Safety of combining vascular endothelial growth factor receptor tyrosine-kinase inhibitors with chemotherapy in patients with advanced non–small-cell lung cancer: A PRISMA-compliant meta-analysis

BACKGROUND: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) have been developed for targeted therapies in non–small-cell lung cancer (NSCLC); moreover, some drug-related toxic reactions among cancer patients have been reported. A meta-analysis of randomized controlled trials (RCTs) to definite the incidence and the risk of grade ≥3 adverse events (AEs), serious and fatal AEs (SAEs and FAEs), with VEGFR-TKIs in advanced/metastatic NSCLC patients was performed. METHODS: A comprehensive literature search was conducted for the clinical trials published up to December 2017. Qualified studies allotted patients with advanced/metastatic NSCLC to receive either chemotherapy alone or in combination with VEGFR-TKIs. Data were extracted by 2 authors. RESULTS: Eighteen RCTs of VEGFR-TKIs plus chemotherapy, involving 8461 advanced NSCLC patients were included. The proportion of patients with grade ≥3 AEs was increased with the addition of VEGFR-TKIs (relative risk, 1.35; 95% confidence interval [CI] 1.19–1.52; incidence, 68.1% vs 50.1%; P < .001). The most common grade ≥3 AEs was neutropenia (24.9% vs 15.4%, P < .001). Addition of VEGFR-TKIs was also related to the increased risk of SAEs (relative risk, 1.34; 95% CI 1.14–1.56; incidence, 37.8% vs 27.9%; P < .001) and FAEs (relative risk, 2.16, 95% CI 1.47–3.19; incidence, 3.4% vs 1.8%). Subgroup analysis suggested there was no difference in the rates of SAEs and FAEs in the second-line settings. No evidence of bias was found between the literatures. The study was registered with PROSPERO (CRD42018099654). CONCLUSIONS: In comparison with chemotherapy alone, the addition of VEGFR-TKIs in advanced NSCLC patients was related to the increased risk of grades ≥3 AEs, SAEs, and FAEs, especially in the first-line settings. Physicians should be aware of some specific grade ≥3 adverse effect, especially haematologic adverse events, and it is also necessary to monitor cancer patients receiving VEGFR-TKIs.