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Biomedicines Aug 2022Background: A wide interindividual variability in mitotane concentrations and treatment-related dyslipidemia have been reported. Here, we aimed to underline the...
Background: A wide interindividual variability in mitotane concentrations and treatment-related dyslipidemia have been reported. Here, we aimed to underline the sex-related differences in the lipid profile in patients that underwent radical surgery of adrenocortical carcinoma during treatment with adjuvant mitotane. Methods: A chromatographic method was used to quantify the drug in plasma collected from adult patients with complete tumor resection, also considering active metabolite o,p’-DDE. Results: We observed different lipid profiles between males and females and between pre- and post-menopausal women. Considering the mitotane-related effects on lipid levels, we observed that higher drug concentrations were correlated with higher HDL in all the considered groups (p < 0.001), with total cholesterol both in males (p = 0.005) and females (p = 0.036), with triglycerides in postmenopausal females (p = 0.002) and with LDL in male patients (p < 0.001). Increases in o,p’-DDE were positively correlated with HDL levels in all the groups (p < 0.001) and negatively with LDL in all the groups (males p = 0.008, pre- and post-menopausal females p < 0.001), with total cholesterol in pre- (p = 0.016) and post-menopausal women (p = 0.01) and with triglycerides in premenopausal females (p = 0.005). Conclusions: This is the first study designed to evaluate sex differences in lipoprotein and lipid levels during mitotane adjuvant treatment; the results suggest that a gender and personalized approach could be useful to prevent and manage alterations in the lipid profile.
PubMed: 36009421
DOI: 10.3390/biomedicines10081873 -
Polish Archives of Internal Medicine Jun 2018Introduction Adrenocortical carcinoma (ACC) is a rare malignancy, associated with poor outcome and few therapeutic options. Despite increasing attention, the knowledge...
Introduction Adrenocortical carcinoma (ACC) is a rare malignancy, associated with poor outcome and few therapeutic options. Despite increasing attention, the knowledge about the clinical course and treatment of these tumors is limited. Objectives Survival rates in ACC are still low and the percentage of relapse is high. Thus, it is crucial to identify the prognostic factors of overall survival (OS) and recurrence‑free survival (RFS). Patients and methods This was a retrospective analysis of 66 patients diagnosed with ACC between 2002 and 2015. Results The median OS was 43.5 months, 78.19 months for stage I + II, 22.95 months for stage III, and 19.54 months for stage IV ACC. Older age, stage IV ACC, margin status R2, and no mitotane treatment were associated with poor OS. Low Ki67 and mitotic indices were related to improved OS in a univariate analysis. The median RFS was 101.1 months. Disease recurrence after potentially curative surgery was reported in 1 patient (25%) with stage I, 12 patients (46%) with stage II, and 9 patients (45%) with stage III ACC. Male sex and no mitotane treatment were associated with a reduced RFS in a multivariate analysis and higher Ki67 and mitotic indices in the univariate analysis. Conclusions Ki67 and mitotic indices should be considered as prognostic factors when planning the adjuvant treatment of ACC. Mitotane treatment may be independently associated with better outcomes regardless of the tumor stage.
Topics: Adrenocortical Carcinoma; Adult; Aged; Female; Humans; Male; Middle Aged; Mitotane; Mitotic Index; Poland; Prognosis; Retrospective Studies; Survival Rate
PubMed: 29726479
DOI: 10.20452/pamw.4260 -
Endocrine Connections Dec 2018Background The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen...
Background The combination of mitotane and platinum-etoposide chemotherapy is a front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Pharmacokinetic drug-drug interaction between mitotane, a strong CYP3A4 inducer, and etoposide, which is a substrate of CYP3A4, may contribute to chemoresistance. The aim of this pilot study was to assess the pharmacokinetic interaction between mitotane and etoposide in ACC patients. Methods Five consecutive ACC patients treated with platinum etoposide (120-150 mg/m2 day 1-2-3 at cycle 1), with or without concomitant mitotane, were included. In the absence of limiting toxicity, a dose escalation of etoposide was proposed since cycle 2. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24 h after each infusion. Clearance and area under the curve (AUC) of etoposide were determined at each cycle. Results Patients received two to six chemotherapy cycles, in association with mitotane (N = 4) or after mitotane discontinuation (N = 1). Etoposide clearance was two-fold higher with concomitant mitotane (4.95 L/h) than after mitotane discontinuation (2.53 L/h, P = 0.014), and 2.5-fold higher than that in reference population not treated with mitotane (1.81 L/h). Etoposide dose escalation was performed in four patients under mitotane, resulting in two minor tumor responses and one severe toxicity (febrile aplasia) at dose of 300 mg/m2/day. Tumor response was associated with higher etoposide AUC (267.3 vs 188.8 mg.h/L, P = 0.04). Conclusion A drug-drug interaction between mitotane and etoposide may contribute to the low efficacy of platinum-etoposide chemotherapy. This pilot study suggests further a potential benefit of increasing etoposide dose in ACC patients receiving mitotane.
