The impact of lenvatinib on sarcopenia in patients with advanced unresectable hepatocellular carcinoma

The impact of lenvatinib on sarcopenia in patients with advanced unresectable hepatocellular carcinoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The impact of lenvatinib on sarcopenia in patients with advanced unresectable hepatocellular carcinoma Michael Praktiknjo, Ana S. Pena Solano, Farsaneh Sadeghlar, Thomas Welchowski, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2771181/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Sep, 2024 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Lenvatinib is a multiple receptor tyrosine kinase inhibitor (TKI) approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). TKI are suspected of exacerbating muscle wasting (sarcopenia) in patients with cancer. In this study, we analyze the role of sarcopenia in patients with advanced HCC treated with lenvatinib. This is a retrospective analysis of a real-life cohort of 25 patients with advanced HCC who were treated with lenvatinib from 2018 to November 2020 in Germany. Patients were stratified for loss of skeletal muscle index (SMI) during the first three months of lenvatinib therapy. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed for all patients, especially regarding development of sarcopenia before and during the first three months of therapy with lenvatinib. Three months after beginning of therapy with lenvatinib, a significant reduction of muscle mass was observed in 60% of patients (p = 0.035). Despite increase of sarcopenia, patients benefitted from lenvatinib in our cohort of patients in terms of OS and PFS and did not experience increased toxicity. Furthermore, muscle loss was not found to be a negative predictor of survival in the univariate analysis. Patients with advanced hepatocellular carcinoma experience muscle wasting with lenvatinib therapy. However, despite progressive sarcopenia, patients benefit from a therapy with lenvatinib in terms of OS and PFS without increased toxicity. However, assessment and prophylaxis of skeletal muscle status should be recommended during a therapy with lenvatinib. Health sciences/Oncology/Cancer/Gastrointestinal cancer/Liver cancer/Hepatocellular carcinoma Biological sciences/Cancer/Cancer therapy/Chemotherapy Figures Figure 1 Figure 2 Figure 3 Introduction Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third leading cause of cancer-related death worldwide. Despite recent advances in the systemic treatment of advanced HCC, the prognosis of HCC is still poor. Chronic viral hepatitis B/C, alcohol use disorder, metabolic liver disease (particularly nonalcoholic fatty liver disease) and aflatoxins are the most frequent risk factors for HCC. The molecular mechanisms of HCC progression have not yet been completely clarified [ 2 – 4 ]. The relevant parameters for determining prognosis and therapy of HCC are defined by the Barcelona Classification for Liver Cancer (BCLC). Further prognostic scores or parameters, such as ALBI, but also ECOG status and clinical symptoms, may be applied to predict HCC prognosis. HCC is often diagnosed at advanced stages (BCLC C). In this case and considering international guidelines, such as EASL or ESMO, first-line systemic therapy with atezolizumab (PD-L1 antibody) in combination with bevacizumab is recommended based on data from the phase III IMbrave150 trial. In case of toxicity or contraindications, oral therapy with sorafenib or lenvatinib is recommended [ 5 – 6 ]. Lenvatinib was approved in 2018 for the treatment of advanced HCC as first-line therapy. Based on results from the randomized phase III REFLECT trial, lenvatinib was not inferior to sorafenib regarding overall survival (OS) [ 1 ]. Side effects related to lenvatinib were manageable with dose modifications. In addition, it has been reported that high serum lenvatinib levels resulted in weight (muscle and fat) loss [ 7 ]. However, weight loss did not serve as a good predictor of prognosis to lenvatinib therapy in contrast to muscle loss [ 8 , 1 ]. Sarcopenia defined as skeletal muscle mass loss and/or grip strength reduction can easily be measured using computed tomography (CT) or magnetic resonance imaging (MRI). We and others have shown that sarcopenia is common in patients with advanced liver disease or malignancies and that it represents a relevant independent prognostic factor in these patients [ 9 – 12 , 32 – 33 ]. For instance, measurement of muscle mass at the third lumbar vertebra (L3) using CT has been shown to be a strong independent predictor of mortality in patients with cirrhosis or HCC [ 13 – 15 ]. Furthermore, muscle depletion can lead to physical disability in patients with HCC resulting in reduced tolerability to chemotherapy and TKI [ 15 ]. Finally, it has been shown that several TKIs can aggravate patients' sarcopenia due to different mechanisms. Only few studies, mostly from Japan, have reported on the clinical impact of sarcopenia on patients with advanced HCC treated with lenvatinib. However, the data are very limited and controversial and do not show the effects of lenvatinib on muscle mass [ 16 – 17 ]. Results Base line characteristics Twenty-five patients treated with lenvatinib were enrolled in the study between June 2018 and November 2020. The median observation period was seven months (range = 0–23 months). Base line characteristics of all patients are presented in Table 1 . Sixteen of the patients were male (64%) and median age was 67 (39–81 years). At the start of lenvatinib therapy, 76% (19) of the patients presented an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (eight patients ECOG 0, 11 patients ECOG 1). All patients had advanced HCC corresponding to BCLC stage C, of whom 12 (48%) patients presented with macroscopic infiltration of the main portal vein and 19 patients (76%) with extrahepatic metastasis. In 48% (12) AFP level was ≥ 200 ng/ml. The ALBI score was 1 in 36% (8), 2 in 14 patients (56%) and 3 in three patients (12%). Regarding comorbidities, 80% (20) had concomitant Child-Pugh A liver cirrhosis and 20% (5) Child-Pugh B liver cirrhosis (four patients with 7 points, one patient with 8 points). Among the causes of liver cirrhosis, the following were