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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

Medulloblastoma

Matt Harkenrider, MD

June 10, 2010

history histology
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
epidemiology
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
presentation
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
work up
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
staging
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
genetics
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
surgery
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
surgery1
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
surgery2
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
surgery3
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
radiotherapy
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
radiation volume
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)
chemotherapy
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
siop i
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
siop i1
SIOP I
  • Results
slide25
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
slide26
CCG
  • Results
    • EFS
      • 59% w/ chemo
      • 50% w/o chemo
    • Benefit of Chemo
      • Chang T3-4
      • Chang M+
siop ii
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
siop ii1
SIOP II
  • Results
siop ii2
SIOP II
  • Reduced XRT Dose
    • Poorer EFS with Chemo followed by reduced dose XRT
    • No difference in the other arms
packer et al
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)
packer et al1
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
pog 9031
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
pog 90311
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%
chemotherapy summary
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)
radiation volume2
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)
radiation volume3
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
radiation volume4
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
radiation volume5
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
radiation dose1
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)
ccg 9892
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
ccg 98921
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
goldwein et al
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
pog 9961
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%
m sfop
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
radiation dose2
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
isodose comparisons
Isodose Comparisons

Photons

IMPhotons

Protons

slide49

Electron/Photon CSI

30Gy

40 Gy

20Gy

54Gy

investigational
Investigational
  • Hyperfractionated Accelerated XRT
    • SIOP (PNET 4) and UKCCSG are addressing the role of hyperfractionation
      • Standard Risk - 1 Gy fractions BID
        • Tumor Bed – 68 Gy
        • Posterior Fossa – 60 Gy
        • Neuraxis – 36 Gy
      • Metastatic - 1.24 Gy fractions BID
        • Posterior Fossa – 62 Gy
        • Neuraxis – 39.68 Gy
  • COG Phase III 2x2 trial for average risk patients
    • 23.4 vs 18 Gy of craniospinal irradiation
    • Posterior fossavs Tumor bed as target of high dose radiation
  • COG investigating the use of carboplatin and isoretinoin in non-average risk patients
  • COG Trial for patients <3 y.o. with intensive induction Chemo +/- Methotrexate followed by stem cell rescue
summary
Summary
  • Medulloblastoma is a rare but serious pediatric malignancy
  • Maximum resection correlates with favorable outcomes and dictates further therapy
  • Advanced surgical and radiotherapy techniques have improved outcomes
summary1
Summary
  • The addition of chemo esp. platinum containing regimens have dramatically improved outcomes even for high risk patients
  • Chemo and modern radiotherapy techniques allow for decreased dose and decreased volume of radiotherapy
  • Further investigation is being pursued by cooperative groups in the U.S. and Europe to continually improve outcomes and reduce toxicity