## 4 Discussion  
Our study focused on HCC patients treated with lenvatinib and, to our knowledge, it is the first to determine the individual effect of handgrip strength and skeletal muscle mass. In our results, patients with low handgrip strength showed significantly shorter survival than those with high handgrip strength, and low handgrip strength was an independent predictor for OS in the multivariate analysis, but skeletal muscle depletion was not. Patients with low handgrip strength tended to discontinue lenvatinib therapy more often than patients with high handgrip strength (Figure 3A), while no significant difference was found between patients with and without muscle depletion (Figure 3B). A significant correlation was observed between the duration of TTF and OS time (r = 0.594, \(p<0.001\)); furthermore, patients with low handgrip strength tended to discontinue lenvatinib therapy due to AEs compared with those with high handgrip strength (\(p\) = 0.099; data not shown). Lenvatinib is recommended as a first-line treatment agent for advanced HCC [16; 17; 18; 19]. In Japan, lenvatinib has been used as a second- or third-line intervention in real-world practice, after its approval in March 2018. A recent study demonstrated that initial lenvatinib therapy followed by conventional  
Figure 3: Comparison of time to treatment failure (TTF) according to the evaluation of handgrip strength, skeletal muscle, or sarcopenia. (**A**) Patients with low handgrip strength tended to discontinue the treatment than those with high handgrip strength (median TTF: low handgrip strength group, 3.6 months; high handgrip strength group, 6.2 months; \(p\) = 0.120). (**B**) No significant difference was found between patients with and without muscle depletion (\(p\) = 0.683). (**C**) Patients with sarcopenia showed significantly worse TTF than those without sarcopenia (median TTF: sarcopenia group, 3.6 months; non-sarcopenia group, 5.3 months; \(p\) = 0.036). transcatheter arterial chemoembolization (cTACE) markedly improved OS compared with initial therapy of cTACE in patients with intermediate-stage HCC beyond up-to-seven criteria [30]. Moreover, the RESORCE study and the post-hoc analysis of the REFLECT study indicated that sequential therapy improved OS [20; 31]. Therefore, using two or more MTAs administered sequentially is necessary to obtain a favorable OS for patients at intermediate and advanced stages of HCC. In addition, AE management should include administration of MTAs for a longer period. Some studies, including our study, have already reported that skeletal muscle depletion was associated with AEs, TTF, and OS in HCC patients treated with sorafenibib [9; 10; 11; 12; 13]. However, to our knowledge, only one study reported the association between skeletal muscle mass and clinical outcome in HCC patients treated with lenvatinib [32]. Sarcopenia is defined as a progressive and generalized skeletal muscle disorder that involves reduction of muscle mass and functional decline [33]. The JSH proposed new diagnostic criteria, which could be used for Japanese patients with liver disease [5]. The JSH diagnostic criteria use identical cut-off values for skeletal muscle mass and grip strength; however, age-related criterion and assessment of physical performance such as walking speed, were not considered. [PERSON] et al. reported that handgrip strength was associated with walking speed and all patients with slow walking speed showed low handgrip strength [34], and this report supports the JSH diagnostic criteria, which does not consider the walking speed. As our study population comprised of only Japanese patients, we adopted the JSH diagnostic criteria in this study. We investigated the individual effect of handgrip strength, skeletal muscle mass, and sarcopenia on clinical outcomes in HCC patients treated with lenvatinib. In this study, we showed the effect of handgrip strength or sarcopenia on OS in HCC patients undergoing lenvatinib. However, skeletal muscle mass was not associated with OS.