Medulloblastoma

Epidemiology

  • Second most common malignant brain tumor of childhood (20% of CNS tumors in children <19 years old).
  • Median age of presentation is 5-7 years old. 75% medulloblastomas occur in children <15 years old.
  • Slight male predominance.
  • Medulloblastoma is most frequently located in 4th ventricle and is most common infratentorial tumor of childhood
  • Local recurrence is mostly in posterior fossa

Presentation

  • Hydrocephalus
  • Cerebellar ataxia
  • Leptomeningeal spread
  • Evidence of spinal and/or CSF metastasis at diagnosis in 1/3 of pts

Work-up

  • Initial endocrinological and neuropsychological assessment
  • MRI brain 1-3 days post-operatively
  • CSF cytology after brain MRI
  • Bilateral bone marrow biopsy
  • Spinal MRI 2-3 wks post-surgery

Pathology

  • Medulloepithelioma is the most primitive embryonal tumor, histologically showing features of primitive medullary epithelium and primitive tubular structures.
  • Medulloblastom (PNET) have characteristic immunohistochemical studies
  • Cam5.2, CK and EMA (Characteristic gene mutations)
  • Ependymoblastoma is a pooly differentiated embryonal tumor including ependymal differentiation signified by multilayered rosettes.
  • Primitive polar spongioblastoma is a rare cerebral tumor thought to be derived rom migrating glial precursor cells.
  • Cerebral neuroblastoma ranges hitologically from an undifferentiated tumor similar to the extra-CNS childhood neuroblastoma often including unilayered Homer Wright rosettes, to lesions demonstrating considerable ganglionic differentiation.
  • Chang’s Staging

T Stage

  • T1 - tumor <3 cm in diameter
  • T2 - tumor ≥3 cm in diameter
  • T3a - tumor >3 cm and with extension into Aqueduct of Sylvius or foramen of Luschka
  • T3b - tumor >3 cm and with unequivocal extension into brainstem
  • T4 - tumor >3 cm with extension past Aqueduct of Sylvius or down past foramen magnum

M Stage

  • M0 - No evidence of gross subarachnoid or hematogenous metastasis
  • M1 - microscopic tumors cells found in CSF
  • M2 - gross nodular seeding intracranially beyond the primary site (in cerebellar/cerebral subarachnoid space or in third or lateral ventricle)
  • M3 - gross nodular seeding in spinal subarachnoid space
  • M4 - metastasis outside cerebrospinal axis

Contemporary Subclassification System

  • Standard Risk (2/3 at presentation) - total or subtotal tumor resection with <1.5 cc residual disease, no visible metastases on craniospinal magnetic resonance imaging (MRI), and no meningeal dissemination on postoperative lumbar puncture CSF cytology.
  • High Risk (1/3 at presentation) - children 3 years or younger, or those with metastatic disease or subtotal resection (>1.5 cc of residual disease) or non-posterior fossa location.

Treatment

Surgery

  • Surgery includes VP shunt in presence of hydrocephalus and maximal resection

Radiation

  • RT delayed children < 3 yrs old. Treated with chemo (VCR/cyclophosphamide alternating with CDDP/etoposide)
  • RT given for > 3 yrs old Or with progression of disease

< 3 years-old

  • Give chemotherapy to try to delay RT
  • M0 completely resected MB EFS 70-80%
  • M0 incompletely resected MB EFS 40-50%
  • M+ MB 25-30%

Low-risk group Radiation

  • CSI to 23.40 Gy concurrently with VCR followed by VCR/CDDP/CCNU x 1 yr
  • Posterior fossa + 0.5 cm to 36 Gy
  • Primary site to 55.8 Gy
    • GTV includes gross residual tumor and/or the tumor bed at the primary site as determined from the initial preoperative MRI. GTV in most cases was a contracted or collapsed tumor bed.
    • CTV = GTV + 2.0 cm confined to the poster fossa
    • GTV = CTV+ 0.5 cm.
    • Start CSI within 28 days of surgery

