<b><i>Background:</i></b> Low skeletal muscle mass is significantly associated with severe adverse events (AEs) from chemotherapy, and low tolerability leads to decreased survival. We aimed to investigate whether body skeletal muscle mass is correlated with tolerability and prognosis in patients with hepatocellular carcinoma (HCC) treated with lenvatinib. <b><i>Methods:</i></b> This multicenter, retrospective study was conducted at five locations in Japan. We included 100 patients with HCC treated with lenvatinib. Skeletal muscle mass was measured by computed tomography and normalized for height in m<sup>2</sup> as skeletal muscle index (SMI). The assessment criteria for low SMI were taken from the sarcopenia criteria of the Japan Society of Hepatology. We investigated the influence of low SMI on drug withdrawal due to severe AEs in the first 2 months and on time to treatment failure (TTF) and overall survival (OS). <b><i>Results:</i></b> The numbers of high- and low-SMI patients were 41 and 59, respectively. Those with severe AEs leading to withdraw in the high- and low-SMI groups were 7 and 23, respectively. The low-SMI group had a higher withdrawal rate than the high-SMI group (<i>p</i> = 0.042). The median TTF in the low- and high-SMI groups was 139 and 230 days, respectively. The median OS in the low- and high-SMI groups was 264 and 353 days, respectively. Patients in the low-SMI group experienced significantly worse OS and TTF than those in the high-SMI group (log-rank test for trend: TTF, <i>p</i> = 0.010; OS, <i>p</i> = 0.021). <b><i>Conclusion:</i></b> Decreased skeletal muscle mass is associated with the occurrence of severe AEs and worse TTF and OS. Skeletal muscle mass can be used as a predictive marker for tolerability and prognosis to lenvatinib in patients with HCC.
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