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European Journal of Cancer (Oxford,... Jan 2024Historically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published...
INTRODUCTION
Historically, stage IV adrenocortical carcinoma (mACC) has a poor prognosis with a median overall survival (OS) of only 5 months. Based on the FIRM-ACT trial published in 2012, guidelines now advise first line systemic treatment with etoposide, cisplatin, doxorubicin and mitotane (EDP-M). The effect of EDP-M on patient survival in clinical practice in the Netherlands is unknown.
METHODS
The data of all patients with mACC (2005-2020) were obtained from the Netherlands comprehensive cancer organization (IKNL). The effect of EDP-M on patient survival was assessed using Kaplan-Meier analysis and multivariate Cox regression analysis including clinical, therapy and tumor characteristics.
RESULTS
In total 167 patients with mACC were included. For patients diagnosed from 2014 onwards, EDP-M (in 22 patients (22%)) lead to a numerically but not statistically significant improved OS compared to those not receiving EDP-M (11.8 vs 5.6 months, p = 0.525). For systemic treatments, patients treated with mitotane only had the best 5-year OS (11.4%, p = 0.006) regardless of year of diagnosis. In multivariate Cox regression analysis EPD-M was not associated with OS; palliative adrenalectomy (HR: 0.26, p = <.001) and local treatment of metastases (HR: 0.35, p = 0.001) were associated with a better OS and a primary tumor Ki-67 index > 20% (HR: 2.67, p = 0.003) with a worse OS from 2014 onwards. Patients diagnosed before 2014 had a significantly poorer OS compared to from 2014 onwards (5-yr: 4.5 vs 8.4%, OS: 6.8 vs 8.3 months, p = 0.032).
CONCLUSION
OS for mACC in the Netherlands has improved in the last decade. Receiving EDP-M did not significantly improve OS for patients with mACC. The use of multimodality treatment including palliative adrenalectomy, mitotane and local treatment of (oligo-)metastases in appropriately selected patients has improved the OS for mACC patients since 2014.
Topics: Humans; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Etoposide; Cisplatin; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37977106
DOI: 10.1016/j.ejca.2023.113424 -
Pituitary Dec 2016Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS.... (Review)
Review
PURPOSE
Endogenous Cushing's syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing's disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25 % of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development.
METHODS
We performed a systematic review of the literature regarding adrenal steroidogenesis inhibitors, focusing on novel drugs.
RESULTS
Currently available adrenal steroidogenesis inhibitors, including ketoconazole, metyrapone, etomidate, and mitotane, have variable efficacy and significant side effects, and none are approved by the US Food and Drug Administration for CS. Therefore, there is a clear need for novel, prospectively studied agents that have greater efficacy and a low rate of adverse side effects. Efficacy and safety data of current and emerging adrenal steroidogenesis inhibitors, including osilodrostat (LCI699) and levoketoconazole (COR-003), show promising results that will have to be confirmed in larger-scale phase 3 studies (currently ongoing).
CONCLUSIONS
The management of CS, and particularly CD, remains challenging. Adrenal steroidogenesis inhibitors can be of major interest to control the hypercortisolism at any time point, either before or after surgery, as discussed in this review.
Topics: Cushing Syndrome; Humans; Steroid Synthesis Inhibitors
PubMed: 27600150
DOI: 10.1007/s11102-016-0742-1 -
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 -
IJU Case Reports Nov 2020
Editorial Comment to Local advanced adrenocortical cancer with a long-term recurrence-free survival treated with complete surgical excision and adjuvant therapy with a very low-dose mitotane.
PubMed: 33163912
DOI: 10.1002/iju5.12215 -
European Journal of Medical Research Dec 2022Adrenocortical carcinoma (ACC) is a rare endocrine neoplasm, which is characterized by poor prognosis and high recurrence rate. Novel and reliable prognostic and...
BACKGROUND
Adrenocortical carcinoma (ACC) is a rare endocrine neoplasm, which is characterized by poor prognosis and high recurrence rate. Novel and reliable prognostic and metastatic biomarkers are lacking for ACC patients. This study aims at screening potential prognostic biomarkers and therapeutic targets of ACC through bioinformatic methods and immunohistochemical (IHC) analysis.
METHODS
In the present study, by using the Gene Expression Omnibus (GEO) database we identified differentially expressed genes (DEGs) in ACC and validated these DEGs in The Cancer Genome Atlas (TCGA) ACC cohort. A DEGs-based signature was additionally constructed and we assessed its prognosis and prescient worth for ACC by survival analysis and nomogram. Immunohistochemistry (IHC) was used to verify the relationship between hub gene-GMNN expressions and clinicopathologic outcomes in ACC patients.
