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MEDULLOBLASTOMA: Current Treatment and Future Directions

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.

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MEDULLOBLASTOMA: Current Treatment and Future Directions

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  1. 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

  2. The Past

  3. Cushing and Pediatric Neurosurgery

  4. Cushing and Pediatric Brain Tumours Acta Pathologica, Microbiologica et Immunologica Scandinavica 7:1-86, 1930 Surgery, Gynecology and Obstetrics 52: 129-204, 1931

  5. 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…”

  6. 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

  7. 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 Cushing’s Collection

  8. 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 Canada’s first neurosurgeon

  9. Medulloblastoma - The Evolution of Pediatric Neuro-radiology • Skull Xrays • Angiography • Ventriculography • Pneumo-encephalography • Myelography • CT Scan • PET • MRI • MEG • DTI

  10. Early CT scans Circa 1976 Air encephalography Early CT Imaging ofPediatric Brain Tumors

  11. 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%

  12. 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

  13. The Present

  14. 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

  15. 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.med.utoronto.ca/neuro/slides.html Met along shunt tubing Diffuse bone mets CSF spread

  16. MEDULLOBLASTOMA RISK SEGREGATION Low RiskHigh Risk > 3 yrs < 3 yrs No residual tumor > 1.5 cm2 residual No distant metastases Metastases All patients with medulloblastoma are high risk Kintomo Takakura

  17. MEDULLOBLASTOMA • IMAGING STUDIES • Hyperdense lesion on CT before contrast • Heterogeneous enhancement after contrast Pre-contrast Post-contrast

  18. MEDULLOBLASTOMA TUMOR LOCATION Midline, vermian Hemispheric CP angle Brainstem (rare) Supratentorial (PNET) Pre-operative MRI Spine!!

  19. MEDULLOBLASTOMA: Spine MRI Pre-operative spinal imaging is mandatory!

  20. MEDULLOBLASTOMA: Imaging Diagnosis of leptomeningeal disease

  21. 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

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

  23. MEDULLOBLASTOMA INTRA-OPERATIVE NUANCES Removing tumor from Floor of IVth Inspecting anatomical Structures with tumor removed

  24. Intra-operative video

  25. MEDULLOBLASTOMA Surgery, XRT And Chemo 5 years Surgery, XRT And Chemo 4 years

  26. With Medulloblastoma, the More Tumor You Remove, the Better!

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

  28. 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! LancetOncology June 2008

  29. MEDULLOBLASTOMAEffects of XRT on the CNS • Neurocognitive • Moya moya • Endocrinopathy • Vasculopathy • Cavernous malformation • Secondary neoplasms

  30. NEJM 2005:352:978-986

  31. 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

  32. 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%

  33. Future Treatment of Medulloblastoma • Advanced Cytogenetics • Differential Gene Expression • SNP array platforms • Next generation sequencing • Epigenetics • Stem Cells

  34. 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

  35. Tissue Microarray Technology Examine a panel of differentially expressed genes in patient samples linked to clinical outcome and survival data.

  36. Tissue Array Prediction of Patient Outcome

  37. MEDULLOBLASTOMA ANDGERMLINE SUFU MUTATION

  38. Nature Genetics 31: 306-310, 2002 The Globe and Mail June 20, 2002

  39. 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

  40. Hybridization Scanning Analysis 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

  41. Medulloblastoma tumor specimens Cell lines HMB1 HMB35 HMB24 HMB19 HMB8 DAOY ONS76 UW426 TE671 BAGE GAGE4 GAGE1 GAGE2 MAGEB4 MAGEB3 GAGE7B GAGE6 MAGEB2 GAGE2 MAGEA8 MAGEA9 GAGE1 MAGEC1 MAGEB1 GAGE3 MAGE1 GAGE7 MAGEA1 MAGEA11 GAGEB1 MAGE10 MGEA12 MAGEE1 MAGEA3 MAGE6 GAGE7 GAGE7B GAGE3 GAGE6 GAGE4 GAGE2 MAGEA9 GAGE1 MAGEE1 MAGEA10 MAGEC1 MAGEB3 BAGE GAGEB1 MGEA12 MAGEA11 MAGE6 MAGEA3 MAGEA8 MAGEB4 MAGEB2 MAGEB1 MAGEA1 MAGE1 Hierarchical Clustering of MAGE and GAGE by microarray

  42. 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)

  43. Previous studies: ~20-30 samples 1-10 Mb “small” dataset Current study: 5-10 Kb 212 samples “large” dataset Resources Resolution Results  =

  44. 212 MBs (201 primaries, 11 cell lines) 100K & 500K GeneChip Mapping Arrays 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

  45. Whole genome copy numberprofiling of MB

  46. 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

  47. MURINE MRI Medulloblastoma in PTCH+/- Mice

  48. Gene Silencing in Medulloblastoma

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