ZXC, JY, MXT and JW contributed to the conception and design this study. angiogenesis inhibitors showed significant improvements in PFS (HR 0.72, 95% CI 0.61-0.84, 0.0001), ORR (OR 1.51, 95% CI 1.17-1.97, P= 0.26). In addition, diarrhea, hypertension, thrombocytopenia, neutropenia, fatigue, rash, and dermatitis acneiform were WS-383 significantly increased in patients treated with angiogenesis inhibitors. Thus, EGFR-TKIs combined with angiogenesis inhibitors were superior to EGFR-TKIs alone in advanced NSCLC due to their effects on PFS, ORR and DCR, but the increased incidence of AEs had an influence on the tolerability of this combination therapy. = 0.0023), and the objective response rate (ORR) was 10.6% versus 6.9% (= 0.0471), respectively. In contrast, the study by Spigel D R13 showed that the OS, PFS, ORR, and DCR were not different in patients with refractory advanced NSCLC administered erlotinib with or without sorafenib. Thus, the overall efficacy and safety of this combination in NSCLC are still confused. In this study, we performed a meta-analysis to update and summarize the efficacy and safety of EGFR-TKIs combined with angiogenesis inhibitors versus EGFR-TKIs combined with placebo in patients with advanced NSCLC. Methods Search strategy An electronic search of the PubMed, PMC and EMBASE databases as well as the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO) databases was performed from inception to March 2019. The detailed search strategy is described in Fig. ?Fig.1.1. The search strategy included a combination of the MeSH term angiogenesis inhibitors or the keywords angiogenetic inhibitors, angiogenic antagonists, angiogenic inhibitors, angiostatic agents, antiangiogenetic agents, angiogenesis factor inhibitor; the MeSH term epidermal growth factor receptor tyrosine kinase inhibitors or the keywords epidermal growth factor receptor inhibitors; the MeSH term non-small-cell lung cancer or the keywords lung cancer. All potentially relevant studies were retrieved, and their references were checked for additional eligible studies. Open in a separate window Figure 1 Flow chart of search process. Definition of EGFR-TKIs and angiogenesis inhibitors We defined angiogenesis inhibitors as drugs which targeted vascular epidermal growth factor (VEGF) and its receptors, which are the key mediators of angiogenesis, and EGFR-TKIs as drugs directed against epidermal growth factor receptor tyrosine kinase. Inclusion criteria Studies which met the following criteria were included: (1) patients must be cytologically or pathologically confirmed as having NSCLC at a clinically WS-383 advanced stage; (2) randomized controlled trials (RCTs) comparing EGFR-TKIs plus angiogenesis inhibitors with EGFR-TKIs plus placebo were eligible; (3) one or more of the following were reported in the trials: overall response rate (ORR) (the sum of complete response [CR] and partial response [PR]), disease control rate (DCR) (the sum of CR, PR and stable disease [SD]), PFS and OS. Data extraction Two independent investigators extracted data from the included studies on the basis of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). When the two investigators disagreed, a third investigator participated in the discussion to resolve the disagreement. Information collected Rabbit Polyclonal to JHD3B from these trials included the first author, year of publication, number of patients, median age, therapeutic regimen, doses, and outcomes. Clinical data collected from the trials included median PFS and median OS, hazard ratios (HRs) for OS and PFS and their 95% confidence WS-383 intervals (CIs), DCR and ORR, odds ratios (ORs) for DCR and ORR, and their 95% CIs. The response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) and classified as a CR, PR, SD, or progressive disease (PD). ORR was defined as CR with PR and DCR was defined as ORR with SD. Quality assessment The risk of bias in WS-383 each study was assessed using the Cochrane Collaboration tool. The following evaluation domains were assessed accordingly: randomization sequence generation, allocation concealment, blinding of participants and study personnel, blinding of outcome assessors, incomplete outcome data, selective reporting, and other biases. The risk of each domain was rated as high risk, unclear risk, or low risk according to the match level between information.