In the 1950's it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with
bromodeoxyuridine (
BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of
BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of
BUdR delivery. To exploit the high mitotic activity of
malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently
implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid
BUdR delivery. Since July 1985, 23 patients with malignant
brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA
BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam
radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the
infusion pump system was implanted;
BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of
radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of
anorexia,
fatigue, ipsilateral forehead
dermatitis,
blepharitis, and
conjunctivitis. Myelosuppression requiring
dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA
BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of
malignant gliomas.