Perotti, Paola

Abstract Background: The ESE-ENSAT guidelines on the management of adrenocortical carcinoma (ACC) suggest adjuvant mitotane for patients at high risk of recurrence following radical surgery. 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 vs. observation in prolonging recurrence-free survival (RFS) in ACC patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane (MIT) or observation (OBS). The primary endpoint of the study was RFS. Patients who refused randomization were offered inclusion in the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in the ADIUVO study. A total of 91 patients were enrolled in ADIUVO, 45 in the MIT and 46 in the OBS arm. Baseline characteristics of patients were perfectly matched between the 2 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%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with MIT and OBS groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohorts could be analyzed in parallel to those of ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. Tumor size was a predictor of RFS in multivariable analysis. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55–3.32, p=0.54) and HR for death 2.171 (95%CI, 0.52–12.12, p=0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed the findings of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-year RFS is about 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care.

Abstract Context Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). Objective, Design, Setting This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. Patients and Methods 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. Results Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). Conclusion Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.