{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T06:45:31Z","timestamp":1769150731521,"version":"3.49.0"},"reference-count":46,"publisher":"Georg Thieme Verlag KG","issue":"05","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Horm Metab Res"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy. For stage I\n                    and II tumors, surgery is a curative option, but even in these cases recurrence\n                    is frequent. Practical guidelines advocate a combination of mitotane with\n                    etoposide, doxorubicin, and cisplatin as first-line therapy for metastatic\n                    adrenocortical carcinoma. However, this scheme presents limited efficacy and\n                    high toxicity. The use of Immune Checkpoint Inhibitors (ICI) and multi-Tyrosine\n                    Kinase Inhibitors (mTKI) has modified the approach of multiple malignancies. The\n                    expectation of their applicability on advanced adrenocortical carcinoma is high\n                    but the role of these new therapies persists unclear. This article provides a\n                    short summary of last years\u2019 findings targeting outcomes, limitations,\n                    and adverse effects of these new therapeutic approaches. The results of recent\n                    trials and case series pointed pembrolizumab as the most promising drug among\n                    these new therapies. It is the most often used ICI and the one presenting the\n                    best results with less related adverse effects when in comparison to the\n                    standard treatment with mitotane. Hereafter, the identification of specific\n                    molecular biomarkers or immune profiles associated with ICI or mTKI good\n                    response will facilitate the selection of candidates for these therapies. So\n                    far, microsatellite instability and Lynch Syndrome related germline mutations\n                    are suggested as predictive biomarkers of good response. Contrarywise, cortisol\n                    secretion has been associated with more aggressive ACC tumors and potentially\n                    poor responses to immunotherapy.<\/jats:p>","DOI":"10.1055\/a-1453-0806","type":"journal-article","created":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T23:01:09Z","timestamp":1620428469000},"page":"285-292","source":"Crossref","is-referenced-by-count":7,"title":["Advanced Adrenocortical Carcinoma: Current Perspectives on Medical\n                    Treatment"],"prefix":"10.1055","volume":"53","author":[{"given":"Alexandra Novais","family":"Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar\n                    Universit\u00e1rio Lisboa Norte, Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Jo\u00e3o","family":"Bugalho","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar\n                    Universit\u00e1rio Lisboa Norte, Lisbon, Portugal"},{"name":"Faculty of Medicine, Lisbon University, Lisbon, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"194","published-online":{"date-parts":[[2021,5,7]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.mce.2011.10.019","article-title":"Molecular epidemiology of adrenocortical tumors in southern Brazil","volume":"351","author":"G Cust\u00f3dio","year":"2012","journal-title":"Mol Cell Endocrinol"},{"key":"ref2","doi-asserted-by":"crossref","first-page":"101434","DOI":"10.1016\/j.beem.2020.101434","article-title":"Next-generation therapies for adrenocortical carcinoma","volume":"34","author":"B Altieri","year":"2020","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"ref3","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1530\/EJE-18-0608","article-title":"European Society of Endocrinology Clinical Practice Guidelines on the management\n                    of adrenocortical carcinoma in adults, in collaboration with the European\n                    Network for the Study of Adrenal Tumors","volume":"179","author":"M Fassnacht","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1210\/er.2013-1029","article-title":"Adrenocortical carcinoma","volume":"35","author":"T Else","year":"2014","journal-title":"Endocr Rev"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2019\/6072863","article-title":"Molecular drivers of potential immunotherapy failure in adrenocortical\n                    carcinoma","volume":"2019","author":"C Fiorentini","year":"2019","journal-title":"J Oncol"},{"key":"ref6","doi-asserted-by":"crossref","first-page":"e307","DOI":"10.1210\/clinem\/dgz141","article-title":"Urine steroid metabolomics as a novel tool for detection of recurrent\n                    adrenocortical carcinoma","volume":"105","author":"V Chortis","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1007\/s40618-020-01306-5","article-title":"The role of immune checkpoint inhibitor therapy in advanced adrenocortical\n                    carcinoma revisited: Review of literature","volume":"43","author":"E P Brabo","year":"2020","journal-title":"J Endocrinol Invest"},{"key":"ref8","first-page":"96370.","article-title":"An eleven-year experience with adrenocortical carcinoma","volume":"112","author":"R F Pommier","year":"1992","journal-title":"Surgery"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1200\/JCO.2002.20.4.941","article-title":"Adrenocortical carcinoma: Clinical, morphologic, and molecular\n                    characterization","volume":"20","author":"A Stojadinovic","year":"2002","journal-title":"J Clin Oncol"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s40880-019-0426-0","article-title":"A