High-risk Group

  • M0-M1
    • CSI 36 Gy concurrently with VCR followed by VCR/CDDP/CCNU x 1 yr
  • M2-M3
    • CSI 39.6 Gy concurrently with VCR followed by VCR/CDDP/CCNU x 1 yr
  • Primary Site
    • Primary site to 55.8 Gy
    • GTV includes gross residual tumor and/or the tumor bed at the primary site as determined from the initial preoperative MRI. GTV in most cases was a contracted or collapsed tumor bed.
    • CTV = GTV + 2.0 cm confined to the poster fossa
    • GTV = CTV+ 0.5 cm.
  • Spinal metastasis
    • Treat spine at 150 cGy/fx, boost gross spinal disease to 50 Gy
    • Pts with overt meningeal seeding at presentation- CSI to 38 Gy
  • Dose should be decreased by 10% for children less than 2 yrs old

RT Technique

  • Pt is prone in immobilization device. BBs at bony canthi. Chin extended. CT simulation
  • PA spine field set up with superior border at C5/C7
  • Inferior border- Bottom of S3 (below conus medullaris)
  • Laterally to include entire vertebral body with 1-cm margin to cover sacral foramina inferiorly
  • Whole brain and upper C spine treated with parallel-opposed lateral fields
  • Superior, anterior, posterior borders should flash
  • Inferior border- at C5/C7 ( block should cover with 1-cm margin cribiform plate and temporal fossa)
  • Brain field collimator is angled to match divergence of posterior spine field
  • Divergence of the lateral brain field into the spine field is taken into account by angling the couch toward the gantry head
  • Gantry is angled 4-5 degrees to superimpose BBs to spare lens.
  • Skin surface gap is calculated for inferior border
  • Posterior fossa is boosted after completion of CSI. Posterior fossa best visualized on sagittal MRI
  • Superior border- midway between foramen magnum and vertex plus 1-cm
  • Inferior border- bottom of C2
  • Anterior border- at posterior clinoid
  • Posterior border- flash

Chemotherapy

  • Chemotherapy should be given during or after radiation and not before (POG 9031 and SIOP II)
  • CCG 9892 (Standard risk)
    • vincristine qwk x 8 concurrent
    • different VCP (vincristine, CCNU(lomustin), cisplatin) x 8 cycles
  • CCG 921 (High Risk)
    • vincristine qwk x 8 concurrent
    • different VCP (vincristine, CCNU(lomustin), prednisone) x 8
  • High-risk patients benefit postoperative and concurrent chemotherapy (CCG-941 and SIOP-1)
  • Standard risk patients chemotherapy is commonly used although studies have not shown it to be better thanradiation alone
  • Cyclophosphamide has the highest response rate as a single agent.

Outcome

  • 5-Yr DFS: 80%
  • Bad prognostic factors: male, age <5 yrs, M1 disease

Complications

Surgery

  • posterior fossa syndrome

Radiation

  • ototoxicity
  • neurocognitive deficits
  • neuroendocrine deficits

Chemotherapy

  • ototoxicity
  • infertility
  • marrow tolerance
  • CNS penetration

Studies

  • Tait et al (1990) “Adjuvant chemo for medulloblastoma: the first multi-centre control trial of the international Society of Pediatric Oncology (SIOP I)” ‡
  • These early preplatinum regimens had no overall survival benefit but did show a significant improvement in disease control and survival among pts with locally advanced, incompletely resected, and metastatic dz and in children younger than 2 yrs old
  • Evans et al (1996) “Adjuvant chemotherapy of childhood posterior fossa ependymoma: cranio-spinal irradiation with or without adjuvant CCNU, vincristine, and prednisone: CCG study ‡
  • Surgery and post-op standard radiation therapy with and without chemotherapy was tested. All pts received craniospinal irradiation to 36 Gy. Results at 5 yrs demonstrate same OS- 65% in both arms. No overall benefit with chemotherapy. However, these studies did document significant improvement with chemotherapy in high-risk pts. 46% vs 0% in T3-T4, M1-M3 disease.
  • Packer et al (1999) “Treatment of children with medulloblastomas with reduced-dose craniospinal RT and adjuvant chemotherapy” CCG study ‡
  • A recent trial that supports the use of 23.4 Gy at 180 cGy/fraction to the neuroaxis for average-risk presentations when combining irradiation and chemo. This recommendation is based upon apparent confirmation that 80% long-term disease control is achievable with 23.4 Gy CSI and platinum-based chemo.
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