The aim of the LR-treatment arm is to confirm the high rate of event-free survival in
patients between the ages of 3 to 5 years and less than 22, with 'standard risk'
medulloblastoma with a low-risk biological profile. Patients eligible for the study will be
those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI
imaging) at diagnosis and low-risk biological profile, defined as ß-catenin nuclear
immuno-positivity by immuno-histochemistry (IHC). Patients will have undergone total or
near-total tumour resection and will receive conventionally fractionated (once a day)
radiotherapy with a dose of 54 Gy to the primary tumor and 18.0 Gy to the craniospinal axis.
Following radiotherapy, patients will receive a reduced-intensity chemotherapy with a total
of 6 cycles of chemotherapy consisting of 3 courses of cisplatin, CCNU and vincristine
alternating with 3 courses of cyclophosphamide and vincristine.
The aim of the SR-arm is to test whether concurrent carboplatin during radiotherapy followed
by 8 cycles of maintenance chemotherapy in patients with 'standard risk' medulloblastoma with
an average-risk biological profile may improve outcome. Patients eligible for the study will
be those with non-metastatic medulloblastoma (by CSF cytology and centrally reviewed MRI
imaging) at diagnosis and average-risk biological profile, defined as ß-catenin nuclear
immuno-negativity by IHC. Patients will have undergone total or near-total tumour resection
and will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy
to the primary tumor and 23.4 Gy to the craniospinal axis. Following radiotherapy, patients
will receive a modified-intensity chemotherapy with a total of 8 cycles of chemotherapy
consisting of 4 courses of cisplatin, CCNU and vincristine alternating with 4 courses of
cyclophosphamide and vincristine.
1. Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22
years (LR-arm: less than 16 years). The date of diagnosis is the date on which surgery
2. Histologically proven medulloblastoma, including the following subtypes, as defined in
the WHO classification (2007): classic medulloblastoma, desmoplastic/nodular
medulloblastoma. 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) on central
- no tumour cells on the cytospin of lumbar CSF
- no clinical evidence of extra-CNS metastasis; Patients with a reduction of
postoperative 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 samples
for the molecular assessment of biological markers (such as the assessment of
myelocytomatosis oncogene (MYC) copy number status) in national biological reference
centers. Submission of blood is mandatory for all patients, who agree on germline DNA
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 WNT
subgroup 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-catenin
mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional
For SR-arm: average-risk biological profile, defined as ß-catenin nuclear
immuno-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. Foreseeable inability
to start radiotherapy within 40 days after surgery renders patients ineligible for the
9. Screening for the compliance with eligibility criteria should be completed, and
patient should be included into the study within 28 days after first surgery (in case
of second surgery within 35 days after first surgery). Inclusion of patients is not
possible later than 40 days after first tumour surgery, or after start of
10. Common toxicity criteria (CTC) grades < 2 for liver, renal, haematological function
11. no significant sensorineural hearing deficit as defined by pure tone audiometry with
bone conduction or air conduction and normal tympanogram showing no impairment ≥ 20
decibel (dB) at 1-3 kilohertz (kHz). If performance of pure tone audiometry is not
possible postoperatively, normal otoacoustic emissions are acceptable, if there is no
history for hearing deficit.
12. No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA
breakage syndromes (e.g. Fanconi Anemia, Nijmegen breakage syndrome), Gorlin Syndrome
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 therapy according
to the laws of each participating country. Information must be provided to the patient
on biological studies (tumour and germline), and written informed consent obtained of
agreement for participation.
15. National and local ethical committee approval according to the laws of each
participating country (to include approval for biological studies).
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 with
extensive nodularity (MBEN), centrally confirmed.
6. Unfavourable or undeterminable biological profile, defined as amplification of MYC or
MYCN, or MYC or MYCN or WNT subgroup status not determinable.
7. Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative
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, familial or
13. Patients in whom non-compliance with toxicity management guidelines can be expected.