Mitotane 500mg tablets

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a high recurrence rate after surgical therapy with curative intent. Adjuvant radiotherapy (RT) and mitotane therapy have been proposed as options following the adrenalectomy. However, the efficacy of adjuvant RT or mitotane therapy remains controversial. We aimed to evaluate the efficacy of adjuvant therapy in patients who underwent adrenalectomy for localised ACC. The PubMed, Scopus, and Web of Science databases were queried on March 2024 for studies evaluating adjuvant therapies in patients treated with surgery for localized ACC (PROSPERO: CRD42024512849). The endpoints of interest were overall survival (OS) and recurrence-free survival (RFS). Hazard ratios (HR) with 95% confidence intervals (95%CI) were pooled in a random-effects model meta-analysis. One randomized controlled trial (n = 91) and eleven retrospective studies (n = 4,515) were included. Adjuvant mitotane therapy was associated with improved RFS (HR: 0.63, 95%CI: 0.44-0.92, p = 0.016), while adjuvant RT did not reach conventional levels of statistical significance (HR:0.79, 95%CI:0.58-1.06, p = 0.11). Conversely, Adjuvant RT was associated with improved OS (HR:0.69, 95%CI:0.58-0.83, p<0.001), whereas adjuvant mitotane did not (HR: 0.76, 95%CI: 0.57-1.02, p = 0.07). In the subgroup analyses, adjuvant mitotane was associated with better OS (HR:0.46, 95%CI: 0.30-0.69, p < 0.001) and RFS (HR:0.56, 95%CI: 0.32-0.98, p = 0.04) in patients with negative surgical margin. Both adjuvant RT and mitotane were found to be associated with improved oncologic outcomes in patients treated with adrenalectomy for localised ACC. While adjuvant RT significantly improved OS in general population, mitotane appears as an especially promising treatment option in patients with negative surgical margin. These data can support the shared decision-making process, better understanding of the risks, benefits, and effectiveness of these therapies is still needed to guide tailored management of each individual patient.

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ContextAdrenocortical carcinoma (ACC) is a rare, aggressive malignancy with a high recurrence and mortality rate even after complete resection. Therefore, intensification of adjuvant therapies is crucial, although their effectiveness remains controversial.ObjectiveThis study aimed to determine the efficacy and safety of available treatments by considering the prognostic factors affecting disease outcomes.MethodsThe search was conducted across 3 databases (PubMed, Embase, and CENTRAL) in October 2024. Eligible studies compared overall survival (OS) and recurrence-free survival (RFS) in patients with ACC treated with and without systemic (mitotane, cytotoxic chemotherapy) or localized (radiotherapy) nonsurgical treatments. In total, 86 studies met the inclusion criteria for the systematic review, and 62 for the meta-analysis. Two reviewers extracted data independently. Adjusted hazard ratios (aHR) with 95% CI were calculated for survival outcomes.ResultsMitotane significantly improves OS (aHR: 0.54; CI: 0.41-0.70) and RFS (aHR: 0.60; CI: 0.43-0.84), even in stage I-III disease (OS aHR: 0.71; CI: 0.52-0.98; RFS aHR: 0.65; CI: 0.50-0.85). Radiotherapy showed a trend toward improved OS (aHR: 0.66; CI: 0.38-1.15) and RFS (aHR: 0.65; CI: 0.35-1.23), with significant benefits in stage I-III (OS aHR: 0.68; CI: 0.50-0.93; RFS aHR: 0.71; CI: 0.63-0.81). The impact of cytotoxic chemotherapy on OS remains uncertain (aHR: 0.61; CI: 0.08-4.78).ConclusionMitotane significantly improves survival outcomes in patients with ACC, while radiotherapy exhibits potential benefits, particularly in localized disease. Further research is needed to verify the efficacy of cytotoxic chemotherapy, and randomized controlled trials are required to provide robust evidence of different treatment approaches.

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Background: Advanced adrenocortical carcinoma (ACC) remains a challenging malignancy with limited therapeutic options. Multi-kinase inhibitors (MKIs), either alone or in combination with immuno-oncology (IO) agents, have been investigated in recent single-arm clinical trials and retrospective series. Methods: We conducted a systematic review and single-arm meta-analysis of studies evaluating MKIs in advanced ACC. Objective response rate (ORR) and disease control rate (DCR) were pooled using random-effects models for single-arm proportions. Overall survival (OS) and progression-free survival (PFS) were summarized descriptively due to limited variance data. Subgroup analyses compared MKI monotherapy versus MKI + IO combinations, and meta-regression was performed to assess the impact of prior mitotane exposure. Results: Eleven studies (n = 208 patients) were included. The pooled ORR was 21% (95%CI, 11-36%), and the DCR was approximately 57%. Subgroup analysis revealed a higher ORR with MKI + IO regimens (26%; 95%CI, 12-48%) compared to MKI monotherapy (15%; 95%CI, 3-47%). Median OS ranged from 5.4 to 30.6 months, and PFS from 2.8 to 13.3 months, both favouring MKI + IO combinations. Meta-regression identified prior mitotane exposure as a significant predictor of ORR (p = 0.0279), particularly within the MKI + IO subgroup. Conclusions: MKI-based regimens, especially when combined with IO, demonstrate promising efficacy in advanced ACC, a disease with few established second-line options. While limited by the non-comparative design of available studies, these findings support further investigation in prospective, randomized clinical trials.

