Increased risk of hemorrhage in metastatic colorectal cancer patients treated with bevacizumab: An updated meta-analysis of 12 randomized controlled trials

BACKGROUND: As an important antivascular endothelial growth factor monoclonal antibody, bevacizumab has been administrated for the treatment of cancer patients. Hemorrhage, one of the common adverse events of angiogenesis inhibitors, sometimes is also fatal and life-threatening. We aimed at determining the incidence and risk of hemorrhage associated with bevacizumab in patients with metastatic colorectal cancer (mCRC). METHODS: We searched PubMed, EMBASE, and the Web of Science databases for relevant randomized controlled trials (RCTs). The overall incidence, overall relative risk (RR), and 95% confidence interval (CI) were calculated by using a random-effects or fixed-effects model based on the heterogeneity of selected trials. RESULTS: A total of 10,555 mCRC patients from 12 RCTs were included in our study. The overall incidence of hemorrhage was 5.8% (95% CI 3.9%–7.8%). Bevacizumab significantly increased the overall risk of hemorrhage with an RR of 1.96 (95% CI 1.27–3.02). The RR of all-grade hemorrhage was 2.39 (95% CI 1.09–5.24) and 1.41 (95% CI 1.01–1.97) for high-grade hemorrhage. The risk of hemorrhage associated with bevacizumab was dose-dependent with an RR of 1.73 (95% CI 1.15–2.61) for 2.5 mg/kg/wk and 4.67 (95% CI 2.36–9.23) for 5 mg/kg/wk. More importantly, the RR of hemorrhage for treatment duration (<= 6 months and > 6 months) based on subgroup analysis was 4.13 (95% CI 2.58–6.61) and 1.43 (95% CI 0.96–2.14), respectively. CONCLUSION: The addition of bevacizumab to concurrent antineoplastic in patients with mCRC significantly increased the risk of hemorrhage. The dose of bevacizumab may contribute to the risk of hemorrhage. And the 1st 6 months of treatment may be a crucial period when hemorrhagic events occur.