Plasmatic and Urinary 5-Hydroxyindolacetic Acid Measurements in Patients With Midgut Neuroendocrine Tumors: A GTE Study.

CONTEXT: Although 24-hour urinary 5-hydroxyindolacetic acid (24u5HIAA) is a key biomarker in midgut neuroendocrine tumors (NETs), it may be inaccurate and inconvenient. OBJECTIVE: We compared the diagnostic performances of 24u5HIAA, overnight urinary 5HIAA (Ou5HIAA), and plasmatic 5HIAA (p5HIAA) in midgut NETs. METHODS: This prospective, multicenter study included 80 patients with metastatic midgut NETs and 17 control patients with irritable bowel syndrome. 24u5HIAA, Ou5HIAA, and p5HIAA were measured in urine and plasma collected on 2 consecutive days following a specific recommended diet. Reproducibility of the biomarkers was evaluated by the Spearman test. Diagnostic performance was assessed by the area under the receiver operating characteristic curve (AUROC). Correlations with the main clinical features and declared observance to the specific diet were assessed using AUROC and logistic regression models. RESULTS: The reproducibility of 24u5HIAA, Ou5HIAA, and p5HIAA were excellent (ρ = 0.916; 0.897; 0.978, respectively, P < .001) with significant discrimination between patients and controls (AUROC = 0.795, P < .001; 0.757, P = .001; 0.717, P = .005, respectively). All 3 markers were correlated with the presence of carcinoid syndrome (AUROC = 0.702, P = .006; 0.701, P = .006; 0.697, P = .007, respectively), carcinoid heart disease (AUROC = 0.896; 0.887; 0.923, P < .001, respectively, P < .001), and liver metastatic involvement greater than 30% (AUROC = 0.827; 0.807; 0.849, P < .001, respectively, P < .001), independent from other traditional prognostic factors. Biomarker levels were similar between patients with optimal or suboptimal diet observance. CONCLUSION: Ou5HIAA and p5HIAA could be used as more convenient alternatives to 24u5HIAA in patients with metastatic midgut NETs. Prospective long-term studies with repeated dosages are needed.

Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial)--a phase II non-randomised trial.

AIM OF THE STUDY: Gastro-intestinal neuroendocrine tumours (GI-NETs) are chemotherapy-resistant tumours. Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), has shown promising results in several phase II trials of gastro-entero-pancreatic-NETs. We assessed bevacizumab combined with capecitabine, specifically in GI-NET patients. PATIENTS AND METHODS: BEvacizumab in The Treament of neuroEndocrine tumoRs (BETTER) was a multicentre, open-label, non-randomised, two-group phase II trial. Here we present the group of patients with progressive, metastatic, well-differentiated GI-NETs. Patients Eastern Cooperative Oncology Group-performance status (ECOG-PS)⩽2, Ki-67 proliferation rate <15% and no prior systemic chemotherapy were treated with bevacizumab (7.5 mg/kg/q3w) and capecitabine (1000 mg/m2 twice daily, orally d1-14, resumed on d22) for 6-24 months. The primary end-point was progression-free survival (PFS); secondary end-points included overall survival (OS), response rate, safety and quality of life. RESULTS: Of the 49 patients included, 53% were men, median age was 60 years (41-82), primary tumour site was ileal in 82% patients and Ki-67 was <15% in 48 patients and not available for one patient. After a maximum of 24 month follow-up per patient, the median PFS by investigator assessment was 23.4 months [95% confidence interval (CI): 13.2; not reached] and the overall disease control rate was 88% (18% partial response, 70% stable disease). The 2-year survival rate was 85%. Median OS was not reached. The most frequent grade 3-4 adverse events were hypertension (31%), diarrhoea (14%) and hand-foot syndrome (10%). CONCLUSION: The combination of bevacizumab and capecitabine showed clinical activity and a manageable safety profile in the treatment of GI-NETs that warrant confirmation in a randomised phase III trial.

Relapse factors for ileal neuroendocrine tumours after curative surgery: a retrospective French multicentre study.

AIM: To evaluate the characteristics of postoperative relapse, predictive factors and time to relapse after curative surgery for well-differentiated neuroendocrine tumours of the ileum, without hepatic or other distant metastases. METHODS: Clinical data of patients entered into the Groupe d'étude des Tumeurs Endocrines database were collected and analysed retrospectively to identify factors predictive of relapse. RESULTS: Among 100 patients followed for a median of 56.5 (range 1-290) months, 42 relapsed after a median follow-up of 57.5 (range 6-176) months, with liver lesions in 27 (64.3%). Median disease-free survival (Kaplan-Meier) was 88 months (95% confidence interval 72-115). Disease-free survival was shorter for emergency surgery patients (p<0.01), patients with distant mesenteric lymph-node metastases (p<0.01), with fortuitous diagnosis (p=0.02), with tumour diameter >20mm (p=0.02), and those with multiple tumours (p=0.07). Multivariate analysis retained emergency surgery (odds-ratio 4.04 [95% confidence interval 2.01-8.11]), distant mesenteric lymph-node metastases (odds-ratio 2.53 [95% confidence interval 1.22-5.25]), and multiple tumours (odds-ratio 2.14 [95% confidence interval 1.01-4.50]), as being significantly associated with relapse. CONCLUSION: Patients who underwent emergency surgery, with distant mesenteric lymph-node metastases or with multiple ileal tumours relapsed earlier. Closer monitoring for the patients with these risk factors may be required.