Despite the increasing incidence of malignant primary brain tumors, and more than two decades of intensive research, these tumors still carry a dismal prognosis. Conventional radiation therapy has improved survival somewhat, but is demanding and cumbersome, and is associated with short and long term complications related to the inevitable exposure of adjacent normal brain to ionizing radiation. In this study, a novel form of radiation therapy will be delivered in a very high, single session dose (40 Gy to the post-operative residual tumor), with extreme precision, using the CO-60 Radiosurgery unit. Concurrently, patients will also receive two courses of radiation- enhancing chemotherapy (cisplatin 50 mg/m2/day for 3 days; 5-fluorouracil 1200 mg/m2/day for 5 days), the first at the time of initial surgery, and the second concurrent with Gamma Knife radiosurgery. This unique combination of treatments should produce dramatic improvements in tumor killing and survival, and the precision of this technique will markedly reduce the toxicity associated with traditional therapies. Thirty-six patients, 18 years or older, with acceptable Karnofsky Performance Scores (> 60%), tumor histologies (GBM, GS, AA), and locations (supratentorial, one hemisphere, unifocal) will be enrolled and treated. Tumor response rate (the primary study end-point) will be examined using a mini-max statistical approach for phase II studies. Survival and quality of life will be examined as secondary study end-points. Toxicity will be monitored with appropriate clinical, radiographic, and hematologic tests. Specimens from viable tumor, necrotic regions of tumor, and tumor- infiltrated """"""""brain around tumor"""""""", obtained at initial surgery, will be analyzed for platinum content to help delineate the human brain pharmacokinetics of continuous infusion cisplatin. Ultimately, the same treatment protocol will provide a safe and effective model for testing multimodal therapy with stereotactically delivered radiation and combinations of standard and innovative radiation-enhancing agents (BUdR, IUdR, N-methyl formamide, AZT, new cisplatin analogues). These agents may be introduced into tumors by way of a polymer-drug delivery system. Both the novel chemotherapeutic agents, and the polymer-drug delivery system are being developed in tandem with this project by other members of this center.
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