SIOP PNET5 MB Trial: History and Concept of a Molecularly Stratified Clinical Trial of Risk-Adapted Therapies for Standard-Risk Medulloblastoma

SIMPLE SUMMARY: The European trial SIOP PNET5 MB was initiated in 2014 and will remain open to recruitment until 2022. It is the first European trial using clinical, histological, and molecular parameters to stratify treatments for childhood medulloblastoma, based on disease risk. In the standard-risk stratum, a randomized intensification of carboplatin concomitant to radiotherapy is investigated. In the favourable-risk stratum, defined by localized WNT subgroup disease, reduction of craniospinal radiotherapy intensity (from 24 to 18 Gy) and reduced maintenance chemotherapy is investigated for children <16 years old at diagnosis. Two additional exploratory strata (WNT-HR and SHH-TP53) have been implemented during the trial. The use of biological parameters for stratification has proven feasible in a prospective multicentre setting, and may improve future risk-adapted treatment. The primary endpoint is 3-year event-free survival. Late effects on hearing, endocrine- and neurologic function, alongside health-related quality of life (e.g., health status, behavioural outcomes), are secondary endpoints. ABSTRACT: Background. SIOP PNET5 MB was initiated in 2014 as the first European trial using clinical, histological, and molecular parameters to stratify treatments for children and adolescents with standard-risk medulloblastoma. Methods. Stratification by upfront assessment of molecular parameters requires the timely submission of adequate tumour tissue. In the standard-risk phase-III cohort, defined by the absence of high-risk criteria (M0, R0), pathological (non-LCA), and molecular biomarkers (MYCN amplification in SHH–MB or MYC amplification), a randomized intensification by carboplatin concomitant with radiotherapy is investigated. In the LR stratum for localized WNT-activated medulloblastoma and age <16 years, a reduction of craniospinal radiotherapy dose to 18 Gy and a reduced maintenance chemotherapy are investigated. Two additional strata (WNT-HR, SHH-TP53) were implemented during the trial. Results. SIOP PNET5 MB is actively recruiting. The availability of adequate tumour tissue for upfront real-time biological assessments to assess inclusion criteria has proven feasible. Conclusion. SIOP PNET5 MB has demonstrated that implementation of biological parameters for stratification is feasible in a prospective multicentre setting, and may improve risk-adapted treatment. Comprehensive research studies may allow assessment of additional parameters, e.g., novel medulloblastoma subtypes, and identification and validation of biomarkers for the further refinement of risk-adapted treatment in the future.