In a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5 mg/day improved investigator-assessed progression-free survival (PFS) ...versus placebo (11.4 versus 5.5 months; HR, 0.42; P < 0.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib.
In this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan–Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses.
Of 171 randomized patients (sunitinib, n = 86; placebo, n = 85), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval CI) PFS was 12.6 (11.1–20.6) months for sunitinib and 5.8 (3.8–7.2) months for placebo (HR, 0.32; 95% CI 0.18–0.55; P = 0.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6–56.4) months for sunitinib and 29.1 (16.4–36.8) months for placebo (HR, 0.73; 95% CI 0.50–1.06; P = 0.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib.
BICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10 months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib.
NCT00428597.
ObjectiveLimited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to ...provide a rationale for their management.MethodsAnalysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas.ResultsAdrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10 mm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40 mm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC.ConclusionsAdrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone–renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.
Context:
Multiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports.
Objective:
To improve the knowledge of MEN1 natural history before 21 years old.
Methods:
...Obtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the “Groupe d'étude des Tumeurs Endocrines” MEN1 cohort.
Results:
The first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n = 9, 16%), hyperparathyroidism (n = 38, 31%), gastrinoma (n = 1, 33%), NSPT (n = 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases.
Conclusions:
Various MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.
ContextMultiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed.ObjectiveThe ...aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1.DesignData regarding a study of 734 cases of MEN1 from the multicenter ‘Groupe d'étude des Tumeurs Endocrines’ were analyzed.ResultsThere were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%).ConclusionThe phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.
Medullary thyroid carcinoma diameter and N1 are associated with disease free survival, whereas preoperative basal CT > 10 or 30 ng/liter, age > 10, and class D are associated with carcinoma and/or ...N1.
Background:
In hereditary medullary thyroid carcinoma (HMTC), prophylactic surgery is the only curative option, which should be properly defined both in time and extent.
Objectives:
To identify and characterize prognostic factors associated with disease-free survival (DFS) in children from HMTC families.
Design:
We conducted a retrospective analysis of a multi-center cohort of 170 patients below age 21 at surgery. Demographic, clinical, genetic, biological data basal and pentagastrine-stimulated calcitonin (CT and CT/Pg, respectively), and tumor node metastasis (TNM) status were collected. DFS was assessed based on basal CT levels. Kaplan–Meier curves, Cox regression, and logistic regression models were used to determine factors associated with DFS and TNM staging.
Results:
No patients with a preoperative basal CT <31 ng/ml had persistent or recurrent disease. Medullary thyroid carcinoma defined by a diameter ≥10 mm hazard ratio (HR): 6.0; 95% confidence interval (95% CI): 1.8–19.8 and N1 status (HR: 20.8; 95% CI: 3.9–109.8) were independently associated with DFS. Class D genotype odds ratio (OR): 48.5, 95% CI: 10.6–225.1, preoperative basal CT >30 ng/liter (OR: 43.4, 95% CI: 5.2–359.8), and age >10 (OR: 5.5, 95% CI: 1.4–21.8) were associated with medullary thyroid carcinoma ≥10 mm. No patient with a preoperative basal CT <31 ng/ml had a N1 status. Class D genotype (OR: 48.6, 95% CI: 8.6–274.1), and age >10 (OR: 4.6, 95% CI: 1.1–19.0) were associated with N1 status.
Conclusion:
In HMTC patients, DFS is best predicted by TNM staging and preoperative basal CT level below 30 pg/ml. Basal CT, class D genotype, and age constitute key determinants to decide preoperatively timely surgery.
Objective
To evaluate the natural history of MEN1-related bronchial endocrine tumors (br-NETs) and to determine their histological characteristics, survival and causes of death.
Summary background ...data
br-NETs frequency ranges from 3 to 13% and may reach 32% depending on the number of patients evaluated and on the criteria required for diagnosis.
Methods
The 1023-patient series of symptomatic MEN1 patients followed up in a median of 48.7 35.5–59.6 years by the Groupe d’étude des Tumeurs Endocrines was analyzed using time-to-event techniques.
