Mitotane in the Treatment of Adrenocortical Carcinoma: Metabolic and Endocrine Disruption

Abstract

Abstract Background: Mitotane is a well-known adrenocytolitic agent resulting in adrenal insufficiency. However, little is known about its multiple and complex metabolic and endocrine effects. Clinical Case: Patient is a 6 year 9 month old female who presented with acne, pubic hair and rapid weight gain. Initial evaluation showed elevated testosterone (64 ng/dL), 17-OH-progesterone (236 ng/dL), DHEA-S (922 mcg/dL), and random cortisol (30.9 mcg/dL) with suppressed ACTH (<2.0 pg/mL). She had an inappropriate lack of suppression after a 1 mg overnight dexamethasone suppression test (cortisol 49 mcg/dL, nl <2 mcg/dL). Abdominal CT showed large necrotic-appearing right adrenal mass (10.7x8.8x15 cm) with no metastasis. Surgical excision was complicated by intraoperative rupture. Pathology confirmed stage III right adrenal cortical carcinoma. Patient was started on etoposide, cisplatin, doxorubicin, and mitotane as adjuvant therapy. 6 days after surgery, her DHEA-S and cortisol levels were undetectable. She was started on glucocorticoid replacement therapy with hydrocortisone at 18 mg/m2/day. Due to severe nausea, she was switched to dexamethasone 5 mg/m2/day (245 mg/m2/day dose equivalent to hydrocortisone). However, the patient developed hypotension, increased nausea and emesis and was switched back to hydrocortisone. The patient’s clinical course was complicated by hyperlipidemia with total cholesterol 215 mg/dL, HDL 48 mg/dL and LDL 150 mg/dL, as well as central hypothyroidism with low FT4 (0.8 ng/dL) and an inappropriately low normal TSH (0.31 mcIU/mL). She was started on levothyroxine with a final dose of 2.6mcg/kg/day to achieve euthyroid state. Mineralocorticoid deficiency has been reported in a small number of case reports of mitotane use. Our patient continues to demonstrate adequate mineralocorticoid function based on her normal electrolytes, aldosterone and plasma renin activity level. Conclusion: Mitotane exerts multiple clinically relevant metabolic and endocrine effects. Patients treated with mitotane should be monitored for complications including mineralocorticoid deficiency, central hypothyroidism, and hyperlipidemia. Dexamethasone must be avoided because of the rapid inactivation by CYP4503A4 leading to adrenal crisis. Typical glucocorticoid replacement dose must be doubled due to induction of CYP3A4 activity that leads to glucocorticoid inactivation.