Research in context
adrenocortical carcinoma, toxicity, malignancy, Adrenal Tumors, tumour
ADRENOCORTICAL CARCINOMA, RECURRENCE, ADRENAL TUMOR, ADRENOCORTICAL CARCINOMA STAGE, TUMOUR, ADRENOCORTICAL CARCINOMA, ADRENOCORTICAL CARCINOMA

Adrenocortical carcinoma is a rare malignancy, and prognosis is poor; however, heterogeneity in prognosis between different groups of patients has been increasingly recognised. Adjuvant mitotane has been extensively applied following tumour resection in most patients with adrenocortical carcinoma on the basis of retrospective studies suggesting that mitotane treatment after tumour removal prolongs the time to recurrence. Given some conflicting findings from other studies and additional challenges associated with mitotane administration, which entails a cumbersome drug regimen, complex hormone replacement, need of careful monitoring, and potential toxicity, the utility of adjuvant mitotane treatment for all patients with adrenocortical carcinoma was questionable. Due to the absence of randomised studies, we recognised that a phase 3 trial was needed to establish whether this therapeutic intervention could benefit patients. In 2008, we initiated the ADIUVO trial with the support of the European Network for the Study of Adrenal Tumors (ENS@T). During preparation of the European Society of Endocrinology and ENS@T 2018 Clinical Guidelines on Management of Adrenocortical Carcinoma, a comprehensive literature search of PubMed, the NHS Economic Evaluation Database, and the Cochrane Database of Systematic Reviews, and the Database of Abstracts of Reviews of Effects was performed, from Jan 1, 1986, to Feb 28, 2018, for all systematic reviews and studies that had assessed adjuvant therapies in adult patients with adrenocortical carcinoma. The search terms were “adrenal”/”adrenocortical cancer”/”carcinoma”/”neoplasm”, “adjuvant”/”additional”/”post-operative therapy”, “mitotane”/”o,p’-DDD”, “recurrence”/”relapse”, “overall survival”. We searched for studies published in English. This search revealed only six retrospective studies that assessed the effect of adjuvant mitotane on recurrence and five studies on survival, including a total of 322 patients on mitotane and 718 patients on surveillance alone. In a meta-analysis, the pooled hazard ratio for recurrence was 0·7 (95% CI 0·5–1·1) and for mortality 0·7 (95% CI 0·5–0·9). We updated our initial literature search (to include literature from March 1, 2018, to March 31, 2023) using the same search terms and language restriction, and identified one additional meta-analysis, three new retrospective studies, and no randomised trials. The results were in line with the findings described above.
Despite the rarity of adrenocortical carcinoma, we were able to prospectively follow up almost 200 patients who were included in the interventional trial (ADIUVO) and the accompanying observational study (ADIUVO Observational); a size rivalled only by the FIRM-ACT trial on advanced adrenocortical carcinoma. ADIUVO is the first randomised trial in the postoperative adjuvant setting for patients with adrenocortical carcinoma. The study indicates that it is possible to identify, with a simple and widely available prognostication scheme based on adrenocortical carcinoma stage, resection status, and Ki67 assessment, a subset of patients whose prognosis is much better than anticipated. The estimated 5-year recurrence-free survival in our patient cohorts approximated 75%, whereas it was previously reported to be less than 40% in retrospective patient cohorts. We showed prospectively that adjuvant mitotane treatment is associated with inherent toxicity, leading to a rate of permanent discontinuation of 19% even in the participating expert centres. Moreover, we found that the quality of life of patients with adrenocortical carcinoma is affected by adjuvant treatment with mitotane. The study did not reach the planned power because recruiting was hampered by the fact that only a minority of patients referred after surgery could be considered as having a low risk of recurrence; therefore, an effect of mitotane cannot be definitively ruled out. However, given the relatively good prognosis of our patient cohort even with surveillance alone, and the challenges associated with adjuvant mitotane treatment, the ADIUVO findings do not support a routine use of adjuvant mitotane after complete removal of a low-grade, localised adrenocortical carcinoma.
Our study has an immediate impact on the management of patients with localised adrenocortical carcinoma, since we show for the first time in a prospective way that patients with low risk of recurrence do exist, and can be identified easily following surgery. Such patients can be spared a challenging and potentially toxic treatment with mitotane and be adequately managed with active surveillance alone. The present evidence improves our capability of providing a more personalised adjuvant treatment. Our findings do not apply to patients with adrenocortical carcinoma at standard or high risk of recurrence, for which adjuvant mitotane remains recommended on the basis of previous evidence.