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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 -
Pituitary Dec 2018To systematically review the effectiveness of medical treatment for Cushing's syndrome in clinical practice, regarding cortisol secretion, clinical symptom improvement,... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To systematically review the effectiveness of medical treatment for Cushing's syndrome in clinical practice, regarding cortisol secretion, clinical symptom improvement, and quality of life. To assess the occurrence of side effects of these medical therapies.
METHODS
Eight electronic databases were searched in March 2017 to identify potentially relevant articles. Randomized controlled trials and cohort studies assessing the effectiveness of medical treatment in patients with Cushing's syndrome, were eligible. Pooled proportions were reported including 95% confidence intervals.
RESULTS
We included 35 articles with in total 1520 patients in this meta-analysis. Most included patients had Cushing's disease. Pooled reported percentage of patients with normalization of cortisol ranged from 35.7% for cabergoline to 81.8% for mitotane in Cushing's disease. Patients using medication monotherapy showed a lower percentage of cortisol normalization compared to use of multiple medical agents (49.4 vs. 65.7%); this was even higher for patients with concurrent or previous radiotherapy (83.6%). Mild side effects were reported in 39.9%, and severe side effects were seen in 15.2% of patients after medical treatment. No meta-analyses were performed for clinical symptom improvement or quality of life due to lack of sufficient data.
CONCLUSIONS
This meta-analysis shows that medication induces cortisol normalization effectively in a large percentage of patients. Medical treatment for Cushing's disease patients is thus a reasonable option in case of a contraindication for surgery, a recurrence, or in patients choosing not to have surgery. When experiencing side effects or no treatment effect, an alternate medical therapy or combination therapy can be considered.
Topics: Cabergoline; Cushing Syndrome; Dopamine Agonists; Humans; Hydrocortisone; Mitotane; Treatment Outcome
PubMed: 29855779
DOI: 10.1007/s11102-018-0897-z -
Clinical Genitourinary Cancer Feb 2023Adrenocortical carcinoma (ACC) is a very rare endocrine cancer and is associated with a poor prognosis. There is a paucity of randomized clinical trials for this rare... (Review)
Review
A Systematic Review of Published Clinical Trials in the Systemic Treatment of Adrenocortical Carcinoma: An Initiative Led on Behalf of the Global Society of Rare Genitourinary Tumors.
Adrenocortical carcinoma (ACC) is a very rare endocrine cancer and is associated with a poor prognosis. There is a paucity of randomized clinical trials for this rare disease. We aimed to perform a systematic review of the literature on systemic therapy options in different stages of ACC. A systematic review was performed using Pubmed and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 24 trials of systemic therapy in the treatment of ACC were identified and included in this review. Only one clinical trial in the adjuvant setting was identified, the negative phase III trial ADIUVO, which tested mitotane in low to intermediate-risk ACC patients. In the treatment of advanced ACC, cisplatin-based chemotherapy was evaluated in small and non-randomized phase II trials, and response rates ranged from 21% to 53.5%. The phase III trial FIRM-ACT compared etoposide, doxorubicin, cisplatin, and mitotane versus treatment with streptozotocin and mitotane and showed no difference in OS, but higher RR and PFS were reported with the multi-drug regimen. Six clinical trials of immunotherapy and seven studies of targeted therapy in advanced ACC were included, with modest activity and no phase 3 trials were identified. Treatment recommendations of ACC are based on retrospective and small studies with limited systemic therapy options. International and multi-center collaboration is essential to expand clinical research and improve outcomes.
Topics: Humans; Adrenocortical Carcinoma; Mitotane; Adrenal Cortex Neoplasms; Cisplatin; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36376169
DOI: 10.1016/j.clgc.2022.10.011 -
BioMed Research International 2018The adjuvant use of mitotane on adrenocortical carcinoma (ACC) has always been in controversy. We aimed to assess the prognostic benefits of adjuvant mitotane after... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The adjuvant use of mitotane on adrenocortical carcinoma (ACC) has always been in controversy. We aimed to assess the prognostic benefits of adjuvant mitotane after resection of ACC in patients without distant metastasis.
