Many second-line therapies are recently approved for patients with advanced hepatocellular carcinoma (HCC), in whom protein malnutrition is prevalent that would affect treatment outcomes. In this study, we aimed to investigate the role of pre-sarcopenia and muscle restoration in patients with sorafenib-failed advanced HCC. From August 2012 to March 2017, 385 patients who developed radiology-proven HCC progression after sorafenib treatment were enrolled in the study. Pre-sarcopenia is defined as

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... transverse psoas muscle thickness per body height < 16.8 mm/m, which was prevalent (64.7%) in our patients. Age > 60 years, female gender, and body mass index < 22 kg/m2 were independent predictors to the development of pre-sarcopenia. Patients with muscle depletion had significantly worse post-progression survival (PPS) compared with their counterparts (median PPS: 3.8 vs. 5.8 months, p = 0.003), particularly in those with intermediate liver reserves (Child–Pugh class B or Albumin-bilirubin grade 2). Besides, pre-sarcopenia independently predicted post-progression mortality in sorafenib-failed HCC (hazard ratio: 1.340, p = 0.012). In patients who developed pre-sarcopenia before sorafenib treatment, muscle restoration was associated with a longer PPS compared with their counterparts (6.3 vs. 3.6 months, p = 0.043). In conclusion, pre-sarcopenia independently determined the outcomes of sorafenib-failed HCC. Nutrition support to restore muscle mass would prolong survival for higher-risk patients.