Original ResearchThe European Neuroendocrine Tumour Society registry, a tool to assess the prognosis of neuroendocrine neoplasms
Introduction
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours increasing incidence and concern [1]. Their widespread anatomic location and specific endocrinological clinical features require the close collaboration of many different specialists for adequate diagnosis and clinical management. Although traditionally considered rare indolent tumours, their biological behaviour varies widely depending on primary tumour site, histological differentiation and proliferation rate, the ability to secrete different peptides/amines and extent of disease. Although the majority are well-differentiated, a subset is poorly-differentiated [2].
Given the low incidence and relatively better prognosis of NENs than their exocrine counterparts, their epidemiology is best studied in large registries with long-term follow-up. To date, the largest source of population-based epidemiological information on NENs is the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program, which covers approximately 30% of the US population and involves 64,971 cases of NENs. A recent analysis published in 2017 [1] showed a 6.4-fold increase in age-adjusted NEN incidence from 1973 (1.09/100,000) to 2012 (6.98/100,000) across all sites, stages and grades. Overall survival (OS) of all NENs has significantly improved between 2000–2004 and 2009–2012 (hazard ratio [HR], 0.79), including patients with metastatic gastroentero-pancreatic NENs. This improved prognosis may be partial due to increased access to better diagnostic tools, leading to earlier detection and stage migration and more effective administered therapy.
In Europe, the largest published database included 20,994 NENs, diagnosed from 1978 to 2002, provided by the project ‘Surveillance of rare cancers in Europe (RARECARE)’, which included 76 population-based cancer registries from 18 countries, 9 of which covering the entire national population [3]. The overall incidence rate for NENs was 2.5/100,000 inhabitants per year; 5-year OS was 50% for well-differentiated NETs and 12% for poorly-differentiated neuroendocrine carcinomas. Survival by primary tumour site was consistent with previously published data, although relevant prognostic factors such as tumour stage, grade or proliferative index were lacking, reflecting suboptimal pathological assessment per current standards. In addition, as more precise diagnostic procedures and effective treatments have evolved since 2002, these figures likely do not properly reflect the current status of NENs in Europe.
The European Neuroendocrine Tumour Society (ENETS) was founded in 2004 to improve the care, research and medical education in NENs [4]. ENETS is a multidisciplinary scientific society that encompasses a wide variety of NEN experts [5]. In this context, the ENETS Registry was created in 2007 to collect information regarding NEN outcomes and prognostic indicators in Europe. This is an institution-based registry, including ENETS Centres of Excellence and several NEN national networks, and aims to provide information on current standards of pathological classification and staging, diagnostic procedures, therapeutic strategies and patients’ outcomes.
Here we present the first analysis of the registry, comprising 10,102 patients with lung and gastroentero-pancreatic–NENs from 7 countries, consisting of the largest European study to date reporting the survival of NENs stratified by major prognostic factors. It provides some insights regarding regional disparities and may help understand differences in epidemiology, clinical presentation and survival of NENs across different European countries.
The ENETS registry collects patient data from several European countries since 07/2015 according to national and institutional data protection rules and ethical requirements. The Oracle database was programmed, hosted and maintained by the company Lohmann&Birkner (Berlin, Germany). Data were provided to the database either by direct pseudonymised data entry (Greece) or pseudonymised (Belgium, Czech Republic, Poland) or anonymised (Germany, Spain, Switzerland) data transfer. Quality data have been priorly provided to the scientific community by several national registries [[6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]].
A thorough data checking and cleaning process of the initial data set (12,327 patients) was performed to identify the missing or inconsistent variables. A series of logic tests as well as monovariate and bivariate analysis were performed, and inconsistent data were set to missing; data imputation was not applied. Data elimination was performed for cases with missing outcome variables (any of the time or event variables); extensive bias analysis was carried out, which did not reveal any significant distortion in the remaining data caused by excluded cases. The final data set included 10,102 patients.
Cancers of unknown primary (CuP, n = 1244) were excluded from bivariate and multivariate analysis because of significant inconsistencies in the definition of this entity and differences in diagnostic procedures between recruiting institutions.
As descriptive statistics mean, median and standard deviation were used for continuous variables and simple proportions were used in bivariate analysis. At initial data assessment, bias analysis was performed, and in preparation for the multivariate analysis, the appropriate statistical tests (including t-test, F-Test and Chi-square tests) were applied.
Kaplan–Meier statistics were applied to estimate survival function and rates, with t being time from diagnosis to either death due to any cause or last contact. To compare two survival functions either log-rank or Tarone–Ware tests were used.
To assess the impact of different risk factors on OS, a multivariate Cox regression model was built using step-forward method finally including age, gender, WHO-grade (per Ki-67 proliferation rate), tumour stage (by ENETS or UICC depending on national specifications) and primary tumour site.
All statistical analyses were performed in IBM SPSS Statistics v.23 (Chicago, Ill., USA). Statistical significance was assumed for p-values <0.05.
Section snippets
Study population
The main characteristics of our study population (10,102 patients) are summarised in Table 1. The median age at diagnosis was 60 years (range: 10–102), 48% were female, and most common primary tumour sites were pancreas (n = 2722, 27%) and small intestine (Si) (n = 2132, 21%). Carcinoid syndrome was the most commonly reported functional syndrome (2184/2716, 80%).
Clinical stage
Overall, 47% of patients had metastases at diagnosis, 49% Pan-NEN and 59% Si-NEN (Fig. 1). Among less common NENs, the tumour sites
Discussion
This is the first European comprehensive analysis from a disease-specific registry of NEN, presenting data from 7 countries. To our knowledge, this is the largest comprehensive European NEN patient data set with detailed information on grade, stage and treatment. It provides relevant information on survival stratified by major prognostic factors. Overall 5-and 10-year survival of the whole cohort was 74.5 and 61%, respectively.
Pancreatic (27%) and Si (21%) NEN were the most common primary
Conclusion
We report for the first time results of a large European NEN database, the ENETS registry, and provide relevant data to improve the prognostic stratification of patients with NEN that shall help in clinical decisions, adequate patient selection and stratification for clinical trials. Further analyses on an increasing number of patients are planned, including broader coverage of European nations, and more in-depth subanalysis of specific patient populations.
Author contributions
IB has been involved in conceptualisation, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, visualisation, writing the original draft, review & editing.
RGC has been involved in investigation, resources, data curation, formal analysis, validation, visualisation, writing the original draft, review & editing.
DB has been involved in data curation, Formal analysis, Methodology, Software, writing the original
Role of the funder
The work was supported by unrestricted grants from Ipsen, Novartis and Pfizer, specifically dedicated to the design, building, implementation and use of the ENETS registry, in good collaboration with the company Lohmann&Birkner. Authors received no personal funding.
Conflict of interest statement
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article.
Acknowledgements
The authors wish to acknowledge all the physicians that participated in the collection and quality of the data; Ursula Plöckinger and Cheryl Berg, respectively, initiator and first data manager of the registry; members of the Registry working group (Barbro Eriksson, Eric Baudin, Pierre Goudet, Eric Van Cutsem); the ENETS executive committees and their successive chairs (Bertram Wiedenmann, Guido Rindi, Kjell Öberg, Wouter De Herder, Philippe Ruszniewski, Martyn Caplin, Massimo Falconi, Dermot
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