{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:07:39Z","timestamp":1784700459398,"version":"3.55.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Mitotane remains the cornerstone of adrenocortical carcinoma. However, its real-world safety profile is poorly defined. This study systemically evaluated mitotane-associated adverse events (AEs) and characterized multivariable patterns of serious outcomes using a combined pharmacovigilance and machine learning approach.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Mitotane-related AE reports (2004-2025) were extracted from the FDA Adverse Event Reporting System (FAERS). Disproportionality analyses were performed via four algorithms. Detected signals were categorized using a clinical priority scoring system based on signal strength, mortality, seriousness, and existing evidence. Time-to-onset was evaluated utilizing Kaplan-Meier methods. Elastic net logistic regression and Extreme Gradient Boosting (XGBoost) models characterized features associated with serious outcomes, with performance assessed by the area under the receiver operating characteristic curve (AUROC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 870 identified reports, 45.7% involved serious outcomes. We detected 75 safety signals, predominantly involving gastrointestinal, neurological, endocrine, and metabolic systems. Notably, 21 signals (28.0%) were assigned moderate clinical priority, with adrenal insufficiency as the highest-priority signal. Time-to-onset analysis showed that endocrine AEs had a significantly longer onset time than non-endocrine AEs. Both models demonstrated consistent characterization of multivariable patterns associated with serious outcomes (elastic net AUROC\u00a0=\u00a00.830, XGBoost AUROC\u00a0=\u00a00.869). Key contributors to serious outcomes included reporting country, medical event designation, organ system involvement, and medication complexity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This large-scale study provides a real-world safety assessment of mitotane. Integrating signal detection, clinical prioritization, and interpretable machine learning reveals multivariable patterns underlying serious AEs. These findings support a risk-stratified monitoring approach to enhance the clinical safety of mitotane therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1862262","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:56:41Z","timestamp":1784699801000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Real-world safety profile of mitotane in adrenocortical carcinoma: a retrospective cross-sectional study integrating pharmacovigilance and interpretable machine learning"],"prefix":"10.3389","volume":"17","author":[{"given":"Jun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Yantai Yuhuangding Hospital Affiliated to Qingdao University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]},{"name":"Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]},{"name":"State Key Laboratory of Neurology and Oncology Drug Development","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]},{"name":"State Key Laboratory of Neurology and Oncology Drug Development","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Yantai Yuhuangding Hospital Affiliated to Qingdao University","place":["Yantai, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-005-0329-x","article-title":"Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress","volume":"30","author":"Kebebew","year":"2006","journal-title":"World J Surg"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.14740\/jocmr3503w","article-title":"The characteristics and trends in adrenocortical carcinoma: a United States population based study","volume":"10","author":"Sharma","year":"2018","journal-title":"J Clin Med Res"},{"key":"B3","doi-asserted-by":"crossref","DOI":"10.1002\/(SICI)1097-0142(20000215)88:4<711::AID-CNCR1>3.0.CO;2-W","article-title":"Adrenocortical carcinoma: clinical and laboratory observations","volume":"88","author":"Wajchenberg","year":"2000","journal-title":"Cancer"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1177\/20406223211033103","article-title":"Adrenocortical carcinoma: current state of the art, ongoing controversies, and future directions in diagnosis and treatment","volume":"12","author":"Shariq","year":"2021","journal-title":"Ther Adv Chronic Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/jco.2008.17.2775","article-title":"Management of endocrine manifestations and the use of mitotane as a chemotherapeutic agent for adrenocortical carcinoma","volume":"27","author":"Veytsman","year":"2009","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1530\/eje-13-0519","article-title":"Adrenocortical carcinoma: clinical outcomes and prognosis of 330 patients at a tertiary care center","volume":"169","author":"Ayala-Ramirez","year":"2013","journal-title":"Eur J Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1093\/ejendo\/lvad066","article-title":"European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors","volume":"189","author":"Fassnacht","year":"2023","journal-title":"Eur J Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1007\/978-0-387-77236-3_9","article-title":"Adrenocortical