Increased tumor cures using combined radiosurgery and BCNU in the treatment of 9L glioma in the rat brain

Purpose: Radiosurgery refers to the delivery of high, single focused beams of ionizing radiation to defined intracranial lesions. 1,3 Bis[2-chloroethy l]-1-nitrosourea (BCNU) and cis-diammine-1,1-cyclobutane-dicarboxylate plat inum (II) (carboplatin) are commonly used cytotoxic agents for the treatmen t of malignant gliomas of the brain. Drug therapies have exhibited a modest enhanced cell killing when combined with radiation in experimental animal tumor systems. The purpose of the present study eras to investigate the rol e of cytotoxic drugs, such as BCNU and carboplatin, in combination with a s ingle high dose of radiosurgery on the tumor control rates of 9L tumors in the rat brain. Methods and Materials: Combined radiosurgery (25 Gy single dose) and/or che motherapy (a single dose of BCNU, 7 mg/kg, i.p. 1.5 or 16 h prior to or 16 h after irradiation or a single dose of carboplatin, 30 mg/kg, administered either 1 h or 4 h prior to irradiation) was delivered 12 days after stereo tactic tumor implantation. For dose escalation study, 4-10 mg/kg of BCNU wa s used. Results: The radiation alone group showed a dose-dependent survival. A sing le dose of 25 Gy to the control group resulted in an increase of the median survival time from 20 days to 42 days, but all animals died of the tumor i n 50 days. A significant prolongation of the median survival time of animal s was more than 100 days, resulting in animal cures of 50% or more when com bined with radiosurgery (25 Gy) and BCNU (7 mg/kg). BCNU alone did not prol ong the median survival time of the animal with the 9L brain tumor. In cont rast, there was no survival improvement when the animals were treated with combined radiosurgery and carboplatin. None of the long-term surviving anim als showed any significant brain tissue damage as evaluated by histopatholo gy and clinical observations. Conclusion: The data clearly suggest that the combined modalities of radios urgery and concomitant BCNU represent an effective therapeutic regimen in t he treatment of radioresistant human malignant gliomas of the brain. This s tudy represents the first experimental report of the effectiveness of combi ned chemotherapy and radiosurgery. (C) 2000 Elsevier Science Inc.