A systematic review and meta-analysis of gastrointestinal events associated with nonoperative therapies for neuroendocrine tumors

The risk of gastrointestinal (GI) events induced by nonoperative therapies in patients with neuroendocrine tumors (NETs) is unclear. Nonoperative therapies include somatostatin analogs, molecular targeted agents, cytotoxic chemotherapy, interferon-α, and peptide receptor radionuclide therapy. We undertook an up-to-date meta-analysis to determine the incidence and relative risks (RRs) of GI events in NET patients treated with these therapies. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched to identify relevant trials. Eligible trials were selected according to the PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random- and fixed-effects models. We included 2,890 patients from 17 randomized controlled trials in this meta-analysis. The experimental treatments led to increased incidence and risks of GI events compared to the control treatments (P<0.05). Diarrhea was the most common GI event. The experimental treatments were associated with increased risks of high-grade nausea (RR 2.36; 95% CI 1.05–5.25; P<0.01) and vomiting (RR 1.89; 95% CI 1.04–3.44; P<0.05). In regard to specific therapy regimens, everolimus led to increased risks of diarrhea (RR 2.97; 95% CI 1.83–4.83; P<0.05), vomiting (RR 2.19; 95% CI 1.38–3.48; P<0.05), and anorexia (RR 3.20; 95% CI 1.69–6.06; P<0.05), whereas VEGFR inhibitors led to increased risk of diarrhea (RR 2.12; 95% CI 1.39–3.25; P<0.05). Additionally, GI NETs led to higher risk of GI events than pancreatic NETs. Thus, nonoperative therapies are associated with increased risks of GI events in NET patients, and rigorous management is warranted to minimize the adverse impact on treatment outcomes and to improve quality of life.