ID #838 Clinico-molecular correlates of quality of survival and neurocognitive outcomes in medulloblastoma a meta-analysis of the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 trials

Introduction

Medulloblastoma (MB) is the most common malignant paediatric brain tumour with standard-risk five-year survival approaching 75%[1][2] . Multimodal therapy imposes substantial neurocognitive burden and diminished health-related quality of life in long-term survivors[1][3]. Identifying biological determinants of survivorship outcomes represents a priority for risk-stratified intervention[3][4][5][6][7][8][9][10].

Methods

We undertook an integrated clinico-molecular analysis of patients from the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials. Quality of survival was assessed in 218 patients using the Health Utilities Index (HUI3), Strength and Difficulties Questionnaire (SDQ), and Pediatric Quality of Life Inventory (PedsQL). Neuropsychometric assessment employed Wechsler Intelligence Scale (WISC IV) in 140 patients. Patients were classified into molecular groups (WNT, SHH, MBGrp3, MBGrp4)[11][12]. In HIT-SIOP-PNET4 patients (n = 74), 39 single nucleotide polymorphisms with reported neurocognitive-modifying effects were genotyped by Agena MassARRAY.

Results

SIOP-UKCCSG-PNET3 patients receiving chemotherapy prior to craniospinal irradiation demonstrated significantly reduced health status (p = 0.019) and increased behavioural difficulties (p < 0.001) compared to both conventional and hyperfractionated radiotherapy arms in HIT-SIOP-PNET4. SHH patients demonstrated superior quality of life relative to WNT and MBgrp4 (p < 0.0191). Neuropsychometric performance showed no association with molecular group or clinico-demographic variables. However, 7 SNPs (rs1050450, rs11611788, rs1695, rs1801131, rs4708867, rs4880, and rs9476886) were significantly associated with WISC domains, with five showing associations across multiple cognitive domains.

Conclusion

This integrated analysis identifies distinct clinical and molecular determinants of survivorship outcomes. Germline genetic modifiers of neurocognitive function provide potential targets for risk stratification and targeted therapeutic development. These findings support integrating biological determinants, patient-reported outcomes, and direct neuropsychometric assessments into clinical trial design to inform risk-adapted therapeutic strategies and precision approaches to counselling, surveillance, intervention and rehabilitation.

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