Endocrine Abstracts

Background: Mitotane is regularly used in patients with adrenocortical carcinoma (ACC) adjuvantly, in patients with high risk of recurrence, and in advanced disease. Multiple effects of mitotane result in adrenal insufficiency in virtually all patients. However, it is unclear how frequently the hypothalamic-pituitary-adrenal (HPA) axis is recovering after treatment discontinuation. Here, we aim to investigate the HPA axis after treatment with mitotane.

Methods: We screened patients with ACC treated with mitotane for ≥12 months since 2000 and discontinued treatment without evidence for disease. Minimum follow-up after mitotane discontinuation was 1 year. Data on patients and tumor characteristics, mitotane treatment, and information on HPA axis were analyzed. Primary endpoint was time to adrenal recovery. Explorative analysis of predictive factors (e.g. sex, age, follow-up in reference center, cumulative mitotane dose and plasma levels, duration of treatment, and dose of hydrocortisone-equivalent replacement) was performed using univariate and multivariate Cox regression.

Results: 56 patients (36 women) treated with mitotane alone (n=47) or in combination with radiotherapy (n=3) or chemotherapy (n=6) were included. Median duration of mitotane treatment was 25 (14-122) months, with a median average daily dose of 2.8 g (0.70-10.10). The average daily dose of hydrocortisone-equivalent replacement during mitotane treatment was in median 49.4 mg (25.7-66.9). Complete adrenal recovery was documented after a median of 26 (95% CI 19.6-32.4) months in 32 (57.1%) patients. Among these, 22 (68.7%) achieved HPA recovery within 24 months. However, when patients were followed in reference centers (n=38), a significantly larger proportion of cases (71.1%) achieved HPA recovery (HR=4.65, 95%CI=1.76-12.25, P=0.002). Partial and insufficient recovery were observed in 9 (16.1%) and 15 (26.8%) patients, respectively. In 4 patients (7.1%) with a follow-up>60 months, a long-term adrenal insufficiency has to be assumed. A maximum mitotane peak ≥27 mg/l as well as plasma levels ≥12 mg/l at discontinuation correlated with significant longer time to adrenal recovery (HR=0.24, 95% CI=0.07-0.85, P=0.03, and HR=0.45, 95% CI=0.21-0.95, P=0.03, respectively). A higher mitotane exposure, as assessed by the area under the curve of mitotane plasma levels, was slightly associated with longer adrenal recovery (HR=0.5, 95% CI=0.2-1.0, P=0.06). At multivariate analysis, only plasma levels ≥12 mg/l at discontinuation slightly correlated with longer time to HPA recovery (HR=0.47, 95% CI=0.21-1.06, P=0.07).

Conclusions: Our study demonstrates that adrenal recovery occurs in most patients treated with mitotane. Testing for adrenal insufficiency is performed more often in reference centers. Therefore, a sufficient patient follow-up including education on glucocorticoid reduction is needed after mitotane discontinuation.