Increased tumor cures using combined radiosurgery and BCNU in the treatment of 9l glioma in the rat brain.
OBJECTIVE
Radiosurgery refers to the delivery of high, single focused beams of ionizing radiation to defined intracranial lesions. 1,3 Bis[2-chloroethyl]-1-nitrosourea (BCNU) and cis-diammine-1, 1-cyclobutane-dicarboxylate platinum (II) (carboplatin) are commonly used cytotoxic agents for the treatment 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 was to investigate the role of cytotoxic drugs, such as BCNU and carboplatin, in combination with a single high dose of radiosurgery on the tumor control rates of 9L tumors in the rat brain.


METHODS
Combined radiosurgery (25 Gy single dose) and/or chemotherapy (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 stereotactic tumor implantation. For dose escalation study, 4-10 mg/kg of BCNU was used.


RESULTS
The radiation alone group showed a dose-dependent survival. A single 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 in 50 days. A significant prolongation of the median survival time of animals was more than 100 days, resulting in animal cures of 50% or more when combined with radiosurgery (25 Gy) and BCNU (7 mg/kg). BCNU alone did not prolong the median survival time of the animal with the 9L brain tumor. In contrast, there was no survival improvement when the animals were treated with combined radiosurgery and carboplatin. None of the long-term surviving animals showed any significant brain tissue damage as evaluated by histopathology and clinical observations.


CONCLUSIONS
The data clearly suggest that the combined modalities of radiosurgery and concomitant BCNU represent an effective therapeutic regimen in the treatment of radioresistant human malignant gliomas of the brain. This study represents the first experimental report of the effectiveness of combined chemotherapy and radiosurgery.
Khil
M S
MS
Department of Radiation Oncology, Henry Ford Health System, Detroit, MI 48202-4689, USA. mkhill@hfhs.org
Kolozsvary
A
A
Apple
M
M
Kim
J H
JH
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D016190:Carboplatin / Q000627:therapeutic use; D002330:Carmustine / Q000627:therapeutic use*; D003037:Cobalt Radioisotopes / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D018316:Gliosarcoma / Q000188:drug therapy* / Q000401:mortality / Q000601:surgery*; D006801:Humans; D008297:Male; D011853:Radiobiology; D016634:Radiosurgery / Q000379:methods*; D051381:Rats; D011916:Rats, Inbred F344
D018906:Antineoplastic Agents, Alkylating; D003037:Cobalt Radioisotopes; D016190:Carboplatin; D002330:Carmustine