the most common: chronic hepatitis B 20% (5), chronic hepatitis C 12% (3), alcohol 24% (6) and NASH/NAFLD 24% (6). Regarding treatment characteristics, nine (36%) patients received 4 mg/day as starting dose of lenvatinib and 52% (13) received 8 mg/day. Only 12% (3) received a 100% lenvatinib dose of 12 mg/day as starting dose. Interestingly, five patients (20%) received lenvatinib as second-line treatment, 8% (2), 4% (1) as third-line, and 4% (1) as fourth- line and even fifth-line therapy. Further previous and follow-up therapies are documented in Table 1 . Regarding weight and muscle mass, 76% (19) of the patients weighed above 60 kg and 72% (14) were overweight with a BMI > 25. Interestingly, from the diagnosis of HCC to the start of lenvatinib therapy, 52% (12) had already lost muscle mass. Table 1 Baseline and therapy characteristics All patients n = 25 (%) Non muscle loss during 3 months lenvatinib n = 6 (%)* Muscle loss during 3 months lenvatinib n = 15 (%)* p-value Age <65 ≥65 12 (48%) 13 (52%) 3 (50%) 3 (50%) 8 (53.2%) 7 (46.6%) 1 Sex male female 16 (64%) 9 (36%) 4 (66.7%) 2 (33.3%) 10 (66.7%) 5 (33.3%) 1 ECOG 0–1 ≥2 19 (76%) 6 (24%) 5 (83.3%) 1 (16.7%) 13 (86.7%) 2 (13.3%) 0.9544 Etiology HBV HCV Alcohol NASH/NAFLD Other/unknown 5 (20%) 3 (12%) 6 (24%) 6 (24%) 5 (20%) 2 (33.3%) 1 (16.7) 1 (16.7%) 1 (16.7%) 1 (16.7%) 2 (13.3%) 2 (13.3%) 3 (20%) 4 (26.7%) 4 (26.7%) 0.911233 Child Pugh score A B 20 (80%) 5 (20%) 4 (66.6%) 2 (33.3%) 13 (86.5%) 2 (13.3%) 0.543558 MELD >6 Points 21 (84%) 5 (83.3%) 12 (79.9%) 1 BCLC C 25 (100%) 6 (100%) 15 (100%) 1 Macroscopic MVP infiltration 12 (48%) 4 (66.6%) 4 (26.6%) 1 Extrahepatic metastasis 19 (76%) 6 (100%) 9 (59.9%) 1 AFP (ng/ml) < 200 ≥ 200 13 (52%) 12 (48%) 4 (66.6%) 2 (33.3%) 7 (46.6%) 8 (53.2%) 0.634617 ALBI Grade 1 Grade 2 Grade 3 8 (36%) 14 (56%) 3 (12%) 3 (49.9%) 3 (49.9%) 0 (0%) 4 (26.6%) 8 (53.2%) 3 (19.9%) 0,446579 BMI ≤ 18.5 > 18.5 - ≤25 > 25 3 (12%) 8 (20%) 14 (72%) 1 (16.7%) 2 (33.3%) 3 (50%) 1 (6.6%) 6 (39.9%) 8 (53.2%) 1 Weight (Kg) ≤ 60 > 60 6 (24%) 19 (76%) 1 (16.7%) 5 (83.3%) 4 (26.6%) 11 (73.3%) 1 Muscle mass assesment at beginning /during 3 months lenvatinib therapy Non-sarcopenia Sarcopenia 14(56%) 11(44%) 2(13.3%) 4(26.6%) 9(59.9%) 6(40%) 0.361303 Previous therapy Liver transplantation RFA Resection TACE SIRT Radiation Sorafenib Regorafenib PD-1 antibody Ramucimumab Cabozantinib 2 (8%) 4 (16%) 12 (48%) 11 (44%) 5 (20%) 1 (4%) 5 (20%) 1 (4%) 2 (8%) 1 (4%) 2 (8%) 0 (0%) 1 (16.7%) 6 (100%) 4 (66.7%) 2 (33.3%) 1 (16.6%) 1 (16.7%) 0 (0%) 1(16.7%) 0 (0%) 1 (16.7%) 2 (13.3%) 3 (20%) 4 (26.6%) 6 (40%) 2 (13.3%) 0 (0%) 3 (20%) 1 (6.7%) 1 (6.7%) 1 (6.7%) 1 (6.7%) 0.873678 Start dosis lenvatinib (mg/d) 4 8 12 9 (36%) 13 (52%) 3 (12%) 1 (16.6%) 5 (83.3%) 0 (0%) 5 (33.3%) 7 (46.7%) 3 (20%) 0.443842 Lenvatinib first line ≥second line 20 (80%) 5 (20%) 5 (83.3%) 1 (16.7%) 12 (80%) 3 (20%) 1 Therapy after lenvatinib Sorafenib Pembrolizumab Pembrolizumab + Lenvatinib Ramucimumab Cabozantinib 6(24%) 1(4%) 1(4%) 2(8%) 1(4%) 0 (0%) 1(16.7%) 1(16.7%) 1(16.7%) 0 (0%) 6(40%) 0 (0%) 0 (0%) 1(6.7%) 1(6.7%) 0.061203 Baseline characteristics of patients at the beginning of lenvatinib and three months after lenvatinib therapy. Numbers are presented as n (%) Abbreviations: ECOG, Eastern Cooperative Oncology Group performance status; BCLC, Barcelona Clinic Liver Cancer; AFP, alpha-fetoprotein; BMI, body mass index; ALBI, albumin-bilirubin score; MVP, main portal vein; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease ; HBV, hepatitis B virus; HCV, hepatitis C virus; SIRT, selective internal radiotherapy; TACE, transarterial chemoembolization; MELD, Model of End Stage Liver Disease; PD-1, programmed cell death protein 1 * Only 21 patients were evaluated, since four patients died before first CT-staging. Muscle development during lenvatinib therapy For the present study, 150 CT imaging data were evaluated at different time-points as described in the methods section. Three months after onset of therapy with lenvatinib, development of muscle mass in 21 patients could be evaluated. Four patients died before first CT staging and had to be ruled out from analysis. Of the remaining 21 patients, 15 patients lost muscle mass during the first three months of treatment with lenvatinib (p = 0.035) as shown in Fig. 1 . Interestingly, in our cohort, patients developing muscle loss during the first three months of lenvatinib intake (n = 15) showed similar baseline and therapy characteristics when compared to patients without muscle loss (n = 6) (Table 1 ). In particular, no differences were detected in performance status according to ECOG score (p = 0.9544). Of note, regarding liver function, 33.3% (2) in the non-sarcopenia group presented with worse liver function at onset of lenvatinib therapy vs. two patients (13.3%) in the sarcopenia group (p = 0.5436). In the non-sarcopenia group, no patients with Albi grade 3 were observed, while in the sarcopenia group, 19.9% (3) featured an ALBI grade 3 (p = 0.4466). The remaining parameters (e.g. age, sex, etiology of HCC or previous treatments) were similar between the two patient groups. Mainly, there was no difference between BMI and muscle mass status during the three months of lenvatinib therapy (Table 1 ). Efficacy of lenvatinib in all patients and influence of sarcopenia on OS, PFS and ORR Efficacy of lenvatinib in our cohort of patients was similar to published data from randomized trials and other retrospective analyses. The estimated median OS and median PFS for all patients (n = 25) were 18.0 months (95%CI:0.42,35.58) and 8.0 months (95%CI:3.52,12.48), respectively (Figs. 2 A and 2 B). There were no complete responses (Table 2 ), while 16% (4) achieved partial remission (PR) as best response to lenvatinib and 20% (5) stable disease (SD). The objective response rate (ORR) was 16% and the disease control rate (DCR) was 36%. Table 2 Objective response rate and disease control rate All patients n = 25 (%) Non muscle loss during 3 months Lenvatinib n = 6 (%)* Muscle loss during 3 months lenvatinib n = 15 (%)* PD 11 (44%) 1 (16.7%) 8 (53.3%) SD 5 (20%) 3 (50%) 1 (6.7%) PR 4 (16%) 1 (16.7%) 3 (20%) CR 0 (0%) 0 (0%) 0 (0%) unknown 5 (20%) 1 (16.7%) 3 (20%) ORR 4 (16%) 1 (16.7%) 3 (20%) DCR 9 (36%) 4 (66.7%) 4 (26.7%) Numbers are presented as n (%) Abbreviations: HCC, hepatocellular carcinoma; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate * Only 21 patients were evaluated, since four patients died before first CT staging. Regarding efficacy of lenvatinib in patients who developed muscle loss in the first three months of lenvatinib, the sarcopenia group showed similar OS of 18.0 months (95%CI:2.12, 33.89) compared to all patients and PFS of 13.0 months (95%CI 7.14, 18.86). Compared to the non-sarcopenia group, OS and PFS in patients of the sarcopenia group did not differ significantly (p = 0.783 and p = 0.396, respectively), (Figs. 2 C and 2 D). ORR was 16.7% in the non-sarcopenia group and 20% in the sarcopenia group (Table 2 ) (p = 1). Partial response was observed in 1 patient (16.7%) in the non-sarcopenia group vs. in three patients (20%) in the sarcopenia group. DCR was 26.7% in the sarcopenia group vs. 66.7% in the non-sarcopenia group. Analysis of factors potentially associated with OS Muscle status before start of lenvatinib therapy was also evaluated. As shown in Table 1 , 44% (11) of all patients (n = 25) presented muscle loss at baseline. Patients suffering from muscle loss before starting lenvatinib therapy seem to have shorter survival in terms of OS and PFS than patients without sarcopenia (Fig. 3 ) (P = 0.031). To further clarify the role of muscle loss before and during lenvatinib therapy, univariate analysis, including prognostic parameters, such as age, ALBI, Child-Pugh, ECOG, serum AFP ≥ 200 ng/ml and portal vein infiltration, were included together with muscle loss before and during lenvatinib therapy. As shown in Table 4 , in the univariate analysis, Child-Pugh score was identified as predictor of survival (HR 2.47, 95% CI 1.217, 5.012). However, presence of sarcopenia at onset of lenvatinib therapy was not found to be a negative predictor of survival. Decreasing SMI during the first three months of lenvatinib therapy was not identified as a poor prognostic factor. Multivariate analysis was not applicable due to small sample size. Table 4 Univariate Regression Analysis of factors associated with OS Parameter p HR 95%-CI Age 0.137 ECOG 0.232 ALBI 0.056 Child-Turcotte-Pugh score 0.012 2.472 1.217–5.012 Serum AFP 0.461 Portal Vein Infiltration 0.095 Muscle Loss before Lenva 0.128 Muscle Loss under Lenva 3M 0.675 n = 21 only patients with 3 months FU Abbreviation: ECOG, Eastern Cooperative Oncology Group performance status; ALBI, albumin-bilirubin score; AFP, alpha-fetoprotein Toxicity In Table 3 , all adverse effects (AEs) are documented. In all patients, AEs were observed during the observation period as follows: 40% (10), 16% (4), 12% (3) and 4% (1) discontinued lenvatinib therapy because of disease progression (PD), deterioration in liver function, serious adverse events, or intolerance, respectively. Three patients (12%) completed the therapy during two years. The most common adverse effects in all patients were fatigue, decreased weight, mucositis, diarrhea, hypertension, and decreased appetite. In 60% of patients (15), grade ≥ 3 adverse events were documented. Table 3 Adverse events during lenvatinib therapy Any grades Grade ≥ 3 Any grades grade ≥ 3 p p (all patients, n = 25) (all patients n = 25) Non muscle loss during 3 months lenvatinib n = 6* muscle loss during 3 months lenvatinib n = 15* Non muscle loss during 3 months lenvatinib n = 6* muscle loss during 3 months lenvatinib n = 15* any grade grade ≥ 3 Total treatment related AEs 25(100%) 15(60%) 6(100%) 15(100%) 5(83.3%) 5(33.3%) - 0.0635 Fatigue 16 (64%) 2 (8%) 5(83.3%) 7(46.7%) 1(16.7%) 0 0.1778 0.2857 Decreased weight 4 (16%) 1(4%) 0 4(26.7%) 0 1(6.7%) 0.2807 1 Mucositis 8 (32%) 1(4%) 4(66.7%) 3(20%) 1(16.7%) 0 1 0.2857 Diarrhoea 7 (28%) 2(8%) 2(33.3%) 5(93.3%) 1(16.7%) 1(6.7%) 1? 0.500 Hypertension 7 (28%) 0 2(33.3%) 4(26.7%) 0 0 1 - Decreased appetite 7 (28%) 0 2(33.3%) 3(20%) 0 0 0.5975 - Polyneuropathy/ Tremor 5 (20%) 0 1(16.7%) 4(26.7%) 0 0 1 - Infection 6 (24%) 3 (12%) 2(33.3%) 2(13.3%) 1(16.7%) 1(6.7%) 0.5439 0.500 Vertigo 4 (16%) 0 1(16.6%) 2(13.3%) 0 0 1 - Pain 6 (24%) 1 (4%) 0 4(26.7%) 0 0 0.2807 - Proteinuria 4 (16%) 0 2(33.3%) 2(13.3%) 0 0 0.5439 - Liver funtion disorder Elevated AST/ALT 3 (12%) 2 (8%) 0 2(13.3%) 0 1(6.7%) 1 1 Nausea 3 (12%) 0 1(16.7%) 2(13.3%) 0 0 1 - Dyspnoe 2 (8%) 0 0 1(6.7%) 0 0 1 - Neutropenia 2(8%) 1(4%) 1(16.7%) 1(6.7%) 1(16.7%) 0 0.500 0.2857 decreased platelet count 2(8%) 1(4%) 1(16.7%) 1(6.7%) 0 1(6.7%) 0.500 1 Arterial lung embolie 2 (8%) 2 (8%) 2(33.3%) 0 2(33.3%) 0 0.0714 0.0714 Pleura effusion/ edema 2 (8%) 0 0 2(13.3%) 0 0 1 - Constipation 1 (4%) 0 0 1(6.7%) 0 0 1 - Hand-Foot Syndrome 1 (4%) 0 0 1(6.7%) 0 0 1 - Pruritus 1 (4%) 0 0 1(6.7%) 0 0 1 - hepatic encephalopathy 1(4%) 0 0 1(6.7%) 0 0 1 - Increased Bilirubin/INR 1(4%) 1(4%) 0 1(6.7% 0 1(6.7%) 1 1 Numbers are presented as n (%) The table includes treatment-related adverse events (AEs) of any grades and grade ≥ 3, observed during treatment with lenvatinib * Only 21 patients were evaluated, since four patients died before first CT staging. Interestingly, patients developing muscle loss had fewer severe adverse effects. However, reduced rate of side effects was not significantly different compared to the patients without muscle loss (p = 0.06). Discussion In this study, we analyzed the effect of lenvatinib on muscle loss development in a non-selected real-life cohort of patients with advanced HCC. The majority of the patients significantly developed progressive muscle loss during the first three months of lenvatinib therapy. Outcome of all patients in terms of OS, PFS and ORR was similar to the published data in the pivotal prospective randomized phase III trial [ 1 ]. Despite muscle loss, patients benefitted from the therapy with lenvatinib since outcomes and toxicity were similar to the outcome of patients without muscle loss. HCC occurs mostly as a consequence of liver cirrhosis and chronic pre-existing liver diseases, such as viral hepatitis C or B, alcohol abuse and non-alcoholic steatohepatitis. As a result of these comorbidities, decreased physical activity and nutritional deficiencies are very common in these patients, causing loss