Beuschlein, Felix

Abstract Background: The ESE-ENSAT guidelines on the management of adrenocortical carcinoma (ACC) suggest adjuvant mitotane for patients at high risk of recurrence following radical surgery. This indication has a limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in ACC patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane (MIT) or observation (OBS). The primary endpoint of the study was RFS. Patients who refused randomization were offered inclusion in the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in the ADIUVO study. A total of 91 patients were enrolled in ADIUVO, 45 in the MIT and 46 in the OBS arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with MIT and OBS groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohorts could be analyzed in parallel to those of ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. Tumor size was a predictor of RFS in multivariable analysis. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55–3.32, p=0.54) and HR for death 2.171 (95%CI, 0.52–12.12, p=0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed the findings of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-year RFS is about 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care.

Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

Abstract Context Appropriate management of adrenal insufficiency (AI) in pregnancy can be challenging due to the rarity of the disease and lack of evidence-based recommendations to guide glucocorticoid and mineralocorticoid dosage adjustment. Objective Multicenter survey on current clinical approaches in managing AI during pregnancy. Design Retrospective anonymized data collection from 19 international centers from 2013 to 2019. Setting and Patients 128 pregnancies in 113 women with different causes of AI: Addison disease (44%), secondary AI (25%), congenital adrenal hyperplasia (25%), and acquired AI due to bilateral adrenalectomy (6%). Results Hydrocortisone (HC) was the most commonly used glucocorticoid in 83% (97/117) of pregnancies. Glucocorticoid dosage was increased at any time during pregnancy in 73/128 (57%) of cases. In these cases, the difference in the daily dose of HC equivalent between baseline and the third trimester was 8.6 ± 5.4 (range 1-30) mg. Fludrocortisone dosage was increased in fewer cases (7/54 during the first trimester, 9/64 during the second trimester, and 9/62 cases during the third trimester). Overall, an adrenal crisis was reported in 9/128 (7%) pregnancies. Cesarean section was the most frequent mode of delivery at 58% (69/118). Fetal complications were reported in 3/120 (3%) and minor maternal complications in 15/120 (13%) pregnancies without fatal outcomes. Conclusions This survey confirms good maternal and fetal outcome in women with AI managed in specialized endocrine centers. An emphasis on careful endocrine follow-up and repeated patient education is likely to have reduced the risk of adrenal crisis and resulted in positive outcomes.

Abstract Context Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). Objective, Design, Setting This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. Patients and Methods 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography–mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. Results Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine “steroid fingerprint” at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). Conclusion Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

Abstract Context Cross-sectional imaging with CT or MRI is regarded as a first-choice modality for tumor localization in patients with pheochromocytoma and paraganglioma (PPGL). 123I-labeled metaiodobenzylguanidine (123I-MIBG) is widely used for functional imaging but the added diagnostic value is controversial. Objective To establish the virtual impact of adding 123I-MIBG scintigraphy to CT or MRI on diagnosis and treatment of PPGL. Design International multicenter retrospective study. Intervention None. Patients Two hundred thirty-six unilateral adrenal, 18 bilateral adrenal, 48 unifocal extra-adrenal, 12 multifocal, and 26 metastatic PPGL. Main Outcome Measures Patients underwent both anatomical imaging (CT and/or MRI) and 123I-MIBG scintigraphy. Local imaging reports were analyzed centrally by two independent observers who were blinded to the diagnosis. Imaging-based diagnoses determined by CT/MRI only, 123I-MIBG only, and CT/MRI combined with 123I-MIBG scintigraphy were compared with the correct diagnoses. Results The rates of correct imaging-based diagnoses determined by CT/MRI only versus CT/MRI plus 123I-MIBG scintigraphy were similar: 89.4 versus 88.8%, respectively (P = 0.50). Adding 123I-MIBG scintigraphy to CT/MRI resulted in a correct change in the imaging-based diagnosis and ensuing virtual treatment in four cases (1.2%: two metastatic instead of nonmetastatic, one multifocal instead of single, one unilateral instead of bilateral adrenal) at the cost of an incorrect change in seven cases (2.1%: four metastatic instead of nonmetastatic, two multifocal instead of unifocal and one bilateral instead of unilateral adrenal). Conclusions For the initial localization of PPGL, the addition of 123I-MIBG scintigraphy to CT/MRI rarely improves the diagnostic accuracy at the cost of incorrect interpretation in others, even when 123I-MIBG scintigraphy is restricted to patients who are at risk for metastatic disease. In this setting, the impact of 123I-MIBG scintigraphy on clinical decision-making appears very limited.

BACKGROUND. Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS. We performed mass spectrometry–based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS. Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION. Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING. Medical Research Council UK, Wellcome Trust, European Commission.