"A derivative of the insecticide DICHLORODIPHENYLDICHLOROETHANE that specifically inhibits cells of the adrenal cortex and their production of hormones. It is used to treat adrenocortical tumors and causes CNS damage, but no bone marrow depression." (MeSH 2013)
Latest Research Publications
Web Resources: Mitotane (5 links)
This list of publications is regularly updated (Source: PubMed).
Oral and vulvo-vaginal lichenoid reactions due to mitotane (Lysodren): A case report.
Medicine (Baltimore). 2017; 96(2):e5075 [PubMed] Free Access to Full Article Related Publications
CASE SUMMARY: This case report is about a 50 years old woman. Six months after the initiation on mitotane treatment, she developed erosive lesions located on the oral and vaginal mucosa. These drug reactions were diagnosed as erosive lichen planus by the biopsy. This lichenoid lesions were resistant to the usual treatments, mitotane being at the time not replaceable.
CONCLUSION: This case describes an unreported adverse effect of mitotane, it is - to our knowledge - the 1st description of erosive lichenoid drug reaction due to Mitotane.
Efficacy and safety of mitotane in the treatment of adrenocortical carcinoma: A retrospective study in 34 Belgian patients.
Ann Endocrinol (Paris). 2016; 77(5):578-585 [PubMed] Related Publications
MATERIAL AND METHODS: This was a multicentre retrospective review of the outcome of 34 patients treated with mitotane for ACC during the period [01/2008-12/2011] (12 diagnosed before and 22 diagnosed during the study period) and evaluated up to 06/2013.
RESULTS: Patient and tumour characteristics were consistent with those generally described for ACC. Mean age at diagnosis was 46.5 years, most patients were female (62%), had functioning ACC (65%) and advanced tumours (ENSAT stages III or IV: 82%). Therapeutic mitotane plasma levels (14-20 mg/L) were achieved at least once in 70% of the cohort, after a median of 4 months, and were maintained for more than 2 months in 61% of evaluable patients. Mitotane-related adverse effects were observed in 66% of patients, were never serious, and included gastrointestinal, neurological, neuropsychological, hormonal, dermatologic and metabolic effects. Most patients (88%) discontinued mitotane, mainly due to tumour progression. Multivariate analysis showed that ENSAT stage was a prognostic factor for overall (OS) and disease-free survival (DFS); OS was also influenced independently by achievement of therapeutic mitotane plasma levels for at least two consecutive months.
CONCLUSION: Patient and tumour characteristics were consistent with previously published data. OS and DFS were mostly influenced by ENSAT stage at diagnosis. Achieving therapeutic levels of mitotane for at least two consecutive months seemed to positively influence OS, but such levels were not reached or sustained in some patients.
Rapid and Complete Remission of Metastatic Adrenocortical Carcinoma Persisting 10 Years After Treatment With Mitotane Monotherapy: Case Report and Review of the Literature.
Medicine (Baltimore). 2016; 95(13):e3180 [PubMed] Free Access to Full Article Related Publications
Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A 13-Institution Study by the US Adrenocortical Carcinoma Group.
J Am Coll Surg. 2016; 222(4):480-90 [PubMed] Free Access to Full Article Related Publications
STUDY DESIGN: Patients who underwent resection of adrenocortical carcinoma from 1993 to 2014 at the 13 academic institutions of the US Adrenocortical Carcinoma Group were included. Factors associated with mitotane administration were determined. Primary end points were recurrence-free survival (RFS) and overall survival (OS).
RESULTS: Of 207 patients, 88 (43%) received adjuvant mitotane. Receipt of mitotane was associated with hormonal secretion (58% vs 32%; p = 0.001), advanced TNM stage (stage IV: 42% vs 23%; p = 0.021), adjuvant chemotherapy (37% vs 5%; p < 0.001), and adjuvant radiation (17% vs 5%; p = 0.01), but was not associated with tumor rupture, margin status, or N-stage. Median follow-up was 44 months. Adjuvant mitotane was associated with decreased RFS (10.0 vs 27.9 months; p = 0.007) and OS (31.7 vs 58.9 months; p = 0.006). On multivariable analysis, mitotane was not independently associated with RFS or OS, and margin status, advanced TNM stage, and receipt of chemotherapy were associated with survival. After excluding all patients who received chemotherapy, adjuvant mitotane remained associated with decreased RFS and similar OS; multivariable analyses again showed no association with recurrence or survival. Stage-specific analyses in both cohorts revealed no association between adjuvant mitotane and improved RFS or OS.
