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| |  AANS: Dose-Escalation Provides Wide Range of Options for Gliadel Wafers Treatment of Malignant Gliomas By Cameron Johnston TORONTO, ON -- April 24, 2001 -- A dose-escalating study involving the polymer wafer Gliadel, has determined that doses of 3.5 percent can be safely administered to patients with malignant gliomas. The same study, reported here at the annual meeting of the American Association of Neurological Surgeons, also found that doses of greater than 20 percent had an unacceptable toxicity in three out of four patients who received it. A 20 percent dose was given to some subjects and was found to be acceptably safe. Gliadel is the trade name for a bio-degradable co-polymer matrix wafer impregnated with polyfeprosen, and carmustine (BCNU), a chemotherapeutic agent. Each wafer contains weighs approximately 200 mg and contains 3.85 percent BCNU by weight, which amounts to approximately 7.7 mg of the active drug per wafer. The 6.5 percent dose is equivalent to 13 mg of the active drug per wafer, while the 28 percent concentration is equivalent to 56 m of the active drug per wafer. The wafer is implanted in the tumor resection cavity following surgical excision, and dissolves over a period of time - beginning as soon as the surgery is complete. The product has been approved for some indications by the Food and Drug Administration in the US. The prognosis for patients with malignant gliomas is poor, noted principal investigator Alessandro Olivi, of the Cancer Institute of Milan. Median survival times range from less than one year for those with glioblastoma multiforme, to less than two years for those with anaplastic astrocytoma. The standard treatment for the condition is surgery followed by radiation but some additional survival benefit has been observed in patients who also receive systemic chemotherapy. However, studies have shown a significant tough modest prolongation of survival time in patients who have received the impregnated wafer as compared with those who received a sham polymer implant. In this study, six patients were assigned to receive wafer doses of 6.5 percent, 10 percent and 14.5 percent. Twenty-one were assigned to receive 20 percent and four received 28 percent. The patients, all adults, had all confirmed history of malignant glioma and had failed previous cyto-reductive surgery, including external beam radiation. Treated tumors were all less than one centimetre. The patients were all implanted with up to eight wafers each following surgical excision. There were no toxicities reported in the first four groups, although three of the four who received the highest dose - 28 percent - experienced serious adverse events including seizure and brain edema. Those subjects in the 20 percent dose group had whole blood measurements of BCNU that were equivalent to c/Max of 27 ng/mL at four hours post implantation. These measurements indicate that BCNU can be measured systemically, but that the concentrations are actually 500 times lower than those known to cause acute toxicity. The results of this study demonstrate that BCNU can be used in varying doses with little toxicity except for those in the highest dose group. However, whether the use of these wafers adds to the survival benefit on top of that seen with conventional treatment remains to be seen, and will require further study, Dr. Olivi reported.
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