in weight and muscle volume. Especially sarcopenia, which is defined as a significant loss of skeletal muscle mass, quality and/or function seemed to have a relevant prognostic role in these patients. In recent works, we and others elucidated the role of sarcopenia in the outcome of patients with liver cirrhosis [ 9 – 10 , 32 – 33 ]. In the last decade, previous studies reported on the prognostic value of sarcopenia also in solid tumors. Shachar et al. described in a meta-analysis that up to 74% of patients with advanced tumors were sarcopenic and that sarcopenia has a significant impact on cancer outcomes including OS and PFS [ 12 ]. Sarcopenia is also not a rare finding in patients with HCC. Moreover, several tyrosine kinase inhibitors (TKI), including sorafenib and lenvatinib, may increase sarcopenia. In patients with advanced HCC and treated with sorafenib, sarcopenia seems to be a prognostic factor for mortality and an independent factor for early dose-limiting sorafenib toxicities [ 15 , 20 ]. Lenvatinib has been approved since 2018 for first-line therapy of advanced HCC based on the results of the phase III REFLECT trial. Although sarcopenia as a possible prognostic parameter before and during therapy with lenvatinib was not analyzed in the REFLECT trial [ 1 ], the high frequency of patients with loss of appetite and weight reported during the therapy with lenvatinib, suggests a possible role in sarcopenia development which can influence on the outcome of patients [ 7 , 15 ]. How far lenvatinib influences the development of muscle mass and not only weight loss is unclear to date. Regarding the role of sarcopenia in patients with advanced HCC and treated with lenvatinib, only limited data, mostly from Japan, have been published to date. Confirming our hypothesis, in our cohort of patients from Germany, we detected a significant decrease of muscle loss (-6.5% ± 3.3%; p = 0.035) in the first three months of lenvatinib therapy in the majority of patients (60%). Moreover, this effect was observed not only in patients with previous muscle loss but also in patients without previous muscle loss. It has been described that several multikinase inhibitors, mainly targeting vascular endothelial growth factor (VEGFR/VEGF) signal cascade, are suspected of inducing muscle mass loss. VEGF seems to promote the proliferation of myogenic fibers. Thus, the effect of TKI could inhibit muscle growth due to this mechanism, exacerbating the muscle mass loss and inducing sarcopenia. Lenvatinib may inhibit tumor cell proliferation by downstream downregulation of PI3K, AKT and mTOR. The suppression of the AKT/mTOR pathway has also been described as being involved in muscle atrophy and may further explain the effects of lenvatinib on muscle mass. However, not all molecular pathways involved in sarcopenia have been fully elucidated to date. Further mechanisms, such as increased systemic inflammatory response and decreased protein synthesis due to chronic liver disease and cancer, are also involved in the aggravation of muscle mass loss in these patients [ 27 ]. Despite the significant muscle loss in our cohort of unselected patients, we observed a benefit in terms of mOS of 18.00 months (95%CI: 0.42, 35.58), PFS of 8.00 months (95%CI:3.52,12.48) and ORR of 16% due to systemic therapy with lenvatinib. In the REFLECT study, lenvatinib showed an OS of 13.6 months (95% CI: 12.1,14.9). The achieved ORR was 24.1% and PFS was 7.4 months (95% CI: 6.9 to 8.8 months). Regarding toxicity, grade ≥ 3 adverse events occurred in 60.0% of patients in our cohort during lenvatinib therapy, which is higher than the results of the REFLECT trial, where serious adverse events were observed in 43.1% of patients. Similar to the REFLECT trial, the most common adverse events found in our cohort were decreased weight in four patients (16%), mucositis in eight (32%), hypertension in seven (28%), diarrhea in seven (28%) and decreased appetite in seven patients (28%). Analyzing the base line characteristics of patients included in the REFLECT study, we found several differences compared to the characteristics of our cohort of patients. For instance, in the REFLECT trial, patients had BCLC stage B or C, Child-Pugh class A cirrhosis and ECOG score of 0 or 1. Additionally, patients with 50% or more liver occupation and/or bile duct or main portal vein invasion were excluded. Our real-life cohort of patients included 20% with Child Pugh B liver cirrhosis, 24% had ECOG ≥ 2 and 48% main infiltration of the portal vein, which were not included in the REFLECT study. Moreover, 100% of our patients had BCLC C, while only 78.2% of patients in the REFLECT trial were BCLC C. Finally, 24% of our patients received lenvatinib after at least one prior systemic therapy. Thus, our findings showed that lenvatinib was beneficial and safe in a European unselected cohort of patients with advanced HCC in daily clinical practice, confirming the data from other real-life cohorts of patients from Asia published to date. [ 28 – 31 ]. Most importantly, in this study, treatment with lenvatinib in patients developing muscle loss was also found to be beneficial in terms of OS and PFS. The mOS of the patients with muscle loss was 18.00 months (95%CI: 2.12, 33.89) and the PFS 13.0 months (95%CI 7.14, 18.86). This was not significantly different compared to the patients without muscle loss development (p = 0.783 and p = 0.396, respectively). ORR was comparable between the two groups. Partial response was observed in 16.7% (1) in the non-sarcopenia group vs. 20% (3) in the sarcopenia group. In the non-sarcopenia group, 50% (3) achieved SD. Regarding toxicity, there was no significant increase in side effects in patients who developed muscle loss during lenvatinib therapy. Indeed, patients developing muscle loss had fewer severe adverse effects, including less worsening of liver function. The presence of presarcopenia or sarcopenia before intake of lenvatinib was found to be a significant prognostic factor and a predictive marker for tolerability to lenvatinib in patients with advanced HCC and treated with lenvatinib in several studies published to date (Table 5 ) [ 16 – 17 , 22 – 24 , 26 ]. We also analyzed the impact of previous muscle