Mitotane, used in the treatment of adrenocortical cancer (ACC), is able to inhibit multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency (AI). Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level.
The aim of the study was to assess the hypothalamic pituitary adrenal (HPA) axis in patients receiving mitotane as adjuvant treatment after radical resection of ACC getting insights on how mitotane affects the HPA axis and looking for markers to assessing AI.
We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical removal of ACC, who were on stable mitotane dose and cortisol replacement therapy for at least 6 months and were disease free at the time of evaluation. Patients underwent standard hormone evaluation and stimulation test with h-CRH. A group of 10 patients with Addisons disease served as controls for the h-CRH test.
At the time of the study, six patients had mitotane levels within the therapeutic range, one had levels >20 mg/l, while nine had levels <14 mg/l. The median dose of cortisone acetate was 62.5 mg daily. Basal serum cortisol was reduced in 14 patients, being undetectable in 7 of them, and in the normal range in only two patients (12.5%); one of them had low mitotane concentrations. Only a non-significant trend between mitotane dose and either serum or salivary cortisol was evident. We demonstrated a close correlation between CBG levels and plasma mitotane levels (P=0.003) and between serum cortisol levels and salivary cortisol levels (P=0.005), while ACTH levels were inversely correlated with the daily dose of cortone acetate (P=0.006). ACTH levels were significantly higher in the Addison group than in ACC patients, both in baseline conditions (P=0.036) than following CRH (P=0.041).
In conclusion, measurement of salivary cortisol did not add useful information for assessing AI in mitotane-treated ACC patients. Assessment of ACTH levels may be of some aid, since levels that are not frankly elevated may herald over-replacement. The observation of lower ACTH levels in ACC patients than in patients with Addison, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary level. However, an effect of high-dose cortisol replacement should not be ruled out.
20 - 23 May 2017
European Society of Endocrinology