PubMed: 30533000
DOI: 10.1530/EC-18-0428 -
Endocrinology, Diabetes & Metabolism... 2016Mitotane (o,p'-DDD) is the standard treatment for advanced adrenocortical carcinoma (ACC). Monitoring of plasma mitotane levels is recommended to look for a therapeutic...
UNLABELLED
Mitotane (o,p'-DDD) is the standard treatment for advanced adrenocortical carcinoma (ACC). Monitoring of plasma mitotane levels is recommended to look for a therapeutic window between 14 and 20mg/L, but its positive predictive value requires optimization. We report the case of an ACC patient with a history of dyslipidemia treated with mitotane in whom several plasma mitotane levels >30mg/L were found together with an excellent neurological tolerance. This observation led us to compare theoretical or measured o,p'-DDD and o,p'-DDE levels in a series of normolipidemic and dyslipidemic plasma samples to explore potential analytical issues responsible for an overestimation of plasma mitotane levels. We demonstrate an overestimation of mitotane measurements in dyslipidemic patients. Mitotane and o,p'-DDE measurements showed a mean 20% overestimation in hypercholesterolemic and hypertriglyceridemic plasma, compared with normolipidemic plasma. The internal standard p,p'-DDE measurements showed a parallel decrease in hypercholesterolemic and hypertriglyceridemic plasma, suggesting a matrix effect. Finally, diluting plasma samples and/or using phospholipid removal cartridges allowed correcting such interference.
LEARNING POINTS
Hypercholesterolemia (HCH) and hypertriglyceridemia (HTG) induce an overestimation of plasma mitotane measurements.We propose a routine monitoring of lipidemic status.We propose optimized methodology of measurement before interpreting high plasma mitotane levels.
PubMed: 27298727
DOI: 10.1530/EDM-15-0135 -
Endocrine Connections Dec 2018To investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing's disease...
To investigate whether low-dose mitotane (up to 2 g/day) could be a temporary therapeutic alternative to transsphenoidal surgery (TSS) in pediatric Cushing's disease (CD). Twenty-eight patients with CD aged 12.2 years (± 2.2) were referred to our center. We compared nine patients treated with mitotane alone for at least 6 months to 13 patients cured after surgery. Primary outcomes were changes in growth velocity, BMI and pubertal development. The following results were obtained: (1) Mitotane improved growth velocity z-scores (-3.8 (±0.3) vs -0.2 (±0.6)), BMI z-scores (2.1 (±0.5) vs 1.2 (±0.5) s.d.) and pubertal development. After 1 year on mitotane, the mean BMI z-score was not significantly different in both groups of patients. (2) Control of cortisol secretion was delayed and inconsistent with mitotane used as monotherapy. (3) Side effects were similar to those previously reported, reversible and dose dependent: unspecific digestive symptoms, concentration or memory problems, physical exhaustion, adrenal insufficiency and hepatitis. (4) In one patient, progressive growth of a pituitary adenoma was observed over 40 months of mitotane treatment, allowing selective adenomectomy by TSS. In conclusions, low-dose mitotane can restore growth velocity and pubertal development and decrease BMI in children with CD, even without optimal control of cortisol secretion. It may promote pituitary tumor growth thus facilitating second-line TSS. However, given its possibly life-threatening side effects (transient adrenal insufficiency and hepatitis), and in the absence of any reliable follow-up procedures, this therapy may be difficult to manage and should always be initiated and monitored by specialized teams.
PubMed: 30352417
DOI: 10.1530/EC-18-0215 -
Endocrine Sep 2022The management of patients with advanced/metastatic adrenocortical carcinoma (ACC) is challenging, EDP-M (etoposide, doxorubicin, cisplatin combined with mitotane) is... (Review)
Review
PURPOSE
The management of patients with advanced/metastatic adrenocortical carcinoma (ACC) is challenging, EDP-M (etoposide, doxorubicin, cisplatin combined with mitotane) is the standard regimen. However, it is quite toxic, so an adequate supportive therapy is crucial to reduce as much as possible the side effects and maintain the dose intensity of cytotoxic agents.
METHODS
We describe the main side effects of the EDP-M scheme and the best way to manage them based on the experience of the Medical Oncology Unit of the Spedali Civili of Brescia. We also deal with the administration of EDP-M in specific frail patients, such as those with huge disease extent and poor performance status (PS) and those with mild renal insufficiency.
RESULTS
In patients with hormone secreting ACC the rapid control of Cushing syndrome using adrenal steroidogenesis inhibitors such as metyrapone or osilodrostat is mandatory before starting EDP-M. Primary prophylaxis of neutropenia with Granulocyte-Colony Stimulating Factors is crucial and should be introduced at the first chemotherapy cycle. Possible mitotane induced hypoadrenalism should be always considered in case of persistent nausea and vomiting and asthenia in the interval between one cycle to another. In case of poor PS. A 24 h continuous infusion schedule of cisplatin could be an initial option in patients with poor PS as well as to reduce the risk of nefrotoxocity in patients with mild renal impairment.
