Association between mitotane and platinum-etoposide chemotherapy is the front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Drug-drug interaction between mitotane -which is a strong pharmacokinetic inductor of CYP3A4 and BRCP- and etoposide –which is a substrate of CYP3A4 and BRCP- may contribute to chemoresistance in ACC. The aim of this study was to evaluate the pharmacokinetic interaction between mitotane and etoposide.
From December 2016 to October 2017, this observational study included 5 consecutive ACC patients treated with platinum-etoposide (120 to 150 mg/m2 J1-J2-J3 at cycle 1) chemotherapy in referral center for rare adrenal diseases and oncology department of Cochin hospital, Paris. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24h after each etoposide infusion. In the absence of dose-limiting toxicity, a dose escalation of etoposide was proposed from cycle 2.
Patients received a median of 3 [2 to 6] chemotherapy cycles, in association with mitotane (4 patients, median mitotane plasma concentration of 14.2 mg/L) or after mitotane discontinuation (1 patient, plasma concentration 1 mg/L). Etoposide clearance was higher in association with mitotane (4.95 L/h [2.67 to 6.20]) than after discontinuation (2.53 L/h [2.02 to 2.78], Wilcoxon p = 0.014) or in a reference population not treated with mitotane (1.81 L/h)1. Etoposide dose escalation was performed in 4 patients treated with mitotane, resulting in 2 minor tumor response at 300mg/m2 and 1 febrile neutropenia.
Drug-drug interaction between mitotane and etoposide may partly explain the low efficacy of platinum-etoposide chemotherapy in ACC. Given the elimination half-life of mitotane is extremely long (18-159 days), this observation suggests further a potential benefit of increasing etoposide dosage in patients receiving mitotane than stopping mitotane before chemotherapy initiation in ACC patients.
Clinical trial identification
Legal entity responsible for the study
Blanchet Benoit and Jouinot Anne.
Has not received any funding.
All authors have declared no conflicts of interest.