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, Jun 2016

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 Dianbao Zhang,1,* Xianfen Zhang,2,* Chunling Zhao1 1Department of Medical Oncology, 2Department of Cardiac Surgery, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan Province, People’s Republic of China *These authors contributed equally to this work 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 non-small-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. Keywords: anti-VEGF agents, toxicity, arterial thromboembolic events, venous thromboembolic events, meta-analysis

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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 - 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 8 1 0 2 l u J 2 1 n o 8 4 . 6 9 . 7 3 1 . 9 7 y b / m o c . s s re . 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 .vdoep lsyeon tfiaoinlu28r–e3,022h–2a5vehebmeeonrrhreapgoer,t2e6,d27 iannpdregvaisoturosinsttuedstiiensa.lAplethrfoourgahw u /ww lan several meta-analyses have been conducted to assess the risk /: o 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)


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Dianbao Zhang, Xianfen Zhang, Chunling Zhao. 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, 2016, pp. 3695-3704, DOI: 10.2147/OTT.S103735