Adrenocortical carcinoma (ACC) is a rare but aggressive
malignancy with a poor prognosis. Complete surgical resection offers the only potential for cure; however, even after apparently successful excision, local or metastatic recurrence is frequent. Treatment options for advanced ACC are severely limited.
Mitotane is the only recognized adrenolytic
therapy available; however, response rates are modest and unpredictable whereas systemic toxicities are significant. Reported responses to conventional cytotoxic
chemotherapy have also been disappointing, and the rarity of ACC had hampered the ability to undertake randomized clinical studies until the establishment of the First International Randomized Trial in Locally Advanced and Metastatic
Adrenocortical Carcinoma. This yet-to-be reported study seeks to identify the most effective first- and second-line cytotoxic regimens. The past decade has also seen increasing research into the molecular pathogenesis of ACCs, with particular interest in the
insulin-like growth factor signaling pathway. The widespread development of small molecule
tyrosine kinase inhibitors in broader oncological practice is now allowing for the rational selection of targeted
therapies to study in ACC. In this review, we discuss the currently available therapeutic options for patients with advanced ACC and detail the molecular rationale behind, and clinical evidence for, novel and emerging
therapies.