Risk of Thromboembolic Events and Anti-EGFR Agents
Purpose Anti-epidermal growth factor receptor (EGFR) agents [monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs)] are targeted therapies used in advanced cancers. Arterial and venous thromboembolic events (ATEs and VTEs excluding catheter-related events) were not investigated with these agents, and the risk of these events is still unknown.
Patients and methods We have carried out a meta-analysis in order to determine the incidence and the relative risk (RR) of VTEs and ATEs associated with these agents. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.
Results A total of 13 studies (7611 patients) was selected for this meta-analysis. The associated RRs of VTEs (11 studies comprising 7073 patients) and ATEs (5 studies consisting of 3030 patients) were 1.32 (95% CI 1.07–1.63; P equals 0.01) and 1.34 (95% CI 0.94–1.9; P equals 0.11) compared with control patients. The analysis of VTEs was also stratified by class of agents: MoAbs (RR 1.34; P equals 0.01) and oral TKIs (RR 1.16; P equals 0.65).
Conclusion Anti-EGFR agents are associated with a significant increase in the risk of VTEs. In particular, the risk is significant with cetuximab and panitumumab in settings where these drugs are currently approved.
Venous and arterial thromboembolism events (VTEs and ATEs) are a major cause of death in cancer patients. The importance of cancer-associated thrombosis comes from the fact that it is exceedingly common in patients with cancer. One-fifth of all VTE events occur in cancer patients and the ones who develop VTE may experience serious consequences. The most important consequence is the risk of mortality; pulmonary embolism (PE) and arterial events such as myocardial infarction and stroke can lead infact to death in cancer patients. In particular, modern targeted therapies as antiangiogenic agents (sunitinib, sorafenib and bevacizumab) targeting vascular endothelial growth factor receptor (VEGFR) are associated with an increased risk of developing VTE and ATEs. The epidermal growth factor receptor (EGFR) signaling pathway comprises a major target against which several new drugs are being currently developed. Cetuximab (C) is a chimeric monoclonal antibody (MoAb) that binds to the EGFR and blocks the EGFR signaling cascade, thus inhibiting the growth of the tumor. Panitumumab (P) is an anti-EGFR MoAb which, like C, binds to the EGFR to prevent ligand binding and inhibits the subsequent activation of key downstream signaling molecules involved in tumorigenesis. Both C and P are parentheral drugs administered as i.v. infusion. Erlotinib and gefitinib are oral small molecules designed to selectively inhibit the phosphorylation of EGFR intracellular kinase domain.
The main toxic effects of these drugs are cutaneous (skin rash), gastrointestinal (diarrhea) and metabolic (hypomagnesemia). Little is known about the risk of vascular events associated with these agents. To our knowledge, no published article explored cardiovascular toxicity associated to these drugs. Since the indications for anti-EGFR agents are increasing, it is important to carefully recognize and document the vascular toxicity patterns of these drugs to perform an early and adequate intervention. In order to determine the risk of VTEs and ATEs associated with the clinical use of anti-EGFR drugs, we have investigated the incidence and the relative risk (RR) of these events in patients treated with C, P, erlotinib or gefitinib. We have then carried out a systematic review and a meta-analysis of the published articles and abstracts presented at the major oncology meetings.
Abstract and Introduction
Abstract
Purpose Anti-epidermal growth factor receptor (EGFR) agents [monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs)] are targeted therapies used in advanced cancers. Arterial and venous thromboembolic events (ATEs and VTEs excluding catheter-related events) were not investigated with these agents, and the risk of these events is still unknown.
Patients and methods We have carried out a meta-analysis in order to determine the incidence and the relative risk (RR) of VTEs and ATEs associated with these agents. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies.
Results A total of 13 studies (7611 patients) was selected for this meta-analysis. The associated RRs of VTEs (11 studies comprising 7073 patients) and ATEs (5 studies consisting of 3030 patients) were 1.32 (95% CI 1.07–1.63; P equals 0.01) and 1.34 (95% CI 0.94–1.9; P equals 0.11) compared with control patients. The analysis of VTEs was also stratified by class of agents: MoAbs (RR 1.34; P equals 0.01) and oral TKIs (RR 1.16; P equals 0.65).
Conclusion Anti-EGFR agents are associated with a significant increase in the risk of VTEs. In particular, the risk is significant with cetuximab and panitumumab in settings where these drugs are currently approved.
Introduction
Venous and arterial thromboembolism events (VTEs and ATEs) are a major cause of death in cancer patients. The importance of cancer-associated thrombosis comes from the fact that it is exceedingly common in patients with cancer. One-fifth of all VTE events occur in cancer patients and the ones who develop VTE may experience serious consequences. The most important consequence is the risk of mortality; pulmonary embolism (PE) and arterial events such as myocardial infarction and stroke can lead infact to death in cancer patients. In particular, modern targeted therapies as antiangiogenic agents (sunitinib, sorafenib and bevacizumab) targeting vascular endothelial growth factor receptor (VEGFR) are associated with an increased risk of developing VTE and ATEs. The epidermal growth factor receptor (EGFR) signaling pathway comprises a major target against which several new drugs are being currently developed. Cetuximab (C) is a chimeric monoclonal antibody (MoAb) that binds to the EGFR and blocks the EGFR signaling cascade, thus inhibiting the growth of the tumor. Panitumumab (P) is an anti-EGFR MoAb which, like C, binds to the EGFR to prevent ligand binding and inhibits the subsequent activation of key downstream signaling molecules involved in tumorigenesis. Both C and P are parentheral drugs administered as i.v. infusion. Erlotinib and gefitinib are oral small molecules designed to selectively inhibit the phosphorylation of EGFR intracellular kinase domain.
The main toxic effects of these drugs are cutaneous (skin rash), gastrointestinal (diarrhea) and metabolic (hypomagnesemia). Little is known about the risk of vascular events associated with these agents. To our knowledge, no published article explored cardiovascular toxicity associated to these drugs. Since the indications for anti-EGFR agents are increasing, it is important to carefully recognize and document the vascular toxicity patterns of these drugs to perform an early and adequate intervention. In order to determine the risk of VTEs and ATEs associated with the clinical use of anti-EGFR drugs, we have investigated the incidence and the relative risk (RR) of these events in patients treated with C, P, erlotinib or gefitinib. We have then carried out a systematic review and a meta-analysis of the published articles and abstracts presented at the major oncology meetings.