Clinical Predictors of Outcome in Advanced Adrenocortical Carcinoma: a multicentre international ENSAT study

Objective: Advanced adrenocortical carcinoma (ACC) is treated with mitotane alone or combined with cytotoxic chemotherapy, yet outcomes remain poor and prognostic models in this setting are lacking. This study aimed to evaluate the prognostic value of clinical parameters in a large cohort of patients with advanced ACC undergoing systemic therapy. Methods: Multicenter, international cohort study investigating 418 patients with advanced ACC (61.5%=women, median age=52 years) from 11 centres. Patients received mitotane monotherapy (n=161), etoposide + doxorubicin + cisplatin ± mitotane (n=178), or second-line regimens (gemcitabine + capecitabine ± mitotane or temozolomide + mitotane, n=79). Variables included age, cortisol excess, performance status (ECOG-PS), tumor burden, and neutrophil-to-lymphocyte ratio (NLR) at start of therapy. Outcomes were overall survival (OS), time to progression (TTP), and best objective response. Results: Tumor burden, cortisol excess, ECOG-PS, and NLR ≥5 independently predicted shorter OS (HR 1.55-2.68). We developed an integrated ENSAT Risk Score for Advanced ACC combining these variables: tumor burden (0-2), cortisol excess (0/1), ECOG-PS (0-2), and NLR (0/1). A score >2 (poor-risk) was significantly associated with worse OS and TTP across all treatment groups (HRs for OS: 3.05-3.96; TTP: 2.53-3.08). It also predicted poorer response to mitotane (p<0.01) and second-line therapies (p=0.04). Conclusions: The ENSAT Risk Score for Advanced ACC is a practical, prognostic tool for patients with advanced ACC receiving systemic therapy. Based on accessible clinical and biochemical markers, it can support treatment decisions and facilitate informed discussions in routine care.