Prospective evaluation of mitotane toxicity in adrenocortical cancer patients treated adjuvantly

Abstract

Toxicity of adjuvant mitotane treatment is poorly known; thus, our aim was to assess prospectively the unwanted effects of adjuvant mitotane treatment and correlate the findings with mitotane concentrations. Seventeen consecutive patients who were treated with mitotane after radical resection of adrenocortical cancer (ACC) from 1999 to 2005 underwent physical examination, routine laboratory evaluation, monitoring of mitotane concentrations, and a hormonal work-up at baseline and every 3 months till ACC relapse or study end (December 2007). Mitotane toxicity was graded using NCI CTCAE criteria. All biochemical measurements were performed at our center and plasma mitotane was measured by an in-house HPLC assay. All the patients reached mitotane concentrations O14 mg/l and none of them discontinued definitively mitotane for toxicity; 14 patients maintained consistently elevated mitotane concentrations despite tapering of the drug. Side effects occurred in all patients but were manageable with palliative treatment and adjustment of hormone replacement therapy. Mitotane affected adrenal steroidogenesis with a more remarkable inhibition of cortisol and DHEAS than aldosterone. Mitotane induced either perturbation of thyroid function mimicking central hypothyroidism or, in male patients, inhibition of testosterone secretion. The discrepancy between salivary and serum cortisol, as well as between total and free testosterone, is due to the mitotane-induced increase in hormone-binding proteins which complicates interpretation of hormone measurements. A low-dose monitored regimen of mitotane is tolerable and able to maintain elevated drug concentrations in the long term. Mitotane exerts a complex effect on the endocrine system that may require multiple hormone replacement therapy.

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

“…Regarding the tolerance of mitotane, we observed frequent mild side effects, mainly affecting the gastrointestinal and nervous systems, as previously reported (42). However, these adverse effects could be managed by tapering the mitotane dose and/or with additional symptomatic treatment in nearly three-quarters of cases.…”

“…No cases of hepatocellular deficiency occurred. Finally, mitotane was associated with a mild increase in LDL-and HDL-cholesterol as previously reported (42,43). This has been attributed to the inhibition of cytochrome P450 (44).…”

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

“…A high-dose regimen has been advocated to allow a rapid rise of plasma mitotane concentrations in order to avoid any delay in drug activity (28,29); however, toxicity associated with such a regimen is of concern. On the other hand, also a lowdose regimen, potentially better tolerated, is able to provide target mitotane concentrations, but with a time lag of several months from treatment start (30). It is noteworthy that in the present series the percentage of patients attaining target mitotane concentrations at the landmark of 3 months did not differ in the high-dose vs low-dose group.…”

“…Despite a possible underreporting of some adverse effects due to the retrospective nature of the study, we confirm that adjuvant mitotane treatment is feasible proven that a careful follow-up and counseling is offered to the patients. The monitoring of mitotane concentrations is of pivotal importance in this context to guide dose adjustments and limit unwanted effects, as it was previously observed (30). Conversely, studies published before the availability of mitotane monitoring reported that a severe and disabling toxicity was associated with mitotane use, which may lead many patients to be unable to perform the usual activities of ordinary life (7).…”

Cytotoxic activity of gemcitabine, alone or in combination with mitotane, in adrenocortical carcinoma cell lines

“…From a clinical standpoint, the toxicity of mitotane is still a major limitation to its use in the treatment of ACC patients (Daffara et al, 2008) and predictive biomarkers correctly identifying patients who will profit from mitotane treatment are still missing. In a recent study from our group, high expression levels of Ribonucleotide Reductase Large Subunit 1 (RRM1) gene were shown to be negative predictors of response to mitotane administration as an adjuvant treatment (Volante et al, 2012).…”