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Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort ( n  = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n  = 25, RX n  = 4, R1 n  = 2; ENSAT Stage II n  = 11, III n  = 16, IV n  = 4, median Ki67 30%, mitotane n  = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09–0.42; P  < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29–0.89, P  = 0.021) and for OS 0.25 (0.09–0.69; P  = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

Measurements of plasma or urinary metanephrines are recommended for diagnosis of pheochromocytoma and paraganglioma (PPGL). What test offers optimal diagnostic accuracy for patients at high and low risk of disease, whether urinary free metanephrines offer advantages over deconjugated metanephrines, and what advantages are offered by including methoxytyramine in panels all remain unclear. A population of 2056 patients with suspected PPGLs underwent prospective screening for disease using mass spectrometric-based measurements of plasma free, urinary deconjugated, and urinary free metanephrines and methoxytyramine. PPGLs were confirmed in 236 patients and were excluded in others on follow-up evaluation. Measurements of plasma free metabolites offered higher ( < 0.01) diagnostic sensitivity (97.9%) than urinary free (93.4%) and deconjugated (92.9%) metabolites at identical specificities for plasma and urinary free metabolites (94.2%) but at a lower ( < 0.005) specificity for deconjugated metabolites (92.1%). The addition of methoxytyramine offered little value for urinary panels but provided higher ( < 0.005) diagnostic performance for plasma measurements than either urinary panel according to areas under ROC curves (0.991 vs 0.972 and 0.964). Diagnostic performance of urinary and plasma tests was similar for patients at low risk of disease, whereas plasma measurements were superior to both urinary panels for high-risk patients. Diagnosis of PPGLs using plasma or urinary free metabolites provides advantages of fewer false-positive results compared with commonly measured deconjugated metabolites. The plasma panel offers better diagnostic performance than either urinary panel for patients at high risk of disease and, with appropriate preanalytics, provides the test of choice. Measurements of methoxytyramine in urine show limited diagnostic utility compared with plasma.

BackgroundInternational guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low.MethodsWe retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses.ResultsIn total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50–60 Gy (n = 20) or 20–49 Gy (n = 69), stereotactic body RT of 35–50 Gy (SBRT) (n = 36), or brachytherapy of 12–25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0–148.6). In comparison to cRT20-49Gy, tTTP was significantly longer for cRT50-60Gy (multivariate adjusted HR 0.10; 95% CI 0.03–0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12–0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22–1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established.ConclusionsThis largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.

Background Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC. Methods A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included. Results Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases ( p  < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival. Conclusions Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome.

Abstract Context Although mitotane is the only approved drug for the treatment of adrenocortical carcinoma (ACC), data on monotherapy in advanced disease are still scarce. Objective To assess the efficacy of mitotane in advanced ACC in a contemporary setting and to identify predictive factors. Design and Setting Multicenter cohort study of three German referral centers. Patients One hundred twenty-seven patients with advanced ACC treated with mitotane monotherapy. Outcome Measures Response Evaluation Criteria in Solid Tumors evaluation, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method, and predictive factors by Cox regression. Results Twenty-six patients (20.5%) experienced objective response, including three with complete remission. Overall, median PFS was 4.1 months (range 1.0 to 73) and median OS 18.5 months (range 1.3 to 220). Multivariate analysis indicated two main predictive factors: low tumor burden (<10 tumoral lesions), hazard ratio (HR) for progression of 0.51 (P = 0.002) and for death of 0.59 (P = 0.017); and initiation of mitotane at delayed advanced recurrence, HR 0.35(P < 0.001) and 0.34 (P < 0.001), respectively. Accordingly, 67% of patients with low tumor burden and mitotane initiation ≥360 days after primary diagnosis experienced a clinical benefit (stable disease >180 days). Patients who achieved mitotane levels >14 mg/L had significantly longer OS (HR 0.42; P = 0.003). Conclusions At 20.5% the objective response rate was slightly lower than previously reported. However, >20% of patients experienced long-term disease control at >1 year. In general, patients with late diagnosis of advanced disease and low tumor burden might especially benefit from mitotane monotherapy, whereas patients with early advanced disease and high tumor burden are probably better candidates for combined therapy of mitotane and cytotoxic drugs. We evaluated the efficacy of mitotane monotherapy in 127 patients with advanced ACC in a contemporary setting and identified factors that predict response to mitotane.

