The term “antiangiogenic” was defined as any therapy whose putative mode of action was either wholly or partly directed against the tumor vasculature. To identify relevant clinical

trials we conducted a PubMed search of citations from January 1995 to December 31, 2011. The search terms employed in our literature search included: “hepatocellular carcinoma,” “antiangiogenic,” “sorafenib,” “sunitinib,” and “bevacizumab.” For the randomized studies we used the nontreatment groups as control and for the nonrandomized single-arm phase 2 studies, which accounted for the majority of the studies, we selleck chemicals llc compared bleeding risk with other HCC single-arm studies not including an antiangiogenic agent. To separate disease-specific effects we also performed a comparison analysis with RCC studies that evaluated 5-Fluoracil chemical structure sorafenib. We confined our analysis to prospective studies that have been published in article form. We analyzed studies that met the

following criteria: phase 1, 2, or 3 trials in HCC; phase 3 studies evaluating sorafenib in RCC; participants assigned to treatment with an agent whose mechanism of action was known to be wholly or partially antiangiogenic; adequate safety data available for bleeding events. For every study we extracted the following information: author name; year of publication; number of enrolled patients; treatment; eligibility criteria regarding platelet count, coagulation, hepatic function, Child-Pugh status; endoscopic requirements. Although we sought to evaluate cross-study variability in entry criteria we did include studies where the eligibility criteria were incomplete, as this was not the primary aim of our analysis. The occurrence of hemorrhagic events of any grade was recorded. We assessed and recorded adverse events according to the National Cancer Institute’s common toxicity criteria (v. 2.0 or 3.0), which were used by all of the clinical trials. To calculate incidence we extracted from the safety profile 上海皓元 the number of bleeding events

(all grade and grade 3-5) and the number of patients in the study. For every study we derived the proportion (and 95% confidence interval [CI]) of patients with adverse outcomes. For studies which contained a control arm the number of events was entered for both arms and the Mantel-Haenszel method used to calculate an odds ratio (OR) and 95% CI. These ORs were plotted in a forest plot where they were assigned a weight, based on sample size and variance, and pooled for an overall effect estimate of antiangiogenesis therapy on bleeding events. Analysis (using the inverse variance method, alpha of 0.05) and forest plots were generated using R statistical software and Review Manager. CTCAE, Common Terminology Criteria for Adverse Events; HCC, hepatocellular carcinoma; RCC, renal cell cancer; VEGF, vascular endothelial growth factor.