Prognostic Significance of VEGF and HIF-1 alpha in Hepatocellular Carcinoma Patients Receiving Sorafenib Versus Metformin Sorafenib Combination

摘要

Background Hepatocellular carcinoma (HCC) is a major health problem. HCC burden has been increasing in Egypt in the past 10 years. Most HCC cases are diagnosed at an advanced stage with limited treatment options. Sorafenib is the standard therapy for advanced HCC, but the effectiveness is not satisfied. Metformin may decrease the risk of HCC development in diabetic patients, reduces tumor invasion, and augments sensitivity to sorafenib; however, safety and efficacy of combined treatment are still unclear. As HCC is characterized by high vascularity, and vascular endothelial growth factor (VEGF) plays an important role in vascularization, many studies questioned if VEGF and HIF-1 alpha could offer information about HCC response to sorafenib. We conducted this study to assess the benefits from adding metformin to HCC treatment, and appraise the role of VEGF and HIF-1 alpha in HCC prognosis. Method This was a prospective, randomized study in which 80 advanced measurable patients consecutively treated with sorafenib plus metformin (arm A) or sorafenib alone (arm B), prognostic value of plasma, and tissue levels of VEGF and HIF-1 alpha were evaluated. Results We enrolled 61 men and 19 women with a median age of 60 years (range 49-68 years). Fifty-seven patients had Child-Pugh A while 23 had early B, the most common etiology of liver disease was hepatitis C (86%). Sixty percent of patients were diabetic. No significant difference was detected between arm A and arm B regarding response to treatment (p = 0.5), time to disease progression (p = 0.3), or overall survival (p = 0.6). Low VEGF and HIF-1 alpha plasma levels were significantly associated with better treatment response (p < 0.001 for both), and higher OS (p < 0.001). Patients with high expressions of VEGF and HIF in HCC tissue had significantly poor treatment outcome (p < 0.001, p = 0.03, respectively), and poor OS (p < 0.001, p < 0.001, respectively). Conclusions No superior efficacy of adding metformin to sorafenib in HCC treatment. VEGF and HIF-1 alpha had promising prognostic value in HCC.