Molecular Subgrouping as a Framework for Treatment Strategies in Pediatric Medulloblastoma (Ages 5–15)

Medulloblastoma is the most common malignant brain tumour of childhood and remains a major cause of cancer-related death and long-term disability in pediatric neuro-oncology. For decades, children aged 5–15 years have been treated with a relatively uniform therapeutic backbone consisting of maximal safe surgical resection, craniospinal irradiation, and multi-agent chemotherapy. Although this approach improved survival, it also produced substantial neurocognitive, endocrine, auditory, and psychosocial late effects during a developmental period in which children remain highly vulnerable to treatment-related injury. Over the past two decades, genomic and epigenomic studies have shown that medulloblastoma is not a single disease, but rather a group of biologically distinct tumours classified into four major molecular subgroups: WNT, SHH, Group 3, and Group 4. These subgroups differ in developmental origin, molecular drivers, metastatic tendency, prognosis, and response to therapy. This thesis argues that molecular subgrouping should function as the primary framework for treatment decision-making in medulloblastoma diagnosed between ages 5 and 15, while remaining integrated with conventional clinical risk markers such as metastatic status, residual disease, and response to treatment. The available evidence suggests that WNT medulloblastoma, and potentially selected low-risk Group 4 tumours, provide the strongest rationale for carefully monitored treatment de-escalation. By contrast, SHH medulloblastoma remains too heterogeneous for broad therapeutic reduction, while Group 3 and high-risk Group 4 disease continue to support biology-guided intensification and investigational strategies. Emerging targeted and immune-based therapies are promising, but at present they are best understood as subgroup-informed additions to adequate disease control rather than universal replacements for standard therapy. Overall, the most defensible treatment model is one that aligns therapy intensity with tumour biology in order to preserve both survival and long-term quality of life.