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Medulloblastoma

Medulloblastoma. Matt Harkenrider , MD June 10, 2010. History & Histology. History First described in 1925 in Bailey and Cushing’s classification of CNS tumors

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Medulloblastoma

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  1. Medulloblastoma Matt Harkenrider, MD June 10, 2010

  2. History & Histology • History • First described in 1925 in Bailey and Cushing’s classification of CNS tumors • The classic description defined the tumor as a primitive or embryonal tumor of the cerebellum, theoretically derived from the medulloblasts located in the external granular layer of the cerebellum • In 1983 Rorke grouped a number of previously recognized “small, round, blue cell tumors” occurring in the CNS based on morphology and similar tendencies to spread throughout the CNS • WHO classification of CNS tumors • Identifies embryonal tumors as a component of ofneuroepithelialneoplasms but are particularly prominent in pediatric patients • Within embryonal subtype of CNS tumors is the primitive neuroectodermal tumors (PNET) group • Included in PNET is medulloblastoma • Definition • Malignant, invasive embryonal tumor arising in the cerebellum, with predominantly neuronal differentiation

  3. Histopathology

  4. Epidemiology • Accounts for 20% of pediatric CNS tumors – about 540 cases per year • Median age at presentation is 6 years old • The tumor is uncommon in adults • Boys are affected more often than girls

  5. Presentation • Majority of tumors arise in the cerebellarvermis and project into the 4th ventricle • Presenting symptoms are usually related to elevated intracranial pressure • Headaches • Morning vomitting • Ataxia • Elevated ICP results from obstructed CSF flow through the 4th ventricle

  6. Work Up • CT and MRI reveal solid mass that usually uniformly enhances with contrast material • MRI of the spinal axis and CSF cytology are important because 30-35% of patients have spinal seeding at diagnosis • CSF may not be obtainable preoperatively due to elevated incracranial pressure and may be deferred several weeks after surgery • Post-surgical imaging with MRI is important within 72 hours to assess the degree of resection

  7. MEDULLOBLASTOMA

  8. T.N. DROP METS AROUND SPINAL CORD PNET

  9. Staging • Medulloblastoma is the classic CNS tumor associated with CSF seeding • Chang Staging • T Stage – No modern evidence that tumor size is of prognostic significance or defines therapy • M0 – No mets • M1 – Tumor cells found in CSF • M2 – Intracranial tumor beyond the primary site (aqueduct of Sylvius, third ventricle, foramen of Luschka, or lateral ventricles) • M3 – Gross nodular seeding in the spinal subarachnoid space • M4 – Mets outside of the central nervous system (usu. bone marrow or bone) • Risk Stratification • Standard Risk • No evidence of CSF dissemination (M0) • Total or near total resection with <1.5 cm2 residual on early postoperative imaging • High Risk • CSF dissemination (M1-4) • Residual disease >1.5 cm2 on postoperative imaging

  10. Genetics • Aneuploidy – favorable • Expression of TrkC – favorable • Deletions of 17p – unfavorable • Amplification of c-Myc – unfavorable • Expression of ErbB-2, ErbB-4 –unfavorable • Gain of 1p or 8q - unfavorable

  11. Overview of Therapy

  12. Surgery • 1930 report by Harvey Cushing had only 1 of 61 patients survive 3 years after surgery including some patients treated with limited radiotherapy • Extent of Resection • Gross total resection (no tumor seen on post-op imaging) • Near total resection (90% resection and <1.5 cm2 residual) • have better outcomes than… • Subtotal resection (51-90%), • Partial resection (11-50%) • Biopsy (<11%) • Survival correlates better with residual tumor as defined by post-op imaging rather than the surgeons estimated resection

  13. Surgery • In an early Children’s Cancer Group study, patients with M0 disease and • <1.5 cm2 residual disease had an EFS of 78% • More extensive residual had an EFS of 54% • A St. Jude’s Children’s Hospital trial • No advantage to pursuing a GTR over a NTR with <1.5 cm2 residual • More morbidity with the pursuit of a more aggressive surgery

  14. Surgery • Surgical mortality is <2% in pediatric neurosurgical centers • Posterior fossa syndrome occurs in 15-25% of patients • Syndrome is signified by difficulty swallowing, truncal ataxia, mutism, and rarely respiratory failure • Occur 12-24 hours post-op • These symptoms generally improve over several months and should not interfere with aggressive therapy

  15. Surgery • VP Shunt • The use of ventriculoperitoneal shunts prior to surgery greatly improved operative morbidity and mortality over the last 40 years • The risk of shunt borne metastases into the peritoneal cavity were initially concerning for M+ patients but are not common enough to warrant a change in management • Currently, preoperative ventriculostomy is preferred and can be converted into VP shunt if hydrocephalus persists

