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The Journal of Clinical Endocrinology... Apr 2018Although mitotane is the only approved drug for the treatment of adrenocortical carcinoma (ACC), data on monotherapy in advanced disease are still scarce.
CONTEXT
Although mitotane is the only approved drug for the treatment of adrenocortical carcinoma (ACC), data on monotherapy in advanced disease are still scarce.
OBJECTIVE
To assess the efficacy of mitotane in advanced ACC in a contemporary setting and to identify predictive factors.
DESIGN AND SETTING
Multicenter cohort study of three German referral centers.
PATIENTS
One hundred twenty-seven patients with advanced ACC treated with mitotane monotherapy.
OUTCOME MEASURES
Response Evaluation Criteria in Solid Tumors evaluation, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method, and predictive factors by Cox regression.
RESULTS
Twenty-six patients (20.5%) experienced objective response, including three with complete remission. Overall, median PFS was 4.1 months (range 1.0 to 73) and median OS 18.5 months (range 1.3 to 220). Multivariate analysis indicated two main predictive factors: low tumor burden (<10 tumoral lesions), hazard ratio (HR) for progression of 0.51 (P = 0.002) and for death of 0.59 (P = 0.017); and initiation of mitotane at delayed advanced recurrence, HR 0.35(P < 0.001) and 0.34 (P < 0.001), respectively. Accordingly, 67% of patients with low tumor burden and mitotane initiation ≥360 days after primary diagnosis experienced a clinical benefit (stable disease >180 days). Patients who achieved mitotane levels >14 mg/L had significantly longer OS (HR 0.42; P = 0.003).
CONCLUSIONS
At 20.5% the objective response rate was slightly lower than previously reported. However, >20% of patients experienced long-term disease control at >1 year. In general, patients with late diagnosis of advanced disease and low tumor burden might especially benefit from mitotane monotherapy, whereas patients with early advanced disease and high tumor burden are probably better candidates for combined therapy of mitotane and cytotoxic drugs.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Disease Progression; Disease-Free Survival; Female; Humans; Male; Middle Aged; Mitotane; Retrospective Studies; Survival Rate; Treatment Outcome; Young Adult
PubMed: 29452402
DOI: 10.1210/jc.2017-02591 -
Cancers Jun 2023Clinical evidence has shown frequent hypogonadism following mitotane (MTT) treatment in male patients with adrenocortical carcinoma. This study aimed to evaluate the...
BACKGROUND
Clinical evidence has shown frequent hypogonadism following mitotane (MTT) treatment in male patients with adrenocortical carcinoma. This study aimed to evaluate the impact of MTT on male gonadal function.
METHODS
Morphological analysis of testes and testosterone assays were performed on adult CD1 MTT-treated and untreated mice. The expression of key genes involved in interstitial and tubular compartments was studied by real-time PCR. Moreover, quantitative and qualitative analysis of spermatozoa was performed.
RESULTS
Several degrees of damage to the testes and a significant testosterone reduction in MTT-treated mice were observed. A significant decline in and mRNA expression in the interstitial compartment confirmed an impairment of androgen production. mRNA expression was unaffected by MTT, proving that Sertoli cells are not the drug's primary target. Sperm concentrations were significantly lower in MTT-treated animals. Moreover, the drug caused a significant increase in the percentage of spermatozoa with abnormal chromatin structures.
CONCLUSION
MTT negatively affects the male reproductive system, including changes in the morphology of testicular tissue and reductions in sperm concentration and quality.
PubMed: 37370841
DOI: 10.3390/cancers15123234 -
International Journal of Molecular... Apr 2023Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin)....
BACKGROUND
Adrenocortical cancer (ACC) is a rare malignancy with a dismal prognosis. The treatment includes mitotane and EDP chemotherapy (etoposide, doxorubicin, and cisplatin). However, new therapeutic approaches for advanced ACC are needed, particularly targeting the metastatic process. Here, we deepen the role of progesterone as a new potential drug for ACC, in line with its antitumoral effect in other cancers.
