Etomidate, Ketoconazole, and Mitotane for Cushing Disease due to Adrenocortical Carcinoma

Introduction: Cushing’s disease due to adrenocortical carcinoma (ACC) has limited treatment options which have high risk for toxicity, prolonged time to therapeutic effect, drug-drug interactions (DDI), and high cost. The Endocrine Society Clinical Practice Guidelines recommend an etomidate infusion (EI) to rapidly decrease cortisol as a bridge to surgical intervention or if patients are unable to take oral medications. A published protocol described EI's prepared as 1 mg/mL (etomidate 40 mg per 40 mL dextrose 5% in water).


Description: A 69-year-old female presented 15 months after right adrenalectomy with acute weakness, dehydration, hyperglycemia, and serum cortisol of 306 µg/dL. An MRI revealed an L1 lytic lesion concerning for malignancy. Etomidate was initiated as a 3 mg bolus and 0.02 mg/kg/hr infusion which decreased serum cortisol to 56.6 µg/dL within 24 hours. The goal cortisol (20-30 µg/dL) was achieved after 114 hours. For ease of compounding, we made larger infusions (80 mg per 80 mL dextrose 5% in water). The EI was titrated up to 0.045 mg/kg/hr based on cortisol levels and adverse effects. Only one episode of somnolence occurred which resolved after decreasing the infusion. Ketoconazole was also initiated and titrated.
Final pathology of the L1 lytic lesion was confirmed ACC. Triple therapy (carboplatin, etoposide, and doxorubicin) was considered but not initiated due to poor functional status. Mitotane was initiated and titrated, but cortisol levels increased again due to a DDI with ketoconazole. Osilodrostrat, mifepristone, metyrapone, and pasireotide were considered but restricted by primary disease and cost. Ultimately, the patient discharged to hospice care after 41 days of admission.


Discussion: This is a report of a patient with Cushing’s disease due to ACC who achieved rapid cortisol reduction with an EI while determining definitive diagnosis. To our knowledge, this is the first time an 80 mg/80 mL infusion was utilized. Her course was complicated by the delay in diagnosis, limited treatment options, DDI's, prolonged time to therapeutic effect of enteral agents, and cost. EI's are safe and effective to reduce cortisol quickly, but many institutions and staff are unfamiliar with its use as a continuous infusion. Many challenges still exist for this difficult and rare disease.