nomogram for individualized estimation of survival among adult patients with\n                    adrenocortical carcinoma after surgery: a retrospective analysis and multicenter\n                    validation study","volume":"39","author":"J Kong","year":"2019","journal-title":"Cancer Commun"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"3566","DOI":"10.1210\/jc.2018-00918","article-title":"Predictors of survival in adrenocortical carcinoma: An analysis from the\n                    National Cancer Database","volume":"103","author":"S H Tella","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"508","DOI":"10.3390\/cancers12020508","article-title":"Adjuvant Therapy in Adrenocortical Carcinoma: Reflections and Future\n                    Directions","volume":"12","author":"S Bedrose","year":"2020","journal-title":"Cancers (Basel)"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1056\/NEJMoa063360","article-title":"Adjuvant Mitotane Treatment for Adrenocortical Carcinoma","volume":"356","author":"M Terzolo","year":"2007","journal-title":"N Engl J Med"},{"issue":"01","key":"ref15","first-page":"78","article-title":"NCCN Clinical Practice Guidelines in\n                Oncology:Neuroendocrine tumors","volume":"13","author":"M Kulk","year":"2015","journal-title":"J Natl Compr Canc Netw"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1056\/NEJMoa1200966","article-title":"Combination Chemotherapy in Advanced Adrenocortical Carcinoma","volume":"366","author":"M Fassnacht","year":"2012","journal-title":"N Engl J Med"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1677\/ERC-09-0281","article-title":"Gemcitabine plus metronomic 5-fluorouracil or capecitabine as a\n                    second-\/third-line chemotherapy in advanced adrenocortical carcinoma: a\n                    multicenter phase II study","volume":"17","author":"P Sperone","year":"2010","journal-title":"Endocr Relat Cancer"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1210\/jc.2008-1456","article-title":"Preclinical targeting of the type I insulin-like growth factor receptor in\n                    adrenocortical carcinoma","volume":"94","author":"F M Barlaskar","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/S1470-2045(15)70081-1","article-title":"Linsitinib (OSI-906) versus placebo for patients with locally advanced or\n                    metastatic adrenocortical carcinoma: A double-blind, randomised, phase 3\n                    study","volume":"16","author":"M Fassnacht","year":"2015","journal-title":"Lancet Oncol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.aan6733","article-title":"Mismatch repair deficiency predicts response of solid tumors to PD-1\n                    blockade","volume":"357","author":"D T Le","year":"2017","journal-title":"Science"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1111\/iju.12903","article-title":"Sunitinib monotherapy instead of mitotane combination therapy for the treatment\n                    of refractory adrenocortical carcinoma","volume":"22","author":"J Zhuang","year":"2015","journal-title":"Int J Urol"},{"key":"ref22","first-page":"105","article-title":"Objective response and prolonged disease control of advanced adrenocortical\n                    carcinoma with cabozantinib","author":"M Kroiss","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"ref23","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.ccell.2016.04.002","article-title":"Comprehensive pan-genomic characterization of adrenocortical carcinoma","volume":"29","author":"S Zheng","year":"2016","journal-title":"Cancer Cell"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1530\/ERC-11-0337","article-title":"Combination of sorafenib and everolimus impacts therapeutically on\n                    adrenocortical tumor models","volume":"19","author":"B Mariniello","year":"2012","journal-title":"J Endocr Relat Cancer"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"253","DOI":"10.21037\/atm.2018.05.52","article-title":"The role of epithelial growth factors and insulin growth factors in the adrenal\n                    neoplasms","volume":"6","author":"A Angelousi","year":"2018","journal-title":"Ann Transl Med"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"bvaa069","DOI":"10.1210\/jendso\/bvaa069","article-title":"Salvage therapy with multikinase inhibitors and immunotherapy in advanced\n                    adrenal cortical carcinoma","volume":"4","author":"K C Miller","year":"2020","journal-title":"J Endocr Soc"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"e001009","DOI":"10.1136\/jitc-2020-001009","article-title":"Combined lenvatinib and pembrolizumab as salvage therapy in advanced adrenal\n                    cortical carcinoma","volume":"8","author":"S Bedrose","year":"2020","journal-title":"J Immunother Cancer"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"3495","DOI":"10.1210\/jc.2012-1419","article-title":"Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm,\n                    open-label trial","volume":"97","author":"M Kroiss","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1055\/a-0715-1946","article-title":"Advanced Adrenocortical Carcinoma - What to do when First-Line Therapy\n                    Fails?","volume":"127","author":"F Megerle","year":"2019","journal-title":"Exp Clin Endocrinol Diabetes"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"e13517","DOI":"10.1097\/MD.0000000000013517","article-title":"Pembrolizumab for metastatic adrenocortical carcinoma with high mutational\n                    