METHODS
NCI-H295R, MUC-1, and TVBF-7 cell lines were used and xenografted in zebrafish embryos. Migration and invasion were studied using transwell assays, and MMP2 activity was studied using zymography. Apoptosis and cell cycle were analyzed by flow cytometry.
RESULTS
Progesterone significantly reduced xenograft tumor area and metastases formation in embryos injected with metastatic lines, MUC-1 and TVBF-7. These results were confirmed in vitro, where the reduction of invasion was mediated, at least in part, by the decrease in MMP2 levels. Progesterone exerted a long-lasting effect in metastatic cells. Progesterone caused apoptosis in NCI-H295R and MUC-1, inducing changes in the cell-cycle distribution, while autophagy was predominantly activated in TVBF-7 cells.
CONCLUSION
Our results give support to the role of progesterone in ACC. The involvement of its analog (megestrol acetate) in reducing ACC progression in ACC patients undergoing EDP-M therapy is now under investigation in the PESETA phase II clinical study.
Topics: Animals; Humans; Adrenocortical Carcinoma; Progesterone; Matrix Metalloproteinase 2; Zebrafish; Cell Line, Tumor; Adrenal Cortex Neoplasms
PubMed: 37047801
DOI: 10.3390/ijms24076829 -
Pediatric Endocrinology, Diabetes, and... 2022The purpose of this work was to present the current state of knowledge on the effects of frequently used therapeutic forms, selected pharmacotherapy (including... (Review)
Review
The purpose of this work was to present the current state of knowledge on the effects of frequently used therapeutic forms, selected pharmacotherapy (including glucocorticosteroids, immune checkpoint inhibitors, mitotane, metyrapone, aminoglutetimide, etomidate, ketoconazole, fluconazole), but also radiation therapy on the functioning of the hypothalamic-pituitary-adrenal axis in children and adolescent during and after oncological treatment. The most common pediatric cancers, where complications of adrenal insufficiency occur, are presented. Moreover, current recommendations how to diagnose the function of the adrenal axis in oncological pediatric patients, as well during oncological treatment as after it, including patients treated with steroids and also patients in severe stages, are reported. The rules of the treatment of adrenal dysfunction in those patients are presented. This understanding is of key importance for oncologists and endocrinologists in the process of diagnosing, treating and developing patient health care, as well as during therapy as after it, offering safety and improving the quality of life.
Topics: Adolescent; Adrenal Glands; Child; Etomidate; Fluconazole; Humans; Hypothalamo-Hypophyseal System; Immune Checkpoint Inhibitors; Ketoconazole; Metyrapone; Mitotane; Pituitary-Adrenal System; Quality of Life
PubMed: 36134674
DOI: 10.5114/pedm.2022.118319 -
The Journal of Clinical Endocrinology... May 2020Objective response of advanced adrenocortical carcinoma (ACC) to mitotane and cytotoxic chemotherapy regimen is only ~20% and early tumor progression is frequent....
BACKGROUND
Objective response of advanced adrenocortical carcinoma (ACC) to mitotane and cytotoxic chemotherapy regimen is only ~20% and early tumor progression is frequent. Previous clinical trials with oral multikinase inhibitors were negative, which has been attributed in part to inadvertent drug interaction with mitotane. Cabozantinib (CABO) is an inhibitor of c-MET, vascular endothelial growth factor receptor 2, AXL, and RET and approved for advanced kidney cancer, liver carcinoma after previous sorafenib, and medullary thyroid carcinoma.
OBJECTIVE
To investigate the clinical efficacy and safety of CABO monotherapy in ACC patients.
DESIGN
Retrospective cohort study.
SETTING
Three referral centers for ACC (Germany, United States).
