Metabolic and hormonal side effects of mitotane treatment for adrenocortical carcinoma: A retrospective study in 50 Danish patients

Abstract

ObjectiveMitotane is used in the treatment of adrenocortical carcinoma (ACC). Metabolic and hormonal side effects of mitotane, the effect of subsequent treatment with statins and hormones and the effects of discontinuation of mitotane were assessed.Patients and methodsFifty patients were included. Lipid profiles, thyroid hormones, sex hormones and adrenal function from first year of mitotane treatment and after cessation were evaluated.ResultsAfter 6 months of mitotane treatment total cholesterol increased from (median) 5.1 (IQR 4.3 to 5.8) to 7.4 (6.2–9.0) mmol/L, p < .001. LDL, HDL and triglyceride also increased, all p ≤ .03. Three months of treatment with statins decreased total and LDL‐cholesterol, and cessation of mitotane led to further reduction in lipids. Plasma thyroxine decreased from 90 (78–111) to 57 (47–63) nmol/L and free thyroxine from 16.0 (13.0–18.3) to 11.7 (10.5–12.6) pmol/L on mitotane, both p < .001, while TSH remained unchanged. Treatment with thyroxin significantly increased plasma thyroxine and free thyroxine and decreased TSH. Cessation of mitotane increased total T4 (p < .001). Mitotane increased plasma SHBG from 36 (22–51) to 189 (85–259) nmol/L and LH from 4.6 (1.6–8.1) to 20.0 (10.0–34.9) IU/L, both p < .001. In males the changes were accompanied by an increase in testosterone from 9.8 (7.2–14.5) to 27.0 (15.3–34.8) nmol/L, p < .03. Fifteen of 24 tested patients regained normal adrenal function 6 (3–16) months after cessation of mitotane.ConclusionsMitotane treatment exerts multiple severe side effects involving both the metabolic and endocrine systems that may require treatment, but the effect appears to be partially reversible.

Metabolic and Endocrine Toxicities of Mitotane: A Systematic Review

“…Only three studies specified the need for increased steroid coverage due to serum ACTH level elevation, or to signs and symptoms of adrenal insufficiency, as an endocrine adverse event (13/53 patients, 24.5%) [ 19 , 22 , 40 ]. Mineralocorticoid replacement was administered in a total of 67 of 182 patients in six studies [ 21 , 29 , 31 , 34 , 40 , 43 ]. Moreover, another study reported the need for fludrocortisone replacement therapy, but the proportion of patients was unclear [ 22 ].…”

“…Unfortunately, the authors failed in the identification of any predictors of the HPA axis recovery [ 34 ]. Accordingly, another study reported that 15 out of 24 patients tested with ACTH stimulation test showed a recovery of adrenal function 6 months after the mitotane therapy discontinuation [ 29 ].…”

“…Four studies reported hypothyroidism as an adverse event, identified by reduction of free thyroxine (FT4) levels, occurring in 68 of 141 patients whose thyroid function was measured [ 21 , 22 , 29 , 31 ]. In three of these studies, FT4 changes occurred after 3–6 months of treatment, while no significant change of thyroid-stimulating hormone (TSH) concentration was recorded [ 21 , 29 , 31 ]. Fifty-four patients were treated with levothyroxine.…”

“…Less frequently, patients also develop mineralocorticoid insufficiency [ 25 , 26 ]. Mitotane can also alter thyroid function [ 21 , 27 ] and lipid metabolism, in particular, leading to hypercholesterolemia [ 28 , 29 , 30 ]. Current guidelines reported both of these latter side effects as very common, defined as a frequency of more than 1 in 10 treated patients [ 10 ].…”

Cushing’s Syndrome Effects on the Thyroid

“…In experimental models, the use of mitotane has been associated to an impaired TSH expression and TRH responsivity [68]. In clinical studies, a marked reduction in FT4 levels (inversely correlated with mitotane concentrations) has been reported, but interestingly, TSH did not change accordingly [69]. The explanation can be attributed to a possible "central hypothyroidism" or alternatively to an impairment of deiodinase activity with a change in FT4/FT3 ratio.…”