carcinoma","volume":"35","author":"Else","year":"2014","journal-title":"Endocr Rev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyae029","article-title":"Adrenocortical carcinomas: molecular pathogenesis, treatment options, and emerging immunotherapy and targeted therapy approaches","volume":"29","author":"Chukkalore","year":"2024","journal-title":"Oncologist"},{"key":"B10","doi-asserted-by":"publisher","first-page":"5255","DOI":"10.3390\/cancers13215255","article-title":"Molecular mechanisms of mitotane action in adrenocortical cancer based on in vitro studies","volume":"13","author":"Lo Iacono","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa063360","article-title":"Adjuvant mitotane treatment for adrenocortical carcinoma","volume":"356","author":"Terzolo","year":"2007","journal-title":"N Engl J Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2020.101415","article-title":"New perspectives for mitotane treatment of adrenocortical carcinoma","volume":"34","author":"Puglisi","year":"2020","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/9362108","article-title":"Benefits of adjuvant mitotane after resection of adrenocortical carcinoma: a systematic review and meta-analysis","volume":"2018","author":"Tang","year":"2018","journal-title":"BioMed Res Int"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds231","article-title":"Adrenal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"23","author":"Berruti","year":"2012","journal-title":"Ann Oncol"},{"key":"B15","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1530\/eje-18-0608","article-title":"European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors","volume":"179","author":"Fassnacht","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.08.2099","article-title":"Adrenocortical carcinomas and Malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Fassnacht","year":"2020","journal-title":"Ann Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.22541\/au.159069174.47481624","article-title":"Pharmacological profile and effects of mitotane in adrenocortical carcinoma","volume":"87","author":"Corso","year":"2021","journal-title":"Br J Clin Pharmacol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1530\/erc-22-0146","article-title":"Key factors for effective mitotane therapy in children with adrenocortical carcinoma","volume":"29","author":"Kuhlen","year":"2022","journal-title":"Endocrine-Related Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2015.03.001","article-title":"Adrenocortical carcinoma","volume":"44","author":"Baudin","year":"2015","journal-title":"Endocrinol Metab Clin North Am"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(23)00193-6","article-title":"Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study","volume":"11","author":"Terzolo","year":"2023","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3724\/sp.j.1009.2013.00314","article-title":"Statistical and graphical approaches for disproportionality analysis of spontaneously-reported adverse events in pharmacovigilance","volume":"11","author":"Zink","year":"2013","journal-title":"Chin J Nat Med"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1001","article-title":"The reporting odds ratio and its advantages over the proportional reporting ratio","volume":"13","author":"Rothman","year":"2004","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B23","doi-asserted-by":"publisher","first-page":"796","DOI":"10.7150\/ijms.6048","article-title":"Data mining of the public version of the FDA Adverse Event Reporting System","volume":"10","author":"Sakaeda","year":"2013","journal-title":"Int J Med Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/pds.677","article-title":"Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports","volume":"10","author":"Evans","year":"2001","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jclinane.2024.111509","article-title":"A pharmacovigilance study of FDA adverse events for sugammadex","volume":"97","author":"Mao","year":"2024","journal-title":"J Clin Anesth"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s002280050466","article-title":"A Bayesian neural network method for adverse drug reaction signal generation","volume":"54","author":"Bate","year":"1998","journal-title":"Eur J Clin Pharmacol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1177\/0962280211403604","article-title":"Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery","volume":"22","author":"Nor\u00e9n","year":"2013","journal-title":"Stat Methods Med Res"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1177\/2047487320915663","article-title":"Adverse events with sacubitril\/valsartan in the real world: emerging signals to target preventive strategies from the FDA adverse event reporting system","volume":"28","author":"Gatti","year":"2021","journal-title":"Eur J Prev Cardiol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2022.996179","article-title":"Gastrointestinal adverse events associated with semaglutide: a pharmacovigilance study based on FDA adverse event reporting system","volume":"10","author":"Shu","year":"2022","journal-title":"Front Public Health"},{"key":"B30","volume-title":"Signal Management: Designated Medical Event (DME) List","year":"2025"},{"key":"B31","volume-title":"Eudravigilance System Overview: Important Medical Event List","year":"2026"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1530\/eje-11-0557","article-title":"High-dose mitotane strategy in adrenocortical carcinoma: prospective analysis of plasma mitotane measurement during the first 3 months of follow-up","volume":"166","author":"Maucl\u00e8re-Denost","year":"2012","journal-title":"Eur J Endocrinol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecl.2015.03.001","article-title":"Impact of monitoring plasma 1,1-dichlorodiphenildichloroethane (o,p'DDD) levels on the treatment of patients with adrenocortical carcinoma","volume":"92","author":"Baudin","year":"2001","journal-title":"Cancer"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1994.183","article-title":"Optimal treatment of adrenocortical carcinoma with mitotane: results in a consecutive series of 96 patients","volume":"69","author":"Haak","year":"1994","journal-title":"Br J Cancer"},{"key":"B35","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/0277-5379(84)90033-6","article-title":"The treatment of adrenocortical carcinoma with o,p'-DDD: prognostic implications of serum level monitoring","volume":"20","author":"van Slooten","year":"1984","journal-title":"Eur J Cancer Clin Oncol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1200\/jco.1992.10.9.1504","article-title":"Neuropsychologic and neurologic side effects of mitotane and reversibility of symptoms","volume":"10","author":"Lanser","year":"1992","journal-title":"J Clin Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1530\/eje-17-0452","article-title":"Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma","volume":"177","author":"Reimondo","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1677\/erc-08-0103","article-title":"Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly","volume":"15","author":"Daffara","year":"2008","journal-title":"Endocr Relat Cancer"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2851","article-title":"Mitotane therapy in adrenocortical cancer induces CYP3A4 and inhibits 5\u03b1-reductase, explaining the need for personalized glucocorticoid and androgen replacement","volume":"98","author":"Chortis","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2639","article-title":"Clinical review: Adrenocortical carcinoma: clinical update","volume":"91","author":"Allolio","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1128061","article-title":"Androgen serum levels in male patients with adrenocortical carcinoma given mitotane therapy: a single center retrospective longitudinal study","volume":"14","author":"Delbarba","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B42","doi-asserted-by":"publisher","first-page":"5001","DOI":"10.3390\/cancers13195001","article-title":"Metabolic and endocrine toxicities of mitotane: a systematic review","volume":"13","author":"Bianchini","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B43","doi-asserted-by":"publisher","first-page":"14","DOI":"10.5114\/pedm.2023.133315","article-title":"Precocious puberty and other endocrine disorders during mitotane treatment for paediatric adrenocortical carcinoma - case series and literature review","volume":"30","author":"Moszczy\u0144ska","year":"2024","journal-title":"Pediatr Endocrinol Diabetes Metab"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1530\/edm-18-0059","article-title":"Mitotane in the treatment of childhood adrenocortical carcinoma: a potent endocrine disruptor","volume":"2018","author":"Oddie","year":"2018","journal-title":"Endocrinol Diabetes Metab Case Rep"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2157","article-title":"Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans","volume":"91","author":"Nader","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9060681","article-title":"Estrogen-like effect of mitotane explained by its agonist activity on estrogen receptor-\u03b1","volume":"9","author":"Rossini","year":"2021","journal-title":"Biomedicines"},{"key":"B47","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1530\/eo-21-0021","article-title":"Characterization of hyperlipidemia secondary to mitotane in adrenocortical carcinoma","volume":"2","author":"Gagnon","year":"2022","journal-title":"Endocr Oncol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"G1","DOI":"10.1007\/s00134-014-3210-2","article-title":"Clinical practice guideline on diagnosis and treatment of hyponatraemia","volume":"170","author":"Spasovski","year":"2014","journal-title":"Eur J Endocrinol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2005.054981","article-title":"Effects of hyperlipidemia on plasma sodium, potassium, and chloride measurements by an indirect ion-selective electrode measuring system","volume":"52","author":"Dimeski","year":"2006","journal-title":"Clin Chem"},{"key":"B50","doi-asserted-by":"crossref","DOI":"10.1093\/oxfordjournals.qjmed.a068705","article-title":"Possible mechanism and treatment of o,p'DDD-induced hypercholesterolaemia","volume":"84","author":"Maher","year":"1992","journal-title":"Q J Med"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1530\/eje-14-0670","article-title":"Ovarian