PURPOSE OF REVIEW: Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma. RECENT FINDINGS: Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences. SUMMARY: Mitotane concentration of 14-20 mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
PURPOSE OF REVIEW: Description of novel findings about the mechanism of action of mitotane and its activity as an adjunctive postoperative measure, or for treatment of advanced adrenocortical carcinoma. RECENT FINDINGS: Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences. SUMMARY:Mitotane concentration of 14-20 mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
Authors: Matthias Kroiss; Timo Deutschbein; Wiebke Schlötelburg; Cristina L Ronchi; Bruno Neu; Hans-Helge Müller; Marcus Quinkler; Stefanie Hahner; Anke Heidemeier; Martin Fassnacht Journal: Horm Cancer Date: 2016-03-09 Impact factor: 3.869
Authors: Elaine Silveira; Isadora Pontes Cavalcante; Jean Lucas Kremer; Pedro Omori Ribeiro de Mendonça; Claudimara Ferini Pacicco Lotfi Journal: Cancer Cell Int Date: 2018-03-01 Impact factor: 5.722
Authors: Nada El Ghorayeb; Geneviève Rondeau; Mathieu Latour; Christian Cohade; Harold Olney; André Lacroix; Paul Perrotte; Alexis Sabourin; Tania L Mazzuco; Isabelle Bourdeau Journal: Medicine (Baltimore) Date: 2016-03 Impact factor: 1.889