Advanced and metastatic adrenocortical carcinoma (ENSAT stage IV or unresectable)

Metastatic adrenocortical carcinoma is often a double problem: a fast-growing cancer and, in the majority of patients, uncontrolled cortisol or androgen excess that itself causes muscle wasting, infections, thrombosis and diabetes. Mitotane, which destroys adrenocortical cells and blocks steroid synthesis, is the backbone of treatment and is started at diagnosis in all patients, with adrenal enzyme inhibitors such as metyrapone or osilodrostat added when cortisol needs to fall quickly; the glucocorticoid receptor antagonist relacorilant is being tested for the same purpose. Tumours with a low burden of disease and a slow course can be treated with mitotane alone or with resection, ablation or stereotactic radiotherapy of metastases, and the ESE/ENSAT guideline advises against debulking surgery unless most of the disease can be removed.

FIRM-ACT (New England Journal of Medicine 2012), the first randomised phase 3 trial in the disease, compared mitotane with etoposide, doxorubicin and cisplatin (EDP-M) against mitotane with streptozocin in 304 patients: EDP-M produced more responses (23.2 against 9.2 percent) and longer progression-free survival (5.0 against 2.1 months) without a significant difference in overall survival, and it has been the first-line standard since. Nothing has matched it in second line. Gemcitabine with capecitabine gives modest disease control; the multikinase inhibitor cabozantinib produced disease stabilisation and a few responses in retrospective series and a phase 2 trial; pembrolizumab produced responses in about one in five patients in two phase 2 trials, more often in the minority of tumours that are mismatch-repair deficient from Lynch syndrome, but most carcinomas are immunologically cold, in part because cortisol suppresses immunity, so trials now combine checkpoint inhibitors with cortisol blockade or with cabozantinib. The steroidogenic enzyme CYP11B1 is a target for radiolabelled tracers and the IGF-2 pathway that drives many tumours proved undruggable in the linsitinib phase 3 trial. Median survival in metastatic disease remains poor, and referral to an ENSAT centre and to trials is recommended for every patient.