Misonidazole in the preoperative and radical radiotherapy of bladder cancer

Abstract

Measurement of intercapillary distances suggests the presence of significant cell hypoxia in Bilharzial bladder cancer. This tumor seems to be capable of reoxygenation in view of the existence of a correlation between prognosis and immediate tumor shrinkage after irradiation. Two programs are presented: 1) Use of misonidazole with concentrated preoperative irradiation where the reoxygenation properties are not used fully. A prospective randomized study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (6.5 Gy X 2F/1 week) with or without misonidazole. the drug is given either orally (in two doses 3 g/m2 each given 3.5 hours prior to each fraction; blood levels: 90-110 micrograms/ml) or intravesically. The intravesical administration is designed in the light of penetration studies and seems to have the advantage of the complete lack of systemic drug toxicity. Twenty-eight patients were included in this study and no drug toxicity was recorded. A second preoperative irradiation study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (4.0 Gy X 5F) with or without misonidazole in individual doses of 2 g/m2. 2) Two radical radiotherapy regimes are presented. One protocol involves a split course (SC) protracted regime making full use of spontaneous reoxygenation. The drug is given in 0.5 g/m2 daily doses (total dose 14 g/m2 spread over 61 days, blood level: 15-20 micrograms/ml). A second protocol involves hyperfractionation stimulating continuous low-dose-rate irradiation. Higher blood levels are attained (60-80 micrograms/ml) after daily doses of 2 g/m2 (total dose: 14 g/m2 spread over 35 days). In a phase II study using SC technic, reversible grade 1 peripheral neuropathy was encountered in 5 of 22 patients. Complete tumor regression 3 months after irradiation was achieved in 18 of 22 patients with 3T tumors. No neuropathy was encountered in four patients subjected to the HF regimen who also showed complete tumor regression.