# Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)

Source: https://onco.cc/cancers/medulloblastoma-group-3-4/  
OnCo record `medulloblastoma-group-3-4` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Group 3 and group 4 medulloblastoma are the two commonest forms of this cerebellar brain tumour and the ones without a druggable driver. Group 3 strikes young children, often with extra copies of MYC and spread through the spinal fluid; group 4 affects older boys. Both get surgery, craniospinal radiotherapy and chemotherapy; trials showed the radiation dose cannot be cut for young children.

## Summary

Groups 3 and 4 arise from the upper rhombic lip and unipolar brush cell lineages and share enough that WHO 2021 groups them as non-WNT/non-SHH medulloblastoma with eight methylation subgroups. Group 3 (about a quarter of medulloblastoma) occurs in infants and young children, often with large-cell/anaplastic histology, MYC amplification in about 17 percent, GFI1 enhancer hijacking, and metastases in 40 to 45 percent at diagnosis. Group 4 (about 35 to 40 percent) affects older children and adolescents, three boys to one girl, with isochromosome 17q in most, KDM6A and PRDM6 alterations and MYCN amplification in some, and metastases in about a third. Metastatic stage, MYC amplification and residual tumour define high risk in both.

The trials that set standard therapy predate the groups. SIOP PNET3 showed pre-radiotherapy chemotherapy improved event-free survival; COG A9961 in 2006 established the average-risk regimen of 23.4 Gy craniospinal radiotherapy with a boost followed by cisplatin, vincristine and cyclophosphamide or lomustine, with five-year event-free survival of 81 percent; HIT-SIOP PNET4 found hyperfractionated radiotherapy no better than standard. ACNS0331, reported in 2021, tried to lower the craniospinal dose to 18 Gy in children aged three to seven with average-risk disease and found it inferior, five-year event-free survival 71.4 percent against 82.9 percent, while confirming that boosting the tumour bed rather than the whole posterior fossa is safe. ACNS0332, for high-risk disease, showed that carboplatin given daily during craniospinal radiotherapy improved five-year event-free survival in group 3 from 53.7 to 73.2 percent with no benefit in group 4, and that isotretinoin maintenance added nothing. Infants with group 3 disease receive intensive chemotherapy with high-dose consolidation and stem cell rescue to avoid or delay radiotherapy.

Relapse in groups 3 and 4 is almost always fatal, recurs in the same molecular group, and typically occurs in the leptomeninges rather than the tumour bed; temozolomide, irinotecan and bevacizumab, re-irradiation and high-dose chemotherapy buy time. The current trials assign therapy by methylation subgroup: SJMB12 and the SIOP PNET5 and HIT-MED studies reduce therapy for low-risk group 4 (chromosome 11 loss or whole chromosome 17 gain without metastases) and intensify it for MYC-amplified group 3. No targeted drug has worked: MYC and MYCN have no inhibitor, and immunotherapy trials to date have shown little in an immunologically cold tumour. The long-term price of craniospinal radiotherapy, in intellect, hearing, endocrine function, stroke and second tumours, is why proton therapy is the preferred modality where available and why the dose question keeps being asked.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Non-WNT/non-SHH medulloblastoma; Group 3 medulloblastoma; Group 4 medulloblastoma; MYC-amplified medulloblastoma
- Tags: subtype-page; paediatric; cns
- Group: paediatric
- Burden: Groups 3 and 4 together make up about 60 to 65 percent of medulloblastoma: group 4 is the commonest single group and group 3, often MYC-amplified and metastatic in young children, the most lethal.
- Subtypes: Group 3 medulloblastoma, MYC-amplified (very high risk; often metastatic); Group 3 medulloblastoma without MYC amplification; Group 4 medulloblastoma, low risk (chromosome 11 loss or whole chromosome 17 gain, non-metastatic); Group 4 medulloblastoma, standard and high risk (metastatic or MYCN-amplified); Non-WNT/non-SHH medulloblastoma in infants (group 3; radiotherapy-avoiding chemotherapy); Large-cell/anaplastic histology (mostly group 3)
- Biomarkers: DNA methylation profiling (non-WNT/non-SHH subgroups I to VIII); MYC and MYCN amplification; Isochromosome 17q; Chromosome 11 loss and whole chromosome 17 gain (low-risk group 4); Metastatic staging by spinal MRI and CSF cytology (Chang M stage); Residual tumour on postoperative MRI; Large-cell/anaplastic histology

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/medulloblastoma-group-3-4/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/medulloblastoma-group-3-4/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/medulloblastoma-group-3-4/#what-it-is [6 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/medulloblastoma-group-3-4/#finding-it [7 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/medulloblastoma-group-3-4/#treating-it [5 settings, 4 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/medulloblastoma-group-3-4/#evidence [3 trials, 5 key papers, 7 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/medulloblastoma-group-3-4/#science [3 targets, 1 pathway]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/medulloblastoma-group-3-4/where-you-are/ [2 centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/medulloblastoma-group-3-4/#living-with-it [19 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/medulloblastoma-group-3-4/coming/ [11 medicines, 3 trials, 1 idea, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/medulloblastoma-group-3-4/data/ [54 connected records]