METHODS
The PubMed, WoS, Embase, and Cochrane Library databases were systematically searched. Recurrence-free survival (RFS) and overall survival (OS) were adopted as measurements. A meta-analysis was conducted based on hazard ratio (HR) with 95% confidence interval (CI). A study was included only if the enrolled patients underwent resection of ACC without adjuvant chemotherapy except mitotane.
RESULTS
A total of 5 retrospective studies reporting on 1249 patients were included for this meta-analysis. The meta-analysis showed that adjuvant mitotane was significantly associated with prolonged RFS (HR = 0.62; 95%CI, 0.42-0.94; P < 0.05) and prolonged OS (HR = 0.69; 95%CI, 0.55-0.88, P < 0.05).
CONCLUSION
After comprehensive review, current evidence suggests that adjuvant mitotane significantly decreases the recurrence rate and mortality after resection of ACC in patients without distant metastasis, but these findings need further demonstration from prospective controlled trials.
Topics: Adolescent; Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Antineoplastic Agents, Hormonal; Chemotherapy, Adjuvant; Female; Humans; Male; Middle Aged; Mitotane; Neoplasm Recurrence, Local; Prospective Studies; Retrospective Studies; Young Adult
PubMed: 29967789
DOI: 10.1155/2018/9362108 -
Frontiers in Endocrinology 2023Adult pure androgen-secreting adrenal tumors (PASATs) are extremely rare, and their characteristics are largely unknown.
BACKGROUND
Adult pure androgen-secreting adrenal tumors (PASATs) are extremely rare, and their characteristics are largely unknown.
METHODS
A rare case of adult bilateral PASATs was reported, and a systematic literature review of adult PASATs was conducted to summarize the characteristics of PASATs.
RESULTS
In total, 48 studies, including 40 case reports and 8 articles, were identified in this review. Analysis based on data of 42 patients (including current case and 41 patients from 40 case reports) showed that average age was 40.48 ± 15.80 years (range of 18-76). The incidence of adult PASAT peaked at 21-30 years old, while that of malignant PASAT peaked at 41-50 years old. Most PASAT patients were female (40/42, 95.23%), and hirsutism was the most common symptom (37/39, 94.87%). Testosterone (T) was the most commonly elevated androgen (36/42, 85.71%), and 26 of 32 tested patients presented increased dehydroepiandrosterone sulfate (DS) levels. In malignancy cases, disease duration was significantly decreased (1.96 vs. 4.51 years, P=0.025), and tumor diameter was significantly increased (8.9 vs. 4.9 cm, p=0.011). Moreover, the androgen levels, namely, T/upper normal range limit (UNRL) (11.94 vs. 4.943, P=0.770) and DS/UNRL (16.5 vs. 5.28, P=0.625), were higher in patients with malignancy. In total, 5 out of 7 patients showed an increase in DS or T in the human chorionic gonadotropin (HCG) stimulation test. Overall, 41 out of 42 patients (including current case) underwent adrenal surgery, and recurrence, metastasis, or death was reported in 5 out of 11 malignant patients even with adjuvant or rescue mitotane chemotherapy.
CONCLUSION
Adult PASAT, which is predominant in women, is characterized by virilism and menstrual dysfunction, especially hirsutism. Elevated T and DS may contribute to the diagnosis of adult PASAT, and HCG stimulation test might also be of help in diagnosis. Patients with malignant PASAT have a shorter disease duration, larger tumor sizes and relatively higher androgen levels. Surgery is recommended for all local PASATs, and Malignancy of PASAT should be fully considered due to the high risk of malignancy, poor prognosis and limited effective approaches.
Topics: Adult; Humans; Female; Adolescent; Young Adult; Middle Aged; Aged; Male; Androgens; Hirsutism; Adrenal Gland Neoplasms; Testosterone; Virilism
PubMed: 37033242
DOI: 10.3389/fendo.2023.1138114 -
Clinical Endocrinology Jan 2014Reported rates of response to medical therapies used in Cushing's disease (CD) vary widely. The aim of this review is to analyse systematically the efficacy of medical... (Review)
Review
OBJECTIVE
Reported rates of response to medical therapies used in Cushing's disease (CD) vary widely. The aim of this review is to analyse systematically the efficacy of medical therapies for CD and to assess the strength of the supporting evidence.
METHODS
Systematic PubMed searches identified studies of medical treatment in CD. The GRADE criteria were imposed to assess the strength of evidence supporting each medication.
