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1.
Eur Radiol ; 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32621242

RESUMO

OBJECTIVES: To evaluate the impact of image-guided ablation of liver and lung metastases from adrenocortical carcinoma (ACC). METHODS: Patients with oligometastatic ACC (liver and lung metastases) who underwent image-guided ablation were retrospectively included in the study. Complete ablation (CA) at the first contrast-enhanced CT control, local tumor progression (LTP), local tumor progression-free survival (LTPFS), liver disease-free survival (LDFS), and overall survival (OS) were evaluated. Correlation between outcomes and other prognostic factors (including Ki67, hormonal secretion, and progression-free survival after primary tumor resection (PR-PFS)) was also analyzed. Kaplan-Meier methods, log-rank tests, and Spearman correlation models were applied. RESULTS: Thirty-two ACC metastases (4 lung and 28 liver) from 16 patients (10 females; mean age 41 years) were treated with RFA or MWA. A single major adverse event was observed (intrahepatic hematoma with subsequent right hemothorax). One patient (2 lesions) was lost to follow-up. CA was obtained in 97% (29/30). During follow-up, LTP was registered in 7/29 cases (24.1%), with a median LTPFS of 21 months (± 12.6). Metastasis size was significantly higher in case of LTP (20 mm vs. 34.5 mm; p = 0.009) and was an independent predictive factor of local tumor control with an AUC of 0.934 (p = 0.0009). Hepatic progression was observed in 66% of the cases, with a median LDFS of 25 months. Median OS was 48.6 months. PR-PFS and hormonal secretion were independent predictors of OS (p < 0.001 and p = 0.045, respectively). CONCLUSIONS: Image-guided ablation achieves adequate local tumor control of ACC liver and lung metastases, providing a safe and effective treatment option in the multidisciplinary management of the oligometastatic ACC. KEY POINTS: • Image-guided ablation allows adequate local tumor control in the oligometastatic adrenocortical carcinoma setting. • After percutaneous thermal ablation, complete ablation was achieved in 29 out of 30 lesions (97%). • Lesion size together with primary resection disease-free survival and hormonal secretion play a significant role in determining outcomes.

2.
J Clin Endocrinol Metab ; 105(8)2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32449514

RESUMO

CONTEXT: Objective response rate to mitotane in advanced adrenocortical carcinoma (ACC) is approximately 20%, and adverse drug effects are frequent. To date, there is no marker established that predicts treatment response. Mitotane has been shown to inhibit sterol-O-acyl transferase 1 (SOAT1), which leads to endoplasmic reticulum stress and cell death in ACC cells. OBJECTIVE: To investigate SOAT1 protein expression as a marker of treatment response to mitotane. PATIENTS: A total of 231 ACC patients treated with single-agent mitotane as adjuvant (n = 158) or advanced disease therapy (n = 73) from 12 ENSAT centers were included. SOAT1 protein expression was determined by immunohistochemistry on formalin-fixed paraffin-embedded specimens. SETTING: Retrospective study at 12 ACC referral centers. MAIN OUTCOME MEASURE: Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). RESULTS: Sixty-one of 135 patients (45%) with adjuvant mitotane treatment had recurrences and 45/68 patients (66%) with mitotane treatment for advanced disease had progressive disease. After multivariate adjustment for sex, age, hormone secretion, tumor stage, and Ki67 index, RFS (hazard ratio [HR] = 1.07; 95% confidence interval [CI], 0.61-1.85; P = 0.82), and DSS (HR = 1.30; 95% CI, 0.58-2.93; P = 0.53) in adjuvantly treated ACC patients did not differ significantly between tumors with high and low SOAT1 expression. Similarly, in the advanced stage setting, PFS (HR = 1.34; 95% CI, 0.63-2.84; P = 0.45) and DSS (HR = 0.72; 95% CI, 0.31-1.70; P = 0.45) were comparable and response rates not significantly different. CONCLUSIONS: SOAT1 expression was not correlated with clinical endpoints RFS, PFS, and DSS in ACC patients with mitotane monotherapy. Other factors appear to be relevant for mitotane treatment response and ACC patient survival.

3.
Cancers (Basel) ; 12(3)2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32245135

RESUMO

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

4.
Cells ; 9(4)2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32260362

RESUMO

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Mitotane, the standard treatment for ACC, impairs adrenocortical steroid biosynthesis and cholesterol metabolism. In the H295R cell line, a standard ACC in vitro model, mitotane was previously reported to enhance the production of some oxysterols. To verify the possible mechanistic involvement of oxysterols in the anti-ACC effect of mitotane, a gas chromatography mass spectrometry (GC-MS) profiling of oxysterols and the main cholesterol precursors was carried out in H295R cells. Among the oxysterols detected in mitotane-treated cells, 27OHC was markedly produced, as well as lanosterol and lathosterol cholesterol precursors. In this cell model, mitotane was confirmed to affect mitochondrial transmembrane potential and induce apoptosis. Such cytotoxic effects were perfectly matched by H295R cell treatment with a single identical micromolar amount of 27OHC. The mitotane-dependent strong increase in 27OHC was confirmed in vivo, in the plasma of ACC patients under treatment with the drug. Moreover, lanosterol, lathosterol, desmosterol and, to a minor extent, 24-hydroxycholesterol and 25-hydroxycholesterol plasma levels were significantly increased in those patients. The cytotoxic effect of mitotane on ACC cells may be partly related to the increased intracellular level of 27OHC induced by the drug itself.

