•This updated ESMO Clinical Practice Guideline provides key recommendations on the management of lung and thymic carcinoids.•Characterisation is best standardised in multidisciplinary expert ...centres.•Prognosis guides the therapeutic management process.•Dedicated lung carcinoids and thymic carcinoids trials are urgently needed.
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.
NETTER-1 est une étude de phase III, multicentrique internationale, stratifiée, ouverte, randomisée, évaluant une radiothérapie interne vectorisée (RIV) par 177 Lu-Dotatate chez les patients porteurs ...de TNE de l’intestin moyen de grade 1–2 inopérables, exprimant les récepteurs de la somatostatine de sous-type-2, progressive selon les critères RECIST sous traitement par octréotide LAR30 mg/28 jours. Les patients étaient randomisés entre RIV par 177 Lu-Dotatate associée à octréotide LAR30 mg/28 jours vs octréotide LAR60 mg/28 jours. Jusqu’en février 2015, 230 patients ont été inclus dans 35 centres européens et 15 centres aux États-Unis. Au moment de l’analyse statistique, la survie sans progression (SSP) médiane, critère principal, n’était pas atteinte pour le bras 177 Lu-Dotatate et était de 8,4 mois pour le bras octréotide LAR60 mg IC95 % : 5,8–11,0 mois, p < 0,0001, avec un Hazard Ratio de 0,21 IC 95 % : 0,13–0,34. Le nombre de progressions tumorales ou de décès était de 23 dans le bras 177 Lu-Dotatate et de 67 dans le bras octréotide LAR60 mg. Le taux de réponses objectives était supérieur dans le bras RIV (19 % vs 3 %, p < 0,0004). Le profil de tolérance de la RIV était comparable à celui observé dans les études de phaseI-II. NETTER-1, première étude de phase III randomisée évaluant l’efficacité de la RIV, confirme l’efficacité du 177 Lu-Dotatate dans le traitement des TNE intestinales progressives sous octréotide LAR. La RIV par 177 Lu-Dotatate allonge de façon statistiquement significative la SSP des patients, présente un profil de toxicité acceptable et devrait s’inscrire dans le panel des options thérapeutiques pour les TNE intestinales exprimant les récepteurs à la somatostatine.
Several studies have demonstrated the antitumor activity of first-generation somatostatin analogs (SSAs), primarily targeting somatostatin receptor (sstr) subtypes 2 and 5, in neuroendocrine tumors ...(NET). Pasireotide, a second-generation SSA, targets multiple sstr subtypes. We compared the efficacy and safety of pasireotide plus everolimus to everolimus alone in patients with advanced, well-differentiated, progressive pancreatic NET.
Patients were randomized 1 : 1 to receive a combination of everolimus (10 mg/day, orally) and pasireotide long-acting release (60 mg/28 days, intramuscularly) or everolimus alone (10 mg/day, orally); stratified by prior SSA use, and baseline serum chromogranin A and neuron-specific enolase. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, objective response rate, disease control rate, and safety. Biomarker response was evaluated in an exploratory analysis.
Of 160 patients enrolled, 79 were randomized to the combination arm and 81 to the everolimus arm. Baseline demographics and disease characteristics were similar between the treatment arms. No significant difference was observed in PFS: 16.8 months in combination arm versus 16.6 months in everolimus arm (hazard ratio, 0.99; 95% confidence interval, 0.64–1.54). Partial responses were observed in 20.3% versus 6.2% of patients in combination arm versus everolimus arm; however, overall disease control rate was similar (77.2% versus 82.7%, respectively). No significant improvement was observed in median overall survival. Adverse events were consistent with the known safety profile of both the drugs; grade 3 or 4 fasting hyperglycemia was seen in 37% versus 11% of patients, respectively.
The addition of pasireotide to everolimus was not associated with the improvement in PFS compared with everolimus alone in this study. Further studies to delineate mechanisms by which SSAs slow tumor growth in NET are warranted.
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.
BackgroundMEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence ...of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe d'étude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.MethodsThe study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.ResultsIntrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.ConclusionThe present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.
Summary
objective To determine the interest of Chromogranin A (CgA) determination for diagnosis and follow‐up in patients with gastroenteropancreatic endocrine tumours (GEP‐ET) and multiple ...endocrine neoplasia type 1 (MEN‐1).
patients and methods CgA levels were measured with an immunoradiometric assay in 124 sporadic GEP‐ET, 34 MEN‐1 and 127 controls. Serial determinations were performed in 56 patients (212 visits). Changes in CgA levels over 25% were considered as significant.
results Using a cut‐off value of 130 µg/l, established from a receiver‐operating characteristic curve, the specificity of CgA was 98·4%, with a sensitivity of 62·9%, higher in secreting than in nonsecreting tumours (73%vs. 45%; P < 0·003) and related to the extent of metastatic spreading (P < 0·001). In nonsecreting tumours, the positive predictive value (PPV) of CgA for the presence of metastases was 100% but the negative predictive value (NPV) was only 50%. In MEN‐1, high CgA levels indicated a pancreatic tumour with a 100% specificity but the sensitivity was 59%. During the follow‐up, the concordance between CgA and tumour evolution was 80%, whatever the secretory status. In patients with carcinoid tumours, the concordance was higher for CgA than for serotonin (81%vs. 54%; P < 0·001).
conclusion Due to its high specificity, CgA determination may help to discriminate the endocrine character of a GEP tumour and to indicate a pancreatic tumour in MEN‐1. However, its low NPV in nonsecreting tumours limits its interest for diagnosis and staging. By contrast, serial evaluation of CgA seems of particular interest for the follow‐up of GEP‐ET tumours.
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