Abstract Background Objective response of advanced adrenocortical carcinoma (ACC) to mitotane and cytotoxic chemotherapy regimen is only ~20% and early tumor progression is frequent. Previous clinical trials with oral multikinase inhibitors were negative, which has been attributed in part to inadvertent drug interaction with mitotane. Cabozantinib (CABO) is an inhibitor of c-MET, vascular endothelial growth factor receptor 2, AXL, and RET and approved for advanced kidney cancer, liver carcinoma after previous sorafenib, and medullary thyroid carcinoma. Objective To investigate the clinical efficacy and safety of CABO monotherapy in ACC patients. Design Retrospective cohort study. Setting Three referral centers for ACC (Germany, United States). Results Sixteen patients (13 female) with progressive ACC received CABO after previous mitotane in 15/16 and 3 (median, range 0-8) further systemic treatments. Prior CABO therapy, mitotane was discontinued in all patients. Mitotane plasma concentration was <2 mg/L in 7/16 patients and discontinued >12 months in 6 additional patients before CABO use. In 4/5 cases with available plasma samples, CABO concentration was in the expected steady-state range. Adverse events of grade 1/2 and 3 were observed in 13 and 3 patients, respectively, and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 5, and progressive disease in 8 patients. Median progression-free and overall survival was 16 and 58 weeks, respectively. Conclusion CABO monotherapy appears to be safe and effective as a monotherapy in advanced ACC after failing prior treatments. Therefore, prospective investigation of CABO in ACC patients is warranted.

Adrenal tumors are among the most common tumors in humans. They are most frequently discovered incidentally during abdominal imaging for other reasons or due to clinical symptoms (e.g. Conn's or Cushing's syndrome, pheochromocytoma or androgen excess). Although over 80% of adrenal tumors are benign, in cases of hormone excess, they are associated with significantly increased morbidity. In highly malignant adrenocortical carcinoma (ACC), early diagnosis is of particular prognostic relevance. Therefore, this review presents the diagnostic procedure for what are referred to as adrenal incidentalomas and provide recommendations for the management of ACC and pheochromocytomas/paragangliomas (PPGL). In primary diagnosis, sufficient hormone diagnostics is required for all adrenal tumors, as this is the only way to identify all patients with relevant hormone excess. Imaging has increasingly improved in recent years and allows a reliable assessment of the tumor's malignancy in most cases. Imaging of first choice is unenhanced computed tomography (CT), while magnetic resonance imaging (MRI) and fluorodeoxyglucose-18 positron emission tomography (FDG-PET/CT) are reserved for special situations, as published evidence on these procedures is more limited. The treatment of ACC and PPGL is complex and is carried out on an interdisciplinary basis at specialized centers. In the case of localized disease, surgery is the only curative treatment option. There are now clear recommendations for individualized adjuvant therapy for ACC. In metastatic disease, mitotane with or without platinum-containing chemotherapy is the standard. Other lines of therapy should be discussed with a reference center. Over 35% of PPGL have a germline mutation; therefore, genetic testing should be offered. In metastatic PPGL, an individual decision is required between active surveillance, radionuclide therapy, sunitinib or chemotherapy.

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. To investigate SOAT1 protein expression as a marker of treatment response to mitotane. 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. Retrospective study at 12 ACC referral centers. Recurrence-free survival (RFS), progression-free survival (PFS), and disease-specific survival (DSS). 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. 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.

