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MEDULLOBLASTOMA: Current Treatment and Future
Directions
• James T Rutka, MD, PhD, FRCSC, FACS• Division of Neurosurgery
• The Hospital for Sick Children• The University of Toronto
The Past
Cushing and Pediatric Neurosurgery
Cushing and Pediatric Brain Tumours
Acta Pathologica, Microbiologica etImmunologica Scandinavica 7:1-86, 1930
Surgery, Gynecology and Obstetrics52: 129-204, 1931
Clinical Presentation of the Child with a Medulloblastoma
• “A preadolescent child previously in good health begins to complain of headaches or of suboccipital discomfort and to have occasional attacks of vomiting without preliminary nausea, usually on first arising in the morning…The family doctor, who has previously suspected some gastro-intestinal disorder, may then have the eyegrounds examined and to the surprise of everyone a choked disk is found…”
Clinical Presentation of the Child with a Medulloblastoma
• “If not recognized so soon…the clumsiness increases, vomiting grows more frequent, the child begins to lose weight, the muscles become wasted and atonic; there may be a slight facial palsy; the internal squint may become bilateral; finally…extensor rigidities occur, ere this child becomes bedridden. The whole story if uninterrupted by operation may cover a period from 8-9 months”
Acta Path Microbiol Immunol Scandinavica 7: 1-86, 1930
MEDULLOBLASTOMA• Contributions of Cushing and
Bailey– Coined term “medulloblastoma” 1925– Described patient presentations– 61 operative cases by 1930– Aware of tendency to invade brainstem
and to disseminate along CSF pathways
Operative sketch ofMedulloblastoma fromCushing’s Collection
MEDULLOBLASTOMA• HISTORICAL LANDMARKS
– 1925 – Described by Cushing and Bailey
– 1953 – Patterson and Farr describe efficacy of craniospinal irradiation
– 1991 – Packer et al. describe efficacy of pre-irradiation chemotherapy
KG McKenzieCanada’s first neurosurgeon
Medulloblastoma - The Evolution of Pediatric Neuro-radiology
• Skull Xrays• Angiography• Ventriculography• Pneumo-
encephalography• Myelography• CT Scan• PET• MRI• MEG• DTI
Early CT Imaging ofPediatric Brain Tumors
Air encephalography
Early CT scansCirca 1976
MEDULLOBLASTOMA• HSC EXPERIENCE (1980 – 1990)
– NUMBER OF PATIENTS = 50– LOW RISK = 26; HIGH RISK = 24– LOW RISK 5 YR SURVIVAL = 70%– HIGH RISK 5 YR SURVIVAL = 40%
MEDULLOBLASTOMA
• IMPROVING PATIENT SURVIVAL– 63 high risk children; cis-plat, VCR, CCNU– PFS @ 5 yrs = 85% for entire group– PFS @ 5 yrs = 67% for children with
metastases– PFS @ 5 yrs = 90% for children with local
disease– Packer et al, J Neurosurg 81: 690, 1994
The Present
MEDULLOBLASTOMA
• Most common malignant neoplasm of the CNS in children (15-20% of childhood brain tumors)
• Peak incidence between 3 and 8 years
• Slight male predominance
MEDULLOBLASTOMA• BIOLOGICAL BEHAVIOUR
– 40% infiltrate the brainstem– 20-50% CSF dissemination along the
neuraxis– 10% systemic metastases (lung,
lymph node, bone)
Diffuse bone mets CSF spread Met along shunt tubing
The Harold J Hoffman Slide Collection
www.surg.med.utoronto.ca/neuro/slides.html
MEDULLOBLASTOMARISK SEGREGATIONLow Risk High Risk
> 3 yrs < 3 yrsNo residual tumor > 1.5 cm2 residualNo distant metastases Metastases
All patients with medulloblastoma are high riskKintomo Takakura
MEDULLOBLASTOMA
• IMAGING STUDIES– Hyperdense lesion
on CT before contrast
– Heterogeneous enhancement after contrast
Pre-contrast Post-contrast
MEDULLOBLASTOMA
TUMOR LOCATIONMidline, vermianHemisphericCP angleBrainstem (rare)Supratentorial (PNET)
Pre-operative MRI Spine!!
MEDULLOBLASTOMA: Spine MRI
Pre-operative spinal imaging is mandatory!
MEDULLOBLASTOMA: Imaging
Diagnosis of leptomeningeal disease
MedulloblastomaLessons learned
• TO SHUNT OR NOT TO SHUNT?– Do not shunt unless the child is
moribund from acute obstructive hydrocephalus
– Most children will be symptomatically controlled by steroids
MEDULLOBLASTOMA
• OPERATIVE APPROACH– Midline, vermian
split– Lateral
hemispheric– Inferior
medullary velum - telovelar
– CP angle
MEDULLOBLASTOMA
Removing tumor fromFloor of IVth
Inspecting anatomical Structures with tumorremoved
INTRA-OPERATIVE NUANCES
Intra-operative video
MEDULLOBLASTOMA
Surgery, XRTAnd Chemo
5 years
Surgery, XRT And Chemo
4 years
With Medulloblastoma, the More Tumor You Remove, the Better!
MEDULLOBLASTOMA
• POST-OPERATIVE COMPLICATIONS– Cerebellar, cranial nerve deficits– Hydrocephalus requiring shunt or ETV– Meningitis– Pseudomeningocele– Cerebellar Mutism
MedulloblastomaHow to avoid cerebellar
mutism?• Nobody knows!• Work quickly and efficiently with the
cavitron• Avoid self retaining retractor
systems.• Be careful with traction on or
dissection into the cerebellar peduncles
• Assess tractography post-op!Lancet Oncology June 2008
MEDULLOBLASTOMAEffects of XRT on the CNS
• Neurocognitive• Moya moya• Endocrinopathy• Vasculopathy• Cavernous
malformation• Secondary
neoplasms
NEJM 2005:352:978-986
Chemotherapy for Medulloblastoma
Proven effective but….