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ImportanceMitotane (Lysodren, o,p'-DDD [1-(o-chlorophenyl)-1-(p-chlorophenyl)-2,2-dichloroethane)] is currently the only United States Food and Drug Administration and European Medicines Agency-approved product for the treatment of adrenocortical carcinoma.ObservationsMitotane is challenging to administer; however, its toxicities (specifically adrenal insufficiency) are well known, and the management of adverse consequences has established approaches. While often viewed through the prism of a cytotoxic agent, it can also interfere with hormone production making it a valuable asset in managing functional ACC. A recently completed prospective trial has shed some light on its use in the adjuvant setting, but further clarity is needed. Many think mitotane has a role in the advanced or metastatic setting, although prospective data are lacking and retrospective analyses are often difficult to interpret.Conclusions and relevanceWhen used carefully and thoughtfully, especially in patients with hormonal excess, mitotane is an important component of the treatment armamentarium for ACC.

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Adrenocortical carcinomas (ACCs) are rare and aggressive malignancies of adrenal cortex, associated with largely unknown mechanisms of biological development and poor prognosis. Currently, mitotane is the sole approved drug for treating advanced adrenocortical carcinomas (ACCs) and is being utilized more frequently as postoperative adjuvant therapy. Although it is understood that mitotane targets the adrenal cortex and disrupts steroid production, its precise mechanism of action requires further exploration. Additionally, mitotane affects cytochrome P450 enzymes, causes the depolarization of mitochondrial membranes, and leads to an accumulation of free cholesterol, ultimately resulting in cell death. Many patients treated with mitotane develop disease progression over time, underlying the need to understand the mechanisms of primary and acquired resistance. In this manuscript, we provide an overview on the intracellular mechanisms of action of mitotane, exploring data regarding predictive factors of response and evidence associated with the development of primary and acquired resistance mechanisms. In this discussion, mitotane is considered a real target therapy.

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IntroductionSarcomatoid Adrenocortical Carcinoma (SAC) is an extremely rare, highly aggressive, and poorly differentiated subtype of Adrenocortical Carcinoma (ACC). To date, only 38 cases have been reported worldwide. No standardized clinical diagnosis and treatment protocols have been established, and the prognosis of affected patients is extremely poor. This study reports a case of SAC in a 60-year-old female patient presenting with an abdominal mass, aiming to analyze the clinical characteristics, diagnosis, and treatment features of this rare tumor.Case presentationA 60-year-old female was admitted to our hospital due to an upper abdominal mass. Imaging examinations revealed a cystic-solid space-occupying lesion in the left retroperitoneum, and the tumor was highly suspected to be of adrenal cortical origin preoperatively. Given the rapid disease progression and the patient's strong demand for urgent surgery, preoperative endocrine function examinations including cortisol, aldosterone, sex hormones and catecholamines were not performed. Laparotomy with complete tumor resection was Sarcomatoid Adrenocortical Carcinomasubsequently performed, and the final pathological diagnosis was SAC. The tumor was composed of 60% carcinomatous components and 40% high-grade sarcomatous components, classified as Fuhrman nuclear grade IV, with extensive parenchymal necrosis and vascular tumor thrombi observed in the lesion. One month after surgery, the patient developed extensive peritoneal metastasis and ascites, and eventually died on the 42nd day postoperatively.ConclusionSAC has non-specific manifestations and high diagnostic difficulty, with histopathology plus immunohistochemistry as the diagnostic gold standard. Highly invasive and rapidly progressive, it is mainly treated with surgical resection by following ACC protocols, yet their pathological features differ significantly. Given the extremely limited number of reported cases, current evidence is insufficient to either support or refute the efficacy of mitotane for SAC, and more multicenter large-sample studies are urgently needed.

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Malignancies arising from adrenal rests are extremely rare. They may occur in locations such as the retroperitoneum, testes/scrotum, ovaries, kidneys, anterior abdominal wall, spinal cord, and liver, in association with embryological development. In this article, we present a patient with ectopic adrenocortical cancer (ACC) located in the pancreas, along with a review of the relevant literature. A 57-year-old female patient was diagnosed with mixed-type breast cancer (lobular and ductal carcinoma). During further diagnostic evaluations, in addition to a malignant-appearing mass in the left breast, imaging revealed a second tumor in the left paraaortic region, located in the pancreas. This mass, measuring 6 cm, was well-circumscribed, partially necrotic, heterogeneous in appearance, and displayed no significant invasion of surrounding tissues. The patient exhibited no signs of hormonal hyperfunction, such as hypertension, electrolyte imbalances, cushingoid appearance, or hyperandrogenism. Following lumpectomy, the mass adjacent to the pancreas was surgically excised. Pathological examination revealed an oncocytic type of ACC, characterized by nuclear abnormalities, a high mitotic index, and high nuclear grade, with positivity for steroidogenic factor 1 (SF-1) (NR5A1) in immunohistochemical staining. Mitotane and glucocorticoid replacement therapy were added to the patient's treatment plan for ACC. At present, there are no signs of recurrence or metastasis. To our knowledge, this is the first reported example of ectopic ACC arising in the pancreas, diagnosed in a 57-year-old patient. ACCs should be considered in the differential diagnosis of tumors arising in nonadrenal regions.

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