Evidence-base for chemotherapy in advanced well-differentiated gastrointestinal (GI) (non-pancreatic) neuroendocrine tumours (NETS): a systematic review and meta-analysis

Background: This systematic review evaluates the role of chemotherapy in the treatment of patients with advanced (inoperable) gastrointestinal well-differentiated non-pNETs. Methods: Eligible studies (identified using MEDLINE) included those which reported response and/or survival data for patients with well-differentiated GI NETs receiving chemotherapy. Primary end-point was overall response (OR)-rate. Secondary end-points were progression-free survival (PFS), overall survival (OS), disease stabilisation (DS) and disease control (DC)-rates. Chemotherapy response data in GI NET and pNET populations were compared in studies including both populations. Results: Searches identified 6,434 studies, of which 20 were eligible: 1 randomised phase III study, 2 randomised phase II studies, 10 single-arm phase II studies and 7 retrospective analyses. Data from 264 chemotherapy-treated patients (multiple combinations/schedules) were available; the median number of patients per study was 11 (range 6-49). The mean “median PFS” and “median OS” were 16.9 months (95%-confidence interval (CI) 3.8-30.04) and 32.2 months (95%-CI 10.4-54.2) respectively. The non-weighted mean OR-rate, DS-rate and DC-rate were 11.5% (95%-CI 5.8-17.2), 56.5% (95%-CI 38.1-74.9) and 70.7% (95%-CI 54.9-86.5), respectively. Meta-analysis showed lower OR-rate in the GI NET patients versus pNET patients [odds ratio 0.35 (95%-CI 0.18-0.66), however significance was lost when high-risk bias studies were excluded in a sensitivity analysis [odds ratio 0.45 (95%-CI 0.19-1.07); p-value 0.07]. Conclusion: Chemotherapy may have some activity in patients with non-pNETs; however, available studies were of poor quality (evidence level C), including heterogeneous populations/regimens and small patient numbers. Prospective studies are needed to define the role of chemotherapy in this setting.