1 / 54

Medulloblastoma

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

yank
Télécharger la présentation

Medulloblastoma

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related