AbstractBACKGROUNDNeurocognitive impairment is one of the key late effects of childhood medulloblastoma and is potentially influenced by surgical resection, chemotherapy and/or radiotherapy. Still, reduction of therapy to reduce neurotoxicity may be associated with a higher risk of relapses.METHODSSIOP-MB6 is a European, prospective, randomized phase II/III trial, aiming to reduce late effects of neurosurgery, radiotherapy and chemotherapy using an improved clinico-molecular risk stratification. Four different interventional questions will be assessed.RESULTSPatients with clinically and biologically standard risk medulloblastoma (non-metastatic, no large cell/anaplastic histology, no MYC/MYCN amplification, SHH-medulloblastoma only if TP53 wildtype) are eligible for this trial. Surgical arm: The aim of surgery is randomized to be maximal safe resection (standard) or safe subtotal/near total resection, i.e. sparing critical structures, intending to leave small residual tumor behind (experimental), with systematic treatment of hydrocephalus. The primary endpoint is neurocognitive functioning. Risk-stratified adjuvant therapy: All patients receive one or two blocks of carboplatin/etoposide chemotherapy depending on degree of resection, risk stratification and randomization, followed by re-resection in case of residual tumor. Very favorable risk: Single arm Phase II trial for WNT-activated medulloblastoma. Intervention: reduction of radiotherapy and chemotherapy. Favorable risk: Single arm phase II trial for SHH medulloblastoma (TP53 wildtype) or non-WNT/non-SHH medulloblastoma (subtype VII or favourable whole chromosomal abberations phenotype). Intervention: reduction of radiotherapy and chemotherapy. Standard risk: Randomized phase III trial for non-WNT/non-SHH medulloblastoma not eligible for the favourable risk arm. Randomization in standard therapy (23.4Gy CSI, 4 cycles of cyclophosphamide/cisplatin based chemotherapy) or experimental tandem high-dose thiotepa with stem cell support, radiotherapy (23.4Gy CSI) and temozolomid maintenance. The primary endpoint of all three arms will be progression-free survival, with neurocognitive functioning among secondary endpoints.DISCUSSIONDetailed rationales for this design will be presented during the presentation.