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

## TL;DR

Gliadel wafers have limited effectiveness against glioblastoma due to drug release issues and resistance, but new delivery systems and models may improve outcomes.

## Contribution

This review outlines the limitations of Gliadel wafers and proposes next-generation local delivery strategies for glioblastoma treatment.

## Key findings

- Gliadel wafers have modest benefits due to shallow drug penetration and tumor resistance.
- Next-gen systems include multidrug depots and biomaterials for controlled release.
- Predictive models like patient-derived organoids can improve preclinical testing.

## Abstract

Glioblastoma is an aggressive brain cancer that almost always returns after surgery. Gliadel wafers are biodegradable disks that contain carmustine and can be placed directly into the surgical cavity to treat newly diagnosed high-grade glioma or recurrent glioblastoma while limiting whole-body exposure. Their benefit has been modest because drug release is front-loaded, tissue penetration is shallow, many tumors are resistant to nitrosoureas, and the implants can cause local complications. In this review, we summarize clinical and laboratory evidence explaining these barriers and outline improved local-delivery designs, including multidrug depots, more conformal biomaterials with slower release, and targeted therapies that may better match glioblastoma biology. We also discuss more predictive translational models that may accelerate the path to clinical testing.

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.