Introduction: Radiofrequency ablation and percutaneous ethanol injection are important treatment modalities for hepatocellular carcinoma patients; Whether a combination treatment yields, additional benefit still remains controversial. Methods: A systematic review and meta-analysis was concluded. Randomized controlled trials published before January 1, 2022, from PubMed, EMBASE, Scopus, and CNKI were searched. Studies were excluded when patients received different ablative treatment or had serious liver dysfunction. The risk of bias assessment was evaluated using the Cochrane Collaboration's tool. Results: Ten studies, encompassing 854 patients, with histologically proven HCC were finally analyzed. The results demonstrated that patients who received RFA-PEI had slightly improvements in 1-year overall survival (OS) [risk ratio (RR): 1.11; 95% confidence interval (CI): 1.03, 1.19, I2 = 10%], 2-year OS (RR: 1.25; 95% CI: 1.12, 1.40, I2 = 0%), 3-year OS (RR: 1.42; 95% CI: 1.11, 1.83, I2 = 38%), 1-year local recurrence-free (LRF) proportion (RR: 1.2; 95% CI: 1.01, 1.42, I2 = 61%), and complete tumor necrosis (CTN) (RR: 1.32; 95% CI: 1.14, 1.53, I2 = 45%). Nevertheless, common complications, such as fever, were found to be significant (RR: 1.78, 95% CI: 1.13, 2.80). Conclusion: Despite RFA-PEI appearing to be superior for HCC patients with a compensated liver in terms of OS, current evidence contained moderate to significant heterogeneity, and it was difficult to draw a definite conclusion regarding the therapeutic management in terms of LRF and CTN.
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