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A fly in the ointment: reassessing mitotane's role in the treatment of adrenocortical carcinoma.

Mitotane (2-[o-chlorophenyl]-2-[p-chloro phenyl]-1,1-dichloroethane or o,p´-DDD), an isomer of the banned pesticide 1,1,1-trichloro2,2-di(4-chlorophenyl)ethane (DDT), is the current standard of care for patients presenting with advanced and metastatic adrenocortical carcinoma (ACC) [1–3]. Mitotane or combinations containing mitotane have remained the standard of care for patients with ACC for over 30 years despite a lack of understanding regarding its mechanism of action or interactions with other agents and a suboptimal effectiveness. The results from the recently reported FIRM-ACT trial [4] and evidence from a study of urine steroid profiles of patients with ACC cast further doubt on the broad use of mitotane in treating ACC patients [5]. These studies highlight a need to identify markers of mitotane resistance and put significant effort into the development of new treatments, and possibly treatment paradigms, in order to improve outcomes for patients with ACC. Why mitotane is the standard of care for the treatment of ACC ACC is an aggressive cancer of the adrenal cortex. The outcome for patients with ACC has remained unchanged in the past 25 years, with the overall 5-year survival of patients undergoing surgical resection being approximately 40% [6]. The disease may have a variable course. Certain patients generally fare better, including those with stage II disease whose 5-year survival rates approach 60%, and improve to greater than 95% if their tumor does not recur within 16 months [7]. However, patients who present with large, locally invasive tumors, have involved surgical margins or present with metastatic disease fare considerably worse with 5-year survival rates of 10–20% [6]. The rationale for using mitotane as treatment for ACC stems from early observations of the adrenolytic effect of the pesticide DDT