Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials

Background Sunitinib and sorafenib are oral vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors used in various cancers. Bleeding has been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to calculate the incidence and relative risk associated with use of sunitinib and sorafenib. Methods We searched PubMed (from January, 1966, to April, 2009) and meeting proceedings of the American Society of Clinical Oncology and the European Society of Medical Oncology (2004-09) for relevant clinical trials. Eligible studies included phase 2 and 3 trials and expanded-access programmes. Statistical analyses were done to calculate summary incidences, relative risks, and 95% CI, using random-effects or fixed-effects models based on the heterogeneity of included studies. Findings 23 trials were selected for the meta-analysis, yielding a total of 6779 patients. The incidence of bleeding events (all grades) was 16.7% (95% CI 12.7-21.5), and that of high-grade events was 2.4% (1.6-3.9). The relative risk of all-grade bleeding events associated with sunitinib and sorafenib (for randomised controlled trials only) was 2.0 (1.14-3.49; p=0.015). Our analysis was also stratified by underlying malignant disease (renal-cell carcinoma vs non-renal-cell carcinoma) and agent used, but no differences were recorded. Interpretation Treatment with the VEGFR tyrosine-kinase inhibitors sunitinib and sorafenib is associated with a significant increase in risk of bleeding.