Abstract
Arterial ischemia and hemorrhage are associated with bevacizumab, an inhibitor of vascular endothelial growth factor that is widely used to treat many types of cancers. As specific types of arterial ischemia and hemorrhage, cerebrovascular events such as central nervous system (CNS) ischemic events and CNS hemorrhage are serious adverse events. However, increased cerebrovascular events have not been uniformly reported by previous studies. New randomized controlled trials (RCTs) have been reported in recent years and we therefore conducted an up-to-date meta-analysis of RCTs to fully characterize the risk of cerebrovascular events with bevacizumab. We searched the databases of PubMed, Web of Science, and the American Society of Clinical Oncology conferences to identify relevant clinical trials up to February 2014. Eligible studies included prospective RCTs that directly compared patients with cancer treated with and without bevacizumab. A total of 12,917 patients from 17 RCTs were included in our analysis. Patients treated with bevacizumab had a significantly increased risk of cerebrovascular events compared with patients treated with control medication, with a relative risk of 3.28 (95% CI, 1.97–5.48). The risks of CNS ischemic events and CNS hemorrhage were increased compared with control, with RRs of 3.22 (95% CI, 1.71–6.07) and 3.09 (95% CI, 1.36–6.99), respectively. Risk varied with the bevacizumab dose, with RRs of 3.97 (95% CI, 2.15–7.36) and 1.96 (95% CI, 0.76–5.06) at 5 and 2.5 mg/kg/week, respectively. Higher risks were observed in patients with metastatic colorectal cancer (RR, 6.42; 95% CI, 1.76–35.57), and no significant risk was observed in other types of tumors. In conclusion, the addition of bevacizumab significantly increased the risk of cerebrovascular events compared with controls, including CNS ischemic events and CNS hemorrhage. The risk may vary with bevacizumab dose and tumor type.
Highlights
The overexpression of vascular endothelial growth factor (VEGF) has been observed in several tumor types and is associated with a poorer patient prognosis [1]
Bevacizumab has been approved by the US Food and Drug Administration for the treatment of metastatic colorectal cancer, advanced non-squamous non-small-cell lung cancer (NSCLC), glioblastoma and metastatic renal cell carcinoma
Most previous studies have focused on the development of arterial thromboembolic events, such as pulmonary embolism and myocardial infarction [31], following bevacizumab treatment
Summary
The overexpression of vascular endothelial growth factor (VEGF) has been observed in several tumor types and is associated with a poorer patient prognosis [1]. Bevacizumab has been shown to increase the risk of arterial ischemia and serious hemorrhage [2,3,4]. There is no evidence supporting an association with increased CNS ischemic events or CNS hemorrhage, the specific types of arterial ischemia and hemorrhage. In 2010, Hapani et al reported that the risk of CNS hemorrhage with bevacizumab appeared to be low [3]. Carden et al concluded that no trial reported evidence supporting an increased risk of intracranial bleeding during anti-VEGF therapy, even in the presence of CNS metastases [6]. It is imperative to find out whether such cerebrovascular disorders develop as a result of bevacizumab treatment
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