Background: Local delivery after resection of high-grade glioma, particularly glioblastoma (GBM), aims to increase intratumoral drug exposure while limiting systemic toxicity. The only U.S. Food and Drug Administration (FDA)-approved implantable intracranial chemotherapy is the carmustine (1,3-bis[2-chloroethyl]-1-nitrosourea; BCNU)-impregnated polyanhydride wafer (Gliadel wafer), indicated for newly diagnosed high-grade glioma and recurrent GBM. More than two decades of clinical use and randomized data show that intracavitary chemotherapy is feasible and confers a modest survival benefit in carefully selected patients. Nevertheless, Gliadel wafer has not altered the overall poor prognosis of GBM because of biological resistance to nitrosoureas, constrained brain-parenchymal pharmacokinetics, and device-related adverse effects. Objective: The aim is to synthesize clinical and preclinical evidence defining the current limitations of Gliadel wafer and to outline strategies for next-generation local delivery systems, with emphasis on GBM within the broader high-grade glioma setting. Methods: A narrative review of randomized and observational clinical studies, pharmacokinetic studies, and preclinical investigations evaluating Gliadel wafer and potential next-generation local delivery systems in GBM and other high-grade gliomas was performed. Results: The literature delineates key limitations of Gliadel wafer: short diffusion distances and burst-weighted carmustine release, high tumor cell resistance to carmustine due to heterogeneity, and device-related side effects. Emerging approaches to address these limitations include (i) multidrug systems with synergistic effects against GBM cells; (ii) advanced biomaterials that enable controlled and sustained release; and (iii) targeted agents with minimal off-target effects. Testing newer generations of local drug-delivery systems in more predictive translational models, such as patient-derived organoids and spontaneous large-animal glioma models, is essential to maximize the translatability of preclinical studies to human studies. However, broader adoption of spontaneous large-animal glioma models is constrained by ethical oversight, animal-welfare considerations, cost, and limited availability compared with rodent platforms. Conclusions: Next-generation local drug-delivery systems should include multiple synergistic tumor-selective drugs that can be released in a controlled, sustained manner deep into the residual tumor. Preclinical testing of these systems should be conducted in clinically relevant animal models that are more translatable than those used in early Gliadel wafer studies.

Medulloblastoma (MB), the most common malignant pediatric brain tumor, has undergone reclassification from a histologically defined disease to a genetically stratified spectrum of distinct subgroups: WNT, SHH, Group 3, and Group 4. Advances in molecular profiling, as captured in the 2021 WHO CNS5 classification, have shown meaningful heterogeneity in terms of tumor biology, prognosis, and therapeutic response. However, translating these insights into precise, less toxic treatments remains an ongoing challenge. This review synthesizes current knowledge on MB subgroup biology, treatment strategies, and emerging therapies such as subgroup-specific inhibitors, immunotherapies, and novel chemotherapeutic regimens. This review also explores risk-adapted approaches while addressing global disparities in access to diagnostics and care. As the field moves toward individualized medicine, closing the gap between molecular understanding and equitable implementation will be crucial to improving outcomes and quality of life for children with medulloblastoma worldwide.

Background: Local delivery after glioblastoma (GBM) resection aims to raise intratumoral drug exposure while limiting systemic toxicity. The only FDA-approved implantable therapy for GBM is the carmustine (BCNU)–impregnated polyanhydride wafer (Gliadel wafer). More than two decades of clinical use and randomized data show that intracavitary chemotherapy is feasible and confers a modest survival benefit in carefully selected patients. Nevertheless, Gliadel wafer has not inherently altered GBM’s overall poor prognosis due to biological resistance to nitrosoureas, constrained brain parenchymal pharmacokinetics, and device‑related adverse effects. Objective: To synthesize in-human and preclinical evidence defining the current limitations of Gliadel wafer and to outline strategies for next‑generation local delivery systems for GBM. Methods: Narrative review of randomized and observational clinical studies, pharmacokinetic studies, and preclinical models, drug-investigating Gliadel wafer and potential next-generation local delivery systems in GBM. Results: The literature delineates key limitations of Gliadel wafer: short diffusion distances and burst‑weighted carmustine release, high tumor cell resistance to carmustine due to its heterogeneity, and device‑related side effects. Emerging approaches to address these limitations include (i) multidrugs with synergistic effects against GBM cells; (ii) advanced biomaterials that enable controlled and sustained release; and (iii) targeted agents with minimal off-target effects. Testing newer generations of local drug-delivery systems in more predictive translational models, such as patient‑derived organoids and spontaneous large‑animal glioma models, is essential to maximize the translatability of preclinical studies to human studies. Conclusions: Next‑generation local drug-delivery systems should include multiple synergistic tumor-selective drugs that can be released in a controlled, sustained manner deep into the residual tumor. Preclinical testing of these systems can be conducted in clinically relevant animal models that are more translatable than those used in early Gliadel wafer studies.