RESULTS
Fifteen studies were included. Ten studies specifically reported response rates for patients with CD. Pasireotide was the only treatment to be assessed in a randomized trial and was supported by a 'moderate' level of evidence. Response rates with pasireotide from three prospective studies were 17-29%. The remaining medications were supported by a 'low' or 'very low' level of evidence. The highest response rates were reported in small retrospective studies of metyrapone (75%, one study) and mitotane (72%, one study). Response rates were 25-50% for cabergoline (four studies) and 45% for ketoconazole (one study). Among studies that included patients with other forms of Cushing's syndrome, response rates were 53-88% for ketoconazole (three studies), 70% for mitotane (one study), 57% for metyrapone (one study) and 38-60% for mifepristone. Again, all of these medications are supported by a 'low' level of evidence.
CONCLUSIONS
There is a paucity of high-quality studies of medical therapy in CD, with only one medication achieving a 'moderate' level of evidence. Caution should be employed when comparing efficacy rates owing to the variability in study design and quality.
Topics: Cabergoline; Ergolines; Female; Humans; Ketoconazole; Male; Metyrapone; Mitotane; Pituitary ACTH Hypersecretion; Somatostatin
PubMed: 24118077
DOI: 10.1111/cen.12345 -
Neurosurgical Focus Feb 2015OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to... (Review)
Review
OBJECT Cushing's disease (CD) can lead to significant morbidity secondary to hormonal sequelae or mass effect from the pituitary tumor. A transsphenoidal approach to resection of the adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma is the first-line treatment. However, in the setting in which patients are unable to undergo surgery, have acute hypercortisolism, or have recurrent disease, medical therapy can play an important role. The authors performed a systematic review to highlight the efficacy of medical treatment of CD and discuss novel molecular insights that could guide the development of future medical treatments of CD. METHODS A search on current medical therapies for CD was performed. After individual medical therapeutic agents for CD were identified, each agent underwent a formal systematic search. The phrase "(name of agent) and Cushing's" was used as a search term in PubMed for all years up to 2014. The abstract of each article was reviewed for studies that evaluated the efficacy of medical treatment of CD. Only studies that enrolled at least 20 patients were included in the review. RESULTS A total of 11 articles on 6 individual agents were included in this review. Specific medical therapies were categorized based on the level of action: pituitary directed (cabergoline and pasireotide), adrenal/steroidogenesis directed (ketoconazole, metyrapone, and mitotane), and end-tissue directed/cortisol receptors (mifepristone). The studies identified consisted of a mix of retrospective reviews and small clinical trials. Only pasireotide and mifepristone have undergone Phase III clinical trials, from which they garnered FDA approval for the treatment of patients with CD. Overall, agents targeting ACTH secretion and steroidogenesis were found to be quite effective in reducing urine free cortisol (UFC) to levels near normal. A significant reduction in UFC was observed in 45%-100% of patients and a majority of patients gained clinical improvement. Similarly, inhibition at the end-tissue level led to clinical improvement in 87% of patients. However, side-effect rates associated with these drugs are high (up to 88%). Ketoconazole has been shown to enhance tumor appearance on MRI to facilitate pituitary resection. Promising molecular targets have been identified, including epidermal growth factor receptor, retinoic acid receptors, and cyclin dependent kinases. These pathways have been linked to the regulation of pro-opiomelanocortin expression, ACTH secretion, and tumor growth. CONCLUSIONS Despite encouraging Phase III clinical trials leading to FDA approval of 2 agents for treatment of patients with CD, no agent has yet produced results comparable to resection. As a result, the molecular insights gained into CD pathogenesis will need to continue to be expanded until they can lead to the development of medical therapies for CD with a favorable side-effect profile and efficacy comparable to resection. Ideally these agents should also reduce tumor size, which could potentially permit their eventual discontinuation.
