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Endocrinology, Diabetes & Metabolism... Oct 2023Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence...
SUMMARY
Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence after resection. In addition, mitotane is considered to have direct adrenolytic effects. Because of its narrow therapeutic-toxic range, therapeutic drug monitoring (TDM) is warranted. In 2020, a left-sided adrenal gland tumor was found (5.8 cm) in a 38-year-old man. Considering the size of this lesion and inability to exclude an adrenocortical carcinoma on imaging, a laparoscopic adrenalectomy was performed. Histopathologic examination determined presence of an adrenocortical carcinoma (pT2N0M0 ENSAT stadium II; ki67 10-15%). There was no evidence for residual or metastatic disease but given the high risk of recurrence, adjuvant therapy with mitotane was initiated. During TDM, a sudden and spuriously high level of mitotane was observed but without signs or symptoms of toxicity. After exploration, it was found that this high concentration was completely due to uncontrolled hypertriglyceridemia. After correction thereof, mitotane levels were again in the therapeutic range. This observation underscores the importance of TDM sampling in a fasting state with concurrent control of prevalent or incident dyslipidemia.
LEARNING POINTS
TDM of mitotane is advocated to achieve therapeutic levels while avoiding toxicity. For correct TDM, sampling should be done at least 12 h after last intake of mitotane. Although sampling in fasting conditions in not explicitly mentioned in the guidelines, fasting state should be considered as elevated serum triglyceride levels might cause spuriously high mitotane levels. In patients undergoing treatment with mitotane and presenting with too high or unexplained fluctuating mitotane levels without signs or symptoms of toxicity, hypertriglyceridemia as a possible cause should be investigated. If dyslipidemia occurs in patients under mitotane treatment, other causes than mitotane (e.g. alcohol abuse and diabetes) should be considered and appropriate treatment should be initiated.
PubMed: 38056082
DOI: 10.1530/EDM-23-0014 -
Cancers Oct 2021Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and is increasingly used for postoperative adjuvant therapy. Mitotane action... (Review)
Review
Mitotane is the only approved drug for the treatment of advanced adrenocortical carcinoma and is increasingly used for postoperative adjuvant therapy. Mitotane action involves the deregulation of cytochromes P450 enzymes, depolarization of mitochondrial membranes, and accumulation of free cholesterol, leading to cell death. Although it is known that mitotane destroys the adrenal cortex and impairs steroidogenesis, its exact mechanism of action is still unclear. The most used cell models are H295-derived cell strains and SW13 cell lines. The diverging results obtained in presumably identical cell lines highlight the need for a stable in vitro model and/or a standard methodology to perform experiments on H295 strains. The presence of several enzymatic targets responsive to mitotane in mitochondria and mitochondria-associated membranes causes progressive alteration in mitochondrial structure when cells were exposed to mitotane. Confounding factors of culture affecting in vitro experiments could reduce the significance of any molecular mechanism identified in vitro. To ensure experimental reproducibility, particular care should be taken in the choice of culture conditions: aspects such as cell strains, culture serum, lipoproteins concentration, and culture passages should be carefully considered and explicated in the presentation of results. We aimed to review in vitro studies on mitotane effects, highlighting how different experimental conditions might contribute to the controversial findings. If the concerns pointed out in this review will be overcome, the new insights into mitotane mechanism of action observed in-vitro could allow the identification of novel pharmacological molecular pathways to be used to implement personalized therapy.
PubMed: 34771418
DOI: 10.3390/cancers13215255 -
Endocrine Oncology (Bristol, England) Jan 2022Adrenocortical carcinoma (ACC) is a rare cancer with high recurrence rates and heterogeneous clinical behavior. The role of adjuvant therapy remains unclear because of... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare cancer with high recurrence rates and heterogeneous clinical behavior. The role of adjuvant therapy remains unclear because of the challenges in collecting high-quality data for a rare cancer. The current treatment recommendations and guidelines for adjuvant therapy are mostly derived retrospectively from national databases and the treatment outcomes of patients seen in referral centers. To better select patients for adjuvant therapy, multiple factors need to be considered including staging, markers of cellular proliferation (such as Ki67%), resection margins, hormonal function, and possibly genetic alterations of the tumor as well as patient-related factors such as age and performance status. Adjuvant mitotane remains the most commonly used adjuvant therapy in ACC based on clinical practice guidelines, though emerging data from ADIUVO trial (mitotane vs observation in low-risk ACC) suggest that mitotane use in low-risk patients may not be needed. An ongoing clinical trial (ADIUVO-2) is evaluating the role of mitotane vs mitotane combined with chemotherapy in high-risk ACC. The use of adjuvant therapy has been controversial but can be justified in select patients with positive resection margins or after the resection of localized recurrence. A prospective study is needed to study the role of adjuvant radiation in ACC as radiation is expected to help only with local control without impact on distant microscopic metastases. There are no recommendations or published data about using adjuvant immunotherapy in ACC, but this may be a future study after establishing the efficacy and safety profile of immunotherapy in metastatic ACC.
