Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study: a multicentre international ENSAT study

Alessandra Mangone; Barbara Altieri; Emanuele Ferrante; Irina Bancos; Michaela Luconi; Barbara Ziółkowska; Anja Barač Nekić; Rosella Libe; Filippo Ceccato; James F. H.  Pittaway; Marta Laganà; Guido Di Dalmazi; Erika Peverelli; Otilia Kimpel; Bahar Bahrani Fard; Letizia Canu; Agnieszka Kotecka-Blicharz; Darko Kastelan; Lucas Bouys; Irene Tizianel; Gillian Bennett; Marc P. Schauer; Yasir Elhassan; Mario Detomas; Lorenzo Zanatta; Maaz Sadiq; Giovanna Mantovani; Cristina L. Ronchi

doi:10.1093/ejendo/lvag046

Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study: a multicentre international ENSAT study

Alessandra Mangone
, Barbara Altieri
, Emanuele Ferrante
, Irina Bancos
, Michaela Luconi
, Barbara Ziółkowska
, Anja Barač Nekić
, Rosella Libe
, Filippo Ceccato
, James F. H. Pittaway
, Marta Laganà
, Guido Di Dalmazi
, Erika Peverelli
, Otilia Kimpel
, Bahar Bahrani Fard
, Letizia Canu
, Agnieszka Kotecka-Blicharz
, Darko Kastelan
, Lucas Bouys
, Irene Tizianel

Gillian Bennett, Marc P. Schauer, Yasir Elhassan, Mario Detomas, Lorenzo Zanatta, Maaz Sadiq, Giovanna Mantovani, Cristina L. Ronchi^*

^*Corresponding author for this work

Metabolism and Systems Science

Research output: Contribution to journal › Article › peer-review

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Abstract

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 centers. 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 (hazard ratio [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 < .01) and second-line therapies (P = .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.

Original language	English
Article number	lvag046
Pages (from-to)	381-392
Number of pages	12
Journal	European Journal of Endocrinology
Volume	194
Issue number	3
Early online date	6 Mar 2026
DOIs	https://doi.org/10.1093/ejendo/lvag046
Publication status	Published - 18 Mar 2026

Keywords

EDP
predictors
adrenal cancer
mitotane
chemotherapy

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Mangone, A., Altieri, B., Ferrante, E., Bancos, I., Luconi, M., Ziółkowska, B., Nekić, A. B., Libe, R., Ceccato, F., Pittaway, J. F. H., Laganà, M., Di Dalmazi, G., Peverelli, E., Kimpel, O., Fard, B. B., Canu, L., Kotecka-Blicharz, A., Kastelan, D., Bouys, L., ... Ronchi, C. L. (2026). Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study: a multicentre international ENSAT study. European Journal of Endocrinology, 194(3), 381-392. Article lvag046. https://doi.org/10.1093/ejendo/lvag046

@article{356513dd093743739634c0947564666d,

title = "Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study: a multicentre international ENSAT study",

abstract = "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 centers. 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 (hazard ratio [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 < .01) and second-line therapies (P = .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.",

keywords = "EDP, predictors, adrenal cancer, mitotane, chemotherapy",

author = "Alessandra Mangone and Barbara Altieri and Emanuele Ferrante and Irina Bancos and Michaela Luconi and Barbara Zi{\'o}{\l}kowska and Neki{\'c}, \{Anja Bara{\v c}\} and Rosella Libe and Filippo Ceccato and Pittaway, \{James F. H.\} and Marta Lagan{\`a} and \{Di Dalmazi\}, Guido and Erika Peverelli and Otilia Kimpel and Fard, \{Bahar Bahrani\} and Letizia Canu and Agnieszka Kotecka-Blicharz and Darko Kastelan and Lucas Bouys and Irene Tizianel and Gillian Bennett and Schauer, \{Marc P.\} and Yasir Elhassan and Mario Detomas and Lorenzo Zanatta and Maaz Sadiq and Giovanna Mantovani and Ronchi, \{Cristina L.\}",

year = "2026",

month = mar,

day = "18",

doi = "10.1093/ejendo/lvag046",

language = "English",

volume = "194",

pages = "381--392",

journal = "European Journal of Endocrinology",

issn = "0804-4643",

publisher = "BioScientifica",

number = "3",

}

Mangone, A, Altieri, B, Ferrante, E, Bancos, I, Luconi, M, Ziółkowska, B, Nekić, AB, Libe, R, Ceccato, F, Pittaway, JFH, Laganà, M, Di Dalmazi, G, Peverelli, E, Kimpel, O, Fard, BB, Canu, L, Kotecka-Blicharz, A, Kastelan, D, Bouys, L, Tizianel, I, Bennett, G, Schauer, MP, Elhassan, Y, Detomas, M, Zanatta, L, Sadiq, M, Mantovani, G & Ronchi, CL 2026, 'Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study: a multicentre international ENSAT study', European Journal of Endocrinology, vol. 194, no. 3, lvag046, pp. 381-392. https://doi.org/10.1093/ejendo/lvag046

Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study: a multicentre international ENSAT study. / Mangone, Alessandra; Altieri, Barbara; Ferrante, Emanuele et al.
In: European Journal of Endocrinology, Vol. 194, No. 3, lvag046, 18.03.2026, p. 381-392.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study

T2 - a multicentre international ENSAT study

AU - Mangone, Alessandra

AU - Altieri, Barbara

AU - Ferrante, Emanuele

AU - Bancos, Irina

AU - Luconi, Michaela

AU - Ziółkowska, Barbara

AU - Nekić, Anja Barač

AU - Libe, Rosella

AU - Ceccato, Filippo

AU - Pittaway, James F. H.

AU - Laganà, Marta

AU - Di Dalmazi, Guido

AU - Peverelli, Erika

AU - Kimpel, Otilia

AU - Fard, Bahar Bahrani

AU - Canu, Letizia

AU - Kotecka-Blicharz, Agnieszka

AU - Kastelan, Darko

AU - Bouys, Lucas

AU - Tizianel, Irene

AU - Bennett, Gillian

AU - Schauer, Marc P.

AU - Elhassan, Yasir

AU - Detomas, Mario

AU - Zanatta, Lorenzo

AU - Sadiq, Maaz

AU - Mantovani, Giovanna

AU - Ronchi, Cristina L.

PY - 2026/3/18

Y1 - 2026/3/18

N2 - 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 centers. 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 (hazard ratio [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 < .01) and second-line therapies (P = .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.

AB - 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 centers. 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 (hazard ratio [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 < .01) and second-line therapies (P = .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.

KW - EDP

KW - predictors

KW - adrenal cancer

KW - mitotane

KW - chemotherapy

UR - https://academic.oup.com/ejendo

U2 - 10.1093/ejendo/lvag046

DO - 10.1093/ejendo/lvag046

M3 - Article

SN - 0804-4643

VL - 194

SP - 381

EP - 392

JO - European Journal of Endocrinology

JF - European Journal of Endocrinology

IS - 3

M1 - lvag046

ER -

Clinical predictors of outcome in advanced adrenocortical carcinoma: a multicenter international ENSAT study: a multicentre international ENSAT study

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Keywords

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