Risk of Arterial Thromboembolic Events With Sunitinib and Sorafenib: A Systematic Review and Meta-Analysis of Clinical Trials

Choueiri, Toni K.; Schutz, Fabio A.B.; Je, Youjin; Rosenberg, Jonathan E.; Bellmunt, Joaquim

doi:10.1200/jco.2009.27.2757

Cited by 394 publications

(243 citation statements)

References 38 publications

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“…For one study that reported zero events in the control arm, we applied the classic half-integer correction to calculate the RR and variance. 18 Between-study heterogeneity What's new? Small molecule tyrosine kinase inhibitors (TKIs) directed against the VEGF receptor have been approved for use in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…[12][13][14][15][16][17] Although VEGFR TKIs related-AEs are generally manageable, the influence of VEGFR-TKIs on some clinically relevant AEs such as venous thromboembolism events (VTEs) and arterial thromboembolism events (ATEs) described in trials remains unclear. Recently, a systematic review and meta-analysis of RCTs with two VEGFR-TKIs (sunitinib and sorafenib) demonstrates a significant increase in the risk of ATEs with these agents, 18 and the anti-vascular endothelial growth factor agent bevacizumab has also been associated with an increase risk of VTEs in previous research. 19 In addition, VEGFR-TKIs associated VTEs have been sporadically reported in severally trials in advanced solid tumors with incidence ranging from 0.3% to 15.4%, 20,21 but the contribution of VEGFR-TKIs to VTEs remains poorly defined due to a limited number of patients included in the trials.…”

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confidence: 99%

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

Min

Shen

et al. 2012

Intl Journal of Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

Min

Shen

et al. 2012

Intl Journal of Cancer

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“…In a trial-based meta-analysis, the incidence of ATE was as rare as 1.4% (95% CI 1.2%~1.6%) in 10,255 patients receiving sorafenib [45]. However, the consequence of ATE is severe, given that ATE is one of the major causes of myocardial ischaemia and cardiac infarction.…”

Section: Arterial Thromboembolic Events (Ates)mentioning

confidence: 99%

“…Sorafenib treatment has been associated with the occurrence of arterial thromboembolic events, regardless of the type of cancer [40,45]. In a trial-based meta-analysis, the incidence of ATE was as rare as 1.4% (95% CI 1.2%~1.6%) in 10,255 patients receiving sorafenib [45].…”

Section: Arterial Thromboembolic Events (Ates)mentioning

confidence: 99%

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

Gao

2015

Basic Clin Pharma Tox

145

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Sorafenib is the first multi-kinase inhibitor (TKI) approved for the treatment of advanced hepatocellular cancer (HCC) and metastatic renal cell cancer (RCC) and is increasingly being used to treat patients with well-differentiated radioiodine-resistant thyroid cancer (DTC). Sorafenib demonstrates targeted activity on several families of receptor and non-receptor tyrosine kinases that are involved in angiogenesis, tumour growth and metastatic progression of cancer. Sorafenib treatment results in longterm efficacy and low incidence of life-threatening toxicities. Although sorafenib has demonstrated many benefits in patients, the adverse effects cannot be ignored. The most common treatment-related toxicities include diarrhoea, fatigue, hand-foot skin reaction and hypertension. Most of these toxicities are considered mild to moderate and manageable to varying degrees; however, cardiovascular events might lead to death. In this MiniReview, we summarize the adverse effects of sorafenib that commonly occur in patients with advanced cancers.Over the past few years, targeted therapy utilizing multi-tyrosine kinase inhibitors (TKIs) has been widely used for treatment of cancers. TKIs are designed to block specific cancer cell processes and are usually better tolerated than most conventional chemotherapeutic drugs. Sorafenib is the first orally active TKI approved by the Food and Drug Administration (FDA). Sorafenib mainly targets vascular endothelial growth factor (VEGFR1-3) and Raf kinases. Other reported targets include K-Ras, BRAF, V599E mutant BRAF, platelet-derived growth factor receptor-b (PDGFR-b), FMS-like tyrosine kinase 3 (FLT3), c-Kit and RET, and several other receptor tyrosine kinases (RTKs) via various modes of action, such as inhibition of the Ras/Raf/MAPK and PI3K/AKT/mTOR signalling pathways [1][2][3]. The anticancer activity of sorafenib thus results from a dual inhibitory effect towards angiogenesis and tumour cell proliferation. Sorafenib also possesses the function of inducing apoptosis in cancer cells by inhibiting the phosphorylation of initiation factor eIF4E and loss of the antiapoptotic protein myeloid cell leukaemia-1(Mcl-1) [4].In 2007, sorafenib was approved by the FDA for the treatment of advanced hepatocellular cancer (HCC) [5,6] and metastatic renal cell cancer (RCC) [7,8]. Oral administration of sorafenib is associated with improved quality of life and prolonged overall survival of patients [9]. Recently, the most positive phase III results were observed in well-differentiated radioiodine-resistant thyroid cancer (DTC) [10], resulting in the increased use of sorafenib to treat patients with DTC.

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“…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%).…”

Section: Discussionmentioning

confidence: 99%

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

Qi¹,

Fu²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Risk of Arterial Thromboembolic Events With Sunitinib and Sorafenib: A Systematic Review and Meta-Analysis of Clinical Trials

Abstract: Treatment with VEGFR TKIs sunitinib and sorafenib is associated with a significant increase in the risk of ATEs.

Cited by 394 publications

References 38 publications

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

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

The Adverse Effects of Sorafenib in Patients with Advanced Cancers

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

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