Risk of liver toxicity with the angiogenesis inhibitor pazopanib in cancer patients

Purpose. The angiogenesis inhibitor pazopanib has been approved for the treatment of advanced renal cell cancer (RCC) and soft tissue sarcoma. Severe and fatal hepatotoxicity has been observed in its clinical studies. This analysis was conducted to determine the risk of liver toxicity by a systematic review and meta-analysis of clinical trials. Patients and methods. Databases from PubMed, Web of Science and abstracts presented at ASCO meetings up to January, 2012 were searched to identify relevant studies. Eligible studies included prospective trials of cancer patients treated with pazopanib starting at 800 mg daily. Summary incidence rates, relative risks, and 95% confidence intervals (CIs) were calculated using a fixed- or random-effects model. Results. A total of 1478 patients from 10 clinical trials were included. The incidences of all-grade aspartate aminotransferase (AST), alanine transaminase (ALT), and bilirubin elevation were 39.6% (95% CI 31.2-48.6%), 41.4% (95% CI 34.1-49.0%), and 24.8% (95% CI 16.3-35.3%), respectively. The incidences of high-grade (Grade 3 and 4) AST, ALT and bilirubin elevation were 6.9% (95% CI 5.5-8.6%), 9.4% (95% CI 7.8-11.4%), and 3.4% (2.4-5.0%), respectively. In comparison with placebo, pazopanib significantly increased the risk of high-grade AST elevation (RR 6.56, 95% CI 2.04-21.07, p = 0.002) and ALT elevation (RR 4.33, 95% CI 1.88-10.0, p = 0.001). However, the risks of high-grade bilirubin elevation (RR 1.31, 95% CI 0.47-3.64) and fatal hepatotoxicity (RR 2.51, 95% CI 0.12-51.91, p = 0.55) were not significantly elevated. Conclusion. The use of pazopanib was associated with a significantly increased risk of severe non-fatal hepatotoxicity in cancer patients.