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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 -
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 -
The Netherlands Journal of Medicine Feb 2007Adrenocortical carcinoma is a rare disease with a poor prognosis. Patients can present with a hormonal syndrome or with general symptoms from an abdominal mass. The... (Review)
Review
Adrenocortical carcinoma is a rare disease with a poor prognosis. Patients can present with a hormonal syndrome or with general symptoms from an abdominal mass. The pathogenesis is unknown. Sometimes the adrenocortical carcinoma is associated with tumour syndromes such as the Beckwith-Wiedemann and Li-Fraumeni syndrome; however, most tumours are sporadic. Using one of the international classification methods, histopathological research can in almost all cases distinguish between adrenocortical adenoma and carcinoma. complete surgical resection is the treatment of choice for adrenocortical carcinoma. Mitotane is given when surgery is not possible, after incomplete resection or for metastatic disease. Frequently used chemotherapeutic combinations are etoposide, doxorubicin, cisplatin and mitotane (EDP/M) and streptozotocin and mitotane (SZ/M). International and national cooperation has resulted in a randomised trial aimed at determining a standard therapy in advanced adrenocortical carcinoma. The Dutch Adrenal Network is a national cooperation of endocrinologists, pathologists and oncologists from all eight academic centres and Máxima Medical centre. The network combines knowledge and expertise and gives patients the opportunity to receive optimal treatment in their own district.
Topics: Academic Medical Centers; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Clinical Trials as Topic; Doxorubicin; Etoposide; Humans; Internationality; Mitotane; Netherlands; Streptozocin
PubMed: 17379929
DOI: No ID Found -
Cancer Treatment and Research... 2023Adrenocortical carcinoma (ACC) is a rare cancer with an estimated incidence of 0.7 to 2.0 cases per 1 million population per year in the United States. It is an... (Review)
Review
Adrenocortical carcinoma (ACC) is a rare cancer with an estimated incidence of 0.7 to 2.0 cases per 1 million population per year in the United States. It is an aggressive cancer originating in the cortex of the adrenal gland with a poor prognosis. The 5-year survival rate is less than 15% among patients with metastatic disease. In this article, we review the epidemiology and pathogenesis of ACC, the diagnostic procedures, the prognostic classification of ACC, and the treatment options from localized and resectable forms to advanced disease detailing recent therapeutic developments such as immunotherapy and molecularly targeted therapy.
Topics: Humans; Adrenocortical Carcinoma; Prognosis; Adrenal Cortex Neoplasms; Immunotherapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37690343
DOI: 10.1016/j.ctarc.2023.100759 -
Endocrinology Sep 2022Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and...
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare aggressive cancer with low overall survival. Adjuvant mitotane improves survival but is limited by poor response rates and resistance. Mitotane's efficacy is attributed to the accumulation of toxic free cholesterol, predominantly through cholesterol storage inhibition. However, targeting this pathway has proven unsuccessful. We hypothesize that mitotane-induced free-cholesterol accumulation is also mediated through enhanced breakdown of lipid droplets.
METHODOLOGY
ATCC-H295R (mitotane-sensitive) and MUC-1 (mitotane-resistant) ACC cells were evaluated for lipid content using specific BODIPY dyes. Protein expression was evaluated by immunoblotting and flow cytometry. Cell viability was measured by quantifying propidium iodide-positive cells following mitotane treatment and pharmacological inhibitors of lipolysis.
RESULTS
H295R and MUC-1 cells demonstrated similar neutral lipid droplet numbers at baseline. However, evaluation of lipid machinery demonstrated distinct profiles in each model. Analysis of intracellular lipid droplet content showed H295R cells preferentially store cholesteryl esters, whereas MUC-1 cells store triacylglycerol. Decreased lipid droplets were associated with increased lipolysis in H295R and in MUC-1 at toxic mitotane concentrations. Pharmacological inhibition of lipolysis attenuated mitotane-induced toxicity in both models.
CONCLUSION
We highlight that lipid droplet breakdown and activation of lipolysis represent a putative additional mechanism for mitotane-induced cytotoxicity in ACC. Further understanding of cholesterol and lipids in ACC offers potential novel therapeutic exploitation, especially in mitotane-resistant disease.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Cholesterol; Humans; Lipid Droplets; Lipolysis; Mitotane
PubMed: 35797592
DOI: 10.1210/endocr/bqac102 -
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 -
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 -
European Endocrinology Sep 2018Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine tumour deriving from the adrenal cortex. A correct therapeutic strategy requires a multidisciplinary... (Review)
Review
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.
PubMed: 30349596
DOI: 10.17925/EE.2018.14.2.62 -
Oncology Letters Apr 2022A previous case report described an adrenal incidentaloma initially misdiagnosed as adrenocortical carcinoma (ACC), which was treated with mitotane. The final diagnosis...
A previous case report described an adrenal incidentaloma initially misdiagnosed as adrenocortical carcinoma (ACC), which was treated with mitotane. The final diagnosis was metastatic melanoma of unknown primary origin. However, the patient developed rapid disease progression after mitotane withdrawal, suggesting a protective role for mitotane in a non-adrenal-derived tumor. The aim of the present study was to determine the biological response of primary melanoma cells obtained from that patient, and that of other established melanoma and ACC cell lines, to mitotane treatment using a proliferation assay, flow cytometry, quantitative PCR and microarrays. Although mitotane inhibited the proliferation of both ACC and melanoma cells, its role in melanoma treatment appears to be limited. Flow cytometry analysis and transcriptomic studies indicated that the ACC cell line was highly responsive to mitotane treatment, while the primary melanoma cells showed a moderate response . Mitotane modified the activity of several key biological processes, including 'mitotic nuclear division', 'DNA repair', 'angiogenesis' and 'negative regulation of ERK1 and ERK2 cascade'. Mitotane administration led to elevated levels of DNA double-strand breaks, necrosis and apoptosis. The present study provides a comprehensive insight into the biological response of mitotane-treated cells at the molecular level. Notably, the present findings offer new knowledge on the effects of mitotane on ACC and melanoma cells.
PubMed: 35261634
DOI: 10.3892/ol.2022.13240