Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma.

Context: Mitotane is the only approved drug for treatment of adrenocortical carcinoma. Its pharmacokinetic properties are not fully elucidated and different dosing regimens have never been compared head to head. Objective: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens. Design/Setting: This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks. Patients/Interventions: Forty mitotane-naive patients with metastatic adrenocortical carcinoma were assigned to a predefined low-or high-dose regimen by the local investigator. Thirty-two patients could be evaluated in detail. Main Outcome Measure: The difference in median mitotane plasma levels between both treatment groups was measured. Results: Despite a difference in mean cumulative dose (440 +/- 142 g vs 272 +/- 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3-29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients onthe high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low-dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 +/- 494 mg/L.d vs 555 +/- 168 mg/L.d (P = .080). Conclusions: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.