Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

Abstract

Context: Mitotane plasma concentrations R14 mg/l have been shown to predict tumor response and better survival in patients with advanced adrenocortical carcinoma (ACC). A correlation between mitotane concentrations and patient outcome has not been demonstrated in an adjuvant setting. Objective: To compare recurrence-free survival (RFS) in patients who reached and maintained mitotane concentrations R14 mg/l vs patients who did not. Design and setting: Retrospective analysis at six referral European centers. Patients: Patients with ACC who were radically resected between 1995 and 2009 and were treated adjuvantly with mitotane targeting concentrations of 14-20 mg/l. Main outcome measures: RFS (primary) and overall survival (secondary). Results: Of the 122 patients included, 63 patients (52%) reached and maintained during a median follow-up of 36 months the target mitotane concentrations (group 1) and 59 patients (48%) did not (group 2). ACC recurrence was observed in 22 patients of group 1 (35%) and 36 patients in group 2 (61%). In multivariable analysis, the maintenance of target mitotane concentrations was associated with a significantly prolonged RFS (hazard ratio (HR) of recurrence: 0.418, 0.22-0.79; PZ0.007), while the risk of death was not significantly altered (HR: 0.59, PZ0.20). Grades 3-4 toxicity was observed in 11 patients (9%) and was managed with temporary mitotane discontinuation. None of the patients discontinued mitotane definitively for toxicity. Conclusions: Mitotane concentrations R14 mg/l predict response to adjuvant treatment being associated with a prolonged RFS. A monitored adjuvant mitotane treatment may benefit patients after radical removal of ACC.

Adrenocortical carcinoma in children: First population-based clinicopathological study with long-term follow-up

“…Expectative management after successful surgery seems to be adequate in patients with localized disease and/or a low Wieneke index, which applies to all patients aged ≤4 years at diagnosis in our study. In adult patients, adjuvant treatment with mitotane is currently being evaluated prospectively, while retrospective studies suggest it is indicated in patients with a Ki-67 index >10% (23,24). based on our data, it is not possible to make recommendations for patients with a high Wieneke index and age ≥5 years.…”

Future directions in the diagnosis and medical treatment of adrenocortical carcinoma

“…3; Terzolo & Berruti 2008, Hermsen et al 2011, Terzolo et al 2013. Kerkhofs et al (2013c), who investigated the optimal dosing strategy, showed that 50% (10/20) of patients from the high dose starting regimen and 33% (4/12) of patients from the low-dose regimen reached the therapeutic level within 3 months.…”

Rak kory nadnercza (ACC) — przegląd piśmiennictwa i doświadczenia własne

“…Monitoring the drug level (therapeutic levels of 14-20 mg/L) is highly important, because a good response to the treatment depends heavily on the drug serum levels [48,49]. In a long term study of patients with regional and metastatic ACC, scientists showed that the levels of o,p'-DDE (mitotane metabolite) were more closely related to clinical improvement or remission than o,p'-DDD levels (1,1-(dichlorophenyl)-2,2-dichloroethane; mitotane) [42].…”

“…W badaniach kontrolnych nadmierne wydzielanie hormonów występuje u 70-75% pacjentów. Monitorowanie stężenia leku (referencyjne wartości terapeutyczne wynoszą 14-20 mg/l) jest niezwykle istotne, ponieważ dobra odpowiedź na leczenie jest zależna od poziomu stężenia leku w osoczu [48,49].…”