SIOP PNET 5 medulloblastoma

Prior treatment

• LR, SR, WNT-HR: Patient previously treated for a brain tumour or any type of malignant disease

Other illness

• LR, SR, WNT-HR: Identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration. Unrefuted clinical suspect for patient or familial APC-associated polyposis conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin Snydrome, Fanconi anaemia, or other hereditary condition that affects tolerance of antitumour treatment, or may prone to secondary tumours

Other

• All arms: One of the inclusion criteria is lacking
• LR, SR: Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or WNT subgroup status not determinable
• LR, SR: Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF)
• SR: Identified somatic TP53 mutation in SHH activated tumours
• SHH-TP53: Patients who refuse testing for germline TP53-mutations
• All arms: Brainstem or supratentorial embryonal tumour
• All arms: Atypical teratoid rhabdoid tumour
• All arms: Patients who are pregnant
• All arms: Female patients who are sexually active and not taking reliable contraception
• All arms: Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons
• All arms: Patients in whom non-compliance with toxicity management guidelines can be expected
• LR, SR: Medulloepithelioma, embryonal tumour with multi-layered rosettes
• LR, SR: Large cell/anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), confirmed on central pathological review

• LR: Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 16 years
• SR: WNT-subgroup negativity
• SR: For patients with SHH activated tumours: exclusion of germline alteration of TP53, PTCH and SUFU is required, and recommended for BRCA2 and PALB2. Exclusion of somatic mutation is sufficient for enrolment of the patient. In case of somatic alteration, urgent diagnostic evaluation for germline alteration after appropriate consent is necessary
• LR: Histologically proven and genetically defined medulloblastoma including the following subgroups, as defined in the WHO classification (2016): medulloblastoma, WNT-activated Histologic subtype: medulloblastoma, classic or medulloblastoma, desmoplastic/nodular; Pre-treatment central pathology review, as well as central molecular confirmation of WNT-activation is considered mandatory
• WNT-HR, SHH-TP53: Age at diagnosis, at least 3–5 years (depending on the country)
• WNT-HR: Histologically proven and genetically defined medulloblastoma including the following subgroups, as defined in the WHO classification (2016): medulloblastoma, WNT-activated; Histologic subtype: classic medulloblastoma, desmoplastic/nodular medulloblastoma, large-cell/anaplastic medulloblastoma
• LR, SR: Clinically standard -risk medulloblastoma
• All arms: Submission of high quality biological material including fresh frozen tumour samples and blood for the molecular assessment of biological markers (such as the assessment of MYC gene copy number status) in national biological reference centersSubmission of CSF is recommended
• LR: No amplification of MYC or MYCN (determined by FISH or aCGH)
• LR: Low-risk biological profile, defined as presence of β-catenin mutation (mandatory testing) resulting in WNT activation
• LR, SR, WNT-HR: No prior therapy for medulloblastoma other than surgery
• LR-, SR-, WNT-HR-arm: No significant sensineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing no impairement ≥ 20 dB at 1-3 kHz (best ear). If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history for hearing deficit
• All arms: Postoperative therapy aiming to start no more than 28 days after surgery. Foreseeable inability to start therapy within 40 days after surgery renders patients ineligible for the study
• All arms: CTC grades < 2 for liver, renal, haematological function
• WNT-HR: Low-risk biological profile, defined as WNT-subgroup positivity
• WNT-HR: Clinical high risk features
• SHH-TP53: Histologically proven medulloblastoma, genetically defined as SHH-activated TP53 mutant, as defined in the WHO classification (2016)
• SHH-TP53: Patients can be included irrespective of histological subtype of medulloblastoma (inclusion of AMB, DMB, CMB, LCMB and MBEN allowed) and irrespective of evidence of MYC/MYCN amplification (inclusion if MYC/MYCN amplification is absent or present)
• SHH-TP53: Complete postoperative staging investigations according to PNET 5 MB – standards (pre- and postoperative MRI, spinal MRI, cytospin of lumbar CSF with sufficient quality and central review where applicable) is required; patients are eligible irrespective of staging result, i.e. with or without residual tumor, and localized or metastatic disease
• SHH-TP53: Evaluation of germline TP53 status is required before start of irradiation. Patients with germline TP53 mutation, TP53 mosaicism and/ or somatic TP53 mutation are eligible.
• SHH-TP53: Diagnosis of SHH-activated TP53-mutant medulloblastoma as first or secondary malignancy
• LR-, SR-, WNT-HR-arm: No identified germline APC, PTCH, SUFU, TP53, PALB2, or BRCA2 gene alteration (evaluation of PALB2 and BRCA2 not mandatory). No unrefuted clinical suspect for patient or familial APC-associated polyposis conditions, biallelic mismatch repair syndrome, Li Fraumeni Syndrome, Gorlin Snydrome, Fanconi anaemia, or other hereditary condition that affects tolerance of antitumour treatment, or may prone to secondary tumours
• All arms: No other medical contraindication to protocol therapy
• All arms: 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
• All arms: National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies)
• SR: Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22 years
• SR: Histologically proven and genetically defined medulloblastoma including the following subtypes, as defined in the WHO classification (2016): - medulloblastoma, SHH-activated and TP53-wildtype - medulloblastoma, non-WNT/non-SHH medulloblastoma, group 3 medulloblastoma, group 4 Histologic subtype: - medulloblastoma, classic - medulloblastoma, desmoplastic/nodular Pre-treatment central pathology review, as well as central molecular diagnosis of genetically defined subgroup is mandatory
• SR: No amplification of MYC or MYCN (determined by FISH or aCGH); MYCN amplification allowed for patients with group 4 medulloblastoma