loss on survival in patients treated with lenvatinib and found that suffering from previous sarcopenia before starting lenvatinib therapy (44%) showed that in these patients, survival in terms of OS and PFS was shorter than in patients without previous sarcopenia. However, in the univariate analysis, presence of muscle loss at onset of lenvatinib therapy and the development of muscle loss were not found to be negative predictors of survival. Table 5: Trials evaluating the effect of sarcopenia in patients with advanced HCC and treated with lenvatinib First Author/ Year Country Study desing N patients Methodes Time of muscle assesment Cut off value Comparison Outcome P Praktiknjo, et al, 2022 Germany Monocentric, Retrospective 25 CT scan: L3 SMI? es At the beginning and 3 months after lenvatinib treatment SMI: M:< 42 cm ² /m ² W: <38 cm ² /m ² Sarcopenia vs. Non-Sarcopenia OS PFS p=0.783 p=0.396 Dong et al, 2022 [33] China Monocentric retrospective 40 CT scan: L3 SMI 1month prior to the initiation of lenvatinib SMI: M:< 42 cm ² /m ² W: <38 cm ² /m ² sarcopenia patients vs. non-sarcopenia patients OS PFS 0.024 0.044 Hiraoka et al, 2021 [25] Japan Multicentric Retrospecive 151 CT scan: L3- PSI 1 month before and 4 weeks after starting lenvatinib treatment SMI: M: 4.24 cm²/m² W: 2.50 cm²/m² Pre-sarcopenia vs non pre-sarcopenia OS PFS <0.001 0.025 Kotoh et al, 2020 [37] Japan Monocentric, Retrospective 53 CT scan: L3- SMI HGS: GS dynamometer Before receiving lenvatinib SMI: M:< 42 cm²/m² W: <38 cm²/m² HGS M:<26 kg W:<18 kg HGS : Low vs. High Muscle depletion vs. Non-Muscle depletion Sarcopenia vs. non- Sarcopenia OS TTF 0.036 Endo et al, 2020 [34] Japan Monocentric Retrospective 63 CT scan: L3- SMI GS: measurement complies with the established guideline (JSH) Before receiving lenvatinib GS: M:<26 Kg W: < 18 Kg SMI: M:<42 cm²/m² W: <38 cm²/m² GS: Normal vs. decreased SMI : Normal SMI vs decreased SMI, OS PFS PPS 0.9 Uojima et al, 2020 [35] Japan Multicentric Retrospective 100 CT scan: L3-SMI before treatment initiation SMI: M: < 42 cm²/m² W: < 38 cm²/m²: SMI : low vs high TTF OS 0.010 0.021 Rinninella et al, 2019 [26] Italy Two case Reports Retrospective 2 CT scan: L3- SMA At baseline and at 24 months after lenvatinib skeletal muscle area treatment - SMA , Baseline vs. 24 months after the start of lenvatinib therapy OS PFS - Abbreviations: SM, skeletal muscle; SMI, skeletal muscle index , calculated as skeletal muscle mass divided by height squared (cm²/m²); HGS, handgrip strength; L3, third lumbar vertebra level; OS, Overall survival; MST, median survival time; n.s., non significant; PFS, progression free survival; PPS, post- progression survival; SMA, skeletal mass area; PSI, psoas muscle area index (muscle area at level of middle of third lumbar vertebra (cm²)/height (m²); TTF, time to treatment failure Comparing our study to data published to date, ours is one of the first analyses on skeletal muscle evolution during lenvatinib therapy in patients with advanced HCC from a European cohort of patients (Table 5 ). Only one report including two cases of patients from the REFLECT study from Italy has been published from Europe to date. In these two patients, muscle mass loss was studied over 24 months. Contrary to our findings, only a minimal reduction of muscle mass was detected in the two patients (2.13% and 10.83%), while 60% (15) in our cohort showed significant muscle mass loss (-6.5% ± 3.3%, p = 0.035) already after three months of lenvatinib therapy. OS of the two Italian patients (34 and 42 months) and duration of lenvatinib therapy (25 and 32 months) were longer than other cases reported to date [ 17 ]. Further monocentric and multicentric studies published to date are reporting on data from Asia (Japan, China). They also reported on the role of sarcopenia in patients with advanced HCC treated with lenvatinib. However, these studies focused on the impact of sarcopenia before therapy with lenvatinib on outcome and tolerability to lenvatinib and not on the impact of lenvatinib on sarcopenia during the treatment. For instance, in the study presented by Uojima et al. 2020 with 100 patients from Japan, decreased muscle mass was shown to be associated with increased severe AEs and reduced OS [ 24 ]. In this study, the majority of patients were ECOG 0 and 49% with BCLC B, while our patients were mostly ECOG 1 or higher and all patients presented with tumor stage BCLC C. Muscle mass assessment was performed only before lenvatinib therapy and defined as skeletal muscle index (SMI). In line with our data, sarcopenia before lenvatinib therapy was associated with reduced survival and PFS. In another large retrospective trial presented by Hiraoka et al. 2021 from Japan with 151 patients, presarcopenia before onset of therapy with lenvatinib was shown to be a significant prognostic factor for survival (HR 1.652, p = 0.042) [ 16 ]. However, no longitudinal analysis of the effects of lenvatinib on sarcopenia were presented in these studies. In our study, CT imaging was selected to quantify muscle mass. This non-invasive method allows correlation with the whole-body mass. Moreover, we and other have already shown that this muscle mass measurement is a strong predictor for mortality in patients with cirrhosis and HCC (32–33). However, some of the studies with HCC patients treated with lenvatinib published to date (Table 5 ) showed the effect of handgrip strength rather than skeletal muscle mass as a negative predictor of survival. For instance, in the 2020 retrospective analysis by Endo K et al., 63 patients with advanced HCC and treated with lenvatinib were analyzed. A decreased grip strength (GS) and decreased skeletal muscle mass index (SMI) were found in 33.3% and 34.9% of the patients, respectively. In this study, only GS seemed to have an impact on survival, since OS of the normal GS group was significantly higher than of the decreased GS group, while that of the normal and decreased SMI groups did not significantly differ, indicating that muscle strength and not just muscle mass alone may be also relevant as a prognostic marker [ 23 ]. Since all published studies to date included only patients from Asia, mostly from Japan, and quantitative and qualitative assessments