  16. Radiotherapy • The efficacy of XRT in addition to surgery was reported about 10 years after Cushing’s initial surgical report • Outcomes were poor with local radiation only • The seminal report by Bloom et al in 1969 showed the addition of craniospinal radiation gave 5 yr OS of 32% and 10 yr DFS of 25% • As radiation techniques improved, so did survival

  17. Radiation Volume • Swedish Study (Landberg et al, Cancer 1980) • Reviewed outcomes as they relate to volume treated from 1946-1975 • Historical survival rates at 10 years • 5% with posterior fossa irradiation alone (1946-1974) • 10% with posterior fossa and spinal canal irradiation (1951-1968) • 53% with craniospinal irradiation (1964-1975)

  18. Standard Photon Craniospinal Radiotherapy b’ a b

  19. Chemotherapy • Phase II trials have shown chemoresponsiveness of medulloblastoma • Alkylating agents (esp. cyclophosphamide) • Platinum (cis & carbo) • Etoposide • Camptothecins (topotecan) • Randomized trials started with lomustine, vincristine +/- prednisone

  20. Role of Chemotherapy

  21. SIOP I • Began in 1975 • 286 patients randomized • All patients treated with radical surgery • VP shunt discouraged • Craniospinal Irradiation • 50-55 Gy to posterior fossa • 35-45 Gy to supratentorial brain • 30-35 Gy to spinal cord • Randomized • Concurrent vincristine and maint. CCNU/vincristine • No chemo

  22. SIOP I • Results

  23. CCG • Began in 1974 • Enrolled 223 patients and stratified by Chang stage • Surgery was as maximal as tolerated • VP shunts were to be avoided • XRT • 50-55 Gy to posterior fossa • 35-40 Gy to neuraxis • Randomized • Concurrent vincristine and maint. CCNU, vincristine, prednisone • No chemo

  24. CCG • Results • EFS • 59% w/ chemo • 50% w/o chemo • Benefit of Chemo • Chang T3-4 • Chang M+

  25. SIOP II • Role of Chemo after surgery but prior to XRT • Rationale: the blood-brain barrier is disrupted without the reduced vascularization as a result of XRT so chemo delivery may be optimal • Enrolled 364 patients, divided into low and high risk • Surgery was maximal resection • Randomized • Chemo – procarbazine, vincristine, methotrexate, leukovorin • No chemo • XRT • 55 Gy to tumor in all patients • Low risk patients could be randomized to • “standard” XRT of 35 Gy to neuraxis • “reduced” XRT of 25 Gy to neuraxis • High risk patients could receive another course of chemo after XRT

  26. SIOP II • Results

  27. SIOP II • Reduced XRT Dose • Poorer EFS with Chemo followed by reduced dose XRT • No difference in the other arms

  28. Packer et al • Potential benefit of platinum containing regimen • 63 patients with high risk medullo • Radical resection • Craniospinal radiation – 50.4-55.8 Gy PF, 36 Gyneuraxis • Concurrent weekly vincristine • Chemo – CCNU, cisplatin, vincristine (8 – six week cycles)

  29. Packer et al • Results • PFS • 90% at 3 years • 85% at 5 years • EFS • 90% at 3 years • 83% at 5 years • 72% at 9 years • DFS • 90% with M0 • 67% with M+ • 3 patients died of a second malignancy

  30. POG 9031 • To compare pre & post radiation CDDP/VP-16 • 224 patients with high risk medullo • Surgery • XRT – PF 53.2-54.4 Gy & Neuraxis 35.2-40 Gy • Randomized • CDDP/VP-16 x3 then XRT then VCR-Cyclo x8 • XRT then CDDP/VP-16 x3 & VCR-Cyclo x8

  31. POG 9031 • Results • EFS @ 5 yrs • PreXRT Chemo – 66% • PostXRT Chemo – 70% (p=ns) • OS @ 5 years • PreXRT Chemo – 73% • PostXRT Chemo – 76% (p=ns) • Overall EFS for M1-3 patients was 65%

  32. Chemotherapy Summary • Addition of chemotherapy improves EFS • 50% with XRT (CCG) • 59% with XRT + Chemo (CCG) • No improvement with Chemo + XRT (SIOP II) • 83% with XRT + Platinum based Chemo (Packer) • High risk patients • No difference between Pre & Post XRT Platinum based chemo (POG) • High risk patients • M+ patients – 65% EFS (POG) & 67% DFS (Packer)

