Risk of venous thromboembolic events associated with VEGFR‐TKIs: A systematic review and meta‐analysis

Abstract

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) have been widely used in advanced cancers. Concerns have arisen regarding the risk of venous thromboembolism with the use of these drugs. Currently, the contribution of VEGFR-TKIs to venous thromboembolism is still unknown. We performed a meta-analysis to determine the incidence and relative risk (RR) of venous thromboembolism events (VTEs) associated with these agents. Eligible studies included phase II and III prospective trials evaluating US Food and Drug Administration approved VEGFR-TKIs (pazopanib, sunitinib, sorafenib and vandetanib), and data on VTEs were available. Overall incidence rates, RR and 95% confidence intervals (CI) were calculated employing fixed-or random-effects models depending on the heterogeneity of included trials. A total of 14 studies (4,430 patients) were selected for this meta-analysis. The incidence of VTEs related to VEGFR-TKIs was 3% (95%CI: 1.7-5.1%), and there was no statistically significant increase in the risk of VTEs for VEGFR-TKIs versus controls in overall population (RR0.912, 95%CI: 0.617-1.348, p 5 0.643). On subgroup analysis, no significant increase in the risk of VTEs was found among different VEGFR-TKIs or tumor types. No evidence of publication bias was observed. The use of VEGFRTKIs does not significantly increase the risk of VTEs, the risk of VTEs in patients with cancer is driven predominantly by tumor types, host factors and concomitant usage of anticancer agents. These results would provide important information for clinicians who use VEGFR-TKIs to treat patients with solid cancer.

Anti-angiogenic-specific adverse events in patients with non-small cell lung cancer treated with nintedanib and docetaxel

“…Meta-analyses have shown that the incidence of hypertension (all grades) in patients receiving bevacizumab was 24%, with 8% of events being Grades 3-4; rates significantly higher compared to controls [22]. Other angiogenesis inhibitors are also associated with hypertension and meta-analyses have found similarly high rates of hypertension in patients treated with sorafenib (all grades, 19%; Grades ≥3, 4%) [23], sunitinib (all grades, 22%; Grades 3-4, 7%) [24], vandetanib (all grades, 24%; Grades 3-4, 6%) [25], pazopanib (all grades, 36%; Grades 3-4, 7%) [26], and axitinib (all grades, 40%; Grades 3-4, 13%) [27]. Treatment-related hypertension appears to be dose-dependent with some anti-angiogenic agents, e.g., sunitinib and axitinib [28,29], and a direct relationship between total drug dose and blood pressure has been reported for some agents (e.g., sunitinib) [28].…”

Efficacy and Toxicity of Anti-VEGF Agents in Patients with Castration-Resistant Prostate Cancer: a Meta-analysis of Prospective Clinical Studies

“…Anti-VEGF agents are known to be associated with a number of severe toxicities (grade 3-4), including hematologic toxicities (Schutz et al, 2011a;Schutz et al, 2011b;Funakoshi et al, 2013), hand foot skin reaction (Balagula et al, 2011;Belum et al, 2013;Chu et al, 2009;Fischer et al, 2013), diarrhea (Santoni et al, 2013), rash (Jia et al, 2009) DOI:http://dx.doi.org/10.7314/APJCP.2014.15.19.8177 Anti-VEGF Agents in Castration-resistant Prostate Cancer Cases thrombosis (Scappaticci et al, 2007;Nalluri et al, 2008;Choueiri et al, 2010;Qi et al, 2013c;) and hypertension (Qi et al, 2013a;Qi et al, 2013b;Qi et al, 2013d;Qi et al, 2014). Our results show that the most frequent severe toxicities associated with anti-VEGF agents are fatigue (8.2%) and hand-foot syndrome 5.2%, with hematologic toxicities, diarrhea, nausea, and rash being rare (≤5%).…”

Risk of gastrointestinal perforation in cancer patients treated with aflibercept: a systematic review and meta-analysis

“…In retrospective studies of patients with colorectal cancer, GI perforations are related to either tumor necrosis; gastric ulcer, diverticulitis, obstruction, or chemotherapy-associated colitis [31][32][33]. And angiogenesis inhibitors might also induce arterial thromboembolic events, including cholesterol emboli syndrome leading to regional ischemic bowel and hence to perforation [34][35][36]. In normal adult mice, inhibition of VEGF signaling causes regression of 34-46 % of capillaries of intestinal villi [37].…”