PubMed: 37435451
DOI: 10.1530/EO-22-0050 -
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 -
Experimental and Clinical Endocrinology... Feb 2019Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of... (Review)
Review
Adrenocortical carcinoma is a rare endocrine malignant disease with a generally unfavorable but heterogeneous prognosis. Although even in advanced stages a subset of patients experiences long-term disease stabilisation, effective systemic treatment options are limited. Mitotane is the only approved drug and the combination of etoposide, doxorubicin and cisplatin (plus mitotane) is currently considered as treatment standard for advanced adrenocortical carcinoma based on the results of a large randomized phase III trial. However, progression-free survival is often limited and further treatment options are frequently needed. Here we summarize the current knowledge about second and third-line therapeutic modalities (local and systemic) in advanced disease. Following the recent ESE-ENSAT guidelines local therapies play an important role for these patients. Regarding systemic therapies the best data are available for gemcitabine+capecitabine or streptozotocin (both with or without mitotane). Furthermore, we introduce our own approach to patients with advanced adrenocortical carcinoma based on our experience as a large multidisciplinary clinic dedicated to the care of patients with this orphan disease.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antibiotics, Antineoplastic; Antimetabolites, Antineoplastic; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Phytogenic; Humans
PubMed: 30469158
DOI: 10.1055/a-0715-1946 -
Endocrine Oncology (Bristol, England) Jan 2022This study examined the magnitude of changes and the time required to observe maximal changes in LDL-c, HDL-c, triglycerides (Tg) and non-HDL-c after the introduction of...
BACKGROUND
This study examined the magnitude of changes and the time required to observe maximal changes in LDL-c, HDL-c, triglycerides (Tg) and non-HDL-c after the introduction of mitotane.
METHODS
Retrospective study of 45 patients with adrenocortical carcinoma who were treated at the Centre hospitalier de l'Université de Montréal. Clinical and biochemical data were collected, including lipid profiles before and during the first year of treatment with mitotane.
RESULTS
Among the 45 studied patients, 26 (58%) had a complete lipid profile before the introduction of mitotane and at least 1 lipid profile during the first year of treatment, and 19 patients (42%) had a lipid profile following initiation of the treatment. Among the 26 patients who had lipid profiles before and after the introduction of mitotane, the increase of LDL-c was 2.19 mmol/L (76%) (< 0.0001), HDL-c was 0.54 mmol/L (35%) (= 0.0002), Tg was 1.80 mmol/L (129%) (< 0.0001) and non-HDL-c was 2.73 mmol/L (79%) (< 0.0001). Between the first and the sixth month of mitotane treatment, peak values ( = 45) of LDL-c and non-HDL-c were reached in 42 patients (93%) and 37 patients (82%), respectively, whereas peak values of HDL-c were reached after 6 months of mitotane treatment in 29 patients (66%). The peak value of Tg was almost equal throughout the first year. The mean peak values of HDL-c, Tg and non-HDL-c showed significant associations with their respective mitotane concentrations (β = 0.352, = 0.03; β = 0.406, = 0.02 and β = 0.339, = 0.05).
CONCLUSION
The introduction of mitotane produces a clinically significant elevation of lipid parameters (LDL-c, HDL-c, Tg and non-HDL-c) during the first year of treatment.
PubMed: 37435450
DOI: 10.1530/EO-21-0021 -
Cancers Oct 2021Despite the pivotal role of mitotane in adrenocortical carcinoma (ACC) management, data on the endocrine toxicities of this treatment are lacking. The aim of this... (Review)
Review
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.
