TY - JOUR
T1 - Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO)
T2 - an international, multicentre, open-label, randomised, phase 3 trial and observational study
AU - Terzolo, Massimo
AU - Fassnacht, Martin
AU - Perotti, Paola
AU - Libé, Rossella
AU - Kastelan, Darko
AU - Lacroix, André
AU - Arlt, Wiebke
AU - Haak, Harm Reinout
AU - Loli, Paola
AU - Decoudier, Bénédicte
AU - Lasolle, Helene
AU - Quinkler, Marcus
AU - Haissaguerre, Magalie
AU - Chabre, Olivier
AU - Caron, Philippe
AU - Stigliano, Antonio
AU - Giordano, Roberta
AU - Zatelli, Maria Chiara
AU - Bancos, Irina
AU - Fragoso, Maria Candida Barisson Villares
AU - Canu, Letizia
AU - Luconi, Michaela
AU - Puglisi, Soraya
AU - Basile, Vittoria
AU - Reimondo, Giuseppe
AU - Kroiss, Matthias
AU - Megerle, Felix
AU - Hahner, Stefanie
AU - Kimpel, Otilia
AU - Dusek, Tina
AU - Nölting, Svenja
AU - Bourdeau, Isabelle
AU - Chortis, Vasileios
AU - Ettaieb, Madeleine Hester
AU - Cosentini, Deborah
AU - Grisanti, Salvatore
AU - Baudin, Eric
AU - Berchialla, Paola
AU - Bovis, Francesca
AU - Sormani, Maria Pia
AU - Bruzzi, Paolo
AU - Beuschlein, Felix
AU - Bertherat, Jerome
AU - Berruti, Alfredo
N1 - Publisher Copyright:
© 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
PY - 2023/10/1
Y1 - 2023/10/1
N2 - Background: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. Methods: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I–III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14–20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. Findings: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67–94) in the mitotane group and 75% (63–90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30–1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89–100] in the mitotane group and 86% [74–100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. Interpretation: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. Funding: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.
AB - Background: Adjuvant treatment with mitotane is commonly used after resection of adrenocortical carcinoma; however, treatment remains controversial, particularly if risk of recurrence is not high. We aimed to assess the efficacy and safety of adjuvant mitotane compared with surveillance alone following complete tumour resection in patients with adrenocortical carcinoma considered to be at low to intermediate risk of recurrence. Methods: ADIUVO was a multicentre, open-label, parallel, randomised, phase 3 trial done in 23 centres across seven countries. Patients aged 18 years or older with adrenocortical carcinoma and low to intermediate risk of recurrence (R0, stage I–III, and Ki67 ≤10%) were randomly assigned to adjuvant oral mitotane two or three times daily (the dose was adjusted by the local investigator with the target of reaching and maintaining plasma mitotane concentrations of 14–20 mg/L) for 2 years or surveillance alone. All consecutive patients at 14 study centres fulfilling the eligibility criteria of the ADIUVO trial who refused randomisation and agreed on data collection via the European Network for the Study of Adrenal Tumors adrenocortical carcinoma registry were included prospectively in the ADIUVO Observational study. The primary endpoint was recurrence-free survival, defined as the time from randomisation to the first radiological evidence of recurrence or death from any cause (whichever occurred first), assessed in all randomly assigned patients by intention to treat. Overall survival, defined as time from the date of randomisation to the date of death from any cause, was a secondary endpoint analysed by intention to treat in all randomly assigned patients. Safety was assessed in all patients who adhered to the assigned regimen, which was defined by taking at least one tablet of mitotane in the mitotane group and no mitotane at all in the surveillance group. The ADIUVO trial is registered with ClinicalTrials.gov, NCT00777244, and is now complete. Findings: Between Oct 23, 2008, and Dec 27, 2018, 45 patients were randomly assigned to mitotane and 46 to surveillance alone. Because the study was discontinued prematurely, 5-year recurrence-free and overall survival are reported instead of recurrence-free and overall survival as defined in the protocol. 5-year recurrence-free survival was 79% (95% CI 67–94) in the mitotane group and 75% (63–90) in the surveillance group (hazard ratio 0·74 [95% CI 0·30–1·85]). Two people in the mitotane group and five people in the surveillance group died, and 5-year overall survival was not significantly different (95% [95% CI 89–100] in the mitotane group and 86% [74–100] in the surveillance group). All 42 patients who received mitotane had adverse events, and eight (19%) discontinued treatment. There were no grade 4 adverse events or treatment-related deaths. Interpretation: Adjuvant mitotane might not be indicated in patients with low-grade, localised adrenocortical carcinoma considering the relatively good prognosis of these patients, and no significant improvement in recurrence-free survival and treatment-associated toxicity in the mitotane group. However, the study was discontinued prematurely due to slow recruitment and cannot rule out an efficacy of treatment. Funding: AIFA, ENSAT Cancer Health F2-2010-259735 programme, Deutsche Forschungsgemeinschaft, Cancer Research UK, and the French Ministry of Health.
UR - http://www.scopus.com/inward/record.url?scp=85172022000&partnerID=8YFLogxK
U2 - 10.1016/S2213-8587(23)00193-6
DO - 10.1016/S2213-8587(23)00193-6
M3 - Article
C2 - 37619579
AN - SCOPUS:85172022000
SN - 2213-8587
VL - 11
SP - 720
EP - 730
JO - The Lancet Diabetes and Endocrinology
JF - The Lancet Diabetes and Endocrinology
IS - 10
ER -