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Teaching pack: Medulloblastoma

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  1. Teaching pack · Cancer · paediatric

    Medulloblastoma

    Medulloblastoma is the most common malignant childhood brain tumour, arising in the cerebellum. Surgery, radiation to the whole brain and spine, and chemotherapy cure about 70%, at a heavy cost to thinking and growth; treatment is now being tailored to four molecular subgroups so that the low-risk children get less.

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  2. What it is

    In two paragraphs

    Medulloblastoma is an embryonal tumour of the posterior fossa with four consensus molecular subgroups (WNT, SHH, Group 3, Group 4) that differ in age, genetics, metastatic tendency and survival: WNT (~10%, CTNNB1 mutations, >95% survival), SHH (~30%, PTCH1/SUFU/SMO, TP53-mutant subset with poor prognosis; infants and adults), Group 3 (~25%, MYC amplification, worst prognosis) and Group 4 (~35%, most common, intermediate). WHO 2021 integrates histology and molecular group.

    Standard therapy is maximal safe resection, craniospinal irradiation (CSI; 23.4 Gy for average risk, 36 Gy for high risk) with posterior fossa/tumour bed boost, and adjuvant cisplatin-based chemotherapy (cisplatin, vincristine, cyclophosphamide, lomustine). Infants under 3 receive radiation-sparing intensive chemotherapy (with high-dose chemotherapy/autologous rescue or intraventricular methotrexate) because CSI is devastating to the developing brain. Risk-adapted trials (SJMB12, ACNS1422, SIOP PNET5) are reducing CSI dose for WNT tumours and testing SMO inhibitors for SHH tumours in skeletally mature patients. Proton therapy reduces exit dose to cochlea, heart and thyroid. Relapse is usually fatal outside infants; MRI-based surveillance, cfDNA in CSF, and survivorship (neurocognition, endocrine, hearing, second cancers, cerebellar mutism) dominate follow-up.

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  3. Standard of care

    What is given today, by setting

    SettingApproachGuideline
    Average risk (≥3 years, M0, <1.5 cm² residual, no MYC amp)Resection, CSI 23.4 Gy with boost to 54 Gy (proton where available), then cisplatin/vincristine/cyclophosphamide or lomustine-based chemotherapy (ACNS0331); WNT tumours receive reduced CSI in trials.not mapped
    High risk (metastatic, residual, anaplastic, MYC)CSI 36 Gy ± concurrent carboplatin (ACNS0332 for Group 3), then multi-agent chemotherapy; high-dose chemotherapy with stem-cell rescue in some protocols.not mapped
    Infants (<3 years)Radiation-avoiding intensive chemotherapy (Head Start, HIT-SKK with intraventricular methotrexate); desmoplastic/SHH infants do well, Group 3 infants poorly.not mapped
    RelapsedRe-irradiation, temozolomide-irinotecan ± bevacizumab, SMO inhibitor (vismodegib/sonidegib) for SHH in post-pubertal patients, clinical trials; cure is rare.not mapped
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  4. State of the art

    Where the field stands

    • Four molecular subgroups (2012) now define trials; the goal is to de-escalate for WNT and SHH-favourable tumours and intensify for MYC-amplified Group 3.
    • Proton CSI reduces long-term hearing, endocrine and cardiac toxicity without loss of control.
    • Survival is ~70-75% overall but neurocognitive decline of 2-4 IQ points per year after CSI in young children is the price.
    • Targeted therapy exists only for SHH (SMO inhibitors) and only after skeletal maturity, because of growth-plate fusion.
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  5. History

    How we got here

    1. 1925Bailey and Cushing name medulloblastoma
    2. 1953Craniospinal irradiation introduced (Paterson and Farr)
    3. 1990Chemotherapy after radiation improves survival (Packer)
    4. 2006Reduced-dose CSI (23.4 Gy) safe for average risk with chemotherapy (CCG 9892/ACNS0331)
    5. 2012Four molecular subgroups agreed (Taylor et al., Acta Neuropathol)
    6. 2016WHO integrates molecular groups into classification
    7. 2017Proton CSI: equivalent control, fewer toxicities (Yock, Lancet Oncol)
    8. 2021SJMB03 subgroup outcomes; ACNS0331 shows CSI dose reduction below 23.4 Gy unsafe for most
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  6. Pipeline

    What is coming

    • Proton therapy (technology)
    • Vismodegib (product)
    • DNA methylation profiling (technology)
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  7. Open problems

    What nobody has solved

    • Group 3 MYC-amplified and SHH TP53-mutant tumours: survival under 50%.
    • Relapse is almost always fatal after craniospinal irradiation.
    • Neurocognitive, endocrine and hearing sequelae in survivors.
    • Infants: curing Group 3 without radiation.
    • Access to proton therapy and methylation profiling globally.
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  8. Sources

    Read the primary sources

    • NCI PDQ: childhood medulloblastoma: https://www.cancer.gov/types/brain/patient/child-medulloblastoma-treatment-pdq
    • Taylor 2012 consensus subgroups: https://doi.org/10.1007/s00401-011-0922-z
    • Children's Oncology Group: https://childrensoncologygroup.org/
    • Wikipedia: https://en.wikipedia.org/wiki/Medulloblastoma
    • Guideline: https://doi.org/10.1200/JCO.20.02730
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