CONCLUSIONS: When accounting for stage and adverse tumor and treatment-related factors, adjuvant mitotane after resection of adrenocortical carcinoma is not associated with improved RFS or OS. Current guidelines should be revisited and prospective trials are needed.
Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression.
Oncotarget. 2016; 7(3):3233-44 [PubMed] Free Access to Full Article Related Publications
Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma.
Eur J Endocrinol. 2016; 174(3):343-53 [PubMed] Related Publications
AIM: Serum mitotane concentrations >14 mg/l are targeted for improved efficacy but not achieved in about half of patients. Here we aimed at a better understanding of intestinal absorption and lipoprotein association of mitotane and metabolites o,p'-dichlorodiphenylacetic acid (o,p'-DDA) and o,p'-dichlorodiphenyldichloroethane (o,p'-DDE).
DESIGN: Lipoproteins were isolated by ultracentrifugation from the chyle of a 29-year-old patient and serum from additional 14 ACC patients treated with mitotane. HPLC was applied for quantification of mitotane and metabolites. We assessed NCI-H295 cell viability, cortisol production, and expression of endoplasmic reticulum (ER) stress marker genes to study the functional consequences of mitotane binding to lipoproteins.
RESULTS: Chyle of the index patient contained 197 mg/ml mitotane, 53 mg/ml o,p'-DDA, and 51 mg/l o,p'-DDE. Of the total mitotane in serum, lipoprotein fractions contained 21.7±21.4% (VLDL), 1.9±0.8% (IDL), 8.9±5.5% (LDL1), 18.9±9.6% (LDL2), 10.1±4.0% (LDL3), and 26.3±13.0% (HDL2). Only 12.3±5.5% were in the lipoprotein-depleted fraction.
DISCUSSION: Mitotane content of lipoproteins directly correlated with their triglyceride and cholesterol content. O,p'-DDE was similarly distributed, but 87.9±4.2% of o,p'-DDA found in the HDL2 and lipoprotein-depleted fractions. Binding of mitotane to human lipoproteins blunted its anti-proliferative and anti-hormonal effects on NCI-H295 cells and reduced ER stress marker gene expression.
CONCLUSION: Mitotane absorption involves chylomicron binding. High concentrations of o,p'-DDA and o,p'-DDE in chyle suggest intestinal mitotane metabolism. In serum, the majority of mitotane is bound to lipoproteins. In vitro, lipoprotein binding inhibits activity of mitotane suggesting that lipoprotein-free mitotane is the therapeutically active fraction.
Mitotane Inhibits Sterol-O-Acyl Transferase 1 Triggering Lipid-Mediated Endoplasmic Reticulum Stress and Apoptosis in Adrenocortical Carcinoma Cells.
Endocrinology. 2015; 156(11):3895-908 [PubMed] Related Publications
Contribution of Therapeutic Monitoring in the Assessment of Toxic Adverse Effects of Mitotane: a Case Report.
Therapie. 2015 Nov-Dec; 70(6):545-6 [PubMed] Related Publications
Mitotane treatment in patients with adrenocortical cancer causes central hypothyroidism.
Clin Endocrinol (Oxf). 2016; 84(4):614-9 [PubMed] Related Publications
OBJECTIVE: To investigate the pathogenesis of thyroid abnormalities in mitotane-treated patients with ACC.
PATIENTS AND METHODS: In five female patients with ACC (median age 47; range 31-65) treated with mitotane (dosage 1·5 g/day; 1·0-3·0), we analysed the pattern of TSH and thyroid function index (FT4, FT3 and FT3/FT4 ratio) compared to an age- and gender-matched control group. The in vivo secretory activity of the thyrotrophic cells was evaluated using a standard TRH test (200 μg), and the response was compared to both a group of age-matched female controls (n = 10) and central hypothyroid patients (n = 10).