of sarcopenia with different cut-off values among the published studies were presented, further direct comparisons among the studies are difficult. Nutritional habits and body composition may differ considerably between Japan and Europe with different impact on the effects of muscle mass during therapy with lenvatinib. To date, there are limited comparable data available including patients from outside Asia. Contrary to our findings, the analysis of two Italian patients published by Rinninella et al. showed only a minimal loss of muscle mass during therapy with lenvatinib [ 17 ]. More data from other cohorts of patients are warranted to clarify the role of sarcopenia in the treatment of patients with advanced HCC. Moreover, preventive and therapeutic interventions to avoid or to reduce sarcopenia, as already indicated [ 15 ], should be included and investigated in clinical studies in more detail. The limitations of the present study include the relatively small number of patients and its retrospective design with patients of a single institution. Therefore, lack of significance between the patients without development of muscle loss and the patients with development of muscle loss could be related to the low number of patients. Moreover, four patients died before assessment of skeletal muscle mass three months after onset of lenvatinib therapy. Thus, sample selection may be biased. We evaluated only a quantitative parameter of skeletal muscle mass, but no quality parameters of the muscle mass, such as grip strength. The strengths of this trial are the inclusion of a European cohort of patients with different clinical body and nutritional features compared to patients from Japan and the assessment of sarcopenia not only at baseline but also over the course of therapy with lenvatinib. In summary, our study in an unselected European cohort of patients with advanced HCC and treated with lenvatinib showed similar outcome in terms of OS, PFS and ORR to published data in the pivotal prospective randomized phase III trial (REFLECT). Three months after starting lenvatinib therapy, most patients experienced a significant loss of skeletal muscle mass. However, despite of developing muscle loss, patients benefitted from the therapy with lenvatinib. No significant difference in OS and PFS between the group of patients developing muscle loss and the non-muscle loss group was found. Further studies are necessary to elucidate the role of muscle loss in patients with advanced HCC treated with lenvatinib. Since several studies showed a negative effect of sarcopenia on OS and tolerability to TKI in cancer patients, including HCC, sarcopenia assessment before and during lenvatinib should be taken into account and, if applicable, nutritional and sports measures should be started early on to prevent or improve sarcopenia both in clinical trials and in everyday practice in order to improve prognosis. Declarations Author contributions MP: sarcopenia measurement, analysis and interpretation of data, drafting of the manuscript and statistical analysis; ASP: acquisition of data, creating and editing of Figures and Tables, drafting of the manuscript; FS : analysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content; CM,TZ, RM, MBM, GF, PB, CB, AS, SM AMS, JL, SN, HM, SM, JCK and CPS: acquisition of data and critical revision of the manuscript for important intellectual content; TW, MS: critical revision of the statistical data and manuscript for important intellectual content; CM: acquisition of data, analysis and interpretation of computer tomography data and critical revision of the manuscript for important intellectual content; MG: acquisition of data, analysis and interpretation of data, drafting of the manuscript, study concept and design. All authors have read and agreed to the published version of the manuscript Ethic Statement: All methods were carried out in accordance with relevant guidelines and regulations. This retrospective study was approved by the Ethics Committee of the Medical Faculty of the University of Bonn (No. 341/17).Written informed consent was obtained from all patients. Conflict of Interest There are no conflicts of interest for any author involved in this study. Data availability The data generated during this study are included in this article. References Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. Mar 24; 391(10126):1163-1173, https://doi.org/10.1016/S0140-6736 (18)30207-1 (2018). Bray, F.et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Nov; 68(6):394-424, https://doi.org/10.3322/caac.21492 (2018). Kanneganti, M. Singal, A.G. INCIDENCE OF HEPATOCELLULAR CARCINOMA IN NONALCOHOLIC FATTY LIVER DISEASE. Gastroenterology. Feb 1:S0016-5085(22)00092-0, https://doi.org/10.1053/j.gastro.2022.01.037 (2022). Llovet, J.M. et al. Hepatocellular carcinoma. Nat Rev Dis Primers. Jan 21; 7(1):6, https://doi.org/10.1038/s41572-020-00240-3 (2021). Vogel, A. Martinelli, E. ESMO Guidelines Committee. [email protected] ; Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. Jun;32(6):801-805, https://doi.org/10.1016/j.annonc.2021.02.014 (2021). European Association for the Study of the Liver. Electronic address: [email protected] ; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. Jul;69(1):182-236, https://doi.org/10.1016/j.jhep.2018.03.019 (2018). Ikeda, K. et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. Apr;52((4)):512–9, https://doi.org/10.1007/s00535-016-1263-4 (2017). Shachar, S.S. et al. Skeletal muscle measures as predictors of toxicity, hospitalization, and survival in patients with metastatic breast cancer receiving taxane-based chemotherapy. Clin Cancer Res. Feb;23((3)):658–65, https://doi.org/10.1158/1078-0432.CCR-16-0940 (2017). Praktiknjo, M. et al. Sarcopenia Is Associated With Development of Acute-on-Chronic Liver Failure in Decompensated Liver Cirrhosis Receiving Transjugular Intrahepatic Portosystemic Shunt. Clin Transl Gastroenterol. Apr;10(4):e00025, https://doi.org/10.14309/ctg.0000000000000025 (2019). Praktiknjo, M. et al. Fat-free muscle mass in magnetic resonance imaging predicts acute-on-chronic liver failure and survival in decompensated cirrhosis. Hepatology. Mar;67(3):1014-1026, https://doi.org/10.1002/hep.29602 (2018). Prado, C.M. et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. Jul;9: 629-35, https://doi.org/10.1016/S1470-2045(08)70153-0 (2008). Shachar, S.S., Williams, G. R., Muss, H. B. , Nishijima, T. F. Prognostic value of sarcopenia in adults with solid tumors: A meta-analysis and systematic review. European Journal of Cancer . Volume 57: 58-67, https://doi.org/10.1016/j.ejca.2015.12.030 (2016). Meza-Junco, J. et al. Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma. J Clin Gastroenterol. Nov-Dec;47(10):861-70, https://doi.org/10.1097/MCG.0b013e318293a825 (2013). Hsu, C.S., Kao, J.H. Sarcopenia and chronic liver diseases. Expert Rev Gastroenterol Hepatol. Dec;12 (12):1229-1244, https://doi.org/10.1080/17474124.2018.1534586 (2018). Marasco, G. et al. Clinical impact of sarcopenia assessment in patients with hepatocellular carcinoma undergoing treatments. J Gastroenterol. Oct;55(10):927-943, https://doi.org/10.1007/s00535-020-01711-w (2020). Hiraoka, A. et al. Real-life Practice Experts for HCC (RELPEC) Clinical importance of muscle volume in lenvatinib treatment for hepatocellular carcinoma: Analysis adjusted with inverse probability weighting. J Gastroenterol Hepatol. Jul; 36(7):1812-1819, https://doi.org/10.1111/jgh.15336 (2021). Rinninella, E. et al. Minimal impact of lenvatinib (Lenvima®) on muscle mass in advanced hepatocellular carcinoma and implications for treatment duration. Two cases from the REFLECT study. European Review for Medical and Pharmacological Sciences.; 23: 10132-10138, https://doi.org/10.26355/eurrev_201911_19583 (2019). Nowak, S, Faron, A, Luetkens, JA. Fully Automated Segmentation of Connective Tissue Compartments for CT-Based Body Composition Analysis: A Deep Learning Approach. Investigative Radiology: June 2020 - Volume 55 - Issue 6 - p 357-366 Luetkens, J.A. et al. Opportunistic Computed Tomography Imaging for the Assessment of Fatty Muscle Fraction Predicts Outcome in Patients Undergoing Transcatheter Aortic Valve Replacement. Research Letter. © 2020 American Heart Association,Inc.Circulation. ; 141:234–236, https://doi.org/10.1161/CIRCULATIONAHA.119.042927 (2020). Chang, K.V. et al. Association between loss of skeletal muscle mass and mortality and tumor recurrence in hepatocellular carcinoma: a systematic review and meta‐analysis. Liver Cancer; 7: 90‐103, https://doi.org/10.1159/000484950 (2018). Nishikawa, H. et al. Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): Recommendation from the working group for creation of sarcopenia assessment criteria. Hepatol Res. Sep;46(10):951-63, https://doi.org/10.1111/hepr.12774 (2016). Dong, D. et al. Prognostic significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib. Medicine (Baltimore). Feb 4; 101(5):e28680, https://doi.org/10.1097/MD.0000000000028680 (2022). Endo, K. et al.Impact of Grip Strength in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib. Cancers (Basel). Aug 3; 12(8):2146, https://doi.org/10.3390/cancers12082146 (2020). Uojima, H. et al. Skeletal Muscle Mass Influences Tolerability and Prognosis in Hepatocellular Carcinoma Patients Treated with Lenvatinib. Liver Cancer. Apr;9(2):193-206, https://doi.org/10.1159/000504604 (2020). Perisetti, A. et al. Sarcopenia in hepatocellular carcinoma: Current knowledge and future directions. World J Gastroenterol. Jan 28; 28(4):432-448, https://doi.org/10.3748/wjg.v28.i4.432 (2022). Kotoh, Y. et al. Effect of Handgrip Strength on Clinical Outcomes of Patients with Hepatocellular Carcinoma Treated with Lenvatinib. Applied Sciences. 10 (16):5403, https://doi.org/10.3390/app10165403 (2020). Meza-Junco, J. et al. Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma. J Clin Gastroenterol; 47: 861-870, https://doi.org/10.1097/MCG.0b013e318293a825 (2013) Shimozato, N. et al. Efficacy and Safety of Lenvatinib for Patients with Advanced Hepatocellular Carcinoma: A Retrospective, Real-world Study Conducted in Japan. Anticancer Res. Jan; 42(1):173-183, https://doi.org/10.21873/anticanres.15471 (2022). Tsuchiya, K. et al, On Behalf Of Japanese Red Cross Liver Study Group. The Real-World Data in Japanese Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib from a Nationwide Multicenter Study. Cancers (Basel). May 26; 13(11):2608, https://doi.org/10.3390/cancers13112608 (2021). Goh, M.J. et al. Efficacy and Safety of Lenvatinib Therapy for Unresectable Hepatocellular Carcinoma in a Real-World Practice in Korea. Liver Cancer. Feb; 10(1):52-62, https://doi.org/10.1159/000512239 (2021). Wang, D.X. et al. Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China. World J Gastroenterol .; 26(30):4465-4478, https://doi.org/10.3748/wjg.v26.i30.4465 (2020). Faron, A. et al. Combination of Fat-Free Muscle Index and Total Spontaneous Portosystemic Shunt Area Identifies High-Risk Cirrhosis Patients. Front Med (Lausanne). Apr 12; 9:831005, https://doi.org/10.3389/fmed.2022.831005 (2022). Tantai, X. et al. Effect of sarcopenia on survival in patients with cirrhosis: A meta-analysis. J Hepatol. Mar; 76(3):588-599, https://doi.org/10.1016/j.jhep.2021.11.006 (2022). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 27 Sep, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 15 Nov, 2023 Reviews received at journal 15 Nov, 2023 Reviewers agreed at journal 14 Nov, 2023 Reviews received at journal 02 Nov, 2023 Reviewers agreed at journal 26 Sep, 2023 Reviewers agreed at journal 28 Jun, 2023 Reviewers invited by journal 12 Jun, 2023 Editor assigned by journal 07 Jun, 2023 Editor invited by journal 25 Apr, 2023 Submission checks completed at journal 25 Apr, 2023 First submitted to journal 03 Apr, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2771181","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":194871407,"identity":"c2745c33-a606-4bbe-84a0-3943caf8d8a7","order_by":0,"name":"Michael Praktiknjo","email":"","orcid":"","institution":"University Hospital Münster","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Praktiknjo","suffix":""},{"id":194871409,"identity":"6656ae03-2015-4c52-91c8-e93242f5291f","order_by":1,"name":"Ana S. Pena Solano","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"S. Pena","lastName":"Solano","suffix":""},{"id":194871411,"identity":"c06db2ee-d606-484a-8cd0-b797c36abf17","order_by":2,"name":"Farsaneh