Role of Mitotane in Adrenocortical Carcinoma – Review and State of the art

Abstract

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine tumour deriving from the adrenal cortex. A correct therapeutic strategy requires a multidisciplinary approach between endocrinologist, surgeon and oncologist. Surgery is the mainstay treatment in ACC while mitotane, deriving from the insecticide dichloro-diphenyl-trichloro-ethane, is the main base of the medical treatment of ACC in consideration of its adrenocytolitic activity. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. A prospective randomised trial (ADIUVO), recruiting patients with low-intermediate risk of recurrence, is evaluating the utility of adjuvant treatment with mitotane in this setting. The therapeutic response is observed with plasma levels of mitotane >14 mg/L. However, the major difficulty in the management of mitotane treatment is related to side effects and to the risk of toxicity, which is related to plasmatic levels >20 mg/L, that is considered the upper limit of the therapeutic window. Mitotane therapy results in adrenal insufficiency, and glucocorticoid replacement therapy has to be administered at higher doses than those used in other aetiologies of primary adrenal insufficiency. Furthermore, other endocrine side effects related to mitotane should be considered, in particular on thyroid hormone and testosterone metabolism. Waiting for new medical strategies on molecular targets, it will be mandatory to optimise the current knowledge by prospective trials and, in consideration of the rarity of the disease, collaborative studies between endocrinologists and oncologists are necessary.

Recovery of Adrenal Insufficiency Is Frequent After Adjuvant Mitotane Therapy in Patients with Adrenocortical Carcinoma

“…Mitotane is an analogue of dichloro-diphenyl-trichloroethane (DDT) insecticide and has been used for ACC since the 1960s. It is known to cause frequent side effects including gastro-intestinal and hepatic disturbances (anorexia, nausea, vomiting and diarrhea, hepatitis, or liver enzyme elevation), central nervous system toxicity (lethargy, somnolence, dizziness, and vertigo), leukopenia, increased serum cholesterol, altered drug metabolism, and endocrine disorders such as hypogonadism and hypothyroidism [9,10]. Mitotane has significant adrenolytic properties, which causes adrenal insufficiency and, for this reason, an actual standard of care requires that simultaneous replacement with sufficient glucocorticoid be given to patients receiving mitotane.…”

Factors Affecting Dexamethasone Suppression Test Results

“…Combined oral contraceptives and hormone replacement therapy are textbook cases, and false-positive results of the low-dose DSTs were documented in patients using these medications [30,[58][59][60]. Mitotane can increase transcortin concentration, nonetheless it also displays adrenolytic properties and impairs steroidogenesis [61,62]. Ketoconazole, etomidate, and metyrapone blunt endocrine function of the suprarenal glands as well -therapeutically they are used as steroidogenesis inhibitors [62][63][64][65][66][67][68][69][70][71][72][73][74].…”

DIAGNOSIS OF ENDOCRINE DISEASE: Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview

“…Acting via interfering with one or more of the enzymes in the steroidogenic pathway, they can cause subsequent decrease in cortisol secretion and adrenal insufficiency. Thus, adrenal function should be monitored closely to these patients, as hydrocortisone replacement may be mandatory (202,203).…”