The Cambridge glioma trial of misonidazole and radiation therapy with associated pharmacokinetic studies.

Fifty-five patients with grade 3 and 4 supratentorial astrocytomas, were randomized into a three-limb study. Patients in group 1 received 5656 rads in 28 fractions in 5 1/2 weeks (202 rads daily). Group 2 received 4352 rads in 12 unequal fractions in 4 weeks (294 rads each Monday and Wednesday and 500 rads on Fridays). Group 3 received the same radiation as in group 2 but were given 3 g/m2 oral misonidazole 4 hours before the 500-rad fraction, i.e., once a week for 4 weeks. The radiation dosage in each group was equal to 1702 ret. At 9 months after the last treatment there were no differences in survival between the treatment groups. No cases of peripheral neuropathy were seen and the plasma misonidazole t1/2 of 8.6 +/- 0.62 (S.D.) hours were low. Investigations into the possible cause of this are presented. It is thought that microsomal enzyme induction by the anticonvulsants phenobarbitone and phenytoin resulted in increased O-demethylation of the misonidazole. Clinical data to confirm this view are presented. Current MRC protocols of misonidazole studies on gliomas and carcinomas of the cervix and head and neck are summarized.