RESULTS
Sixteen patients (13 female) with progressive ACC received CABO after previous mitotane in 15/16 and 3 (median, range 0-8) further systemic treatments. Prior CABO therapy, mitotane was discontinued in all patients. Mitotane plasma concentration was <2 mg/L in 7/16 patients and discontinued >12 months in 6 additional patients before CABO use. In 4/5 cases with available plasma samples, CABO concentration was in the expected steady-state range. Adverse events of grade 1/2 and 3 were observed in 13 and 3 patients, respectively, and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 5, and progressive disease in 8 patients. Median progression-free and overall survival was 16 and 58 weeks, respectively.
CONCLUSION
CABO monotherapy appears to be safe and effective as a monotherapy in advanced ACC after failing prior treatments. Therefore, prospective investigation of CABO in ACC patients is warranted.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Anilides; Cohort Studies; Disease Progression; Female; Germany; Humans; Male; Middle Aged; Neoplasm Staging; Progression-Free Survival; Pyridines; Registries; Retrospective Studies; Salvage Therapy; Treatment Outcome; United States; Young Adult
PubMed: 31900481
DOI: 10.1210/clinem/dgz318 -
International Journal of Pharmaceutics Dec 2022We employ differential scanning calorimetry, broadband dielectric spectroscopy and optical microscopy to investigate the glass transition, molecular relaxation dynamics,...
We employ differential scanning calorimetry, broadband dielectric spectroscopy and optical microscopy to investigate the glass transition, molecular relaxation dynamics, and isothermal recrystallization kinetics of amorphous mitotane, the only drug approved for the pharmacological treatment of adrenocortical carcinoma. Amorphous mitotane displays a glass transition at T = 243 ± 1 K, characterized by relatively low fragility index of 68 ± 2. Besides the structural and Johari-Goldstein relaxations, amorphous mitotane displays an intramolecular relaxation with activation energy of 25 ± 1 kJ mol. The same relaxation process, with virtually the same activation energy and relaxation times, is observed in the closely-related o,p'-dichlorobenzophenone compound, which allows identifying it as the rotation of the chlorobenzene ring with the chlorine closest to the central carbon. Such conformational relaxation is active at human body temperature, and may thus be potentially relevant for the mechanism of action of the drug. Our study shows that the comparative study of the relaxation map of related molecular species is a powerful tool to identify and classify secondary relaxation processes. The amorphous drug is found to be unstable against recrystallization at as well as slightly below room temperature, and to display-two-dimensional growth with only sporadic nucleation, characterized by an Avrami kinetic exponent of 2.05 ± 0.05. The kinetic stability of the amorphous form of mitotane, observed at room temperature in micellar formulations, is therefore limited to the nanoconfined sample and is not observed in the bulk compound.
Topics: Humans; Crystallization; Mitotane; Vitrification; Calorimetry, Differential Scanning; Kinetics; Glass
PubMed: 36379398
DOI: 10.1016/j.ijpharm.2022.122390 -
Cureus Jun 2021Adrenocortical carcinoma (ACC) is a rare and highly aggressive tumor with a poor prognosis. The literature on prognosis from low-income or low-middle-income countries is...
Adrenocortical carcinoma (ACC) is a rare and highly aggressive tumor with a poor prognosis. The literature on prognosis from low-income or low-middle-income countries is limited and scarce. This study aimed to determine the clinical and histopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and the factors affecting ACC's prognosis. This was a retrospective study of patients that presented with ACC to the Shaukat Khanum Memorial Cancer & Research Center, Lahore, Pakistan, between January 2011 and May 2018. Information regarding demographics and clinical and histopathological variables were extracted and analyzed. Of the 25 subjects, 16 (64%) were female. The median age of the sample was 35 years (range; 21 - 72 years). Statistically significant associations were found between RFS and functional status of the tumor (p = 0.014), cortisol overproduction (p = 0.02), androgen excess (testosterone [p = 0.03] and dehydroepiandrosterone sulfate [DHEA SO4] [p = 0.004]), Ki-67 score (p = 0.03), mitotic rate (p = 0.02), stratified mitotic rate (p = 0.01), and composite variable of disease (p = 0.004). The OS was found to have statistical associations with cortisol hypersecretion (p = 0.02), DHEA SO4 excess (p = 0.01), Modified Weis Score (p < 0.001), mitotic rate (p = 0.02), stratified mitotic rate (p = 0.003), and composite variable of disease (p = 0.001). Linear regression (forward-type) analysis suggested that the functional status of the tumor and the disease recurrence index statistically predicted the variance in RFS and OS, respectively. Multiple clinical and histopathological variables appear to affect the prognosis of ACC. However, based on multivariable analysis, it appears that the functional status of the tumor and the composite variable of disease recurrence are predictors of RFS and OS, respectively.
