Systemic Therapy in Locally Advanced or Metastatic Adrenal Cancers: A Critical Appraisal and Clinical Trial Update

The management of patients with adrenocortical carcinoma (ACC) is difficult. Surgery is the mainstay of treatment. Mitotane and cytotoxic chemotherapy are currently the only systemic treatments available for locally advanced or metastatic ACC not amenable to surgery. Owing to the rarity of the disease, there was uncertainty for many years regarding the efficacy of mitotane and chemotherapy. Only recently an international task force demonstrated that longterm maintenance of mitotane levels >14 mg/dl is predictive of survival in patients with metastatic ACC [1] and that mitotane may be effective in the adjuvant setting according to a case-control study [2], supported by demonstration of the prognostic role of drug serum levels in this setting [3]. The most relevant finding was demonstration of the efficacy of chemotherapy in a multicenter, multinational, prospective randomized phase 3 trial (FIRM-ACT) trial [4]. In this trial, etoposide, doxorubicin, and cisplatin plus mitotane (EDP-M) [5] was superior to streptozotocin plus mitotane (SZ-M) [6] in terms of response rate and progression-free survival (PFS). EDP-M also yielded better overall survival, without reaching statistical significance because of the crossover design whereby patients who progress on first-line treatment could receive the alternative regimen. All these data represent an important step forward in the management of this rare and challenging disease, but several issues remain unaddressed. (1) The combination of chemotherapy and mitotane is only supported by preclinical data showing a synergism between these two treatments [7] and by indirect comparison of results from case series or phase 2 trials [8]. (2) It has not been demonstrated that the efficacy of EDP-M is superior to that