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Background and objective Vandetanib is a small molecule inhibitor against vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). The aim of this study is to evaluate the efficacy and safety of vandetanib as a second-line treatment for advanced non-small cell lung cancer (NSCLC). Methods We selected randomized controlled trials (RCTs) on vandetanib for NSCLC from PubMed, Medline, Embase, VIP and CNKI. Meta-analysis was completed using software Review Manager 5.0. Results Compared with the control group (single other targeted therapy or chemotherapy group), there were statistical differences in progression free survival (PFS) (OR=1.23, 95%CI: 1.05-1.45), partial response (PR) (OR=2.15, 95%CI: 1.59-2.93), disease control (DC) (OR=1.22, 95%CI: 1.06-1.40), diarrhea (OR=1.59, 95%CI: 1.38-1.83), nausea (OR=0.69, 95%CI: 0.57-0.83), rash (OR=2.07, 95%CI: 1.71- 2.49), constipation (OR=0.81, 95%CI: 0.67-0.97), and vomiting (OR=0.72, 95%CI: 0.60-0.87) in the vandetanib group, but there were no differences in overall survival (OS), stable disease (SD), fatigue, cough, anorexia and dyspnea. Conclusion Vandetanib might have more superior efficacy as a second-line treatment for NSCLC, but its advantages in terms of safety were not demonstrated.