ASCO GU 2022: First Randomized Trial on Adjuvant Mitotane in Adrenocortical Carcinoma Patients: The ADIUVO Study

( The 2022 GU ASCO Annual meeting included a rare tumors oral abstract session featuring work from Dr. Alfredo Berruti and colleagues presenting results of the ADIUVO study, the first randomized trial on adjuvant mitotane in adrenocortical carcinoma patients. The incidence of adrenocortical carcinoma incidence is 0.7-2.0 new cases per million people per year. Among these patients, 50-70% are hormone-secreting tumors, 50% of patients undergo radical surgery, however 40-70% of patients relapse after surgery. The European Society of Endocrinology-European Network for the Study of Adrenal Tumors guidelines on adrenocortical carcinoma management suggest adjuvant mitotane for patients at high risk of recurrence. This indication has a limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment versus observation in prolonging recurrence-free survival in patients at low-intermediate risk of recurrence.

 The main inclusion criteria were: stage I-III adrenocortical carcinoma, surgical resection with negative margins, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane or observation, and the primary endpoint of the study was recurrence-free survival. The study design for this trial is as follows:




 A total of 91 patients were randomized in ADIUVO, 45 in the mitotane and 46 in the observation arm. This occurred between March 2008 and December 2018 at which point the trial was closed secondary to poor accrual. Baseline characteristics of patients were well-matched between the two arms: median age 51 vs. 50.5 years, female 73% vs. 67%, stage I 20% vs. 26%, stage II 67% vs. 63%, stage III, 13% vs. 11%, adrenocortical carcinoma secretion 44% vs. 36%, Weiss 5 vs. 5, respectively. Patients who refused randomization were eligible for the ADIUVO observational study. In this prospective, observational study, patients were managed as in ADIUVO except for randomization. In ADIUVO observational, 42 patients were treated with mitotane and 53 were untreated (between January 2011 and December 2018). Baseline characteristics of patients were matched between the two groups and with mitotane and observation groups in ADIUVO. As such, the ADIUVO observational cohort was analyzed in parallel to deal with the lower than expected recruitment in ADIUVO.

 In the ADIUVO study, the median follow-up was 48 months over which there were 8 recurrences in the mitotane and 11 in the observation arm, while deaths were recorded for two and five patients, respectively. Recurrence-free survival (HR 0.74, 95% CI 0.30-1.85) did not significantly differ between the two arms:




Overall survival (HR 0.46, 95% CI 0.08-1.92) also did not significantly differ between the two arms:




In the ADJUVO observation, there also was no difference relapse-free survival (HR 0.67, 95% CI 0.27-1.69) or overall survival (HR 1.04, 95% CI 0.23-4.80):




The survival analysis in the ADIUVO observational study confirmed that of the ADIUVO randomized trial. Given the outcome of both studies, the number needed to treat is 55.


Dr. Berruti concluded his presentation of the ADIUVO study of adjuvant mitotane in adrenocortical carcinoma patients with the following take-home messages:

  • Adrenocortical carcinoma patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected and do not benefit significantly from adjuvant mitotane
  • The results of the ADIUVO study do not support the routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment
  • This is an important step toward the personalization of adrenocortical carcinoma care


Presented By: Alfredo Berruti, MD, The University of Brescia, Brescia, Italy

Co-Authors: Martin Fassnacht, Rossella Libè, Andrè Lacroix, Darko Kastelan, Harm Haak, Weibke Arlt, Bénédict Decoudier, Hélène Lasolle, Irina Bancos, Markus Quinkler, Maria Candida Barisson Villares Fragoso, Letizia Canu, Soraya Puglisi, Isabelle Bourdeau, Eric Baudin, Paola Berchialla, Felix Beuschlein, Jerome Bertherat, Massimo Terzolo

Affiliations: University Hospital, Department of Endocrinology Cochin Hospital, Service d'Endocrinologie et Centre de Recherche du CHUM (CRCHUM), Department of Endocrinology, University Hospital Centre, Zagreb, Croatia, Máxima Medisch Centrum, University of Birmingham, Birmingham, United Kingdom, Service d'Endocrinologie, Hôpital Robert Debré, Centre Hospitalier Universitaire Reims, Endocrinology Department, Reference Centre for Rare Pituitary Diseases HYPO, "Groupement Hospitalier Est" Hospices Civils de Lyon, Mayo Clinic, Rochester, MN, Endocrinology in Charlottenburg, Berlin, Germany, Serviço de Endocrinologia da Clínica de Bases do Instituto do Câncer do Estado de São Paulo, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy, Internal Medicine Unit, Clinical and Biological Sciences Department, University of Turin, San Luigi Gonzaga University Hospital, Orbassano, Italy, Division of Endocrinology, Department of Medicine and Research Center, Centre Hospitalier de l'Université de Montréal (CHUM), Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy Cancer Campus, Villejuif, France, University of Turin, Torino, Italy, Endokrinologie, Diabetologie und Klinische Ernährung, Department of Endocrinology, Hôpital Cochin, Internal Medicine, Department of Clinical and Biological Sciences, San Luigi Gonzaga Hospital, University of Turin, Orbassano, Italy


Written By: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2022 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, Thursday Feb 17 – Saturday Feb 19, 2022