Management of Endocrine Manifestations and the Use of Mitotane As a Chemotherapeutic Agent for Adrenocortical Carcinoma

Abstract

Adrenal cortical carcinoma (ACC) is a rare malignancy in which patients have poor overall 5-year survival. Patients with ACC can present with symptoms of hormone excess, including Cushing's syndrome, virilization, feminization, or—less frequently—hypertension with hypokalemia. In many patients with ACC, advanced disease at presentation precludes surgery or is followed by local relapse or distant metastatic disease that cannot be managed surgically. In these instances, chemotherapy is often tried, but its limited efficacy all too often leaves the problem of persistent hormonal excess. Physicians who treat patients with ACC and severe hypercortisolism should recognize that uncontrolled hormone production is a malignant disease, which has severe consequences that require aggressive management. Because chemotherapy benefits only a small percentage of patients, steroidogenesis inhibitors, including mitotane, ketoconazole, metyrapone, and etomidate, should be used singly or in combination even as chemotherapy is administered. Diligent management with frequent adjustments is required, especially in patients with chemotherapy-refractory tumors that continue to grow. In the absence of randomized, controlled trials, adjuvant use of mitotane remains controversial, although the authors of a recent case-control study argue for its use. Despite difficulty administering effective doses, most clinicians agree that mitotane should be used if the tumor cannot be removed surgically or should be used as adjuvant therapy if there is a high likelihood of recurrence. The option of long-term monotherapy is restricted to patients who tolerate mitotane and either experience a clinical response or are at high risk for recurrence. Recommendations are provided to help manage patients with this difficult disease and to improve the quality of their lives.

Mitotane levels predict the outcome of patients with adrenocortical carcinoma treated adjuvantly following radical resection

“…More than 50 years after the introduction of mitotane in clinical practice (8), its use as a postoperative adjunctive measure remains a matter of debate (11,12,23). This study shows for the first time that mitotane levels may influence the outcome of patients treated adjuvantly following radical resection of ACC and validate the concept of a therapeutic value for a cutoff of mitotane concentrations at 14 mg/l.…”

Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center

“…In addition to enzyme-inhibitory activity against 11b-hydroxylation and cholesterol side chain cleavage, mitotane has a strong adrenolytic effect that confers long-lasting activity and could limit the escape phenomenon observed with other anti-cortisolic drugs (17). There is now evidence for the anti-proliferative and anti-secretory effects of mitotane in adrenocortical cancer (18,19,20), but there are no recent data on its long-term efficacy or safety in the treatment of CD. The largest study to date was published from our center in 1979 and included 62 patients treated with mitotane, of whom 24 also received pituitary irradiation (21).…”

New developments in the medical treatment of Cushing's syndrome

“…Mitotane or o,p'-DDD is a derivative of DDT (dichlorodiphenyltrichloroethane) and is mainly used in the treatment of ACCs because of its adrenolytic properties (Veytsman et al 2009, Fassnacht et al 2011. It has been shown to inhibit cortisol production via inhibition of multiple steroidogenic enzymes and to be efficacious in the treatment of CD (Young et al 1973, Luton et al 1979.…”

“…Mitotane is the first-choice treatment for ACC considering its antiproliferative and antisecretory effects (Veytsman et al 2009, Fassnacht et al 2011. When hypercortisolism cannot be controlled by mitotane monotherapy or when the late-onset effects of mitotane cannot be awaited for, other adrenal blocking drugs, e.g.…”