RESULTS: Basal TSH (median 1·54 mU/l; range 1·20-2·17) was normal and scattered around our median reference value, FT3 levels (median 3·80 pmol/l; 3·30-4·29) were normal but below the median reference value of 4·37 pmol/l and FT4 levels were below the normal range in all patients (median 8·40 pmol/l; 7·6-9·9). FT3/FT4 ratio was in the upper range in 4 patients and higher than normal in one patient. A blunted TSH response to TRH was observed in mitotane-treated patients. ΔTSH (absolute TSH response, peak TSH minus basal TSH) was 3·65 (range 3·53-5·26), 12·37 (range 7·55-19·97) and 1·32 mU/l (range 0·52-4·66) in mitotane-treated patients, controls and central hypothyroid patients, respectively. PRL secretion was normal.
CONCLUSIONS: Mitotane-treated patients with ACC showed low FT4, normal FT3 and TSH and impaired TSH response to TRH, characteristic of central hypothyroidism. Furthermore, the elevated FT3/FT4 ratio of these subjects reflects an enhanced T4 to T3 conversion rate, a compensatory mechanism characteristic of thyroid function changes observed in hypothyroid conditions. This finding thus confirms in vitro studies and may have a therapeutic implication for treatment with thyroid hormones, as suggested by current guidelines for this specific condition.
Lipoprotein-Free Mitotane Exerts High Cytotoxic Activity in Adrenocortical Carcinoma.
J Clin Endocrinol Metab. 2015; 100(8):2890-8 [PubMed] Related Publications
OBJECTIVE: The aim of our study was to evaluate the in vivo and in vitro biological implication of serum lipoproteins on pharmacological action of mitotane. Distribution and concentration of mitotane were studied in plasma and adrenal tissue samples from mitotane-treated patients. The effect of lipoprotein-bound or lipoprotein-free (LP-F) mitotane was analyzed on proliferation and apoptosis of human adrenocortical H295R cells. A retrospective study of patients with ACC treated or not with statins was also performed.
RESULTS: o,p'-DDD distribution among very low-density lipoprotein, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and LP-F fractions obtained after plasma ultracentrifugation of 23 of mitotane-treated patients was widely distributed in each subfraction. A positive correlation was observed between mitotane levels in plasma and in LDL, HDL, but also LP-F compartment. Intratumor o,p'-DDD concentrations in five ACC samples of mitotane-treated patients were found to be independent of cholesterol transporter expression, scavenger receptors, and LDL receptors. In vitro studies showed significant higher antiproliferative and proapoptotic effects and higher cell and mitochondrial uptake of mitotane when H295R cells were grown in LP-F medium. Finally, retrospective study of an ACC cohort of 26 mitotane-treated patients revealed that statin therapy was significantly associated with a higher rate of tumor control.
CONCLUSIONS: Altogether, our in vitro and in vivo studies provided compelling evidence for a greater efficacy of LP-F mitotane. Patients with ACC may thus benefit from therapeutic strategies that aim to increase LP-F mitotane fraction.
Endocrinol Metab Clin North Am. 2015; 44(2):411-34 [PubMed] Related Publications
Effects of adrenolytic mitotane on drug elimination pathways assessed in vitro.
Endocrine. 2015; 49(3):842-53 [PubMed] Related Publications
RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization.
Mol Cell Endocrinol. 2015; 401:105-10 [PubMed] Related Publications
Ovarian macrocysts and gonadotrope-ovarian axis disruption in premenopausal women receiving mitotane for adrenocortical carcinoma or Cushing's disease.
Eur J Endocrinol. 2015; 172(2):141-9 [PubMed] Related Publications
OBJECTIVE: To evaluate the ovarian and gonadotrope effects of mitotane therapy in premenopausal women.
PATIENTS: We studied 21 premenopausal women (ACC: n=13; CD: n=8; median age 33 years, range 18-45 years) receiving mitotane at a median initial dose of 3 g/day (range 1.5-6 g/day).