Cycles of chemotherapyStem cell transplantInfectious complicationsToxic mortality
6 year old maleShort history GTRExcellent post-op course
MEDULLOBLASTOMA
• CURRENT BEST TREATMENT• Maximum safe neurosurgical resection• Radiation therapy (reduced craniospinal
irradiation, avoid irradiating children < 3 yrs)
• Chemotherapy (active agents, autologous stem cell transplant, new agents)
5 year survival standard risk – 70%5 year survival high risk – 50%
Future Treatment of Medulloblastoma
• Advanced Cytogenetics
• Differential Gene Expression
• SNP array platforms• Next generation
sequencing• Epigenetics• Stem Cells
Advanced Cancer Cytogenetics
Chromosomes 7 & 17 rearrangementsGene amplification in 30% (2q)Loss of chromosome 10Three techniques led to identificationOf greatest number genetic alterations
Examine a panel of differentially expressed genes in patient samples linked to clinical outcome and survival data.
Tissue Microarray Technology
Tissue Array Prediction of Patient Outcome
MEDULLOBLASTOMA ANDGERMLINE SUFU MUTATION
The Globe and Mail June 20, 2002
Nature Genetics 31: 306-310, 2002
Gene DiscoverycDNA microarray analysis
• Atlas 1200 gene cancer array
• Ability to find genes that are both up- and down-regulated compared to normal cerebellum
• Gene discovery strategy
SamplesMedulloblastoma cell lines (DAOY, TE671, UW426, ONS76 ) and Human adult cerebellum
Gene Discovery Experiment Using:GeneChip Affymetrix Human Genome U133 Plus 2.0 ArrayComprehensive coverage of the human genomeMore than 47,000 transcripts studied
Hybridization Scanning Analysis
Flowchart of the procedure
The Future of Medulloblastoma
Hierarchical Clustering of MAGE and GAGE by microarray
UW
426
DA
OY
ON
S76
TE
671
GAGE7GAGE7BGAGE3GAGE6GAGE4GAGE2MAGEA9GAGE1MAGEE1MAGEA10MAGEC1MAGEB3BAGEGAGEB1MGEA12MAGEA11MAGE6MAGEA3MAGEA8MAGEB4MAGEB2MAGEB1MAGEA1MAGE1
Cell lines
BAGE GAGE4GAGE1 GAGE2MAGEB4MAGEB3GAGE7BGAGE6MAGEB2GAGE2MAGEA8MAGEA9GAGE1MAGEC1MAGEB1GAGE3MAGE1GAGE7MAGEA1MAGEA11GAGEB1MAGE10MGEA12MAGEE1MAGEA3MAGE6
Medulloblastoma tumor specimens
HM
B1
HM
B19
HM
B24
HM
B35
HM
B8
Advanced Genetic Platforms
for Medulloblastoma1. Single nucleotide polymorphism (SNP) array platforms (CNAs)
2. PCR-directed exon resequencing3. DNA methylation assays (epigenetics)4. DNA histone alterations (epigenetics)5. Next generation (“deep”) DNA
sequencing (454 Roche, Solexa Illumina, SOLiD Applied Bioscience)
Resources Resolution Results
1-10 Mb
5-10 Kb
“small” dataset
“large” dataset
~20-30 samples
212 samples
Previous studies:
Current study:
=
100K & 500K GeneChip Mapping Arrays
Amplifications: 191
Homozygous Deletions: 159
212 MBs
(201 primaries, 11 cell lines)
Known genes/pathways
- Myc family
- PDGF signaling
- OTX2
Novel genes/pathways
- chromatin: H3K9
Strategy for identification of novel genetic events in medulloblastoma…
Whole genome copy numberprofiling of MB
Animal Models More Reliably Predicting Clinical Response
• Ptch• Ptch + p53• XRCC4 knockout• Smo activation• Shh injection• Lig4 + p53• Parp + p53• Shh + Akt or IGF2 Sufu
Sufu + Costal2Gli2
MURINE MRI
Medulloblastoma in PTCH+/- Mice
Gene Silencing in Medulloblastoma
--Chromatin remodelerHistones --Transcription
--Histone tails
MicroRNAsChromosome
DNA methylationEpigenetic MechanismsIn Medulloblastoma
Nature, 2008
Role of epigenetic silencing in medulloblastoma
Cancer Res Dec 2008
Mice Implanted with SPINT2 Expressing MB Cells Have Prolonged Survival
What is SPINT2?A Novel Target for HGF/cMET inhibition
• Chr 19q13• 28.2 kDa• Serine protease
inhib• Dissection of
downstream signaling pathways
• HGF/cMET pathway inhibition (small molecule PHA-665752)
STEM CELLS AND MEDULLOBLASTOMA
Stem Cells andHuman Malignant Brain
Tumors
CD15/ LeX /SSEA1Gal1-4(Fuc1-3)GlcNAc-
Sally TempleNeuron 35: 865, 2002Developmental Biology 291:300, 2006
Adult Brain Embryonic Brain
GFAP
A new stem cell marker!
Targeting the Brain Tumor Stem CellImplications for Treatment
Reya et al, Nature 414: 105-111, 2001
Medulloblastoma: Prediction 2019
• Imaging diagnosis of tumor• Stereotactic biopsy for molecular
profiling and subclassification• Chemotherapy alone (conventional
and novel pharmacotherapeutics)• Aggressive surgical therapy and
radiation therapy will be relegated to the past
Thank you!