胶质瘤,74,LimitationsNo direct benefit f,Necker series,65 stereotactic biopsies of DIPG4 patients refused Number of samples increased 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,多伦多病童医院脑干胶质瘤,75,Necker series65 stereotactic b,Biopsy,Cohort 1 MGMT- EGFR-,Cohort 2 MGMT- EGFR+,Cohort 3 MGMT+ EGFR-,Cohort 4 MGMT+EGFR+,RT Bevacizumab,RTBevacizumab Erlotinib,RTBevacizumabTemozolomide,RTBevacizumab ErlotinibTemozolomide,4 Weeks Bevacizumab,4 Weeks Bevacizumab Erlotinib,4 Weeks Bevacizumab,4 Weeks Bevacizumab Erlotinib,Maintenance Bevacizumab,Maintenance Bevacizumab Erlotinib,MaintenanceBevacizumab Temozolomide,Maintenance Bevacizumab ErlotinibTemozolomide,MRI Diagnosis DIPG,TREATMENT SCHEMA,Enrollment,Tissue Analyses,Boston/UCSF protocol,多伦多病童医院脑干胶质瘤,76,BiopsyCohort 1 Cohort 2 Cohor,Convection delivery (Lonser J Child Neurol 2008),Brainstem gliomaPatient 3-year, 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 discoordination,多伦多病童医院脑干胶质瘤,77,Convection delivery (Lonser J,Convective delivery,Brainstem gliomaPerfuse the hypointense region of tumorIL13-PE (0.125 mcg/ml)Gadolinium-DTPA (1 mM)Intraoperative MR-imagingT1 and FLAIR-imaging,多伦多病童医院脑干胶质瘤,78,Convective deliveryBrainstem g,Convective delivery,Brainstem gliomaResultsIntraoperative MR-imagingRate of infusion of 0.5 to 5 microliters/minutePerfusion of 1.4 ml,多伦多病童医院脑干胶质瘤,79,Convective deliveryBrainstem g,Convective delivery,Brainstem gliomaResults,多伦多病童医院脑干胶质瘤,80,Convective deliveryBrainstem g,多伦多病童医院脑干胶质瘤,81,多伦多病童医院脑干胶质瘤81,多伦多病童医院脑干胶质瘤,82,多伦多病童医院脑干胶质瘤82,Dec 2013,Oct 2013,30 Gy in 17 sessions,Oct 2012: 54 Gy in 30 sessions,多伦多病童医院脑干胶质瘤,83,Dec 2013Oct 201330 Gy in 17 se,多伦多病童医院脑干胶质瘤,84,多伦多病童医院脑干胶质瘤84,DIPG STUDY,Collecting post-mortem tumor and matched normal brain samples from DIPG patientsLinked to DIPG clinical trial at SickKids Drs. Bouffet and BartelsPerforming high-resolution DNA microarray analysis (whole-genome single nucleotide polymorphism arrays (Affymetrix 500K and 6.0),多伦多病童医院脑干胶质瘤,85,DIPG STUDYCollecting post-mort,多伦多病童医院脑干胶质瘤,86,多伦多病童医院脑干胶质瘤86,DIPGs,HGAs,1,3,5,7,9,11,2,4,6,8,10,13,15,17,19,21,X,12,14,16,18,20,22,1,3,5,7,9,11,13,15,17,19,21,X,2,4,6,8,10,12,14,16,18,20,22,DIPGs are genetically distinct from supratentorial high grade astrocytomas,多伦多病童医院脑干胶质瘤,87,DIPGsHGAs135791124681013151719,DIPG,HGA,1,2,3,4,5,6,7,8,9,10,11,1,2,3,4,5,6,7,8,9,10,11,Chromosome 14,Chromosome 17,p13,p12,p11.2,q11.1,q11.2,q12,q13.1,q21.1,q21.2,q21.3,q23.1,q22.1,q23.2,q23.3,q24.1,q24.2,q24.3,q31.1,q31.3,q32.13,q32.2,q32.33,p13.3,p13.2,p13.1,p11.2,p12,q11.2,q12,q21.2,q21.31,q21.32,q21.33,q22,q23.2,q24.1,q24.2,q24.3,q25.1,q25.3,p13,p12,p11.2,q11.1,q11.2,q12,q13.1,q21.1,q21.2,q21.3,q23.1,q22.1,q23.2,q23.3,q24.1,q24.2,q24.3,q31.1,q31.3,q32.13,q32.2,q32.33,p13.3,p13.2,p13.1,p11.2,p12,q11.2,q12,q21.2,q21.31,q21.32,q21.33,q22,q23.2,q24.1,q24.2,q24.3,q25.1,q25.3,DIPGs are genetically distinct from supratentorial high grade astrocytomas,多伦多病