METHODS: Gynecological history was collected and ovarian ultrasound was performed. Four women also underwent ovarian CT or magnetic resonance imaging. Serum gonadotropin, estradiol (E2), androgens, sex hormone-binding globulin (SHBG), and circulating mitotane levels were determined at diagnosis and during mitotane therapy.
RESULTS: In the women included, ovarian macrocysts (bilateral in 51%) were detected after a median 11 months (range: 3-36) of mitotane exposure. The median number of macrocysts per woman was two (range: 1-4) and the median diameter of the largest cysts was 50 mm (range: 26-90). Menstrual irregularities and/or pelvic pain were present in 15 out of 21 women at macrocyst diagnosis. In two women, the macrocysts were revealed by complications (ovarian torsion and hemorrhagic macrocyst rupture) that required surgery. Mitotane therapy was associated with a significant decrease in androstenedione and testosterone levels and a significant increase in LH levels. Serum FSH and E2 levels were also increased, and SHBG levels rose markedly.
CONCLUSIONS: Mitotane therapy causes significant morphological and ovarian/gonadotrope hormonal abnormalities in premenopausal women. Follicular thecal steroid synthesis appears to be specifically altered and the subsequent increase in gonadotropins might explain the development of macrocysts. The mechanisms underlying these adverse effects, whose exact prevalence in this population still needs to be determined, are discussed.
Mitotane and Carney Complex: ten years follow-up of a low-dose mitotane regimen inducing a sustained correction of hypercortisolism.
Hormones (Athens). 2015 Apr-Jun; 14(2):300-4 [PubMed] Related Publications
DESIGN: We evaluated a low-dose mitotane regimen for treating severe hypercortisolism in a 27-year-old woman with CC. She presented with severe hypercortisolism and a history of surgeries for breast ductal adenoma, atrial cardiac myxomas with cerebral and peripheral arterial embolism, and near-total thyroidectomy because of an oxyphilic adenoma. The patient refused further surgery for adrenalectomy.
RESULTS: During the first 7 months of mitotane (Lysodren, HRA Pharma, Paris, France), the daily oral dose was progressively increased from 0.5 to 4 g/day and then stopped because of the appearance of sustained signs of hypoadrenalism, that required a replacement therapy with 5 mg of prednisone o.d. A 10-month mitotane off-therapy follow-up was performed and when an increase in urine free cortisol (UFC) was noted, the mitotane regimen was restarted at lower doses (0.750-1 g/day). Serum morning cortisol levels and UFC were then maintained within the normal range, with plasma mitotane ranging between 2 and 4 mg/L. A sustained regression of Cushing's features without inducing hypoadrenalism was achieved, which still persists after 122 months of follow-up. Minimal initial gastric discomfort was the only side effect of which the patient complained and only during the first higher dose mitotane course.
CONCLUSIONS: Long-term administration of a low maintenance dose of mitotane may be suggested as treatment for hypercortisolism in CC patients who refuse or are at high risk for surgical adrenalectomy.
Marked transient hypercholesterolemia caused by low-dose mitotane as adjuvant chemotherapy for adrenocortical carcinoma.
J Atheroscler Thromb. 2014; 21(12):1326-9 [PubMed] Related Publications
Short-term variation in plasma mitotane levels confirms the importance of trough level monitoring.
Eur J Endocrinol. 2014; 171(6):677-83 [PubMed] Related Publications
DESIGN: A prospective case-control study was conducted to investigate the variation in plasma mitotane levels.
METHODS: Patients who had been treated for at least 24 weeks and had reached the therapeutic plasma level (14 mg/l) at least once were eligible. In the first group, mitotane levels were determined hourly for the duration of 8 h after administration of a single morning dose. In the second group, mitotane levels were assessed similarly without administration of a morning dose.