Topics: Clinical Trials as Topic; Drug Delivery Systems; Female; Forecasting; Humans; Male; Mitotane; Pituitary ACTH Hypersecretion; Receptors, Retinoic Acid; Retrospective Studies; Somatostatin
PubMed: 25639313
DOI: 10.3171/2014.10.FOCUS14700 -
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 -
Clinical Nuclear Medicine Aug 2016Adrenocortical cancer (ACC) is an uncommon primary neoplasm of the adrenal cortex with dismal prognosis. It often presents with symptoms and signs of adrenal cortical... (Review)
Review
Adrenocortical cancer (ACC) is an uncommon primary neoplasm of the adrenal cortex with dismal prognosis. It often presents with symptoms and signs of adrenal cortical hormone hypersecretion and abdominal mass effect or is incidentally detected as an adrenal mass on imaging performed for other indications. Endocrine evaluation, comprehensive staging, and meticulous resection are crucial to ensure the best possible outcome. Despite extensive initial surgical resection, local and distant metastases are not uncommon with disappointing 5-year survival, although progress is being made at high-volume centers. Accurate restaging of recurrent disease is important to guide further management. Mitotane, external beam radiation and chemotherapy, and newer anticancer systemic treatments are used as adjunctives for inoperable disease and distant metastases. Contrast-enhanced CT and MRI are first-line imaging modalities for evaluation of ACC to characterize adrenal masses and to determine tumor resectability. Emerging literature supports F-FDG PET/CT use to determine the malignant potential of adrenal masses. In patients with a diagnosis of ACC, FDG PET/CT is sensitive for detecting metastatic disease, and its tumor accumulation has been correlated to pathology, Weiss scores, and prognosis. Metomidate, labeled with C for PET or with I for SPECT/CT, allows characterization of an adrenal mass as being of adrenocortical origin with high specificity. Taking advantage of its adrenocortical avidity, metomidate has been labeled with I for radionuclide therapy in a subset of ACC. In this review, we describe how nuclear medicine imaging, and specifically PET, can assist surgical management of ACC.
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Humans; Magnetic Resonance Imaging; Molecular Imaging; Positron Emission Tomography Computed Tomography; Radiopharmaceuticals; Single Photon Emission Computed Tomography Computed Tomography
PubMed: 26825212
DOI: 10.1097/RLU.0000000000001112 -
Therapeutic Drug Monitoring Jun 2023Dried blood spot (DBS) sampling is a convenient alternative to whole-blood sampling for therapeutic drug monitoring (TDM) in clinical practice. The aim of this study was...
BACKGROUND
Dried blood spot (DBS) sampling is a convenient alternative to whole-blood sampling for therapeutic drug monitoring (TDM) in clinical practice. The aim of this study was to systematically review studies that have examined and used DBS sampling for the TDM of chemotherapy and targeted therapy agents for the treatment of patients with solid cancers.
METHODS
Using the PRISMA guidelines, a systematic literature search of EMBASE and PUBMED was performed to identify eligible clinical studies that used DBS sampling to monitor chemotherapy or targeted therapy for the treatment of solid cancers.
RESULTS
Of the 23 eligible studies, 3 measured concordance between drug concentrations determined by DBS and whole-blood, 7 developed analytical methods of DBS, and 13 performed both. DBS was employed for the TDM of everolimus (3 studies), vemurafenib (2 studies), pazopanib (2 studies), abiraterone (2 studies), mitotane, imatinib, adavosertib, capecitabine, 5-fluorouracil, gemcitabine, cyclophosphamide, ifosfamide, etoposide, irinotecan, docetaxel, gefitinib, palbociclib/ribociclib, and paclitaxel (one study each). The studies included a median of 14 participants (range: 6-34), with 10-50 μL of blood dispensed on DBS cards (20) and Mitra devices (3). Seventeen of the 20 studies that used DBS found no significant impact of the hematocrit on the accuracy and precision of the developed method in the normal hematocrit ranges (eg, 29.0%-59.0%). DBS and plasma or venous concentrations were highly correlated (correlation coefficient, 0.872-0.999) for all drugs, except mitotane, which did not meet a predefined level of significance (r > 0.872; correlation coefficient, r = 0.87, P < 0.0001).
CONCLUSIONS
DBS provides an alternative sampling strategy for the TDM of many anticancer drugs. Further research is required to establish a standardized approach for sampling and processing DBS samples to allow future implementation.
Topics: Humans; Mitotane; Antineoplastic Agents; Everolimus; Neoplasms; Vemurafenib
PubMed: 36750444
DOI: 10.1097/FTD.0000000000001082