International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma

Inclusion Criteria:

1. Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22years (LR-arm: less than 16 years). The date of diagnosis is the date on whichsurgery is undertaken.

2. Histologically proven medulloblastoma, including the following subtypes, as definedin the WHO classification (2007): classic medulloblastoma, desmoplastic/nodularmedulloblastoma. Pre-treatment central pathology review is considered mandatory.

3. Standard-risk medulloblastoma, defined as;

• total or near total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual tumour on early post-operative MRI,without and with contrast, on central review;

• no central nervous system (CNS) metastasis on MRI (cranial and spinal) oncentral review;

• no tumour cells on the cytospin of lumbar CSF

• no clinical evidence of extra-CNS metastasis; Patients with a reduction ofpostoperative residual tumor through second surgery to less than or equal to 1.5 cm2 are eligible, if if timeline for start of radiotherapy can be kept.

4. Submission of high quality biological material including fresh frozen tumor samplesfor the molecular assessment of biological markers (such as the assessment ofmyelocytomatosis oncogene (MYC) copy number status) in national biological referencecenters. Submission of blood is mandatory for all patients, who agree on germlineDNA studies. Submission of CSF is recommended.

5. No amplification of MYC or MYCN (determined by FISH).

6. For LR-arm: Low-risk biological profile, defined as WNT subgroup positivity. The WNTsubgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing),or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-cateninmutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing). For SR-arm: average-risk biological profile, defined as ß-catenin nuclearimmuno-negativity by IHC (mandatory) and mutation analysis (optional).

7. No prior therapy for medulloblastoma other than surgery.

8. Radiotherapy aiming to start no more than 28 days after surgery. Foreseeableinability to start radiotherapy within 40 days after surgery renders patientsineligible for the study.

9. Screening for the compliance with eligibility criteria should be completed, andpatient should be included into the study within 28 days after first surgery (incase of second surgery within 35 days after first surgery). Inclusion of patients isnot possible later than 40 days after first tumour surgery, or after start ofradiotherapy.

10. Common toxicity criteria (CTC) grades < 2 for liver, renal, haematological function

11. no significant sensorineural hearing deficit as defined by pure tone audiometry withbone conduction or air conduction and normal tympanogram showing no impairment ≥ 20decibel (dB) at 1-3 kilohertz (kHz). If performance of pure tone audiometry is notpossible postoperatively, normal otoacoustic emissions are acceptable, if there isno history for hearing deficit.

12. No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNAbreakage syndromes (e.g. Fanconi Anemia, Nijmegen breakage syndrome), GorlinSyndrome or other reasons as defined by patient's clinician.

13. No identified Turcot and Li Fraumeni syndrome.

14. Written informed consent (and patient assent where appropriate) for therapyaccording to the laws of each participating country. Information must be provided tothe patient on biological studies (tumour and germline), and written informedconsent obtained of agreement for participation.

15. National and local ethical committee approval according to the laws of eachparticipating country (to include approval for biological studies).

Exclusion Criteria:

1. One of the inclusion criteria is lacking.

2. Brainstem or supratentorial primitive neuro-ectodermal tumour.

3. Atypical teratoid rhabdoid tumour.

4. Medulloepithelioma; Ependymoblastoma

5. Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma withextensive nodularity (MBEN), centrally confirmed.

6. Unfavourable or undeterminable biological profile, defined as amplification of MYCor MYCN, or MYC or MYCN or WNT subgroup status not determinable.

7. Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperativelumbar CSF).

8. Patient previously treated for a brain tumour or any type of malignant disease.

9. DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other,or identified Gorlin,Turcot, or Li Fraumeni syndrome.

10. Patients who are pregnant.

11. Female patients who are sexually active and not taking reliable contraception.

12. Patients who cannot be regularly followed up due to psychological, social, familialor geographic reasons.

13. Patients in whom non-compliance with toxicity management guidelines can be expected.