title: Risk of gastrointestinal perforation in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a systematic review and meta-analysis.
abstract: BACKGROUND
  The use of vascular-endothelial growth factor (VEGF) antibody bevacizumab is associated with an increased risk of gastrointestinal (GI) perforation, but the incidence and risk of GI perforation associated with vascular endothelial growth factor tyrosine-kinase inhibitors (VEGFR-TKIs) has not been well described. We conduct a systematic review and meta-analysis of published trials to evaluate the overall incidence and risk of GI perforation associated with VEGFR-TKIs.
  
  
  METHODS
  Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to March 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating VEGFR-TKIs in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.
  
  
  RESULTS
  A total of 5352 patients with a variety of solid tumors from 20 clinical trials were included in our analysis. The incidence of GI perforation was 1.3% (95%CI: 0.8-2.0%) among patients receiving VEGFR-TKIs, with a mortality of 28.6% (15.0-47.6%). Patients treated with VEGFR-TKIs did not significantly increase the risk of GI perforation compared with patients treated with control medication, with an OR of 2.99 (95%CI: 0.85-10.53, p=0.089). Sub-group analysis showed that the incidence of GI perforation did not significantly vary with tumor types, VEGFR-TKIs and treatments regimens. No evidence of publication bias was observed.
  
  
  CONCLUSIONS
  The use of VEGFR-TKIs dose not significantly increase the risk of GI perforation in comparison with the controls. Further studies are recommended to investigate this association and the risk differences among different tumor types, VEGFR-TKIs or treatment regimens.
authors.affiliation: Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, No. 600, Yishan Road, Shanghai 200233, China.
authors.forename: Wei-Xiang
authors.initials: WX
authors.lastname: Qi
authors.affiliation: Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, No. 600, Yishan Road, Shanghai 200233, China.
authors.forename: Yuan-Jue
authors.initials: YJ
authors.lastname: Sun
authors.affiliation: Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, No. 600, Yishan Road, Shanghai 200233, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Tang
authors.affiliation: Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, No. 600, Yishan Road, Shanghai 200233, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Oncology, The Sixth People's Hospital, Shanghai Jiao Tong University, No. 600, Yishan Road, Shanghai 200233, China. Electronic address: qwxzlk@163.com.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yao
mesh_terms: D006801:Humans; D007416:Intestinal Perforation / Q000150:complications*; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Axitinib; Cancer; Cediranib; Gastrointestinal perforation; Meta-analysis; Pazopanib; Sorafenib; Sunitinib; Vandetanib