Mitotane In Adrenocortical Carcinoma Research Articles

Management and outcomes of patients treated with mitotane for adrenocortical carcinoma in a tertiary adrenal tumour centre in Ireland

Management and outcomes of patients treated with mitotane for adrenocortical carcinoma in a tertiary adrenal tumour centre in Ireland

Decrease in anticortisolic drmg osilodrostat plasma exposure in patients treated with mitotane for adrenocortical carcinoma

Decrease in anticortisolic drmg osilodrostat plasma exposure in patients treated with mitotane for adrenocortical carcinoma

Growth differentiation factor 15 (GDF-15) is induced by mitotane in adrenocortical carcinoma and associated with poor prognosis and impaired responsiveness to immunotherapy

Growth differentiation factor 15 (GDF-15) is induced by mitotane in adrenocortical carcinoma and associated with poor prognosis and impaired responsiveness to immunotherapy

Neurological adverse events of mitotane in adrenocortical carcinoma: results of a pilot study.

Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects including neurotoxicity. The aim of our study is to investigate the relationship between mitotane plasma levels and neurological toxicity. We have considered five patients affected by adrenocortical carcinoma treated with mitotane. The neurological assessment included a neurological examination, an electroencephalogram, event-related potentials (P300), and a neuropsychological assessment. All of the patients were first considered at the onset of symptoms of neurotoxicity or when mitotanemia levels were above 18 mg/L, for the second time at mitotanemia normalization and subsequently at its further increase, or in case of persistent neurological abnormalities, some months after normalization. At the first neurotoxicity, four patients showed impaired neurological examination, electroencephalogram, and P300; three patients had impaired neuropsychological assessment; one patient, only P300. At mitotanemia normalization, the neurological examination became normal in all patients and electroencephalogram normalized in one patient, improved in another one, continuing to be altered in the other three. P300 latency and neuropsychological assessment normalized in two patients and persisted altered in the patient experiencing long-term mitotane toxicity. At the third evaluation, in the patient with prolonged mitotane toxicity, the normal mitotanemia in the previous 9 months restored P300 and improved the electroencephalogram but not the neuropsychological assessment. In the two patients experiencing a further rise of mitotanemia, neurological examination was normal but P300 and electroencephalogram were altered. The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L.

Mitotane in adrenocortical carcinoma: a profile of its use

AbstractThe adrenal cytotoxic agent mitotane (Lysodren®) has a central role in the systemic treatment of adrenocortical carcinoma (ACC), a rare and aggressive cancer of the adrenal glands. Although its precise mechanism of action remains unclear, mitotane has been evaluated and used for more than 60 years and, to date, is the only drug specifically approved for the treatment of ACC. Although ACC continues to be associated with a poor prognosis, mitotane has been shown to provide clinically significant benefit in a good proportion of ACC patients treated with the drug, both in the advanced (unresectable/metastatic) disease and adjuvant therapy settings. While mitotane has generally manageable tolerability with most adverse events (including neurotoxicity) being reversible with dose reduction or treatment interruption, regular monitoring of drug plasma concentrations during treatment is important to help ensure optimal use of mitotane while minimising the impact of drug toxicity.

Metabolic and Endocrine Toxicities of Mitotane: A Systematic Review.

Simple SummaryThis is, to our knowledge, the first systematic review conducted on the endocrine effects of mitotane, which aims to collect all available evidence in the literature and provide complete and useful information regarding the management of the endocrine and metabolic side effects of mitotane in clinical practice.Despite the pivotal role of mitotane in adrenocortical carcinoma (ACC) management, data on the endocrine toxicities of this treatment are lacking. The aim of this systematic review is to collect the available evidence on the side effects of mitotane on the endocrine and metabolic systems in both children and adults affected by adrenal carcinoma. Sixteen articles on 493 patients were included. Among the adrenal insufficiency, which is an expected side effect of mitotane, 24.5% of patients increased glucocorticoid replacement therapy. Mineralocorticoid insufficiency usually occurred late in treatment in 36.8% of patients. Thyroid dysfunction is characterized by a decrease in FT4, which occurs within 3–6 months of treatment in 45.4% of patients, while TSH seems to not be a reliable marker. Dyslipidemia is characterized by an increase in both LDL-c and HDL-c (54.2%). Few studies have found evidence of hypertriglyceridemia. In males, gynecomastia and hypogonadism can occur after 3–6 months of treatment (38.4% and 35.6%, respectively), while in pre-menopausal women, mitotane can cause ovarian cysts and, less frequently, menstrual disorders. Most of these side effects appear to be reversible after mitotane discontinuation. We finally suggest an algorithm that could guide metabolic and endocrine safety assessments in patients treated with mitotane for ACC.

Pharmacological profile and effects of mitotane in adrenocortical carcinoma.

Mitotane is the only adrenolytic drug approved by the Food and Drug Administration for treating adrenocortical carcinoma (ACC). This drug has cytotoxic effects on tumour tissues; it induces cell death and antisecretory effects on adrenal cells by inhibiting the synthesis of adrenocortical steroids, which are involved in the pathogenesis of ACC. However, high doses of mitotane are usually necessary to reach the therapeutic plasma concentration, which may result in several adverse effects. This suggests that important pharmacological processes, such as first pass metabolism, tissue accumulation and extensive time for drug elimination, are associated with mitotane administration. Few studies have reported the pharmacological aspects and therapeutic effects of mitotane. Therefore, the aim of this review was to summarize the chemistry, pharmacokinetics and pharmacodynamics, and therapeutic and toxic effects of mitotane. This review also discusses new perspectives of mitotane formulation that are currently under investigation. Understanding the pharmacological profile of mitotane can improve the monitoring and efficacy of this drug in ACC treatment and can provide useful information for the development of new drugs with specific action against ACC with fewer adverse effects.

