The efficacy of pharmacokinetic monitoring and dose modification of etanidazole on the incidence of neurotoxicity: results from a phase II trial of etanidazole and radiation therapy in locally advanced prostate cancer.

Fifty-four patients have been entered on a Phase II trial to study the efficacy of etanidazole (ETA) for locally advanced prostate cancer. The primary goal was to study the incidence of and time to a complete response for patients receiving ETA and radiation therapy. The secondary goal was to prospectively evaluate the utility of pharmacokinetic monitoring and dose-modification of the incidence and severity of the dose-limiting peripheral neurotoxicity. Within a constant radiation therapy regimen, the dose of ETA was either (a) unmodified (2 g/m2, 3 times weekly for 17 doses); (b) altered by a schedule modification of either number of doses or dose adjustment; or (c) individualization of single dose size so that the total number of doses (19 doses) were maintained but the single dose size was adjusted to keep the total AUC of plasma concentration versus time to less than 40 mM-hr. Sufficient efficacy data are not yet available. The use of drug dose modification has reduced the incidence of neurotoxicity from (a) unmodified: 17/26 = 65% (1 grade II); (b) schedule adjustment: 5/9 = 55% (no grade II); and (c) individualized dose modification: 1/19 (no grade II) = 6%. The minimum number of time points needed to accurately assess the AUC will be determined. Pharmacokinetic monitoring will be important in the use of ETA so that drug underdosing can be avoided while minimizing the risk of serious neurotoxicity.