Zusammenfassung Nebennierentumoren gehören zu den häufigsten Tumoren beim Menschen. Am häufigsten fallen sie zufällig im Rahmen einer abdominellen Bildgebung aus anderen Gründen oder durch klinische Symptome auf (beispielsweise Conn- oder Cushing-Syndrom, Phäochromozytom oder Androgenexzess). Zwar sind über 80 % der Nebennierentumoren gutartig, diese gehen aber bei Hormonexzess mit einer deutlich erhöhten Morbidität einher. Beim hochmalignen Nebennierenkarzinom ist eine frühzeitige Diagnose prognostisch besonders relevant. In der vorliegenden Übersichtsarbeit stellen wir deshalb das diagnostische Vorgehen bei den sogenannten Nebenniereninzidentalomen vor und geben Empfehlungen zum Management von Nebennierenkarzinomen und Phäochromozytomen/Paragangliomen (PPGL). In der Primärdiagnostik ist bei allen Nebennierentumoren eine suffiziente Hormondiagnostik erforderlich, da nur so alle PatientInnen mit relevantem Hormonexzess identifiziert werden. Die Bildgebung hat sich in den letzten Jahren zunehmend verbessert und lässt in den meisten Fällen eine sichere Beurteilung der Dignität des Tumors zu. Bildgebung der ersten Wahl ist die native Computertomographie (CT), während Magnetresonanztomographie (MRT) und Fluordesoxyglukose-Positronenemissionstomographie/Computertomographie (FDG-PET/CT) Spezialsituationen vorbehalten sind, da die Datenlage zu diesen Verfahren limitierter ist. Die Therapie des Nebennierenkarzinoms und der PPGL ist komplex und erfolgt interdisziplinär an hierfür spezialisierten Zentren. Bei lokalisierten Erkrankungen ist die Operation die einzige Möglichkeit der Heilung. Beim Nebennierenkarzinom gibt es inzwischen klare Empfehlungen zu einer individualisierten adjuvanten Therapie. Bei metastasierter Erkrankung ist Mitotan mit oder ohne platinhaltige Chemotherapie der Standard. Weitere Therapielinien sind mit einem Referenzzentrum abzusprechen. Über 35 % der PPGL weisen eine Keimbahnmutation auf, sodass eine humangenetische Diagnostik angeboten werden soll. Bei metastasierten PPGL wird individuell zwischen „active surveillance“, Radionuklidtherapie, Behandlung mit Sunitinib oder Chemotherapie entschieden.

Abstract Disclosure: B. Altieri: None. O. Kimpel: None. F. Megerle: None. M. Detomas: None. I.O. Chifu: None. C.T. Fuss: None. M. Quinkler: None. M. Kroiss: None. M. Fassnacht: None. Background: Mitotane is the standard therapy of adrenocortical carcinoma (ACC), both adjuvantly in patients with high risk of recurrence and palliative setting, due to its relative selectivity of its cytotoxic effects towards adrenocortical cells. Therefore, it virtually always leads to adrenal insufficiency. However, frequency and characteristics of hypothalamic-pituitary-adrenal (HPA) axis recovery after discontinuation are not well defined. Methods: Retrospective study of patients with ACC adjuvantly treated with mitotane for ≥12 months who were disease-free at mitotane stop and had a minimum follow-up ≥1 year. Data on patients and tumor characteristics, mitotane treatment, and information on HPA axis were analyzed. Primary endpoint was the adrenal recovery. Explorative analysis of predictive factors (e.g. sex, age, follow-up in reference center, cumulative mitotane dose and plasma levels, duration of treatment, and dose of hydrocortisone-equivalent replacement) was performed using Cox regression. Mitotane plasma elimination rate and hormonal changes after mitotane stop were also investigated. Results: 56 patients (36 women) treated with mitotane for a median time of 25 months and an average daily dose of 2.8 g (interquartile range 1.8-3.4) were included. The average hydrocortisone-equivalent replacement daily dose during mitotane treatment was in median 49.4 mg (41.1-53.5). Mitotane plasma levels decreased slowly after discontinuation, but with a very high variability between individual patients. Median time until mitotane levels dropped below 5 mg/L, 2 mg/L, and the detection limit was 152 days (114-202), 280 days (192- 37 370), and 395 days (227-546), respectively. Full adrenal recovery was documented in 32 (57%) patients after a median time of 26 months (95%CI=19.6-32.4). Among these, 22 (69%) achieved HPA recovery within 24 months. To note, a complete recovery after more than 67 months did not occur. Partial and insufficient recovery were observed in 10 (18 %) and 14 (25%) patients, respectively. In four patients (7.1%) adrenal insufficiency persisted >5 years after discontinuation. Mitotane peak ≥27mg/L significantly correlated with longer time to adrenal recovery (HR=0.2, 95%CI=0.1-0.8, p=0.03). 27/38 patients (71%) followed in reference centers achieved adrenal recovery compared to only 5/18 (28%) followed-up in non-reference centers (HR=4.51, 95%CI=1.71-11.89, p=0.002). Other investigated factors were not associated with adrenal function after discontinuation. Conclusions: Our study demonstrates that adrenal recovery occurs in most patients after stopping mitotane, particularly when followed-up in specialized centers, but not in all. Elimination time of mitotane after treatment discontinuation is very long, but individually quite variable. Presentation: 6/2/2024