PubMed: 34277297
DOI: 10.7759/cureus.15721 -
Clinical Pharmacokinetics Jan 2021Mitotane is the only approved treatment for patients with adrenocortical carcinoma (ACC). A better explanation for the variability in the pharmacokinetics (PK) of...
BACKGROUND
Mitotane is the only approved treatment for patients with adrenocortical carcinoma (ACC). A better explanation for the variability in the pharmacokinetics (PK) of mitotane, and the optimization and individualization of mitotane treatment, is desirable for patients.
OBJECTIVES
This study aims to develop a population PK (PopPK) model to characterize and predict the PK profiles of mitotane in patients with ACC, as well as to explore the effect of genetic variation on mitotane clearance. Ultimately, we aimed to facilitate mitotane dose optimization and individualization for patients with ACC.
METHODS
Mitotane concentration and dosing data were collected retrospectively from the medical records of patients with ACC taking mitotane orally and participating in the Dutch Adrenal Network. PopPK modelling analysis was performed using NONMEM (version 7.4.1). Genotypes of drug enzymes and transporters, patient demographic information, and clinical characteristics were investigated as covariates. Subsequently, simulations were performed for optimizing treatment regimens.
RESULTS
A two-compartment model with first-order absorption and elimination best described the PK data of mitotane collected from 48 patients. Lean body weight (LBW) and genotypes of CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to significantly affect mitotane clearance (CL/F), which decreased the coefficient of variation (CV%) of the random inter-individual variability of CL/F from 67.0 to 43.0%. Fat amount (i.e. body weight - LBW) was found to significantly affect the central distribution volume. Simulation results indicated that determining the starting dose using the developed model is beneficial in terms of shortening the period to reach the therapeutic target and limit the risk of toxicity. A regimen that can effectively maintain mitotane concentration within 14-20 mg/L was established.
CONCLUSIONS
A two-compartment PopPK model well-characterized mitotane PK profiles in patients with ACC. The CYP2C19 enzyme and SLCO1B1 and SLCO1B3 transporters may play roles in mitotane disposition. The developed model is beneficial in terms of optimizing mitotane treatment schedules and individualizing the initial dose for patients with ACC. Further validation of these findings is still required.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Humans; Liver-Specific Organic Anion Transporter 1; Mitotane; Pharmacogenomic Testing; Precision Medicine; Retrospective Studies
PubMed: 32607875
DOI: 10.1007/s40262-020-00913-y -
European Journal of Endocrinology Oct 2017Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal...
OBJECTIVE
Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane.
DESIGN AND METHODS
We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test.
RESULTS
We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L = 0.016).
CONCLUSIONS
The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adrenocorticotropic Hormone; Adult; Aged; Antineoplastic Agents, Hormonal; Female; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Mitotane; Pituitary-Adrenal System; Prospective Studies; Treatment Outcome
PubMed: 28780517
DOI: 10.1530/EJE-17-0452 -
Frontiers in Oncology 2023Mitotane, the only drug approved by the Food and Drug Administration (FDA) for the treatment of adrenocortical carcinoma, is associated with several side effects...
INTRODUCTION
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.
METHODS
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.
RESULTS
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.
CONCLUSION
The results of our study highlighted the presence of neurophysiological and neuropsychological abnormalities associated with mitotane values above 18 mg/L.
PubMed: 37645432
DOI: 10.3389/fonc.2023.1222002