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!