Low-Dose Monitored Mitotane Treatment Achieves the Therapeutic Range with Manageable Side Effects in Patients with Adrenocortical Cancer¹

Abstract

Eight patients with adrenocortical cancer were treated with low doses of mitotane (2-3 g daily) while monitoring drug plasma levels. When the mitotane concentrations reached the therapeutic range (defined as mitotane plasma levels between 14-20 microg/mL), a dose reduction was performed to avoid toxicity. Thereafter, the mitotane dose was tailored according to plasma levels. A progressive increase in plasma mitotane concentrations was observed during treatment, and a highly significant linear correlation was found between plasma drug levels and the total mitotane dose. The therapeutic threshold was reached in all patients after 3-5 months and a total mitotane dose of 283-387 g/days (median, 363). The duration of treatment was 8-40 months (median, 9). Toxicity was manageable in all but one patient, who discontinued treatment. It is therefore possible to design a standard low dose schedule, e.g. 3 g/daily for about 3-4 months with following dose adjustments guided by the monitoring of plasma mitotane levels. This approach is able to provide therapeutic mitotane concentrations and limit the unwanted effects. The present data provide a rationale to change the approach to mitotane treatment in patients with adrenocortical carcinoma from high dose to low dose regimens.

A new simple HPLC method for measuring mitotane and its two principal metabolites

“…Tel. : +39 011 6705442; fax: +39 011 9038649. still not clear [7,8]. Adverse reactions are common mainly to the gastrointestinal, central nervous system, and derma, but nontolerable toxic events are rare when the plasma concentration is less than 15 g/ml.…”

A simple HPLC method for plasma level monitoring of mitotane and its two main metabolites in adrenocortical cancer patients

“…The antitumor effect of mitotane is related to the maintenance of adequate plasma drug levels [7][8][9][10]. It is suggested that patient plasma mitotane levels ≥14 g/ml lead to a 55-60% response rate, whereas those with lower levels have a low chance of response.…”

“…In addition, significant side effects have generally only been observed in patients with plasma levels greater than 20 g/ml [7,10]. Plasma level monitoring of mitotane during treatment allows the more rapid attainment of a therapeutic plasma level (14-20 g/ml), as well as minimization of adverse effects due to an excessively high plasma level [9,11].…”

“…1) by ␣-and ␤-hydroxylation, respectively [12], with DDA levels increasing rapidly to high levels [13][14][15][16][17][18] while DDE levels rise slowly. The importance of measuring plasma mitotane and its metabolites DDE and DDA has been documented in a number of studies [9,[13][14][15][16][17]19]. A recent long term follow up study [17] suggests that the plasma concentrations of DDE were more closely related to clinical improvement or remission than the mitotane levels.…”

Therapeutic drug monitoring of mitotane: Analytical assay and patient follow‐up

“…Several dosing regimens have been proposed to achieve a plasma concentration between 14 and 20 mg L −1 . Low dosing regimens begin with 3 g per day for 3-4 months then continue with 1-2 g per day and allow to achieve the therapeutic range with manageable side effects in 3-5 months (European Medicines Agency, n.d.-a; Terzolo et al, 2000).…”