Role of Mitotane in Adrenocortical Carcinoma - Review and State of the art.

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine tumour deriving from the adrenal cortex. A correct therapeutic strategy requires a multidisciplinary approach between endocrinologist, surgeon and oncologist. Surgery is the mainstay treatment in ACC while mitotane, deriving from the insecticide dichloro-diphenyl-trichloro-ethane, is the main base of the medical treatment of ACC in consideration of its adrenocytolitic activity. However, the use of mitotane as adjuvant therapy is still controversial, also in consideration of the retrospective nature of several studies. A prospective randomised trial (ADIUVO), recruiting patients with low-intermediate risk of recurrence, is evaluating the utility of adjuvant treatment with mitotane in this setting. The therapeutic response is observed with plasma levels of mitotane >14 mg/L. However, the major difficulty in the management of mitotane treatment is related to side effects and to the risk of toxicity, which is related to plasmatic levels >20 mg/L, that is considered the upper limit of the therapeutic window. Mitotane therapy results in adrenal insufficiency, and glucocorticoid replacement therapy has to be administered at higher doses than those used in other aetiologies of primary adrenal insufficiency. Furthermore, other endocrine side effects related to mitotane should be considered, in particular on thyroid hormone and testosterone metabolism. Waiting for new medical strategies on molecular targets, it will be mandatory to optimise the current knowledge by prospective trials and, in consideration of the rarity of the disease, collaborative studies between endocrinologists and oncologists are necessary.

Efficacy and safety of mitotane in the treatment of adrenocortical carcinoma: A retrospective study in 34 Belgian patients

ObjectivesEvaluation of patient characteristics and mitotane use in the treatment of adrenocortical carcinoma (ACC) over a 4-year period in Belgium. Material and methodsThis 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. ResultsPatient 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. ConclusionPatient 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.

Gaining Traction in the Treatment of Adrenocortical Carcinoma

Gaining Traction in the Treatment of Adrenocortical Carcinoma

Pregnancy in a Patient With Adrenal Carcinoma Treated With Mitotane: A Case Report and Review of Literature

Adrenocortical carcinoma (ACC) affects patients in a broad age group, including young women. Mitotane, an adrenolytic agent, is the mainstay of treatment after surgical removal of the tumor. There is extreme paucity of information regarding the effect of mitotane on childbearing potential and pregnancy outcome. The aim of the study was to describe and discuss the case of an ACC patient who conceived while on mitotane treatment. Current literature is reviewed. A 33-year-old woman received mitotane treatment for 4 years due to metastatic ACC. Despite nearly therapeutic blood levels of the drug, the patient had regular menstruation and was able to conceive. Mitotane was stopped at gestation week 6. Although the drug continued to be detected in considerable amounts, the fetus developed normally, including morphologically intact adrenal glands. At gestation week 21, pregnancy was terminated due to ACC recurrence. Mitotane levels were undetectable in fetal cord blood and amniotic fluid. Our report suggests that mitotane, despite its action as an endocrine disruptor, does not affect normal gonadal function or an ability to conceive. The concern of placental transfer by this hydrophobic compound is not supported by our findings. However, we do not recommend drawing conclusions regarding the safety of mitotane in pregnancy, based on 1 or several case reports. Until more data are available, pregnancy should be avoided in women being treated with mitotane for ACC.

Ribonucleotide Reductase Large Subunit (RRM1) Gene Expression May Predict Efficacy of Adjuvant Mitotane in Adrenocortical Cancer

Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane. Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests. ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane. Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC.

Plasma Concentrations of o,p′DDD, o,p′DDA, and o,p′DDE as Predictors of Tumor Response to Mitotane in Adrenocortical Carcinoma: Results of a Retrospective ENS@T Multicenter Study

In patients with adrenocortical carcinoma (ACC) mitotane activity has been suggested to depend on plasma levels 14 mg/liter or greater and metabolite formation. The study was performed to confirm the correlation of the currently used mitotane (o,p'DDD) threshold of 14 mg/liter with tumor response and to evaluate the additional value of 1,1-(o,p'-dichlorodiphenyl) acetic acid (o,p'DDA) and o,p'DDE (1,1-(o,p'-dichlorodiphenyl)-2,2 dichloroethene) levels for predicting tumor response. Plasma samples collected within 3 months of best response from 91 patients on mitotane therapy for advanced ACC were analyzed retrospectively. O,p'DDD and metabolites were assessed and related to tumor response and survival. Receiver operating characteristic curves were used. Sensitivity and specificity were calculated for different cutoff levels of o,p'DDD and metabolites. Objective tumor response was observed in 19% of patients. Median o,p'DDD level was higher in responders (P = 0.03). More responders were found among patients achieving o,p'DDD levels 14 mg/liter or greater (P = 0.02). Univariate and multivariate analysis showed significantly longer survival for patients with o,p'DDD levels 14 mg/liter or greater (hazard ratio 0.52, P = 0.04, hazard ratio 0.46, P = 0.03). An o,p'DDD cutoff value of 14 mg/liter was associated with a sensitivity of 65% and specificity 69%. An o,p'DDD level 20 mg/liter or greater or 14 mg/liter or greater combined with o,p'DDA level 92 mg/liter or greater was associated with a specificity of 90 and 92%, respectively. Our data confirm the value of o,p'DDD plasma monitoring as well as targeting the 14 mg/liter cutoff level in the therapeutic management of ACC patients. Furthermore, our results suggest additional benefit of higher levels of o,p'DDD and combined measurement of o,p'DDD and o,p'DDA.