Abstract
Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.
Highlights
The last years have witnessed an unprecedented development in medical oncology, with the introduction in clinics of targeted drugs and immune therapies that changed the prognosis of several cancers
Mitotane remained the backbone of therapy because the duration of treatment was prolonged till patient death in most cases while different lines of treatment were superimposed during the disease course
We found that patients with adrenocortical carcinoma (ACC) progression had a lower time in the target range than patients experiencing clinical benefit from first-line treatment, and in multivariable analysis, TTR was a predictor of overall survival (OS)
Summary
The last years have witnessed an unprecedented development in medical oncology, with the introduction in clinics of targeted drugs and immune therapies that changed the prognosis of several cancers This advancement has not included medical therapy of adrenocortical carcinoma (ACC), which remains based on a drug that has been developed in the sixties, mitotane. The European Society of Endocrinology and the European Network for the Study of Adrenal Tumors (ESE-ENSAT) guidelines on management of ACC suggest mitotane monotherapy for patients harboring advanced ACC with favorable prognostic parameters, while mitotane associated with chemotherapy is indicated in patients with perceived worse prognosis (i.e., aggressive tumors) [2]. This indication has a limited evidence base, since only one randomized controlled study is available on the association of mitotane with chemotherapy in advanced ACC [3].
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