RESULTS
A total of 24 DEGs correlated with the prognosis of ACC were screened from the TCGA and GEO databases. Five DEGs were subsequently selected in a signature which was closely related to the survival rates of ACC patients and GMNN was identified as the core gene in this signature. Univariate and multivariate Cox regression showed that the GMNN was an independent prognostic factor for ACC patients (P < 0.05). Meanwhile, GMNN was closely related to the OS and PFI of ACC patients treated with mitotane (P < 0.001). IHC confirmed that GMNN protein was overexpressed in ACC tissues compared with normal adrenal tissues and significantly correlated with stage (P = 0.011), metastasis (P = 0.028) and Ki-67 index (P = 0.014).
CONCLUSIONS
GMNN is a novel tumor marker for predicting the malignant progression, metastasis and prognosis of ACC, and may be a potential therapeutic target for ACC.
Topics: Humans; Adrenocortical Carcinoma; Prognosis; Survival Analysis; Biomarkers, Tumor; Adrenal Cortex Neoplasms; Geminin
PubMed: 36539849
DOI: 10.1186/s40001-022-00950-2 -
Endocrinology, Diabetes & Metabolism... 2018Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of...
UNLABELLED
Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.
LEARNING POINTS
Adrenocortical carcinoma is an important differential diagnosis for virilization in young childrenMitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosisMitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completedIn our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.
PubMed: 30159150
DOI: 10.1530/EDM-18-0059 -
Frontiers in Endocrinology 2022This study aimed to characterise the clinicopathological features and prognostic factors of a large cohort of Hungarian patients with adrenocortical cancer diagnosed...
OBJECTIVES
This study aimed to characterise the clinicopathological features and prognostic factors of a large cohort of Hungarian patients with adrenocortical cancer diagnosed between 2000-2021.
PATIENTS AND METHODS
This retrospective study included seventy-four patients (27 men and 47 women) with histologically confirmed adrenocortical cancer in a single tertiary referral endocrine centre. Descriptive statistics were performed, providing summaries of selected clinical and pathological parameters. Clinicopathological factors contributing to overall survival were analysed.
RESULTS
The median age of patients was 48,5 years (17-84 years) at diagnosis. The majority of cases were diagnosed at ENSAT stage II (39,2%) and stage IV (33,8%). At diagnosis, the median tumour size was 9,0 cm (4,5-20 cm). In 47 patients (71,6%), the tumour was hormonally active. The median overall survival and the 5-year survival rate were 23,5 months (95% CI, 17-30,5 months) and 18,3%, respectively. Primary tumour resection was performed in 68 patients (91,8%); R0 surgical resection was achieved in 30 patients. In univariate Cox regression model, tumours with stages III and IV, high proliferative activity (Ki67-index > 10%), R1-R2 surgical resection state and hormonal activity were associated with poorer survival. Cortisol excess, both isolated and combined with androgen production, was associated with poorer survival. Fifty-five patients were treated with mitotane. The overall survival of patients achieving therapeutic mitotane plasma concentration was significantly better compared to those who never reached it [27.0 (2-175) months vs 18.0 (2-83) months; p<0.05)]. The median age, the distribution of gender, ENSAT stage, resection state and Ki67-index did not differ between these two groups. The time needed to reach the therapeutic range of serum mitotane was 96.5 days (95% CI, 75-133 days).
CONCLUSION
Our results confirm previous data that disease stage, mitotic activity, the resection state and the mitotane treatment achieving therapeutic concentration are the most critical parameters influencing the prognosis of adrenocortical cancer. Our data suggest that hormonal activity may be more frequent than described previously, and it is a strong and independent prognostic factor of overall survival. To our knowledge, this is the first single-centre study confirming the prognostic importance of achieving therapeutic mitotane concentration.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Androgens; Antineoplastic Agents, Hormonal; Female; Humans; Hydrocortisone; Ki-67 Antigen; Male; Mitotane; Prognosis; Retrospective Studies
PubMed: 36246926
DOI: 10.3389/fendo.2022.952418 -
American Journal of Cancer Research 2024Adrenocortical carcinoma (ACC) is a malignant tumour that originates from the adrenal cortex. It is a highly aggressive cancer characterised by a poor prognosis with an... (Review)
Review
The effect of adjuvant mitotane therapy of the adrenocortical carcinoma on the endometrium and its clinical consequences in menstruating women. Literature review and authors' own experiences.
