Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial

Simon Bailey, Nicolas André, Lorenza Gandola, Maura Massimino, Keith Wheatley, Simon Gates, Victoria Homer, Stefan Rutkowski, Steven Clifford

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Abstract

Simple Summary
Patients with medulloblastoma receive treatment according to a risk stratification, which is a combination of clinical and biological factors. To date there have been a limited number of trials for high-risk disease in children older than 3 years, with a wide range of treatment philosophies that usually involve higher doses of radiotherapy delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, to date, trials in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international, biomarker-driven, randomised clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens.

Abstract
Medulloblastoma patients receive adapted therapies stratified according to their risk-profile. Favourable, standard, and high disease-risk groups are each defined by the status of clinical and pathological risk factors, alongside an evolving repertoire of diagnostic and prognostic biomarkers. Medulloblastoma clinical trials in Europe are coordinated by the International Society for Paediatric Oncology (SIOP-Europe) brain tumour group. Favourable and standard-risk patients are eligible for the SIOP-PNET5-MB clinical trial protocol. In contrast, therapies for high-risk disease worldwide have, to date, encompassed a range of different treatment philosophies, with no clear consensus on approach. Higher radiotherapy doses are typically deployed, delivered either conventionally or in hyper-fractionated/accelerated regimens. Similarly, both standard and high-dose chemotherapies were assessed. However, trials to date in high-risk medulloblastoma have commonly been institutional or national, based on modest cohort sizes, and have not evaluated the relative performance of different strategies in a randomised fashion. We describe the concepts and design of the SIOP-E high-risk medulloblastoma clinical trial (SIOP-HR-MB), the first international biomarker-driven, randomised, clinical trial for high-risk medulloblastoma. SIOP-HR-MB is programmed to recruit >800 patients in 16 countries across Europe; its primary objectives are to assess the relative efficacies of the alternative established regimens. The HR-MB patient population is molecularly and clinically defined, and upfront assessments incorporate a standardised central review of molecular pathology, radiology, and radiotherapy quality assurance. Secondary objectives include the assessment of (i) novel therapies within an upfront ‘window’ and (ii) therapy-associated neuropsychology, toxicity, and late effects, alongside (iii) the collection of materials for comprehensive integrated studies of biological determinants within the SIOP-HR-MB cohort.
Original languageEnglish
Article number374
JournalCancers
Volume14
Issue number2
DOIs
Publication statusPublished - 13 Jan 2022

Bibliographical note

Funding
This work was supported by Cancer Research UK A2524 and is run by the Cancer Research UK Clinical Trials unit based at Birmingham University. Biological studies within SIOP-HR-MB are funded by the G & K Boyes Foundation and Cancer Research UK (C8464/A23391). The French participation in the trial is funded by PHRC-K (18-114) INCA and the Italian participation by FRRB (Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia) (2011). German participation in the trial is funded by of HRMB is funded by the German Childhood Cancer Aid (Ref. DKS-2019.08).

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