Risk of venous and arterial thromboembolic events associated with anti-VEGF agents in advanced non-small-cell lung cancer: a meta-analysis and systematic review
OncoTargets and Therapy
r isk of venous and arterial thromboembolic events associated with anti-VegF agents in advanced non-small-cell lung cancer : a meta-analysis and systematic review
Dianbao Zhang 1
Xianfen Zhang 0
0 Department of cardiac surgery, The First a ffiliated h ospital of h enan University of science and Technology , luoyang, henan Province, People's republic of china
1 Department of Medical Oncology
PowerdbyTCPDF(ww.tcpdf.org) chunling Zhao 1 Aims: To assess the incidence and risk of arterial and venous thromboembolic events (ATEs and VTEs) associated with antivascular endothelial growth factor (VEGF) agents, including VEGF receptor-tyrosine kinase inhibitors and VEGF monoclonal antibodies, in advanced nonsmall-cell lung cancer (NSCLC) patients. Methods: We performed a broad search of PubMed for relevant trials. Prospective randomized trials evaluating therapy with or without anti-VEGF agents in patients with advanced NSCLC were included for analysis. Data on VTEs and ATEs were extracted. The overall incidence, Peto odds ratio (Peto OR), and 95% confidence intervals (CIs) were pooled according to the heterogeneity of included trials. Results: A total of 13,436 patients from 23 trials were included for analysis. Our results showed that anti-VEGF agents significantly increased the risk of developing high-grade ATEs (Peto OR: 1.44, 95% CI: 1.00-2.07, P=0.048), but not for all-grade ATEs (Peto OR: 0.94, 95% CI: 0.56-1.59, P=0.82) compared with controls. Additionally, no increased risk of all-grade and high-grade VTEs (Peto OR: 0.94, 95% CI: 0.67-1.31, P=0.71 and Peto OR: 0.95, 95% CI: 0.73-1.22, P=0.67, respectively) was observed in advanced NSCLC patients receiving anti-VEGF agents. Conclusion: The use of anti-VEGF agents in advanced NSCLC patients significantly increased the risk of high-grade ATEs, but not for VTEs. Clinicians should be aware of the risk of severe ATEs with administration of these drugs in advanced NSCLC patients. Angiogenesis, the formation of new blood vessels, is critical for tumor progression, invasion, and metastasis in many solid tumors.1-3 Basic research shows that this process is mainly driven by vascular endothelial growth factor (VEGF), and thus angiogenesis inhibitors targeting the VEGF signal pathway are a potential treatment options for solid tumors.4,5 In the past two decades, many novel anti-VEGF agents, including VEGF monoclonal antibodies and multitarget VEGF receptor (VEGFR)-tyrosine kinase inhibitors (TKIs)/monoclonal antibodies, have been proven to improve survival benefits in many solid tumors including non-small-cell lung cancer (NSCLC). Until now, three anti-VEGF agents, including bevacizumab, ramucirumab, and nintedanib,
anti-VEGF agents; toxicity; arterial thromboembolic events; venous thromboembolic
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open access to scientific and medical research
O r i g i n a l r e s e a r c h
*These authors contributed equally
to this work
Introduction
have been approved by the US Food and Drug Administration (FDA) for the treatment
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of advanced NSCLC,6–9 and it is anticipated that the use of
these agents in cancer patients would be increased in the
near future.
However, the VEGF signal pathway plays a critical role in
physiological functions and homeostasis in the cardiovascular
and renal systems. Previous research has found that VEGF is
of great importance to regulate angiogenesis and the vascular
tone.10 Other vascular proteins, such as tissue factor (TF) and
endothelial nitric oxide synthase, have also been involved
in controlling endothelial thrombogenicity and regulation of
vascular tone. While TF and its distinct isoforms can induce
the expression of VEGF, and interact with VEGF and its
pro-/antiangiogenic isoforms could in turn leads to
modifications of essential biological processes.11 Thus, inhibition
of angiogenesis pathway could cause a variety of adverse
effects.12 Indeed, a variety of toxicities associated with
anti-VEGF signal pathway including hypertension,13–17
proteinuria or renal dysfunction,18–21 congestive heart
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/ww lan several meta-analyses have been conducted to assess the risk
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tsp rse of arterial and venous thromboembolic events (VTEs and
trhom rpoF ATEs) associated with anti-VEGF agents, all these studies
fd include different tumor types.31–38 It has been reported that
eda some tumor-dependent intrinsic mechanisms have been
lonw related to VTEs or ATEs, and patient baseline characteristics
yod differ between tumor types. Additionally, time to treatment
rpae failure and follow-up duration vary according to tumor
hT types, and these factors are closely related to the likelihood
dan of developing and detecting VTEs and ATEs. As a result, the
trsge risk of VTEs and ATEs associated with anti-VEGF agents
aoT in advanced NSCLC remains unknown. W (...truncated)