Adrenocortical carcinoma (ACC) is a malignant tumour that originates from the adrenal cortex. It is a highly aggressive cancer characterised by a poor prognosis with an annual incidence estimated to be up to 2 cases per million. In the adult population, ACC is diagnosed typically between 40 and 50 years of age, more often in women. Complete surgical resection of the tumour is the primary treatment method for ACC. Unfortunately, despite properly performed adrenalectomy, regional recurrences or distant metastases are detected in up to 90% of the patients. For that reason, adjuvant therapy is recommended. Mitotane is the most effective adrenal-specific agent used in adjuvant and palliative therapy. Two menstruating patients, after adrenalectomy due to ACC, during adjuvant mitotane therapy, have been included in the study. The study aimed to assess the effect of mitotane therapy on the endometrium and its clinical consequences, based on the analysis of these two cases and a review of the literature. It seems that menorrhagia may be expected during adjuvant mitotane therapy of ACC in menstruating women. Heavy uterine bleeding during menstruation may appear several months after the beginning of therapy. The likely mechanism for heavy menstrual bleeding is complex. Menorrhagia can occur due to the toxic effect of mitotane in the form of a haemorrhagic diathesis, while long-term treatment (over ten months) can lead to relative hypoestrogenism resulting in endometrial hyperplasia. Clinical signs of hypoestrogenism during mitotane treatment, have been described (including pre-puberty girls) and should be considered as a side-effect of the therapy. Menorrhagia may lead to severe anaemia, so this should be considered when planning mitotane treatment. Continuous gestagen therapy is helpful in the treatment of the above disorders. After over 60 years of experience with mitotane usage, knowledge about it is still insufficient, and further studies are required.
PubMed: 38726272
DOI: 10.62347/QKWF9884 -
PloS One 2018Mitotane is the reference drug for adrenocortical carcinoma (ACC) and the metabolic activation of the drug is considered as essential for its activity. The aim of this...
Mitotane is the reference drug for adrenocortical carcinoma (ACC) and the metabolic activation of the drug is considered as essential for its activity. The aim of this study was to assess the role of CYP11B1 on mitotane action and metabolism in H295R ACC cells to understand whether this enzyme may influence mitotane action. The simultaneous incubation with mitotane and metyrapone, an adrenolytic molecule targeting 11-beta-hydroxylase, did not influence mitotane-mediated cytotoxic effect and metabolism in H295R ACC cells. CYP11B1 silencing confirmed the lack of a significant metyrapone effect on mitotane action. The present findings do not support the view that CYP11B1 catalyzes a crucial step in the metabolic activation of mitotane and that CYP11B1 confers the adrenal specificity to mitotane.
Topics: Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cell Proliferation; Humans; Metyrapone; Mitotane; Steroid 11-beta-Hydroxylase
PubMed: 29734384
DOI: 10.1371/journal.pone.0196931 -
Journal of Surgical Oncology Feb 2020Chemotherapeutic options for patients with recurrent/metastatic adrenocortical carcinoma (ACC) are limited, leading to consideration for surgical management. We sought...
BACKGROUND AND OBJECTIVES
Chemotherapeutic options for patients with recurrent/metastatic adrenocortical carcinoma (ACC) are limited, leading to consideration for surgical management. We sought to determine characteristics associated with an unequivocal survival benefit amongst patients undergoing re-resection or metastasectomy.
METHODS
Patients who underwent surgery for recurrent/metastatic ACC were identified and stratified into two groups: those with postoperative survival comparable with what has been reported with chemotherapy alone (<12 months) and those surviving twice that duration (>24 months). Those who survived between 12 and 24 months were excluded, as the objective was to characterize patients who most distinctly benefited from resection. Clinicopathologic and treatment variables were evaluated for associations with survival.
RESULTS
Forty-three patients survived more than 24 months and 15 patients died less than 12 months after reoperation. Tumor stage (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.45-0.96) and disease-free interval (DFI; OR, 3.23; 95% CI, 1.68-6.22) were associated with prolonged survival. Tumor size, hormonal status, resection margin, and treatment with chemotherapy, radiation, and mitotane were not associated with prolonged survival. Patients who survived more than 24 months underwent more procedures for subsequent recurrences (median 4 vs 2; P < .001).
CONCLUSION
Stage and DFI can help select optimal candidates for resection of recurrent/metastatic ACC. Patients selected for surgical management should be informed of the likelihood of requiring multiple interventions.
PubMed: 31808558
DOI: 10.1002/jso.25790