CONCLUSION
A careful and accurate supportive care is essential to mitigate EDP-M side effects as much as possible and avoid that, due to toxicity, patients have to reduce doses and or postpone cytotoxic treatment with a negative impact on efficacy of this chemotherapy regimen.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Humans; Mitotane
PubMed: 35567656
DOI: 10.1007/s12020-022-03075-y -
Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study.British Journal of Cancer Oct 2021After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed.... (Comparative Study)
Comparative Study
BACKGROUND
After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy.
METHODS
In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias.
RESULTS
Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007).
CONCLUSIONS
Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.
Topics: Adolescent; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Case-Control Studies; Chemotherapy, Adjuvant; Child; Child, Preschool; Female; Humans; Male; Middle Aged; Neoplasm Staging; Platinum; Propensity Score; Retrospective Studies; Survival Analysis; Treatment Outcome; Young Adult
PubMed: 34400803
DOI: 10.1038/s41416-021-01513-8 -
Journal of the Endocrine Society Sep 2022Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis for both locally advanced and metastatic disease. Standard treatment with combination...
CONTEXT
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis for both locally advanced and metastatic disease. Standard treatment with combination etoposide-doxorubicin-cisplatin-mitotane (EDP-M) is highly toxic and some patients benefit from mitotane monotherapy. However, identification of these patients remains challenging.
OBJECTIVE
We present a summary of the Israeli national referral center's 20 years of experience in treating advanced ACC, with the aim of identifying prognostic factors and assisting in treatment decision making.
METHODS
We conducted a retrospective multivariate analysis of patients treated for metastatic or locally advanced ACC at Hadassah Medical Center between 2000 and 2020 to determine clinical, pathological, and treatment factors correlated with overall survival (OS).
RESULTS
In our cohort of 37 patients, a combination of modified European Network for the study of Adrenal Tumors (mENSAT) staging with either grade and R status, or age and symptoms was validated to stratify prognosis ( = .01 and = .03, respectively). Patients who underwent R0 resection followed by radiotherapy or metastasectomy for oligometastatic disease had longer OS than patients with residual disease: median OS of 55 months vs 14 months, respectively, hazard ratio 3.1 (CI 1.4-6.7, = .005). Patients treated with mitotane monotherapy had a significantly better prognosis, yet this result was attenuated in a multivariate analysis controlling for mENSAT and R status. Of patients treated with EDP-M, 41.4% experienced grade 3 or higher adverse events.
CONCLUSION
Patients with advanced ACC achieving R0 status have a better prognosis and might benefit from mitotane monotherapy.
PubMed: 35949453
DOI: 10.1210/jendso/bvac112 -
Cancers May 2020DNA methylation profiling has been suggested a reliable technique to distinguish between benign and malignant adrenocortical tumors, a process which with current... (Review)
Review
DNA methylation profiling has been suggested a reliable technique to distinguish between benign and malignant adrenocortical tumors, a process which with current diagnostic methods remains challenging and lacks diagnostic accuracy of borderline tumors. Accurate distinction between benign and malignant adrenal tumors is of the essence, since ACC is a rare but aggressive endocrine disease with an annual incidence of about 2.0 cases per million people per year. The estimated five-year overall survival rate for ACC patients is <50%. However, available treatment regimens are limited, in which a radical surgical resection is the only curable option. Nevertheless, up to 85% of patients with radical resection show recurrence of the local disease often with concurrent metastases. Adrenolytic therapy with mitotane, administered alone or in combination with cytotoxic agents, is currently the primary (palliative) treatment for patients with advanced ACC and is increasingly used in adjuvant setting to prevent recurrence. Prognostic stratification is important in order to individualize adjuvant therapies. On April 1, 2020, there were 7404 publications on adrenocortical carcinoma (adrenocortical carcinoma) OR adrenocortical carcinoma [MeSH Terms]) OR adrenal cortex cancer[MeSH Terms]) OR adrenal cortical carcinoma [MeSH Terms]) OR adrenal cortex neoplasm [MeSH Terms]) OR adrenocortical cancer [MeSH Terms]), yet the underlying pathophysiology and characteristics of ACC is not fully understood. Knowledge on epigenetic alterations in the process of adrenal tumorigenesis is rapidly increasing and will add to a better understanding of the pathogenesis of ACC. DNA methylation profiling has been heralded as a promising method in the prognostication of ACC. This review summarizes recent findings on epigenetics of ACC and its role in diagnosis, prognosis and therapeutic strategies.
PubMed: 32414074
DOI: 10.3390/cancers12051218 -
Cancers Mar 2020Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane...
Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.
PubMed: 32245135
DOI: 10.3390/cancers12030740