title: Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).
abstract: Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.|Centre for Reviews and Dissemination, University of York, York, United Kingdom.
authors.forename: Marco
authors.initials: M
authors.lastname: Miroddi
authors.affiliation: Centre for Reviews and Dissemination, University of York, York, United Kingdom. helo.sterrantino@york.ac.uk.|Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. helo.sterrantino@york.ac.uk.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Sterrantino
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.
authors.forename: Mark
authors.initials: M
authors.lastname: Simmonds
authors.affiliation: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Caridi
authors.affiliation: Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Calapai
authors.affiliation: Centre for Reviews and Dissemination, University of York, York, United Kingdom.|Department of Paediatric Oncology Haematology, Leeds General Infirmary, Leeds, United Kingdom.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Phillips
authors.affiliation: Centre for Reviews and Dissemination, University of York, York, United Kingdom.
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Stewart
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000068818:Cetuximab / Q000008:administration & dosage / Q000009:adverse effects*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology; D000077544:Panitumumab; D016032:Randomized Controlled Trials as Topic; D013923:Thromboembolism / Q000139:chemically induced* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: adverse events; anti-EGFR; cancer; cetuximab; meta-analysis; panitumumab; pharmacovigilance; safety; systematic review; thromboembolism