On August 21, the final results of the ADIUVO trial have been published online in The Lancet Diabetes & Endocrinology, https://doi.org/10.1016/S2213-8587(23)00193-6.
ADIUVO is the first randomized trial to assess the efficacy and safety of adjuvant mitotane treatment in patients with completely resected adrenocortical carcinoma (ACC). The ADIUVO trial was an independent, investigator-initiated study supported by public funding and endorsed by the European Network for the Study of Adrenal Tumours (ENSAT). The study was the result of a tremendous effort of the ENSAT community. Despite limited funding, the trial was done in 23 ENSAT centers across 7 countries thanks to the passion and commitment of many people. The researches had to overcome several hurdles to run the study. In particular, recruitment was slow because of the rarity of the study population; moreover, a high number of patients refused randomization because patients dislike the idea that the decision between treatment and no treatment is taken by chance. Therefore, a parallel, observational study was organized to capture data of the patients who did not consent to be randomized. As a result of huge work, about 200 patients with ACC have been included in the ADIUVO trial and the companion ADIUVO Observational study, a size rivalled only by the FIRMACT trial conducted in patients with advanced ACC, another huge achievement of ENSAT.
The main finding of ADIUVO and ADIUVO Observational is that prognosis of patients at low risk of recurrence is much better than anticipated, with a 5-year rate of recurrence-free survival (the primary endpoint) approximating 80% in both studies, even in patients on surveillance alone. Treatment with mitotane was able to provide only a modest, non-significant advantage in survival compared to surveillance alone, even if a benefit of treatment cannot be excluded since the ADIUVO trial was terminated early, and this resulted in a low statistical power. However, the rather good prognosis of patients bearing low-risk ACC without any treatment is a strong argument against routine use of adjuvant mitotane, which entails a cumbersome treatment regimen, complex supportive therapy and potential toxicity. The issues associated with adjuvant mitotane treatment were well demonstrated in the ADIUVO trial that showed how patient quality of life was affected by treatment.
The outcome of the ADIUVO trial has an immediate impact on clinical practice, showing that it is possible to identify a subset of patients with better prognosis who can be spared a complex and potentially toxic therapeutic regimen, thus simplifying management and resulting in better quality of life for patients and lower costs for healthcare systems. Prognostication can be done with assessment of ki67 index that is widely available; therefore, these findings represent a first step toward personalization of management of patients with ACC. However, the outcome of ADIUVO and ADIUVO Observational cannot be generalized to patients with high-risk ACC.
The ADIUVO trial exemplifies well the challenges of conducting a randomized trial in a rare cancer like ACC, since the trial lasted 10 years, and was underfunded compared to the standard of randomized trial supported by pharmaceutic companies. On the other hand, the ADIUVO story tells that it is possible to undertake prospective studies in ACC whether a team of passionate and committed investigators do a collaborative effort to achieve a common goal. And this is just one of the purposes for which ENSAT was born.
Ciao,
Massimo Terzolo, ACC WG lead
