Mitotane Concentrations Influence the Risk of Recurrence in Adrenocortical Carcinoma Patients on Adjuvant Treatment.

Soraya Puglisi,Barbara Altieri,Salvatore Cannavò,Massimo Torlontano,Giorgio Arnaldi,Silvia Della Casa,Antonio Stigliano,Filippo Ceccato,Giuseppina De Filpo,Chiara Simeoli,Paola Perotti,Anna Calabrese,Paola Berchialla,Massimo Terzolo,Pasqualino Malandrino,Letizia Canu,Carla Scaroni,Vittoria Basile,Paola Loli,Giuseppe Reimondo,L Saba

doi:10.3390/jcm8111850

Abstract

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28–62) with a median maintenance dose of 2.0 g/day (IQR 1.5–2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5–19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7–M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88–0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

Highlights

Treatment of adrenocortical carcinoma (ACC) is based on surgery that is usually the first and most effective therapeutic strategy [1,2,3,4]
Complete removal of the tumor may lead to a cure; ACC has a strong propensity to recur after surgery, even when R0 operations are completed by skilled surgeons [5]
The European Society of Endocrinology (ESE) - European Network for the Study of Adrenal Tumors (ENSAT) guidelines on management of ACC indicate adjuvant mitotane treatment for patients at high risk of recurrence, they recognize a low level of evidence, based only on retrospective, non-randomized studies [6]

Summary

Introduction

Treatment of adrenocortical carcinoma (ACC) is based on surgery that is usually the first and most effective therapeutic strategy [1,2,3,4]. The European Society of Endocrinology (ESE) - European Network for the Study of Adrenal Tumors (ENSAT) guidelines on management of ACC indicate adjuvant mitotane treatment for patients at high risk of recurrence, they recognize a low level of evidence, based only on retrospective, non-randomized studies [6]. The evidence supporting a target range when mitotane is used as an adjuvant measure is limited and conflicting [8,10], and this may be due to the challenge in assessing the optimal exposure to mitotane in chronic treatments. To evaluate whether plasma mitotane concentrations have prognostic implication in ACC patients on adjuvant mitotane treatment, we reviewed retrospectively the experience of 11 tertiary centers for the care of ACC patients in Italy, adopting a novel method to assess target mitotane concentrations

Experimental Section

Results

Conclusions