Limitations of Gliadel Wafer and Strategies for Next-Generation Local Delivery Systems for Glioblastoma

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.