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

Lancet Oncol. 2009 Oct;10(10):967-74. doi: 10.1016/S1470-2045(09)70222-0. Epub 2009 Sep 18.


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.

Funding: None.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antineoplastic Agents / adverse effects*
  • Benzenesulfonates / adverse effects*
  • Clinical Trials as Topic
  • Hemorrhage / chemically induced*
  • Hemorrhage / epidemiology*
  • Humans
  • Incidence
  • Indoles / adverse effects*
  • Niacinamide / analogs & derivatives
  • Phenylurea Compounds
  • Pyridines / adverse effects*
  • Pyrroles / adverse effects*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*
  • Risk Assessment
  • Sorafenib
  • Sunitinib


  • Antineoplastic Agents
  • Benzenesulfonates
  • Indoles
  • Phenylurea Compounds
  • Pyridines
  • Pyrroles
  • Niacinamide
  • Sorafenib
  • Receptors, Vascular Endothelial Growth Factor
  • Sunitinib