GLIADEL® Wafer (polifeprosan 20 with carmustine) is designed to deliver carmustine directly into the surgical cavity created when a brain tumor is resected. On exposure to the aqueous environment of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid. The carmustine released from GLIADEL® Wafer (polifeprosan 20 with carmustine) diffuses into the surrounding brain tissue and produces an antineoplastic effect by alkylating DNA and RNA.

Carmustine has been shown to degrade both spontaneously and metabolically. The production of an alkylating moiety, hypothesized to be chloroethyl carbonium ion, leads to the formation of DNA cross-links.

The tumoricidal activity of GLIADEL® Wafer (polifeprosan 20 with carmustine) is dependent on release of carmustine to the tumor cavity in concentrations sufficient for effective cytotoxicity.

More than 70% of the copolymer degrades by three weeks. The metabolic disposition and excretion of the monomers differ. Carboxyphenoxypropane is eliminated by the kidney and sebacic acid, an endogenous fatty acid, is metabolized by the liver and expired as CO₂ in animals.

The absorption, distribution, metabolism, and excretion of the copolymer in humans is unknown. Carmustine concentrations delivered by GLIADEL® Wafer (polifeprosan 20 with carmustine) in human brain tissue have not been determined. Plasma levels of carmustine after GLIADEL® Wafer (polifeprosan 20 with carmustine) implant were not determined. In rabbits implanted with wafers containing 3.85% carmustine, no detectible levels of carmustine were found in the plasma or cerebrospinal fluid.

Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m², the average terminal half-life, clearance, and steady-state volume of distribution were 22 minutes, 56 mL/min/kg, and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200 mg/m² dose of 1⁴C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO₂.

GLIADEL® Wafer (polifeprosan 20 with carmustine) s are biodegradable in human brain when implanted into the cavity after tumor resection. The rate of biodegradation is variable from patient to patient. During the biodegradation process, a wafer remnant may be observed on brain imaging scans or at re-operation even though extensive degradation of all components has occurred. Data obtained from review of CT scans obtained 49 days after implantation of GLIADEL® Wafer (polifeprosan 20 with carmustine) demonstrated that images consistent with wafers were visible to varying degrees in the scans of 11 of 18 patients. Data obtained at re-operation and autopsies have demonstrated wafer remnants up to 232 days after GLIADEL® Wafer (polifeprosan 20 with carmustine) implantation.

Wafer remnants removed at re-operation from two patients with recurrent malignant glioma, one at 64 days and the second at 92 days after implantation, were analyzed for content. The following table presents the results of analyses completed on these remnants.

COMPOSITION OF WAFER REMNANTS REMOVED FROM TWO PATIENTS ON RE-OPERATION

The wafer remnants consisted mostly of water and monomeric components with minimal detectable carmustine present.

Clinical Studies

Primary Surgery

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with newly-diagnosed high-grade malignant glioma undergoing initial craniotomy for tumor resection. This trial determined the safety and efficacy of GLIADEL® Wafer (polifeprosan 20 with carmustine) implants plus surgery and radiation therapy compared to placebo implants plus surgery and radiation therapy. Two hundred and forty patients with newly-diagnosed malignant glioma were enrolled. The most common tumor type was Glioblastoma Multiforme (GBM) (n=207), followed by anaplastic oligoastrocytoma (n=11), anaplastic oligodendroglioma (n=11), and anaplastic astrocytoma (n=2). GLIADEL® Wafer (polifeprosan 20 with carmustine) s were implanted at the time of the surgery in 120 patients and placebo wafers were implanted in 120 patients. The majority of patients received 6-8 wafers. The majority of patients (93/120, 77.5% in the GLIADEL® Wafer (polifeprosan 20 with carmustine) group and 98/120, 81.7% in the placebo group) with newly-diagnosed malignant glioma received a standard course of radiotherapy (55 to 60 Gy) typically starting 3 weeks after surgery. There were 17 patients (14.2%) in the GLIADEL® Wafer (polifeprosan 20 with carmustine) group and 12 patients (10.0%) in the placebo group who received systemic chemotherapy during the study. All six patients with anaplastic oligodendroglioma received chemotherapy within 30 days of GLIADEL® Wafer (polifeprosan 20 with carmustine) implantation. Patients were followed for at least three years or until death. Only one patient was lost to follow-up. Median survival increased from 11.6 months with placebo to 13.8 months with GLIADEL® Wafer (polifeprosan 20 with carmustine) (p-value < 0.05, log-rank test). The hazard ratio for GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment was 0.73 (95% CI: 0.56-0.95).

Kaplan-Meier Overall Survival Curves for Patients Undergoing Initial Surgery for a High-Grade Malignant Glioma

When only patients with glioblastoma multiforme were included in the analysis, the hazard ratio with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment was 0.78 (95% CI: 0.59-1.03, p=0.08, log-rank test).

Surgery for Recurrent Disease

A randomized, double-blind, placebo-controlled clinical trial was conducted in adult patients with recurrent malignant glioma. This trial determined the safety and efficacy of GLIADEL® Wafer (polifeprosan 20 with carmustine) implants plus surgery compared to placebo implants plus surgery.

Ninety-five percent of the patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) had 7-8 wafers implanted. Chemotherapy was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery in patients undergoing re-operation for malignant glioma. In 222 patients with recurrent malignant glioma who had failed initial surgery and radiation therapy, the six-month survival rate after repeat surgery increased from 47% (53/112) for patients receiving placebo to 60% (66/110) for patients treated with GLIADEL® Wafer (polifeprosan 20 with carmustine) Median survival increased by 33%, from 24 weeks (5.5 months) with placebo to 32 weeks (7.4 months) with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment. In patients with GBM, the six-month survival rate increased from 36% (26/73) with placebo to 56% (40/72) with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment. Median survival of GBM patients increased by 41% from 20 weeks (4.6 months) with placebo to 28 weeks (6.4 months) with GLIADEL® Wafer (polifeprosan 20 with carmustine) treatment. In patients with pathologic diagnoses other than GBM at the time of surgery for tumor recurrence, GLIADEL® Wafer (polifeprosan 20 with carmustine) produced no survival prolongation.

6-MONTH KAPLAN-MEIER SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

KAPLAN-MEIER OVERALL SURVIVAL CURVES FOR PATIENTS UNDERGOING SURGERY FOR RECURRENT GBM

Last reviewed on RxList: 3/6/2009
This monograph has been modified to include the generic and brand name in many instances.