Benefit to risk ratio of mitotane high starting dose strategy in 22 patients with adrenocortical carcinoma (ACC): a prospective evaluation
Sophie Mauclère-Denost1, Sophie Leboulleux1, Isabelle Borget1, Abir Al Ghuzlan1, Jacques Young2, Laurence Drouard1, Angelo Paci1, Philippe Chanson2, Martin Schlumberger1 & Eric Baudin1
Background: The benefit to risk ratio of mitotane high starting dose regimen in ACC remains unknown.
Methods: To evaluate a high starting dose strategy, we performed a single-center, prospective study with three main objectives: 1) to assess the time taken to reach a mitotane plasma level above 14 mg/l (benefit); 2) to evaluate mitotane tolerance (risk) in the first 3 months of treatment and 3) to analyse the correlation using a regression analysis test between the shortest length of time to reach the mitotane therapeutic window (1 month) and the following parameters: age, BMI, treatment for dyslipidemia, tumour weight and size, hormone production, Weiss score, ENSAT Staging and mitotane dose.
Twenty-two patients with ACC have been prospectively enrolled. Mitotane has been administrated at a starting dosage of 23 g/d which was rapidly increased up to the maximal tolerated dose (max 9 g/d) within 2 weeks. Plasma mitotane levels were measured monthly using HPLC.
Results: The mitotane high starting dose strategy (median 6 g/d within two weeks) allowed the therapeutic threshold of >14 mg/l to be reached at 1, 3 or 6 months in 6/22 patients (27%) 7/22 patients (32%) and 10/19 patients (53%), respectively. Finally, 16 out of 22 patients (73%) reached the therapeutic window during the total follow-up period (median, 2 months; range 127 months). Eleven patients (50%) interrupted transiently the treatment for toxicity. Grade 34 neurological or haematological toxicities were observed in three patients (13.6%). There was a tendency for an association between a concomitant lipid-lowering treatment and a shorter time for reaching mitotane therapeutic window (OR=0.143; CI 0.0161.265; P=0.08).
Conclusions: High starting dose of mitotane allows o,pDDD therapeutic levels to be reached within 1 month in 27% of patients with an acceptable tolerance. Lipid-lowering therapy could be associated with a shorter time to achieve mitotane therapeutic levels.