5.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31633759

RESUMO

CONTEXT: We investigated the role of Gallium 68 dodecanetetraacetic acid Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography/computed tomography (PET/CT) in detecting somatostatin receptors (SSTRs) in 19 patients with metastatic adrenocortical carcinoma (ACC) and explored the activity of yttrium-90/lutetium-177 (90Y/177Lu-DOTATOC) peptide receptor radionuclide therapy (PRRT). CASE DESCRIPTION AND METHODS: 68Ga uptake in metastatic sites was scored in terms of intensity and anatomical uptake distribution of standard uptake value (SUV). Tissue expression of SSTR2A and SSTR5 was also evaluated by immunohistochemistry (IHC) on primary tumors. Eight (42%) patients displayed radiometabolic uptake of any-grade intensity with focal and limited distribution. Two (11%) patients displayed strong uptake in multiple lesions and were treated with PRRT. Both obtained an overall disease control lasting 4 and 12 months, respectively. CONCLUSIONS: ACC can express SSTRs as detected by IHC and 68Ga-DOTATOC PET. SSTRs-based PRRT may represent a potential treatment opportunity for a minority of patients with advanced ACC. This treatment modality deserves further investigation.

6.
J Clin Med ; 8(11)2019 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-31684071

RESUMO

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28-62) with a median maintenance dose of 2.0 g/day (IQR 1.5-2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5-19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7-M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88-0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

7.
Eur J Endocrinol ; 181(6): 681-689, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639772

RESUMO

Objective: Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro. Design: On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy. Methods: We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety. Results: Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8-53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1-2 according to WHO criteria. Conclusion: Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.


Assuntos
Carcinoma Adrenocortical/tratamento farmacológico , Temozolomida/efeitos adversos , Temozolomida/uso terapêutico , Carcinoma Adrenocortical/metabolismo , Adulto , Idoso , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Proteínas Supressoras de Tumor/metabolismo
8.
Expert Rev Anticancer Ther ; 18(11): 1125-1133, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30117750

RESUMO

INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare tumor characterized by poor prognosis in most cases. Moreover, in most cases ACC produces an excess of adrenal steroid hormones with relevant clinical consequences. Areas covered: After an extensive literature search, this narrative review addresses diagnostic management, including hormonal, radiological and pathological assessment, and treatment, which should be directed toward both cancer and hormone related problems. While surgery is the first option in ACC without evidence of metastatic disease, and the only possibility of cure, the therapeutic management of metastatic patients is centered on systemic therapy including mitotane alone or in combination with chemotherapy. Mitotane is also used in the adjuvant setting, because up to 80% of patients with nonmetastatic ACC show locoregional or distant metastases after an apparent complete surgical excision. Expert commentary: Management of ACC patients is fraught with many difficulties and should be limited to experienced physicians. Each step of clinical management, such as diagnosis, prognostication, treatment (both surgical and medical) is challenging and carries the possibility of severe mistakes. For this reason, each step of the management strategy should be decided in the setting of a multidisciplinary team including different expertise (endocrinology, radiology, pathology, oncology), in expert centers.


Assuntos
Neoplasias do Córtex Suprarrenal/terapia , Carcinoma Adrenocortical/terapia , Tomada de Decisões , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Antineoplásicos Hormonais/uso terapêutico , Quimioterapia Adjuvante/métodos , Humanos , Mitotano/uso terapêutico , Equipe de Assistência ao Paciente/organização & administração , Prognóstico
9.
Eur J Endocrinol ; 177(4): 361-367, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28780517

RESUMO

OBJECTIVE: Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic-pituitary-adrenal axis in patients with ACC receiving mitotane. DESIGN AND METHODS: We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test. RESULTS: We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04-275.00) vs 24.53 (6.16-121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32-275.00) vs 67.43 (8.8-179.52) pmol/L P = 0.016). CONCLUSIONS: The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.


Assuntos
Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Carcinoma Adrenocortical/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Mitotano/uso terapêutico , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Neoplasias do Córtex Suprarrenal/sangue , Carcinoma Adrenocortical/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Idoso , Antineoplásicos Hormonais/sangue , Antineoplásicos Hormonais/farmacologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Pessoa de Meia-Idade , Mitotano/sangue , Mitotano/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Estudos Prospectivos , Resultado do Tratamento
10.
Pharmacogenet Genomics ; 23(6): 293-300, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23524664

RESUMO

OBJECTIVE: The aim of this study was to assess the potential impact of the pharmacogenetic variability of CYP2B6 and ABCB1 genes on the pharmacokinetics of mitotane. METHODS: A retrospective analysis was carried out on 27 patients with adrenocortical carcinoma on postoperative adjunctive mitotane. CYP2B6 and ABCB1 polymorphisms were genotyped and tested for an association with plasma trough concentration after 3, 6, 9, and 12 months of therapy. RESULTS: Patients with the GT/TT genotype had higher mitotane plasma concentrations compared with patients with GG at 3 months (14.80 vs. 8.01 µg/ml; P=0.008) and 6 months (17.70 vs. 9.75 µg/ml; P=0.015). Multivariate logistic regression analysis showed that only the CYP2B6 rs3745274GT/TT genotype (odds ratio=10.7; P=0.017) was a predictor of mitotane plasma concentrations of at least 14 µg/ml after 3 months of treatment. Mitotane concentrations were not influenced by the polymorphisms of the ABCB1 gene. CONCLUSION: Evaluation of the CYP2B6 polymorphism enabled prediction of the individual response to adjuvant mitotane treatment.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Mitotano/farmacocinética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/enzimologia , Neoplasias do Córtex Suprarrenal/genética , Adulto , Citocromo P-450 CYP2B6 , Relação Dose-Resposta a Droga , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mitotano/administração & dosagem , Mitotano/sangue , Mitotano/uso terapêutico , Análise Multivariada
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