Prognostic factors for disease relapse in patients with neuroendocrine tumours who underwent curative surgery

Introduction: Relapse occurs frequently in patients with neuroendocrine tumours(NETs) treated by surgery with curative intent. Limited information is available aboutprognostic factors for relapse. The aim of this study was to identify prognostic factors associated with disease relapse following resection of NET.Methods: All patients presenting to The Christie NHS Foundation Trust, Manchester, UK, with well-differentiated grade (G) 1 or G2 NETs who had undergone curative surgery between February 2002 and June 2014 were included. Relapse-free survival (RFS) was estimated using the Kaplan-Meier method, and prognostic factors using univariate and multivariable Cox regression analyses. Prognostic factors included in the analyses were: age, gender, stage, tumour localisation, functionality, genetic predisposition, presence of multiple NETs, other active malignancy, grade (Ki-67-based), presence of vascular and/or perineural invasion, necrosis, surgical margin (R0/R1), ECOG performance status and ACE co-morbidity score.Results: One hundred and eighty-eight patients were identified with a median age of60 years (range 16-89). Median follow-up for all patients was 2.6 years and 93% had an ECOG performance status of 0/1.Ninety one patients were male (48%) and the most frequent primary site was the small bowel (n = 61; 32%), followed by pancreas (n = 54; 29%), appendix (n = 30; 16%), bronchopulmonary (n = 17; 9%), colon/caecum/rectum (n = 13; 7%) and others (n = 13; 7%). The most frequent recorded T-stage was T3 (n = 60; 32%). In 96 cases (51%) there was nodal involvement present and in 11 cases (6%) there were potentially-resectable distant metastases. Production of functional hormones pre-surgery was documented in 18 patients (10%). Ten patients (5%) had genetic predisposition and 33 (18%) had second malignancies. Grade 1 NET was identified in 137 cases (73%), G2 in 51 (27%). Vascular invasion was reported in 75 patients (40%) and/or perineural invasion in 50 patients (27%). Tumour necrosis was present in 10 patients (5.3%). Surgical margin was R0 in 155 patients (82%). A total of 43 relapses occurred. Estimated median relapse-free survival (RFS) for the entire cohort was 8.0 years (95% confidence interval [CI] 5.9-10.0 years). In univariate analysis, primary NET location (p = 0.01), ENETS T- (HR 1.4; 95% CI 1.0-2.0, p = 0.026), N- (HR 2.0, 95% CI 1.1-3.9, p = 0.026) and M-stage (HR 2.6, 95% CI 1.1-6.3, p = 0.052), grade (Ki-67%-based) (HR 2.5; 95% CI 1.4-4.7; p = 0.003) and perineural invasion (HR 2.1; 95% CI 1.1-3.9; p = 0.029) were prognostic factors for relapse. Factors remaining significant after multivariable analysis were tumour size (HR 1.67; 95% CI 1.04-2.70; p = 0.03), presence of nodal involvement (HR 2.61; 95% CI 1.17-5.83; p = 0.013) and Ki-67 level measured at the time of diagnosis (HR 1.93; 95% CI 1.24-3.0; p = 0.002).Conclusion: Size of tumour, lymph node involvement and Ki-67% were independentprognostic factors for relapse after potentially curative surgery in NET. Theinformation gleaned from this study should enable informed proposals for adjuvantclinical trials in NET patients who have had definitive surgery.