A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma

Abstract

A previous placebo-controlled trial has shown that biodegradable 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) wafers (Gliadel wafers) prolong survival in patients with recurrent glioblastoma multiforme. A previously completed phase 3 trial, also placebo controlled, in 32 patients with newly diagnosed malignant glioma also demonstrated a survival benefit in those patients treated with BCNU wafers. Because of the small number of patients in that trial, a larger phase 3 trial was performed to confirm these results. Two hundred forty patients were randomized to receive either BCNU or placebo wafers at the time of primary surgical resection; both groups were treated with external beam radiation postoperatively. The two groups were similar for age, sex, Karnofsky performance status (KPS), and tumor histology. Median survival in the intent-to-treat group was 13.9 months for the BCNU wafer-treated group and 11.6 months for the placebo-treated group (log-rank P -value stratified by country = 0.03), with a 29% reduction in the risk of death in the treatment group. When adjusted for factors affecting survival, the treatment effect remained positive with a risk reduction of 28% ( P = 0.03). Time to decline in KPS and in 10/11 neuroperformance measures was statistically significantly prolonged in the BCNU wafer-treated group ( P </= 0.05). Adverse events were comparable for the 2 groups, except for CSF leak (5% in the BCNU wafer-treated group vs. 0.8% in the placebo-treated group) and intracranial hypertension (9.1% in the BCNU wafer-treated group vs. 1.7% in the placebo group). This study confirms that local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to patients with newly diagnosed malignant glioma.

Local Intracerebral Administration of Paclitaxel with the Paclimer® Delivery System: Toxicity Study in a Canine Model

“…Biodegradable controlled-release polymers loaded with carmustine have been established as a safe and effective therapy for patients with malignant gliomas (8)(9)(10)(11)(12). Given the inherent advantages of locally-delivered chemotherapy, there has been continued interest in the development of additional controlled-release drug delivery systems suitable for intraparenchymal administration of novel antineoplastic compounds.…”

Interstitial Docetaxel (Taxotere), Carmustine and Combined Interstitial Therapy: a Novel Treatment for Experimental Malignant Glioma

“…The introduction of biodegradable polymers that release chemotherapeutic agents directly into the tumor has proved to be a promising strategy at increasing the local delivery of the drug. Nitrosoureas, including BCNU, are a class of chemotherapeutic agents that have been incorporated into biodegradable polymers and, upon intracranial implantation, have demonstrated efficacy in phase III clinical trials in patients with both recurrent and newly diagnosed malignant gliomas [3,36,40]. Importantly, in contrast to systemic administration of nitrosoureas, this treatment has not been associated with systemic side effects.…”

“…Since most gliomas recur within 2 cm of the original tumor site [14,18], this anti-tumor strategy has the potential to control both local recurrence and improve overall survival. This approach has been evaluated in Phase III clinical trials with the nitrosourea, carmustine (BCNU) and has demonstrated significant improvement in survival in patients with malignant gliomas both at recurrence and at initial presentation [3,36,40].…”

Inhibition of C6 glioma in vivo by combination chemotherapy of implantation of polymer wafer and intracarotid perfusion of transferrin-decorated nanoparticles

“…The enhanced MRI with Gd-DTPA (gadolium-diethylenetriamine pentaacetic acid) was used for monitoring the tumor size at different periods in the same animal and for comparison of the development of tumors in different groups of rats. The performance of MRI has been previously described (12). Whenever the rats died naturally or were sacrificed at one of the various time points, their brains were removed.…”

“…The Gliadels ® wafer, another intracavitary treatment using a controlled release system, has also been developed (10). The therapeutic effect of the Gliadels wafer was tested in two phase III clinical trials (11,12). The median survival time obtained in the treated patients was significantly prolonged in comparison to untreated patients, but the improvement was still limited since only a 2-month increase in survival time could be obtained.…”