Increased Risk of High-Grade Hemorrhage in Cancer Patients Treated with Gemcitabine: A Meta-Analysis of 20 Randomized Controlled Trials

Purpose: Gemcitabine, a third-generation anticancer agent, has been shown to be active in several solid tumors. High-grade hemorrhage (grade >= 3) has been reported with this drug, although the overall risk remains unclear. We conducted a meta-analysis of randomized controlled trials evaluating the incidence and risk of high-grade hemorrhage associated with gemcitabine. Methods: Pubmed was searched for articles published from January 1, 1990 to December 31, 2012. Eligible studies included prospective randomized controlled phase II and III trials evaluating gemcitabine-based vs non-gemcitabine-based therapy in patients with solid tumors. Data on high-grade hemorrhage were extracted. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed-or random-effects models depending on the heterogeneity of included trials. Results: A total of 6433 patients from 20 trials were included. Among patients treated with gemcitabine-based chemotherapy, the overall incidence of high-grade hemorrhage was 1.7% (95% CI: 0.9-3.1%), and the RR of high-grade hemorrhage was 2.727 (95% CI: 1.581-4.702, p<0.001). Exploratory subgroup analysis revealed the highest RR of hemorrhage in non-small-cell lung cancer (NSCLC) patients (RR: 3.234; 95% CI, 1.678-6.233; p<0.001), phase II trials (RR 7.053, 95% CI: 1.591-31.27; p = 0.01), trials reported during 2006-2012 (RR: 3.750; 95% CI: 1.735-8.108, p<0.001) and gemcitabine used as single agent (RR 7.48; 95% CI: 0.78-71.92, p = 0.081). Conclusion: Gemcitabine is associated with a significant increase risk of high-grade hemorrhage in patients with solid tumors when compared with non-gemcitabine-based therapy.