Antineoplastic effect of block-and-replace strategy for managing hypercortisolism caused by adrenal cortical carcinoma

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy frequently associated with cortisol hypersecretion, which confers substantial morbidity and a worse prognosis. In metastatic ACC, rapid control of Cushing syndrome is essential to allow systemic therapy. Although the block-and-replace strategy using steroidogenesis inhibitors is well established for cortisol control, its potential antineoplastic effects have not been previously reported. We describe 2 patients with metastatic ACC and severe Cushing syndrome treated with block-and-replace using osilodrostat or metyrapone. In both, cortisol normalized rapidly and safely, with marked clinical improvement. Unexpectedly, both experienced significant radiological tumor responses before exposure to effective cytotoxic chemotherapy and before therapeutic mitotane plasma concentrations were achieved. These cases suggest that steroidogenesis inhibition within a block-and-replace strategy may exert a direct or indirect antineoplastic effect in ACC. Although causality cannot be established, the temporal association between cortisol blockade and tumor response is compelling and warrants further prospective and translational investigation.