Results
br-NETs were found in 51 patients (4.8%, 95% CI 3.6–6.2%) and were discovered by imaging in 86% of cases (CT scan, Octreoscan, Chest X-ray, MRI). Median age at diagnosis was 45 years 28–66. Histological examination showed 27 (53%) typical carcinoids (TC), 16 (31%) atypical carcinoids (AC), 2 (4%) large cell neuroendocrine carcinomas (LCNEC), 3(6%) small cell neuroendocrine carcinomas (SCLC), 3(6%) TC associated with AC. Overall survival was not different from the rest of the cohort (HR 0.29, 95% CI 0.02–5.14). AC tended to have a worse prognosis than TC (
p
= 0.08). Seven deaths were directly related to br-NETs (three AC, three SCLC and one LCNEC). Patients who underwent surgery survived longer (
p
= 10
−4
) and were metastasis free, while 8 of 14 non-operated patients were metastatic. There were no operative deaths.
Conclusions
Around 5% of MEN1 patients develop br-NETs. br-NETs do not decrease overall survival in MEN1 patients, but poorly differentiated and aggressive br-NETs can cause death. br-NETs must be screened carefully. A biopsy is essential to operate on patients in time.
Background
The natural history of multiple endocrine neoplasia type 1 (MEN1) is known through single-institution or single-family studies. We aimed to analyze the risk factors and causes of death in ...a large cohort of MEN1 patients.
Methods
Overall, 758 symptomatic MEN1 patients were identified through the GTE network (Groupe d’étude des Tumeurs Endocrines), which involves French and Belgian genetics laboratories responsible for MEN1 diagnosis and 80 clinical reference centers. The causes of death were analyzed. A frailty model, including time-dependent variables, was used to assess the impact of each clinical lesion, except for hyperparathyroidism, on survival.
Results
The median follow-up was 6.3 years. Female gender, family history of MEN1, and recent diagnosis were associated with a lower risk of death. Compared with nonaffected patients, those with thymic tumors (hazard ratio HR = 4.64, 95% CI = 1.73-12.41), glucagonomas–vipomas–somatostatinomas (HR = 4.29, 95% CI = 1.54-11.93), nonfunctioning pancreatic tumors (HR = 3.43, 95% CI = 1.71-6.88), and gastrinoma (HR = 1.89, 95% CI = 1.09-3.25) had a higher risk of death after adjustment for age, gender, and diagnosis period. The increased risk of death among patients with adrenal tumors was not significant, but three patients died from aggressive adrenal tumors. Pituitary tumors, insulinomas, and bronchial tumors did not increase the risk of death. The proportion of MEN1-related deaths decreased from 76.8 to 71.4% after 1990.
Conclusions
The prognosis of MEN1 disease has improved since 1980. Thymic tumors and duodenopancreatic tumors, including nonsecreting pancreatic tumors, increased the risk of death. Rare but aggressive adrenal tumors may also cause death. Most deaths were related to MEN1. New recommendations on abdominal and thoracic imaging are required.
Introduction Une meilleure caractérisation des phéochromocytomes et paragangliomes malins (PPM) issus de larges séries constitue la première étape du progrès thérapeutique. Méthode Étude ...rétrospective multicentrique des PPMs caractérisés par une TDM ou IRM cervico-thoraco-abdominopelvienne au diagnostic de métastases au sein des réseaux français comete et européen ENS@T entre 1998 et 2010. Résultats Nous avons inclus 177 patients issus de 18 centres européens (97 hommes, 80 femmes, âge moyen : 47 ± 16 ans). Un bilan complet a été pratiqué comprenant : une évaluation symptomatique sécrétoire ou tumorale (174 et 172 patients), le dosage d’au moins un biomarqueur (153 patients, métanéphrines pour 134 et chromogranine A pour 79), une recherche de mutation SDHx (151 patients), et une scintigraphie TEP-FDG (102 patients). Les principales caractéristiques retrouvées sont : un primitif type phéochromocytome ou paragangliome dans 51 ou 49 % des cas, des symptômes tumoraux ou sécrétoires dans 55 % et 60 % des cas, des biomarqueurs hormonaux positifs dans 78 % des cas, une mutation SDHB, SDHD, un VHL ou une NF1 dans 42 %, 4 %, 3 % et 2 % des cas, une TEP-FDG positive dans 95 % des cas, une tumeur primitive supérieure à 5 cm dans 75 % des cas, des métastases le plus souvent osseuses (51 %), ganglionnaires (43 %), pulmonaires (26 %) et hépatiques (24 %), métachrones dans 65 % des cas (délai moyen d’apparition 78 mois). Conclusion Ces données caractérisent la plus grande cohorte européenne de PPMs à ce jour. L’impact pronostique des paramètres identifiés est en cours d’analyse.
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