burden: Two case reports","volume":"97","author":"J M Mota","year":"2018","journal-title":"Medicine (Baltimore)"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1053\/j.seminoncol.2018.12.005","article-title":"Letter to Editor: Reply to R.T. Casey (Semin Oncol 2018; 45:\n                    151\u2013155)","volume":"46","author":"M Caccese","year":"2019","journal-title":"Semin Oncol"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1111\/cen.14258","article-title":"Sustained remission of Lynch syndrome-associated metastatic adrenocortical\n                    carcinoma following checkpoint inhibitor therapy-associated multiorgan\n                    autoimmunity","volume":"93","author":"A Nevgi","year":"2020","journal-title":"Clin Endocrinol"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"4172","DOI":"10.1038\/s41467-018-06366-z","article-title":"Metastatic adrenocortical carcinoma displays higher mutation rate and tumor\n                    heterogeneity than primary tumors","volume":"9","author":"S K Gara","year":"2018","journal-title":"Nat Commun"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40425-015-0078-9","article-title":"Pembrolizumab","volume":"3","author":"L Khoja","year":"2015","journal-title":"J Immunother Cancer"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"e000347","DOI":"10.1136\/jitc-2019-000347","article-title":"Phase 2 study of pembrolizumab in patients with advanced rare cancers","volume":"8","author":"A Naing","year":"2020","journal-title":"J Immunother Cancer"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"e000469","DOI":"10.1136\/jitc-2019-000469","article-title":"Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the\n                    prognosis of adrenocortical carcinoma","volume":"8","author":"L-S Landwehr","year":"2020","journal-title":"J Immunother Cancer"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1200\/JCO.19.01586","article-title":"PD-1 Blockade in Advanced Adrenocortical Carcinoma","volume":"38","author":"N Raj","year":"2020","journal-title":"J Clin Oncol"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1186\/s40425-019-0722-x","article-title":"Phase II clinical trial of pembrolizumab efficacy and safety in advanced\n                    adrenocortical carcinoma","volume":"7","author":"M A Habra","year":"2019","journal-title":"J Immunother Cancer"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"6193","DOI":"10.1210\/jc.2019-00600","article-title":"Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2\n                    Trial","volume":"104","author":"B A Carneiro","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s40425-018-0424-9","article-title":"Avelumab in patients with previously treated metastatic adrenocortical\n                    carcinoma: phase 1b results from the JAVELIN solid tumor trial","volume":"6","author":"C Le Tourneau","year":"2018","journal-title":"J Immunother Cancer"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1210\/js.2019-00305","article-title":"Response to Immunotherapy in Combination With Mitotane in Patients With\n                    Metastatic Adrenocortical Cancer","volume":"3","author":"L Head","year":"2019","journal-title":"J Endocr Soc"},{"key":"ref42","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s40425-017-0212-y","article-title":"Immunotherapy resistance: the answers lie ahead - not in front - of us","volume":"5","author":"M C Andrews","year":"2017","journal-title":"J Immunother Cancer"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.ecl.2018.02.003","article-title":"Adrenocortical Carcinoma with Hypercortisolism","volume":"47","author":"S Puglisi","year":"2018","journal-title":"Endocrinol Metab Clin North Am"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1080\/21645515.2016.1199310","article-title":"Pembrolizumab (Keytruda)","volume":"12","author":"G Kwok","year":"2016","journal-title":"Hum Vaccin Immunother"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/phar.2076","article-title":"Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor","volume":"38","author":"J N Markowitz","year":"2018","journal-title":"Pharmacotherapy"},{"key":"ref46","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1053\/j.seminoncol.2018.06.001","article-title":"Rapid disease progression in a patient with mismatch repair-deficient and\n                    cortisol secreting adrenocortical carcinoma treated with pembrolizumab","volume":"45","author":"R T Casey","year":"2018","journal-title":"Semin Oncol"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"R51","DOI":"10.1530\/EJE-20-0800","article-title":"ENSAT Registry-Based Randomized Clinical Trials for Adrenocortical\n                    Carcinoma","volume":"184","author":"J Crona","year":"2021","journal-title":"Eur J Endocrinol"}],"container-title":["Hormone and Metabolic Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.thieme-connect.de\/products\/ejournals\/pdf\/10.1055\/a-1453-0806.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,7]],"date-time":"2021-05-07T23:01:56Z","timestamp":1620428516000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.thieme-connect.de\/DOI\/DOI?10.1055\/a-1453-0806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5]]},"references-count":46,"journal-issue":{"issue":"05","published-online":{"date-parts":[[2021,5,7]]},"published-print":{"date-parts":[[2021,5]]}},"URL":"https:\/\/doi.org\/10.1055\/a-1453-0806","relation":{},"ISSN":["0018-5043","1439-4286"],"issn-type":[{"value":"0018-5043","type":"print"},{"value":"1439-4286","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5]]}}}