Plasma-guided mitotane for the treatment of adrenocortical carcinoma: adjuvant care to advanced disease

Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy with limited therapeutic options and a substantial risk of postoperative recurrence. Mitotane remains the only US Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) approved agent specifically for ACC. Its antitumor activity involves disruption of cholesterol trafficking, inhibition of steroidogenic enzymes, and mitochondrial dysfunction, leading to selective cytotoxicity in adrenocortical cells. Current evidence indicates that maintaining therapeutic plasma concentrations between 14 mg/L and 20 ​mg/L is critical for clinical benefit, underscoring the importance of therapeutic drug monitoring. Mitotane is used in both adjuvant and advanced disease settings; however, its highly variable pharmacokinetics, broad endocrine disruptions, and frequent gastrointestinal and neurological toxicities require individualized dosing strategies and comprehensive supportive care. This review summarizes recent advances in the understanding of mitotane’s molecular mechanisms, pharmacogenetic determinants, clinical efficacy, and adverse-effect profile, with an emphasis on laboratory monitoring and practical considerations for optimizing treatment in ACC.