Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: a New Approaches to Brain Tumor Therapy CNS Consortium trial.

PURPOSE: This New Approaches to Brain Tumor Therapy CNS Consortium study sought to determine the maximum-tolerated dose (MTD) of carmustine (BCNU) that can be implanted in biodegradable polymers following resection of recurrent high-grade gliomas and the systemic BCNU exposure with increasing doses of interstitial BCNU. PATIENTS AND METHODS: Forty-four adults underwent tumor debulking and polymer placement. Six patients per dose level were studied using polymers with 6.5%, 10%, 14.5%, 20%, and 28% BCNU by weight. Toxicities were assessed 1 month after implantation by a safety monitoring committee to determine whether subsequent escalations should occur. Nine additional patients were studied at the MTD to confirm safety. BCNU blood levels were obtained before and after polymer implantation.
RESULTS: No dose-limiting toxicities were identified at the 6.5%, 10%, or 14.5% dose levels, although difficulties with wound healing, seizures, and brain edema were noted. At the 20% dose, these effects seemed more prominent, and six additional patients were treated at this dose and tolerated treatment well. Three of four patients receiving the 28% polymers developed severe brain edema and seizures, and accrual to this cohort was stopped. Nine additional patients received 20% polymer, confirming this as the MTD. Maximum BCNU plasma concentrations with the 20% loaded polymers were 27 ng/mL. Overall median survival was 251 days.
CONCLUSION: The MTD of BCNU delivered in polymer to the surgical cavity is 20%. This polymer provides five times more BCNU than standard commercially available BCNU polymers and results in minimal systemic BCNU exposure. Additional studies are needed to establish the efficacy of high-dose BCNU polymers.