## Standard of care

- Average risk (aged 3 or over, no metastases, residual under 1.5 square centimetres): Maximal safe resection, 23.4 Gy craniospinal radiotherapy with tumour-bed boost (ACNS0331 showed 18 Gy is inferior), then cisplatin, vincristine and cyclophosphamide or lomustine. ([Proton therapy](https://onco.cc/technologies/proton-therapy/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Vincristine](https://onco.cc/drugs/vincristine/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Lomustine (CCNU)](https://onco.cc/drugs/lomustine/), [COG ACNS0331](https://onco.cc/trials/acns0331/))
- High risk (metastatic, residual disease or MYC amplification): 36 Gy craniospinal radiotherapy with boost, daily carboplatin during radiotherapy for group 3 (ACNS0332), then cisplatin, vincristine and cyclophosphamide. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Proton therapy](https://onco.cc/technologies/proton-therapy/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Vincristine](https://onco.cc/drugs/vincristine/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/))
- Infants under three: Intensive chemotherapy with methotrexate, then high-dose consolidation with stem cell rescue, to avoid or delay craniospinal radiotherapy. ([Methotrexate](https://onco.cc/drugs/methotrexate/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Vincristine](https://onco.cc/drugs/vincristine/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Thiotepa](https://onco.cc/drugs/thiotepa/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/))
- Relapsed: Temozolomide with irinotecan, bevacizumab, re-irradiation or high-dose chemotherapy; almost never curative; early-phase trials. ([Temozolomide](https://onco.cc/drugs/temozolomide/), [Irinotecan (and liposomal irinotecan)](https://onco.cc/drugs/irinotecan/), [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- Survivorship: Neurocognitive, endocrine, hearing, vascular and second-tumour follow-up for life. ([Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/))

## State of the art

- Craniospinal radiotherapy at 23.4 Gy plus chemotherapy cures about four in five average-risk children, and ACNS0331 showed the dose cannot be lowered to 18 Gy in young children.
- Carboplatin during radiotherapy improved event-free survival in high-risk group 3 in ACNS0332.
- Methylation subgroups now steer trials: less therapy for low-risk group 4, more for MYC-amplified group 3.

## Open problems

- MYC and MYCN have no inhibitor, and relapse is almost always fatal.
- Craniospinal radiotherapy dose cannot be reduced in young children without losing cures.
- Immunotherapy has shown little in an immunologically cold tumour.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Medulloblastoma
- Wikipedia: Medulloblastoma: https://en.wikipedia.org/wiki/Medulloblastoma
- NCI PDQ: Childhood Medulloblastoma Treatment: https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq

## Connected records

- cancers: [Medulloblastoma](https://onco.cc/cancers/medulloblastoma/), [SHH-activated medulloblastoma](https://onco.cc/cancers/medulloblastoma-shh/), [WNT-activated medulloblastoma](https://onco.cc/cancers/medulloblastoma-wnt/)
- technologies: [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Proton therapy](https://onco.cc/technologies/proton-therapy/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/)
- drugs: [Bevacizumab](https://onco.cc/drugs/bevacizumab/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Irinotecan (and liposomal irinotecan)](https://onco.cc/drugs/irinotecan/), [Isotretinoin](https://onco.cc/drugs/isotretinoin/), [Lomustine (CCNU)](https://onco.cc/drugs/lomustine/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Thiotepa](https://onco.cc/drugs/thiotepa/), [Vincristine](https://onco.cc/drugs/vincristine/)
- companies: [Children's Oncology Group (COG)](https://onco.cc/companies/childrens-oncology-group/)
- institutions: [SIOP Europe (European Society for Paediatric Oncology)](https://onco.cc/institutions/siop-europe/), [St. Jude Children's Research Hospital](https://onco.cc/institutions/st-jude/)
- pathways: [MYC](https://onco.cc/pathways/myc/)
- terms: [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Medulloblastoma molecular groups (WNT, SHH, group 3, group 4)](https://onco.cc/terms/medulloblastoma-molecular-groups/)
- trials: [COG ACNS0331](https://onco.cc/trials/acns0331/), [COG ACNS0332](https://onco.cc/trials/acns0332/), [SJMB12](https://onco.cc/trials/sjmb12/)
- key papers: [ACNS0331: reduced-dose and reduced-volume radiotherapy with chemotherapy for average-risk medulloblastoma](https://onco.cc/key-papers/paper-acns0331-michalski-jco-2021/), [ACNS0332: carboplatin during radiotherapy and isotretinoin maintenance in high-risk medulloblastoma](https://onco.cc/key-papers/paper-acns0332-leary-jama-oncol-2021/), [Intertumoural heterogeneity within medulloblastoma subgroups](https://onco.cc/key-papers/paper-cavalli-medulloblastoma-subtypes-cancer-cell-2017/), [Molecular subgroups of medulloblastoma: the current consensus](https://onco.cc/key-papers/paper-taylor-medulloblastoma-consensus-acta-neuropathol-2012/), [The 2021 WHO classification of tumours of the central nervous system: a summary](https://onco.cc/key-papers/paper-who-2021-cns-louis-neuro-oncology-2021/)
- ideas: [Pooled coverage-with-evidence for proton therapy across all centres](https://onco.cc/ideas/idea-fund-proton-coverage-with-evidence/)
- people: [Sarah E. S. Leary](https://onco.cc/people/sarah-leary/)

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JSON: https://onco.cc/api/v1/entities/medulloblastoma-group-3-4.json