  33. Radiation Volume

  34. Radiation Volume • Swedish Study (Landberg et al, Cancer 1980) • Reviewed outcomes as they relate to volume treated from 1946-1975 • Historical survival rates at 10 years • 5% with posterior fossa irradiation alone (1946-1974) • 10% with posterior fossa and spinal canal irradiation (1951-1968) • 53% with craniospinal irradiation (1964-1975)

  35. Radiation Volume • French Study (Bouffet, 1992) • Investigated limited volume (posterior fossa and spinal axis withoutsupratentorial brain) with high dose chemo • Desire to avoid toxicity associated with supratentorial radiotherapy • Study closed due to early neuraxis failures • 18% recurrence free survival at 6 years with posterior fossa and spinal irradiation

  36. Radiation Volume • Tumor Bed or Posterior Fossa as the target • Patterns of failure studies from MSKCC revealed posterior fossa failures occur in the tumor bed • MSKCC, St. Jude Cancer Research Hospital, and the French group (M-SFOP 98) • Full dose prescribed to tumor bed rather than the entire posterior fossa • Event Free Survival was 84%, 92% and 83% respectively • Tumor bed boost provides similar EFS compared to posterior fossa boost • Failures tend to be leptomeningeal in location • COG trial assessing posterior fossa vs. tumor bed boost

  37. Radiation Volume • Historical survival rates at 10 years (1946-1975) • 5% with posterior fossa irradiation alone • 10% with posterior fossa and spinal canal irradiation • 53% with craniospinal irradiation • 18% recurrence free survival at 6 years with posterior fossa and spinal irradiation even with chemo (Bouffet, 1992) • 83-92% EFS with CSI & tumor bed boost not posterior fossa boost (MSKCC, SJCRH, M-SFOP) • COG Trial randomizing to tumor bed vs. posterior fossa boost for average risk patients

  38. Radiation Dose

  39. Radiation Dose • EFS @ 5 years • 50% with CSI 35-40 Gy alone (CCG) • 60% with CSI 35 Gy alone (SIOP II) • 69% with CSI 25 Gy alone (SIOP II) (p=ns) • 83% with CSI 36 Gy with platinum based chemo – high risk pts (Packer)

  40. CCG-9892 • Role for reduced craniospinal dose • Began in 1989 • Enrolled 65 children with average risk medullo • Maximal resection • Radiation • 55.8 Gy posterior fossa • 23.4 Gycraniospinal • Concurrent vincristine • Adjuvant lomustine, vincristine, cisplatin

  41. CCG-9892 • Results • PFS • 86% at 3 years • 79% at 5 years • EFS • 83% at 3 years • 78% at 5 years • Outcomes compare favorably to full dose craniospinal irradiation

  42. Goldwein et al • 10 patients <5 yo with average risk medullo from Children’s Hospital of Philadelphia • 1988-1990 • 18 Gy to neuraxis and 50.4-55.8 Gy to posterior fossa with platinum based chemo • 70% survival at 6 years • No change in IQ for surviving patients compared to baseline • 5 of 7 surviving patients had decreased growth velocity

  43. POG 9961 • Phase III study evaluating chemotherapy regimens, but all patients received low dose CSI 23.4 Gy • 379 average risk patients • EFS @ 5 years – 81% • OS @ 5 years – 86%

  44. M-SFOP • French Study • 1998-2001 • 55 patients with surgical resection • Hyperfractionated CSI – • Tumor Bed – 68 Gy in 68 fractions BID • Neuraxis - 36 Gy in 36 fractions BID • No chemotherapy • EFS – 83% at 2.5 years • OS – 94% at 2.5 years

  45. Radiation Dose • EFS @ 5 years • 50% with CSI 35-40 Gy alone (CCG) • 60% with CSI 35 Gy alone (SIOP II) • 69% with CSI 25 Gy alone (SIOP II) (p=ns) • 83% with CSI 36 Gy with platinum based chemo – high risk pts(Packer) • 78% with CSI 23.4 Gy with Pt based chemo – average risk pts (CCG 9892) • 81% with CSI 23.4 Gy with Pt based chemo – average risk pts (POG 9961) • 70% DFS with CSI 18 Gy with Pt based chemo – <5yo average risk pts (CHOP) • No difference with hyperfractionation (M-SFOP) • COG trial comparing 23.4 Gy vs. 18 Gy CSI for average risk pts opened

  46. Isodose Comparisons Photons IMPhotons Protons

  47. Electron/Photon CSI 30Gy 40 Gy 20Gy 54Gy

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