{"entity":{"id":"advanced-adrenocortical-carcinoma","kind":"cancer","name":"Advanced and metastatic adrenocortical carcinoma (ENSAT stage IV or unresectable)","aka":["Metastatic ACC","Stage IV adrenocortical carcinoma","Unresectable adrenal cortical carcinoma","Recurrent adrenocortical carcinoma"],"tldr":"Advanced adrenocortical carcinoma is adrenal cortex cancer that has spread to distant organs or cannot be removed, one of the hardest endocrine cancers to treat. The standard is mitotane with etoposide, doxorubicin and cisplatin, established by the FIRM-ACT trial; limited spread is treated locally, hormone excess with steroid-blocking drugs, and immunotherapy helps a minority.","summary":"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.\n\nFIRM-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.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Adrenocortical_carcinoma","links":[{"label":"FIRM-ACT (NEJM 2012)","url":"https://doi.org/10.1056/NEJMoa1200966"},{"label":"ESE/ENSAT guideline 2018","url":"https://doi.org/10.1530/EJE-18-0608"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Adrenocortical_carcinoma"}],"tags":["subtype-page","endocrine"],"related":["localised-adrenocortical-carcinoma","adrenocortical","metastatic-ppgl"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","checkpoint-inhibitor","kinase-inhibitors","thermal-ablation","sbrt"],"targets":["tp53","pd1","vegf"],"drugs":["mitotane","etoposide","doxorubicin","cisplatin","gemcitabine","capecitabine","cabozantinib","pembrolizumab","relacorilant"],"companies":[],"institutions":[],"pathways":[],"terms":["adrenalectomy","germline-vs-somatic","msi","tmb"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-firm-act-edp-mitotane-adrenocortical-carcinoma-nejm-2012","paper-ese-ensat-adrenocortical-carcinoma-guideline-eur-j-endocrinol-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"endocrine","burden":"A third or more of patients present with metastases, usually to the liver, lungs and peritoneum, and many more relapse after surgery; median survival is measured in months to a few years.","subtypes":["Synchronous metastatic adrenocortical carcinoma (liver, lung, peritoneum)","Recurrent adrenocortical carcinoma after resection","Low-burden, slow-growing metastatic disease (mitotane alone, local therapy)","High-burden or rapidly progressing disease (EDP-M)","Cortisol-secreting metastatic adrenocortical carcinoma (steroid blockade needed)","Mismatch-repair-deficient adrenocortical carcinoma (Lynch syndrome; checkpoint inhibitor responsive)"],"biomarkers":["Ki-67 index and tumour burden (pace of disease)","Hormone profile, above all cortisol (steroid blockade)","Plasma mitotane level (14 to 20 mg/L)","Mismatch repair status and tumour mutational burden (immunotherapy)","Germline TP53 and Lynch syndrome testing","Molecular subgroups (CIMP-high, C1A) as prognostic markers in research"],"standardOfCare":[{"setting":"All patients","approach":"Mitotane from diagnosis with glucocorticoid replacement; adrenal enzyme inhibitors (metyrapone, osilodrostat, ketoconazole) for cortisol excess; thromboprophylaxis and infection vigilance.","refs":["mitotane"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"Low-burden, indolent disease","approach":"Mitotane alone, with resection, thermal ablation or stereotactic radiotherapy of limited metastases.","refs":["mitotane","thermal-ablation","sbrt","adrenalectomy"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"High-burden or progressive disease, first line","approach":"Etoposide, doxorubicin and cisplatin with mitotane (EDP-M, FIRM-ACT).","refs":["etoposide","doxorubicin","cisplatin","mitotane","cytotoxic-chemotherapy"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"After EDP-M","approach":"Gemcitabine with capecitabine; cabozantinib; pembrolizumab, especially for mismatch-repair-deficient tumours; streptozocin-mitotane; clinical