RESULTS: Ten patients were included in this study, and three patients participated in both groups. Median plasma level at baseline was 16.2 mg/l (range 11.3-23.3 mg/l) in the first group (n=7) and 17.0 mg/l (13.7-23.8) in the second group (n=6). Plasma levels displayed a median increase compared with baseline of 24% (range 6-42%) at t=4 after morning dose and a change of 13% (range -14 to 33%) at t=4 without morning dose (P=0.02).
CONCLUSION: A substantial increase in mitotane plasma levels was observed in steady-state patients within a period of 8 h after morning dosing. Without morning dose, mitotane curves showed a variable profile throughout the day. This implies that random sampling could yield incidentally high levels. For this reason, we recommend early-morning trough sampling as standard management in monitoring mitotane treatment.
CYP2W1 is highly expressed in adrenal glands and is positively associated with the response to mitotane in adrenocortical carcinoma.
PLoS One. 2014; 9(8):e105855 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.
MATERIAL AND METHODS: CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples).
RESULTS: CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0-1) in 72% of non-adrenal normal tissues, but high (H-score 2-3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01).
CONCLUSION: CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.
Mitotane enhances doxorubicin cytotoxic activity by inhibiting P-gp in human adrenocortical carcinoma cells.
Endocrine. 2014; 47(3):943-51 [PubMed] Related Publications
The lack of antitumor effects of o,p'DDA excludes its role as an active metabolite of mitotane for adrenocortical carcinoma treatment.
Horm Cancer. 2014; 5(5):312-23 [PubMed] Free Access to Full Article Related Publications
Development of a pharmacokinetic model of mitotane: toward personalized dosing in adrenocortical carcinoma.
Ther Drug Monit. 2015; 37(1):58-65 [PubMed] Related Publications
METHODS: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients.
RESULTS: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The mean prediction error was 14% ± 13%.
CONCLUSIONS: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.
The combination of insulin-like growth factor receptor 1 (IGF1R) antibody cixutumumab and mitotane as a first-line therapy for patients with recurrent/metastatic adrenocortical carcinoma: a multi-institutional NCI-sponsored trial.
Horm Cancer. 2014; 5(4):232-9 [PubMed] Free Access to Full Article Related Publications
Practical treatment using mitotane for adrenocortical carcinoma.
Curr Opin Endocrinol Diabetes Obes. 2014; 21(3):159-65 [PubMed] Related Publications
RECENT FINDINGS: Several in-vitro studies have shown that mitotane suppresses gene transcription of different enzymatic steps of the steroidogenetic pathway. Moreover, mitotane induces CYP3A4 expression, thus accelerating the metabolic clearance of a variety of drugs including steroids. Retrospective studies provided evidence that adjunctive mitotane can prolong recurrence-free survival of treated patients. The concept of a therapeutic window of mitotane plasma concentrations was confirmed also for adjunctive treatment, but the relationship between mitotane concentration and given dose is loose. Genetic variability of the P450-dependent enzymes metabolizing mitotane may explain individual differences.
SUMMARY: Mitotane concentration of 14-20 mg/l should be reached and maintained during treatment also in an adjunctive setting. In advanced adrenocortical carcinoma, a high-dose starting regimen should be employed when mitotane is used as monotherapy. The combination of mitotane with other drugs should consider the possibility of pharmacologic interactions due to mitotane-induced activation of drug metabolism. This concept applies also to steroid replacement in mitotane-treated patients, who need higher doses to adjust for increased steroid metabolism.
Hair cortisol measurement in mitotane-treated adrenocortical cancer patients.
Horm Metab Res. 2014; 46(4):299-304 [PubMed] Related Publications
Prognostic role of overt hypercortisolism in completely operated patients with adrenocortical cancer.
Eur Urol. 2014; 65(4):832-8 [PubMed] Related Publications
OBJECTIVE: To assess the prognostic role of clinical symptoms of hypercortisolism in a large series of patients with completely resected ACC.
DESIGN, SETTING, AND PARTICIPANTS: A total of 524 patients followed at referral centers for ACC in Europe and the United States entered the study. Inclusion criteria were ≥18 yr of age, a histologic diagnosis of ACC, and complete surgery (R0). Exclusion criteria were a history of other malignancies and adjuvant systemic therapies other than mitotane.