PubMed: 34638485
DOI: 10.3390/cancers13195001 -
Advances in Clinical and Experimental... 2015Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Patients may present with hormone excess or a local mass effect. The most common imaging... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis. Patients may present with hormone excess or a local mass effect. The most common imaging techniques (CT and MRI) use both size and appearance to distinguish between benign and malignant tumors. Open surgery by an expert surgeon with R0 target is the treatment of choice. Mitotane (alone or in combination with cytotoxic drugs) may be administered after surgery or in patients not amenable to surgery. The role of radiotherapy as an adjuvant treatment is uncertain whereas targeted radionuclide therapy seems to be a promising option. New adjuvant treatment options, even after complete tumor removal, are desired because postoperative disease-free survival at 5 yrs is only around 30%. The establishment of detailed guidelines with the purpose of optimizing therapy with only mitotane but also in combination with other antineoplasmatic drugs is still a task to be done. Future advances in the management of ACC will probably be connected with better understanding of the molecular pathogenesis.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Animals; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Neoplasm Staging; Phenotype; Predictive Value of Tests; Signal Transduction; Treatment Outcome
PubMed: 25931348
DOI: 10.17219/acem/30645 -
Frontiers in Cell and Developmental... 2015Adrenocortical carticnoma (ACC) is a rare malignancy with an incidence of 0.7-2.0 cases/million habitants/year. The diagnosis of malignancy relies on careful... (Review)
Review
Adrenocortical carticnoma (ACC) is a rare malignancy with an incidence of 0.7-2.0 cases/million habitants/year. The diagnosis of malignancy relies on careful investigations of clinical, biological, and imaging features before surgery and pathological examination after tumor removal. Most patients present with steroid hormone excess or abdominal mass effects, but 15% of patients with ACC is initially diagnosed incidentally. After the diagnosis, in order to assess the ACC prognosis and establish an adequate basis for treatment decisions different tools are proposed. The stage classification proposed by the European Network for the Study of Adrenal Tumors (ENSAT) is recommended. Pathology reports define the Weiss score, the resection status and the proliferative index, including the mitotic count and the Ki67 index. As far as the treatment is concerned, in case of tumor limited to the adrenal gland, the complete resection of the tumor is the first option. Most patients benefit from adjuvant mitotane treatment. In metastatic disease, mitotane is the cornerstone of initial treatment, and cytotoxic drugs should be added in case of progression. Recently, the First International Randomized (FIRM-ACT) Trial in metastatic ACC reported the association between mitotane and etoposide/doxorubicin/cisplatin (EDP) as the new standard in first line treatment of ACC. In last years, new targeted therapies, including the IGF-1 receptor inhibitors, have been investigated, but their efficacy remains limited. Thus, new treatment concepts are urgently needed. The ongoing "omic approaches" and next-generation sequencing will improve our understanding of the pathogenesis and hopefully will lead to better therapies.
PubMed: 26191527
DOI: 10.3389/fcell.2015.00045 -
Clinics (Sao Paulo, Brazil) Dec 2018Malignancy must be considered in the management of adrenal lesions, including those incidentally identified on imaging studies. Adrenocortical carcinomas (ACCs) are rare... (Review)
Review
Malignancy must be considered in the management of adrenal lesions, including those incidentally identified on imaging studies. Adrenocortical carcinomas (ACCs) are rare tumors with an estimated annual incidence of 0.7-2 cases per year and a worldwide prevalence of 4-12 cases per million/year. However, a much higher incidence of these tumors (>15 times) has been demonstrated in south and southeastern Brazil. Most ACCs cause hypersecretion of steroids including glucocorticoids and androgens. ACC patients have a very poor prognosis with a 5-year overall survival (OS) below 30% in most series. Pheochromocytoma or paraganglioma (PPGL) is a metabolically active tumor originating from the chromaffin cells of the adrenal medulla. The incidence of PPGL is 0.2 to 0.9 cases per 100,000 individuals per year. Pheochromocytomas are present in approximately 4-7% of patients with adrenal incidentalomas. Classically, PPGL manifests as paroxysmal attacks of the following 4 symptoms: headaches, diaphoresis, palpitations, and severe hypertensive episodes. The diagnosis of malignant PPGL relies on the presence of local invasion or metastasis. In this review, we present the clinical and biochemical characteristics and pathogenesis of malignant primary lesions that affect the cortex and medulla of human adrenal glands.
Topics: Adrenal Cortex Neoplasms; Adrenal Gland Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Humans; Mitotane; Paraganglioma; Pheochromocytoma
PubMed: 30540124
DOI: 10.6061/clinics/2018/e756s