High-dose mitotane strategy in adrenocortical carcinoma: prospective analysis of plasma mitotane measurement during the first 3 months of follow-up

Abstract

Background: The benefit-to-risk ratio of a high-dose strategy at the initiation of mitotane treatment of adrenocortical carcinoma (ACC) remains unknown. Methods: To evaluate the performance of a high-dose strategy, defined as the highest tolerated dose administered within 2 weeks and maintenance therapy over 4 weeks, we conducted a single-center, prospective study with two main objectives: to evaluate the percentage of patients who achieve a plasma mitotane level above 14 mg/l and to evaluate the tolerance of mitotane within the first 3 months of treatment. Plasma mitotane levels were measured monthly using HPLC. Results: Twenty-two patients with ACC were prospectively enrolled. The high-dose mitotane strategy (4 g/day or more in all patients, with a median of 6 g/day within 2 weeks) enabled to reach the therapeutic threshold of O14 mg/l at 1, 2, or 3 months in 6/22 patients (27%), 7/22 patients (32%), and 7/22 patients (32%) respectively. In total, a therapeutic plasma mitotane level was reached in 14 out of 22 patients (63.6%) during the first 3 months in ten patients, and after 3 months in four patients. Grade 3-4 neurological or hematological toxicities were observed in three patients (13.6%). Conclusion: Employing a high-dose strategy at the time of mitotane initiation enabled therapeutic plasma levels of mitotane to be reached within 1 month in 27% of the total group of patients. If this strategy is adopted, we suggest that mitotane dose is readjusted according to plasma mitotane levels at 1 or/and 2 months and patient tolerance.

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

“…In our study, either high-dose or low-dose regimens were employed reflecting this controversy. 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).…”

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

“…For the antisteroidogenic effect, lower levels are likely to be effective; therefore, in hypercortisolaemia we are aiming for levels above 8.5 mg/l (8). Mitotane has poor bioavailability following oral administration (40%), and it is therefore possible that a significant number of treated patients may not achieve therapeutic levels for several months following the onset of treatment (145).…”

Ovarian macrocysts and gonadotrope–ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease

“…Plasma mitotane concentrations were measured by HPLC after an overnight fast, as described previously (10). Intra-assay CV values were 20% at low values and 15% at high values.…”