trials.","refs":["gemcitabine","capecitabine","cabozantinib","pembrolizumab","checkpoint-inhibitor","kinase-inhibitors"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}},{"setting":"Trials","approach":"Relacorilant with checkpoint inhibition for cortisol-secreting tumours; cabozantinib with immunotherapy; radiolabelled CYP11B tracers.","refs":["relacorilant","cabozantinib","pembrolizumab"],"guideline":{"version":"ESE/ENSAT guideline on adrenocortical carcinoma 2018","url":"https://doi.org/10.1530/EJE-18-0608"}}],"stateOfArt":["FIRM-ACT gave the disease its only randomised first-line standard.","Controlling cortisol excess is as important as controlling the tumour.","Immunotherapy helps a minority, and combinations that overcome cortisol-driven immunosuppression are the main hope."],"history":[{"year":1990,"title":"Etoposide, doxorubicin and cisplatin with mitotane (Berruti regimen) developed in Italy","refs":["etoposide","doxorubicin","cisplatin","mitotane"]},{"year":2012,"title":"FIRM-ACT: EDP-M beats streptozocin-mitotane on response and progression-free survival","refs":["etoposide","doxorubicin","cisplatin","mitotane"]},{"year":2015,"title":"Linsitinib phase 3 fails: IGF-1 receptor blockade does not work","refs":[]},{"year":2020,"title":"Pembrolizumab phase 2 trials report responses in about a fifth of patients","refs":["pembrolizumab"]},{"year":2024,"title":"Cabozantinib phase 2 reports disease control in advanced adrenocortical carcinoma","refs":["cabozantinib"]}],"pipeline":["cabozantinib","pembrolizumab","relacorilant","mitotane"],"openProblems":["No second-line therapy has randomised evidence.","Most tumours are immunologically cold and cortisol excess worsens that.","Mitotane's narrow therapeutic window and slow onset limit it in fast disease.","The rarity of the disease has meant only one completed phase 3 trial in fifty years."],"parent":"adrenocortical"},"route":"/cancers/advanced-adrenocortical-carcinoma/","neighbours":{"cancer":[{"id":"adrenocortical","kind":"cancer","name":"Adrenocortical carcinoma","route":"/cancers/adrenocortical/"},{"id":"localised-adrenocortical-carcinoma","kind":"cancer","name":"Localised adrenocortical carcinoma (ENSAT stage I to III, resectable)","route":"/cancers/localised-adrenocortical-carcinoma/"},{"id":"metastatic-ppgl","kind":"cancer","name":"Metastatic pheochromocytoma and paraganglioma","route":"/cancers/metastatic-ppgl/"}],"technology":[{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"thermal-ablation","kind":"technology","name":"Thermal ablation (RFA, microwave, cryo)","route":"/technologies/thermal-ablation/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"capecitabine","kind":"drug","name":"Capecitabine","route":"/drugs/capecitabine/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/"},{"id":"etoposide","kind":"drug","name":"Etoposide","route":"/drugs/etoposide/"},{"id":"gemcitabine","kind":"drug","name":"Gemcitabine","route":"/drugs/gemcitabine/"},{"id":"mitotane","kind":"drug","name":"Mitotane","route":"/drugs/mitotane/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"relacorilant","kind":"drug","name":"Relacorilant","route":"/drugs/relacorilant/"}],"term":[{"id":"adrenalectomy","kind":"term","name":"Adrenalectomy","route":"/terms/adrenalectomy/"},{"id":"germline-vs-somatic","kind":"term","name":"Germline vs somatic mutations","route":"/terms/germline-vs-somatic/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"paper":[{"id":"paper-ese-ensat-adrenocortical-carcinoma-guideline-eur-j-endocrinol-2018","kind":"paper","name":"European Society of Endocrinology and ENSAT clinical practice guidelines on the management of adrenocortical carcinoma in adults","route":"/key-papers/paper-ese-ensat-adrenocortical-carcinoma-guideline-eur-j-endocrinol-2018/"},{"id":"paper-firm-act-edp-mitotane-adrenocortical-carcinoma-nejm-2012","kind":"paper","name":"FIRM-ACT: combination chemotherapy in advanced adrenocortical carcinoma","route":"/key-papers/paper-firm-act-edp-mitotane-adrenocortical-carcinoma-nejm-2012/"}]}}