INTRA-ARTERIAL BUDR RADIOSENSITIZATION-MALIGNANT

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The purpose of this phase I/II study is to develop an improved treatment program for patients with unilateral malignant cerebral gliomas using intra-arterial (IA) infusions of a radiosensitizing drug in conjunction with radiotherapy. The results of a recent study indicate that carotid infusion of BUdR should deliver an 11- to 16-fold higher concentration of BUdR to cerebral tumors compared to intravenous (IV) administration. It was concluded that a safe carotid delivery system is necessary to maximize the efficacy of BUdR. We have developed such a carotid drug delivery system and propose to utilize it for investigations in monkeys and clinical trials in man. Prior to human studies, we will examine the effects of IA BUdR and radiotherapy on the normal primate brain. These studies have been requested by the National Cancer Institute and the Food and Drug Administration prior to the initiation of human clinical trials. We will also determine the regional advantage of IA BUdR and 5-FU by measuring the internal carotid artery blood levels of BUdR and 5-FU in the monkey after both intracarotid and IV administration. 5-FU will be studied because of its potential to increase BUdR incorporation into DNA and enhance BUdR radiosensitization. A phase I/II clinical trial of IA BUdR and radiotherapy will begin after the completion of primate toxicity studies. Patients will undergo a craniotomy for diagnosis and maximum resection of their tumors, followed one week later by placement of a totally implantable pump capable of delivering drugs by either bolus or continuous infusion directly into the internal carotid artery. They will receive continuous infusion of the radiosensitizer BUdR at 500 mg/m2/day. The infusion will begin 14 days prior to and continue during radiation therapy. Radiation therapy will consist of 6000 rads delivered to the tumor bed and a 3 cm margin. Patients whose tumors fail radiosensitization and radiotherapy will receive intermittent bolus infusions of high dose BCNU (150 mg/m2) via the pump sideport at 6-week intervals. We anticipate that this study will further knowledge about the IA administration of radiosensitizers and chemotherapeutic agents. We further hope this treatment program will increase survival for patients with malignant gliomas and eventually lead to the development of Phase III cooperative studies.