ECE2023 Oral Communications Oral Communications 9: Adrenal and Cardiovascular Endocrinology 2 (6 abstracts)
Prolonged exposure to target mitotane concentrations is associated with better recurrence-free survival in patients with adrenocortical carcinoma on adjuvant treatment
Soraya Puglisi 1 , Anna Calabrese 1 , Vittoria Basile 1 , Otilia Kimpel 2 , Barbara Altieri 2 , Anna Angelousi 3 , Gregory Kaltsas 3 , Urszula Ambroziak 4 , Marialuisa Appetecchia 5 , Maura Arosio 6 , Alfredo Berruti 7 , Deborah Cosentini 7 , Letizia Canu 8 , Filippo Ceccato 9 , Guido Di Dalmazi 10 , Lucas Bouys 11 , Rossella Libe 11 , Lucyna Papierska 12 , James Pittaway 13 , Tina Kienitz 14 , Marcus Quinkler 14 , Yasir Elhassan 15,16 , Cristina Ronchi 15,16 , Leonard Saiegh 17 , Antonio Stigliano 18 , Tina Dusek 19,20 , Darko Kastelan 19,20 , Martin Fassnacht 2 & Massimo Terzolo 1
1Internal Medicine, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy; 2Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, University of Würzburg, Würzburg, Germany; 3Unit of Endocrinology, First Department and Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece; 4Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw,, Poland; 5Oncological Endocrinology Unit, Regina Elena National Cancer Institute – IFO IRCCS, Rome, Italy; 6Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 7Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, ASST Spedali Civili, Brescia, Italy; 8Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy; 9Endocrinology Unit, Department of Medicine DIMED, University-Hospital of Padua, Padua, Italy; 10Department of Experimental, Diagnostic and Specialty Medicine, Policlinico S. Orsola-Malpighi, Alma Mater Studiorum-University of Bologna, Bologna, Italy; 11Service d’Endocrinologie, National Referent Center for Adenal Cancer, ENDOCAN-COMETE, Hôpital Cochin-Port Royal, Assistance Publique des Hôpitaux de Paris, Paris, France; 12Department of Endocrinology, Medical Centre for Postgraduate Education, Warsaw, Poland; 13Department of Endocrinology, St Bartholomew’s Hospital, London, United Kingdom; 14Endocrinology in Charlottenburg, Berlin, Germany; 15Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom; 16Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, United Kingdom; 17Department of Endocrinology, Bnai-Zion Medical Center, Ruth & Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel; 18Endocrinology, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy; 19Department of Endocrinology, University Hospital Centre Zagreb, Zagreb, Croatia; 20School of Medicine, University of Zagreb, Zagreb, Croatia
Background: The management of adjuvant mitotane therapy in patients with adrenocortical carcinoma (ACC) is challenging. Plasma mitotane concentrations>14 mg/l have been associated with efficacy in the treatment of advanced ACC; however, data in the adjuvant setting are mixed. Moreover, there is no consensus on how to assess the optimal exposure to mitotane and all the proposed methods have inherent limitations. We have recently proposed a new method analogous to what is established for the anticoagulant warfarin, the time in target range (TTR). We aimed to evaluate whether the TTR is a factor influencing recurrence-free survival (RFS) in patients with ACC on adjuvant mitotane.
Methods: This is an international, retrospective, cohort study undertaken in 18 centers in 8 countries, under the auspices of the European Network for the Study of Adrenal Tumors (ENSAT), including adult patients with ACC who were treated with adjuvant mitotane for at least 1 year following tumor resection, with the availability of at least 3 mitotane measurements per year. TTR was calculated with the Rosendaal method and expressed as the number of months with plasma mitotane concentration>14 mg/l. The following potential predictive factors for RFS have been investigated: patient sex and age, ENSAT stage, hormone secretion, resection status, Weiss score, Ki67 index, and TTR. Data are expressed as median and interquartile range.
Results: From a total of 254 patients, 157 fulfilled inclusion criteria and were analyzed (F/M 94/63; age 49, 41-58 years), with a follow-up of 49 (33-92) months. The key baseline features were: 7.0% stage I, 69.4% II, 22.3% III, 1.3% IV; 51.6% secreting tumors; 87.2% R0, 2.6% R1, 10.2% RX; Weiss score 5 (4-7); Ki67 index 11 (5-20). All patients initiated mitotane within 3 months from surgery and were treated for 25 (22-36) months, with a TTR of 14 (6-21) months. At multivariate analysis, Ki67 index (HR 1.07, 95% CI, 1.02-1.12; P<0.01) and Weiss score (HR 1.7, 95% CI, 1.16-2.47; P<0.01) were associated with an increased risk of recurrence, while female sex (HR 0.14, 95% CI, 0.04-0.58; P<0.01) and TTR (HR 0.80, 95% CI, 0.70-0.90; P<0.001) were associated with a reduced risk.
Conclusions: The present findings show that the patients who are exposed to plasma mitotane>14 mg/l for longer periods have better RFS. These findings provide indirect evidence of the value of adjuvant therapy with mitotane and support the importance of drug monitoring and dose adjustment in clinical practice to improve treatment response.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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