Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials

Abstract

AimBevacizumab and ramucirumab are antiangiogenic monoclonal antibodies, which target vascular endothelial growth factor-A and vascular endothelial growth factor receptor-2, respectively, used in various cancers. Bleeding events have been described with these two agents. We conducted an up-to-date meta-analysis to determine the relative risk (RR) associated with the use of antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab.MethodsThis meta-analysis of randomized controlled trials was performed after searching PubMed, American Society for Clinical Oncology Abstracts, European Society for Medical Oncology Abstracts, and the proceedings of major conferences for relevant clinical trials. RR and 95% CIs were calculated by random-effects or fixed-effects models for all-grade and high-grade bleeding events related to the angiogenesis inhibitors.ResultsEighty-five randomized controlled trials were selected for the meta-analysis, covering 46,630 patients. The results showed that antiangiogenic monoclonal antibodies significantly increased the risk of all-grade (RR: 2.38, 95% CI: 2.09–2.71, p<0.00001) and high-grade (RR: 1.71, 95% CI: 1.48–1.97, p<0.00001) bleeding compared with control arms. In the subgroup analysis, bevacizumab significantly increased the risk of all-grade (RR: 2.73, 95% CI: 2.24–3.33, p<0.00001) and high-grade bleeding (RR: 1.98, 95% CI: 1.68–2.34, p<0.00001), but ramucirumab only increased the risk of all-grade bleeding (RR: 1.94, 95% CI: 1.76–2.13, p<0.00001) and no difference was observed for the risk of high-grade bleeding (RR: 1.04, 95% CI: 0.78–1.39, p=0.79) compared with the control group. For lung cancer patients, bevacizumab significantly increased the risk of all-grade (RR: 4.72, 95% CI: 1.99–11.19, p=0.0004) and high-grade pulmonary hemorrhage (RR: 3.97, 95% CI: 1.70–9.29, p=0.001), but no significant differences in the risk of all-grade (RR: 1.09, 95% CI: 0.76–1.57, p=0.64) and high-grade (RR: 1.22, 95% CI: 0.35–4.21, p=0.75) pulmonary hemorrhage were observed for ramucirumab. The increased risk of all-grade and high-grade bleeding was also observed in colorectal cancer or non-colorectal tumors and low-dose or high-dose angiogenesis inhibitors.ConclusionAntiangiogenic monoclonal antibodies are associated with a significant increase in the risk of all-grade and high-grade bleeding. Ramucirumab may be different from bevacizumab in terms of the risk of high-grade bleeding and the risk of all-grade and high-grade pulmonary hemorrhage in lung cancer patients.

<p>Efficacy and Safety of Apatinib Treatment for Patients with Advanced Intrahepatic Cholangiocarcinoma</p>

“…Compared with other angiogenesis inhibitors, the side effects of apatinib are similar or less. 13 , 17 , 18 Therefore, apatinib could be considered a safe and promising alternative therapy for patients with cancer after multiline treatments.…”

The roles and mechanisms of hypoxia in liver fibrosis

“…In addition, Feng found bevacizumab could down-regulate the expression of α-SMA and TGF-β1, block the effect of VEGF on HSCs to reduce liver fibrosis and protect liver function [ 96 ]. It should be noted that bevacizumab treatment could raise bleeding risk and that adequate bleeding prophylaxis needs to be given [ 97 ].…”

Intratumoral pseudoaneurysm within a liver metastasis of gastric cancer: a case report

“…RAM is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) receptor-2, preventing its activation. Bleeding is a major adverse event reported in some clinical trials caused by angiogenesis inhibitors disrupting the tumor vasculature by inhibiting VEGF signaling, leading to thrombosis or bleeding [24,25]. RAM may inhibit endothelial growth, thus resulting in a vessel wall breach and pseudoaneurysm formation.…”