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Introduction: Optimal treatment of hepatocellular carcinoma (HCC) beyond the Milan criteria is in debate. We aimed to identify candidates for surgical resection (SR) in Barcelona Clinic Liver Cancer (BCLC) –A/B HCC beyond the Milan criteria with survival benefit. Methods: Patients with BCLC-A/B HCC beyond the Milan criteria at the National Taiwan University Hospital during 2005 and 2019 were screened and those who received transarterial chemoembolization (TACE) or SR were consecutively included. The tumor burden was classified by the seven-eleven criteria into low (≤7), intermediate (7-11) or high (>11). Multivariable cox proportional hazard regression analysis was used for outcome prediction. Results: Overall, 474 patients who received SR (n=247), and TACE (n=227) were enrolled. Patients underwent SR were significantly younger with better liver reserve. There were 76 (31%), and 129 (57%) deaths in the SR and TACE groups after a median follow-up of 3.9 and 2.1 years, respectively. The seven-eleven criteria could distinguish median overall survival (OS) among low (n=149), intermediate (n=203), and high (n=122) tumor burden groups (7.7 vs. 6.9 vs. 2.8 years, respectively, P < 0.001). Patients receiving SR had a significantly higher median OS compared with TACE in those with intermediate (8.2 vs. 2.6 years, P < 0.001) and high (5.6 vs. 1.5 years, P = 0.001) tumor burden. After adjustment for age, sex, and liver reserve, SR was predictive for better OS in intermediate (adjusted hazard ratio [aHR]: 0.45, 95% CI: 0.27-0.75) and high tumor burden groups (aHR: 0.54, 95% CI: 0.32-0.92). The survival benefit of SR especially confines to patients within 3 tumors. Conclusions: In patients with BCLC-A/B HCC beyond the Milan criteria with tumor burden beyond the up-to-7 criteria but within 3 tumors, SR has better OS than TACE and should be considered in resectable patients.

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