Discussion
adrenocortical carcinoma, generalised, toxicity
ADRENOCORTICAL CARCINOMA, RECURRENCE, RARE DISEASE, ADVERSE EVENTS, PROLIFERATION, DISEASE, BLIND, RARE DISEASES
To our knowledge, ADIUVO is the first randomised trial to investigate an adjuvant treatment protocol in patients with completely resected adrenocortical carcinoma and, therefore, provides the best level of evidence currently available. Before the ADIUVO trial, limited evidence was available on adjuvant mitotane treatment, and the indications of available guidelinesDespite the participation of many centres from different countries, the trial did not include the planned number of patients, which is not uncommon in investigator-sponsored trials in rare diseases. Furthermore, it is unlikely that a larger cohort will be recruited in the near future, because almost all international reference centres for this rare disease participated in the trial.The prognosis of the ADIUVO cohort comprising patients with presumed low risk of recurrence was much better than previously anticipated, and this is a key finding of the study that has an impact on clinical practice. In previous studies including unselected cohorts of patients with adrenocortical carcinoma, 5-year recurrence-free survival was consistently less than 40%,Because of its low power, the ADIUVO trial cannot rule out an effect of adjuvant mitotane (In the future, analysis of molecular markers might further refine individual prognosis and indication to treatment.The ADIUVO trial confirms in a prospective setting that adjuvant mitotane therapy is demanding even at reference centres, with 19% of patients discontinuing treatment definitively for toxicity before completing the scheduled 2-year period. Although this figure cannot be dismissed in an adjuvant setting, the ADIUVO trial shows that most patients can tolerate mitotane when they are managed at expert centres. The pattern of observed toxicity was expected, and most adverse events occurred quite early in the course of treatment independently on mitotane concentrations, thus outlining the role of individual sensitivity.A low-dose mitotane regimen was used in most centres and the presumed therapeutic mitotane concentrations of 14–20 mg/LIn the ADIUVO trial, survival of patients who did attain the target mitotane concentrations was not significantly different than that of patients who did not, either when considering the peak value of mitotane concentrations or the time in range, a method recently proposed to take into account the fluctuations of concentrations over time.To our knowledge, for the first time, the ADIUVO trial provides measures of the quality of life collected prospectively in patients receiving adjuvant mitotane treatment. Although the low compliance in answering the questionnaires limits the interpretation of data, our findings suggest that patients receiving mitotane experienced a worse quality of life than patients on active surveillance.Furthermore, the ADIUVO trial confirms in a prospective setting the concept that adrenocortical carcinoma is not a uniform disease, substantiating genomic studies that have identified specific molecular signatures associated with differences in prognosis in localised adrenocortical carcinoma.The ADIUVO findings further validate prospectively the value of the proliferation marker Ki67 for prognosticationWe acknowledge that the ADIUVO trial has limitations, including the fact that the study was small, terminated early, had an open-label design, and is possibly prone to the effect of time in estimating the treatment response. However, we considered a blind, placebo-controlled study to be unfeasible because high-dose preventive steroid replacement is needed with mitotane treatment.In summary, the ADIUVO findings provide insufficient evidence of mitotane efficacy and suggest that active surveillance is the most adequate concept for patients with low-grade, localised adrenocortical carcinoma. ADIUVO indicates that a complex and toxic treatment can be spared and management can be simplified for this cohort with better quality of life and lower costs. However, the results of the ADIUVO trial should not be generalised to patients with adrenocortical carcinoma at standard or high risk of recurrence for whom adjuvant mitotane treatment should still be considered standard of care.