macrocysts and gonadotrope-ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease","volume":"172","author":"Salenave","year":"2015","journal-title":"Eur J Endocrinol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.3390\/cancers12092615","article-title":"Unwanted hormonal and metabolic effects of postoperative adjuvant mitotane treatment for adrenocortical cancer","volume":"12","author":"Basile","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B53","doi-asserted-by":"publisher","first-page":"893","DOI":"10.3892\/mmr.2012.1244","article-title":"The effect of mitotane on viability, steroidogenesis and gene expression in NCI-H295R adrenocortical cells","volume":"7","author":"Lehmann","year":"2013","journal-title":"Mol Med Rep"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.13869","article-title":"Ovarian cyst formation in women of reproductive age receiving mitotane as part of the treatment of adrenocortical carcinoma: Clinical and experimental observations","volume":"99","author":"Abrahamsson","year":"2020","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B55","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1530\/joe-17-0203","article-title":"Effect of mitotane on mouse ovarian follicle development and fertility","volume":"234","author":"Innocenti","year":"2017","journal-title":"J Endocrinol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-2839","article-title":"Pregnancy in a patient with adrenal carcinoma treated with mitotane: a case report and review of literature","volume":"98","author":"Tripto-Shkolnik","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.62347\/qkwf9884","article-title":"The effect of adjuvant mitotane therapy of the adrenocortical carcinoma on the endometrium and its clinical consequences in menstruating women. Literature review and authors' own experiences","volume":"14","author":"Szkodziak","year":"2024","journal-title":"Am J Cancer Res"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/0277-5379(91)90233-4","article-title":"Prolonged bleeding time due to mitotane therapy","volume":"27","author":"Haak","year":"1991","journal-title":"Eur J Cancer"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.5603\/gp.a2017.0104","article-title":"Use of a levonorgestrel-releasing intrauterine device for menorrhagia treatment during adjuvant therapy of adrenocortical carcinoma with mitotane","volume":"88","author":"Szkodziak","year":"2017","journal-title":"Ginekologia Polska"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1093\/ejendo\/lvae038","article-title":"International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects","volume":"190","author":"Riedmeier","year":"2024","journal-title":"Eur J Endocrinol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-022-03075-y","article-title":"Supportive therapies in patients with advanced adrenocortical carcinoma submitted to standard EDP-M regimen","volume":"77","author":"Turla","year":"2022","journal-title":"Endocrine"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1530\/endoabs.32.p516","article-title":"Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma","volume":"98","author":"Kerkhofs","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1530\/acta.0.1240526","article-title":"Mitotane increases the blood levels of hormone-binding proteins","volume":"124","author":"van Seters","year":"1991","journal-title":"Acta Endocrinol (Copenh)"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1210\/jc.85.6.2234","article-title":"Low-dose monitored mitotane treatment achieves the therapeutic range with manageable side effects in patients with adrenocortical cancer","volume":"85","author":"Terzolo","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1210\/mtp4.9781936704941.ch5","article-title":"Clinical management of adrenocortical carcinoma","volume":"23","author":"Fassnacht","year":"2009","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgad115","article-title":"Central hypothyroidism is frequent during mitotane therapy in adrenocortical cancer patients: Prevalence and timeline","volume":"108","author":"Poirier","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"key":"B67","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1097\/FTD.0000000000000102","article-title":"Development of a pharmacokinetic model of mitotane: Toward personalized dosing in adrenocortical carcinoma","volume":"37","author":"Kerkhofs","year":"2015","journal-title":"Ther Drug Monit"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200023060-00004","article-title":"A retrospective evaluation of a data mining approach to aid finding new adverse drug reaction signals in the WHO international database","volume":"23","author":"Lindquist","year":"2000","journal-title":"Drug Saf"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1862262\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:56:43Z","timestamp":1784699803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1862262\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,22]]},"references-count":68,"alternative-id":["10.3389\/fendo.2026.1862262"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1862262","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,22]]},"article-number":"1862262"}}