INTERVENTION: All ACC patients were completely resected, and adjuvant mitotane therapy was prescribed at the discretion of the investigators.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival (OS). The secondary end points were recurrence-free survival (RFS) and the efficacy of adjuvant mitotane therapy according to cortisol secretion.
RESULTS AND LIMITATIONS: Overt hypercortisolism was observed in 197 patients (37.6%). Patients with cortisol excess were younger (p=0.002); no difference according to sex and tumor stage was observed. The median follow-up of the series was 50 mo. After adjustment for sex, age, tumor stage, and mitotane treatment, the prognostic significance of cortisol excess was highly significant for both RFS (hazard ratio [HR]: 1.30; 95% confidence interval [CI], 1.04-2.62; p=0.02) and OS (HR: 1.55; 95% CI, 1.15-2.09; p=0.004). Mitotane administration was associated with a reduction of disease progression (adjusted HR: 0.65; 95% CI, 0.49-0.86; p=0.003) that did not differ according to the patient's secretory status. A major limitation is that only symptomatic patients were considered as having hypercortisolism, thus excluding information on the prognostic role of elevated cortisol levels in the absence of a clinical syndrome.
CONCLUSIONS: Clinically relevant hypercortisolism is a new prognostic factor in patients with completely resected ACC. The efficacy of adjuvant mitotane does not seem to be influenced by overt hypercortisolism.
Comparison of two mitotane starting dose regimens in patients with advanced adrenocortical carcinoma.
J Clin Endocrinol Metab. 2013; 98(12):4759-67 [PubMed] Related Publications
OBJECTIVE: The objective of the study was to investigate the relationship between mitotane dose and plasma concentration comparing two dosing regimens.
DESIGN/SETTING: This was a prospective, open-label, multicenter trial of a predefined duration of 12 weeks.
PATIENTS/INTERVENTIONS: Forty mitotane-naïve patients with metastatic adrenocortical carcinoma were assigned to a predefined low- or high-dose regimen by the local investigator. Thirty-two patients could be evaluated in detail.
MAIN OUTCOME MEASURE: The difference in median mitotane plasma levels between both treatment groups was measured.
RESULTS: Despite a difference in mean cumulative dose (440 ± 142 g vs 272 ± 121 g), median maximum plasma levels were not significantly different between the two groups [high dose 14.3 mg/L (range 6.3-29.7, n = 20) vs 11.3 mg/L (range 5.5-20.0, n = 12), P = .235]. Ten of 20 patients on the high-dose regimen reached plasma concentrations of 14 mg/L or greater after 46 days (range 18-81 d) compared with 4 of 12 patients on the low-dose regimen after 55 days (range 46-74 d, P = .286). All patients who reached 14 mg/L at 12 weeks displayed a level of 4.1 mg/L or greater on day 33 (100% sensitivity). There were no significant differences in frequency and severity of adverse events. Among patients not receiving concomitant chemotherapy mitotane exposure was higher in the high-dose group: 1013 ± 494 mg/L · d vs 555 ± 168 mg/L · d (P = .080).
CONCLUSIONS: The high-dose starting regimen resulted in neither significantly different mitotane levels nor a different rate of adverse events, but concomitant chemotherapy influenced these results. Thus, for mitotane monotherapy the high-dose approach is favorable, whereas for combination therapy a lower dose seems reasonable.
Cytotoxic activity of gemcitabine, alone or in combination with mitotane, in adrenocortical carcinoma cell lines.
Mol Cell Endocrinol. 2014; 382(1):1-7 [PubMed] Related Publications
Lack of long-lasting effects of mitotane adjuvant therapy in a mouse xenograft model of adrenocortical carcinoma.
Mol Cell Endocrinol. 2013; 381(1-2):66-9 [PubMed] Related Publications
Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function.
J Endocrinol. 2013; 218(3):275-85 [PubMed] Related Publications
Morphofunctional effects of mitotane on mitochondria in human adrenocortical cancer cells.
Endocr Relat Cancer. 2013; 20(4):537-50 [PubMed] Related Publications