title: Design and Validation of the GI-NEC Score to Prognosticate Overall Survival in Patients With High-Grade Gastrointestinal Neuroendocrine Carcinomas.
abstract: Prognostic markers for risk stratification of patients with gastrointestinal high-grade neuroendocrine carcinomas (GI-NECs) are lacking; we designed and validated a prognostic score for overall survival (OS).
  
  
  
  Consecutive patients diagnosed in five neuroendocrine specialist European centers were included. Patients were divided into three cohorts: a training cohort (TC), an external validation cohort (EVC), and a prospective validation cohort (PVC). Prognostic factors were identified by log-rank test, Cox-regression, and logistic regression analyses. The derived score was internally and externally validated. All statistical tests were two-sided.
  
  
  
  Of 395 patients screened, 313 were eligible (TC = 109 patients, EVC = 184 patients, and PVC = 20 patients). The derived prognostic score included five variables: presence of liver metastases, alkaline phosphatase (ALK), lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group performance status (ECOG PS), and Ki67. In multivariable analysis, the score was prognostic for OS (hazard ratio [HR] = 1.86, 95% confidence interval [CI] = 1.47 to 2.35, P < .001) and had good discrimination (C-index = 0.76) and calibration (mean error = 0.021, 90th percentile = 0.037) in the TC. These results were validated in the EVC and PVC, in which our score was able to prognosticate for OS when adjusted for other prognostic variables in the multivariable analysis (HR = 1.85, 95% CI = 1.27 to 2.71, P = .001; and HR = 4.51, 95% CI = 1.87 to 10.87, P = .001, respectively). The score classified patients into two groups with incremental risk of death: group A (0-2 points, 181 patients [63.9%], median OS = 19.4 months, 95% CI = 16.1 to 25.1) and group B (3-6 points, 102 patients [36.1%], median OS = 5.2 months, 95% CI = 3.6 to 6.9).
  
  
  
  The GI-NEC score identifies two distinct patient cohorts; it provides a tool for clinicians when making treatment decisions and may be used as a stratification factor in future clinical trials.
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Lamarca
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Walter
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Marianne
authors.initials: M
authors.lastname: Pavel
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Ivan
authors.initials: I
authors.lastname: Borbath
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Freis
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Nuñez
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Alexa
authors.initials: A
authors.lastname: Childs
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Mairéad G
authors.initials: MG
authors.lastname: McNamara
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hubner
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Rocio
authors.initials: R
authors.lastname: Garcia-Carbonero
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Juan W
authors.initials: JW
authors.lastname: Valle
authors.affiliation: Affiliations of authors: Department of Medical Oncology, The Christie NHS Foundation Trust (ENETS Centre of Excellence), Manchester, UK (AL, MGM, RAH, JWV, JB); Department of Medical Oncology, Hospices Civils de Lyon Edouard Herriot Hospital, University of Lyon, Lyon, France (TW, PF); Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany (MP); Department of Gastroenterology, Cliniques Universitaires Saint-Luc, Bruxelles, Belgium (IB); Department of Medical Oncology, Doce de Octubre University Hospital, Madrid, Spain (BN, RGC); Department of Medical Oncology, Royal Free London NHS Foundation Trust (ENETS Centre of Excellence), London, UK (AC, TM); Institute of Cancer Sciences (MGM, JWV) and Faculty of Biology, Medicine and Health (JB), University of Manchester, Manchester, UK.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barriuso
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000097:blood; D014408:Biomarkers, Tumor / Q000032:analysis; D018278:Carcinoma, Neuroendocrine / Q000737:chemistry / Q000556:secondary*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000737:chemistry / Q000473:pathology*; D006305:Health Status Indicators; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase