MEDULLOBLASTOMA: Current Treatment and Future Directions

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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

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The Past
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Cushing and Pediatric Neurosurgery
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Cushing and Pediatric Brain Tumours
Acta Pathologica, Microbiologica et Immunologica
Scandinavica 71-86, 1930
Surgery, Gynecology and Obstetrics 52 129-204,
1931
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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 morningThe
  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

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Clinical Presentation of the Child with a
Medulloblastoma

• If not recognized so soonthe 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
  finallyextensor 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
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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 of Medulloblastoma
from Cushings Collection
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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 McKenzie Canadas first neurosurgeon
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Medulloblastoma - The Evolution of Pediatric
Neuro-radiology

• Skull Xrays
• Angiography
• Ventriculography
• Pneumo-encephalography
• Myelography
• CT Scan
• PET
• MRI
• MEG
• DTI

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Early CT Imaging ofPediatric Brain Tumors
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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

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MEDULLOBLASTOMA

• IMPROVING PATIENT SURVIVAL
• 63 high risk children cis-plat, VCR, CCNU
• PFS _at_ 5 yrs 85 for entire group
• PFS _at_ 5 yrs 67 for children with metastases
• PFS _at_ 5 yrs 90 for children with local disease
• Packer et al, J Neurosurg 81 690, 1994

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The Present
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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

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MEDULLOBLASTOMA

• BIOLOGICAL BEHAVIOUR
• 40 infiltrate the brainstem
• 20-50 CSF dissemination along the neuraxis
• 10 systemic metastases (lung, lymph node, bone)

The Harold J Hoffman Slide Collection www.surg.me
d.utoronto.ca/neuro/slides.html
Met along shunt tubing
Diffuse bone mets
CSF spread
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MEDULLOBLASTOMA

• RISK SEGREGATION
• Low Risk High Risk
• gt 3 yrs lt 3 yrs
• No residual tumor gt 1.5 cm2 residual
• No distant metastases Metastases

All patients with medulloblastoma are high
risk Kintomo Takakura
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MEDULLOBLASTOMA

• IMAGING STUDIES
• Hyperdense lesion on CT before contrast
• Heterogeneous enhancement after contrast

Pre-contrast Post-contrast
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MEDULLOBLASTOMA

• TUMOR LOCATION
• Midline, vermian
• Hemispheric
• CP angle
• Brainstem (rare)
• Supratentorial (PNET)

Pre-operative MRI Spine!!
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MEDULLOBLASTOMA Spine MRI
Pre-operative spinal imaging is mandatory!
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MEDULLOBLASTOMA Imaging
Diagnosis of leptomeningeal disease
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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

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MEDULLOBLASTOMA

• OPERATIVE APPROACH
• Midline, vermian split
• Lateral hemispheric
• Inferior medullary velum - telovelar
• CP angle

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MEDULLOBLASTOMA
INTRA-OPERATIVE NUANCES
Removing tumor from Floor of IVth
Inspecting anatomical Structures with
tumor removed
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Intra-operative video
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MEDULLOBLASTOMA
Surgery, XRT And Chemo
5 years
Surgery, XRT And Chemo
4 years
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With Medulloblastoma, the More Tumor You Remove,
the Better!
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MEDULLOBLASTOMA

• POST-OPERATIVE COMPLICATIONS
• Cerebellar, cranial nerve deficits
• Hydrocephalus requiring shunt or ETV
• Meningitis
• Pseudomeningocele
• Cerebellar Mutism

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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
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MEDULLOBLASTOMAEffects of XRT on the CNS

• Neurocognitive
• Moya moya
• Endocrinopathy
• Vasculopathy
• Cavernous malformation
• Secondary neoplasms

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NEJM 2005352978-986
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Chemotherapy for MedulloblastomaProven effective
but.
6 year old male Short history GTR Excellent
post-op course
Cycles of chemotherapy Stem cell
transplant Infectious complications Toxic
mortality
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MEDULLOBLASTOMA

• CURRENT BEST TREATMENT
• Maximum safe neurosurgical resection
• Radiation therapy (reduced craniospinal
  irradiation, avoid irradiating children lt 3 yrs)
• Chemotherapy (active agents, autologous stem cell
  transplant, new agents)

5 year survival standard risk 70 5 year
survival high risk 50
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Future Treatment of Medulloblastoma

• Advanced Cytogenetics
• Differential Gene Expression
• SNP array platforms
• Next generation sequencing
• Epigenetics
• Stem Cells

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Advanced Cancer Cytogenetics
Chromosomes 7 17 rearrangements Gene
amplification in 30 (2q) Loss of chromosome
10 Three techniques led to identification Of
greatest number genetic alterations
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Examine a panel of differentially expressed genes
in patient samples linked to clinical outcome and
survival data.
Tissue Microarray Technology
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Tissue Array Prediction of Patient Outcome
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MEDULLOBLASTOMA ANDGERMLINE SUFU MUTATION
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Nature Genetics 31 306-310, 2002
The Globe and Mail June 20, 2002
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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

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The Future of Medulloblastoma
Gene Discovery Experiment Using GeneChip
Affymetrix Human Genome U133 Plus 2.0
Array Comprehensive coverage of the human
genome More than 47,000 transcripts studied
Samples Medulloblastoma cell lines (DAOY, TE671,
UW426, ONS76 ) and Human adult cerebellum
Flowchart of the procedure
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Hierarchical Clustering of MAGE and GAGE by
microarray
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Advanced Genetic Platformsfor Medulloblastoma

• Single nucleotide polymorphism (SNP) array
  platforms (CNAs)
• PCR-directed exon resequencing
• DNA methylation assays (epigenetics)
• DNA histone alterations (epigenetics)
• Next generation (deep) DNA sequencing (454
  Roche, Solexa Illumina, SOLiD Applied Bioscience)

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Resources
Resolution
Results
?

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Strategy for identification of novel genetic
events in medulloblastoma
Amplifications 191 Homozygous Deletions 159

• Known genes/pathways
• - Myc family
• - PDGF signaling
• OTX2

Novel genes/pathways - chromatin H3K9
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Whole genome copy numberprofiling of MB
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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 Costal2 Gli2
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MURINE MRI
Medulloblastoma in PTCH/- Mice
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Gene Silencing in Medulloblastoma
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DNA methylation
Epigenetic Mechanisms In Medulloblastoma
--Chromatin remodeler
Histones
--Transcription
--Histone tails
MicroRNAs
Chromosome
Nature, 2008
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Role of epigenetic silencing in medulloblastoma
Cancer Res Dec 2008
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Mice Implanted with SPINT2 Expressing MB Cells
Have Prolonged Survival
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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)

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STEM CELLS AND MEDULLOBLASTOMA
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Stem Cells andHuman Malignant Brain Tumors
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CD15/ LeX /SSEA1Galb1-4(Fuca1-3)GlcNAcb-
Adult Brain
Embryonic Brain
GFAP
Sally Temple Neuron 35 865, 2002 Developmental
Biology 291300, 2006
A new stem cell marker!
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Targeting the Brain Tumor Stem CellImplications
for Treatment
Reya et al, Nature 414 105-111, 2001
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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

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Thank you!