ID #635 Multimodal CNS-Directed Therapy Incorporating Intraventricular Chemotherapy in High-Risk Medulloblastoma

Abstract

Over the past five decades, outcomes of medulloblastoma have improved substantially with multimodal therapy. Advances in molecular characterization now enable more refined risk stratification beyond traditional staging and histopathology. However, patients with high-risk disease who receive maximally tolerated chemotherapy and radiation continue to experience significant morbidity and poor outcomes, underscoring the need for novel therapeutic strategies. While medulloblastoma is generally chemosensitive, treatment intensity is often constrained by dose-limiting toxicities, particularly hematologic suppression. One strategy to enhance therapeutic exposure without increasing systemic toxicity is the incorporation of intraventricular chemotherapy. We describe three patients with high-risk medulloblastoma treated with integrated intraventricular chemotherapy, etoposide daily for 3–5 days and cytarabine twice weekly for two weeks, within 4-week cycle of systemic chemotherapy. A 6-year-old girl with WNT medulloblastoma disseminated throughout the CNS axis received combined systemic and intraventricular chemotherapy, resulting in a significant reduction in tumor burden, then underwent radiation therapy. A 34-year-old man with localized SHH-activated medulloblastoma harboring PTCH1, TP53 mutations and GLI2 amplification underwent standard-dose craniospinal irradiation, then received integrated systemic and intraventricular chemotherapy, followed by maintenance therapy with vismodegib. An 18-year-old boy with metastatic Group 4 medulloblastoma recurring two years after completing frontline therapy received intraventricular chemotherapy incorporated into the ACNS0821 regimen. All three patients completed the combined intraventricular and systemic therapy without delay of scheduled therapy. Despite their expected poor prognosis with current high-risk protocols, they are alive 34 months, 19 months, and 13 months post-therapy respectively at last follow-up. Integrated intraventricular chemotherapy delivered concurrently with systemic treatment was well tolerated in three patients with high-risk medulloblastoma at different stages in their treatment course. This approach may enhance antitumor efficacy without disrupting systemic therapy schedule. These promising early observations warrant further evaluation in clinical trials and may represent a potential avenue to improve survival outcomes.