Sadeghlar","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Farsaneh","middleName":"","lastName":"Sadeghlar","suffix":""},{"id":194871412,"identity":"75ed7926-ebe1-4b49-afc9-6a4f160fa176","order_by":3,"name":"Thomas Welchowski","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Welchowski","suffix":""},{"id":194871413,"identity":"286eb072-595c-4ee6-879c-139e3d644ace","order_by":4,"name":"Matthias Schmid","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Schmid","suffix":""},{"id":194871414,"identity":"25bf1dbd-dbdd-4b3c-a634-204a8372eb14","order_by":5,"name":"Christian Möhring","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Möhring","suffix":""},{"id":194871415,"identity":"67356859-6e4a-41f0-aeec-54d6e29a20e6","order_by":6,"name":"Taotao Zhou","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Taotao","middleName":"","lastName":"Zhou","suffix":""},{"id":194871416,"identity":"95638b2b-f6f1-49c6-bd1e-72191fd4ca1c","order_by":7,"name":"Robert Mahn","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Mahn","suffix":""},{"id":194871417,"identity":"52470f5c-7df3-4415-9048-f322b569b9dc","order_by":8,"name":"Malte B. Monin","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Malte","middleName":"B.","lastName":"Monin","suffix":""},{"id":194871418,"identity":"1418ac9e-4b4a-44d8-9f3d-f451a3e43245","order_by":9,"name":"Carsten Meyer","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Carsten","middleName":"","lastName":"Meyer","suffix":""},{"id":194871419,"identity":"01a8bbc3-9bc1-46c4-a1ae-0a5e6634f245","order_by":10,"name":"Georg Feldmann","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Georg","middleName":"","lastName":"Feldmann","suffix":""},{"id":194871420,"identity":"97d6b10a-fff1-4281-ad43-ad427992f0c1","order_by":11,"name":"Peter Brossart","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Brossart","suffix":""},{"id":194871421,"identity":"498451a0-cbce-4f64-b3e6-f815012fa63f","order_by":12,"name":"Cornelius Beekum","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Cornelius","middleName":"","lastName":"Beekum","suffix":""},{"id":194871422,"identity":"f66ab471-2652-45f9-939a-7afe6117aac3","order_by":13,"name":"Alexander Semaan","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Alexander","middleName":"","lastName":"Semaan","suffix":""},{"id":194871423,"identity":"e38a0cc1-398d-453f-b3c6-38a68d954414","order_by":14,"name":"Hanno Matthaei","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Hanno","middleName":"","lastName":"Matthaei","suffix":""},{"id":194871424,"identity":"5bcb3894-e5fc-4cbb-aa63-dcf6335db7b8","order_by":15,"name":"Steffen Manekeller","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Steffen","middleName":"","lastName":"Manekeller","suffix":""},{"id":194871425,"identity":"4e8d07e8-194f-44ca-b8e7-2764773a925a","order_by":16,"name":"Alois M. Sprinkart","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Alois","middleName":"M.","lastName":"Sprinkart","suffix":""},{"id":194871426,"identity":"a64ae05d-1c32-4070-9275-955b14212de2","order_by":17,"name":"Sebastian Nowak","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Sebastian","middleName":"","lastName":"Nowak","suffix":""},{"id":194871427,"identity":"28720a17-b6de-4cfe-a14a-df067dc214db","order_by":18,"name":"Julian Luetkens","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Julian","middleName":"","lastName":"Luetkens","suffix":""},{"id":194871428,"identity":"93c4bfd4-0a6a-4ba6-9be0-addaf8126f3f","order_by":19,"name":"Jörg C. Kalff","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Jörg","middleName":"C.","lastName":"Kalff","suffix":""},{"id":194871429,"identity":"d231bfa5-4c60-4eae-99e2-22662c391153","order_by":20,"name":"Christian P. Strassburg","email":"","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"P.","lastName":"Strassburg","suffix":""},{"id":194871430,"identity":"4f644249-d1d0-43a2-b027-0adef537a553","order_by":21,"name":"Maria A. Gonzalez -Carmona","email":"data:image/png;base64,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","orcid":"","institution":"University Hospital Bonn","correspondingAuthor":true,"prefix":"","firstName":"Maria","middleName":"A. Gonzalez","lastName":"-Carmona","suffix":""}],"badges":[],"createdAt":"2023-04-03 10:44:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2771181/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2771181/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-66766-8","type":"published","date":"2024-09-27T15:57:56+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":36399049,"identity":"8f1b743f-2cd1-4553-9dab-9994babc57f7","added_by":"auto","created_at":"2023-04-27 22:15:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56963,"visible":true,"origin":"","legend":"\u003cp\u003eThree months after starting of lenvatinib therapy, development of muscle mass of 21 patients could be evaluated. Of these, 15 showed muscle atrophy (p=0.035). A significant decrease of muscle loss (-6.5% ± 3.3%; p=0.035) in the first three months of lenvatinib therap in the majority of patients (60%) was detected.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2771181/v1/66bba4606be8e6a8e151a90b.jpg"},{"id":36398677,"identity":"eb027ea3-8d03-4f90-8b81-e58618044e1a","added_by":"auto","created_at":"2023-04-27 22:07:53","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":90783,"visible":true,"origin":"","legend":"\u003cp\u003eC/D. Kaplan–Meier curves for OS (C) and PFS (D) in sarcopenia patients (n=15) and non-sarcopenia (n=6) patients during three months of lenvatinib therapy. \u0026nbsp;Median OS was 18 months in the sarcopenia and in the non-sarcopenia group (p=0.783). Median PFS was 13 months in sarcopenia patients and in non-sarcopenia patients, respectively (p=0.396).\u003c/p\u003e\n\u003cp\u003eOS = overall survival, PFS = progression free survival.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2771181/v1/403d5dd22251276fc7060b5e.jpg"},{"id":36398676,"identity":"f162f234-9ef5-4f05-b16d-94d9077c99c4","added_by":"auto","created_at":"2023-04-27 22:07:53","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":39435,"visible":true,"origin":"","legend":"\u003cp\u003eMuscle status of patients before onset of lenvatinib therapy.\u003c/p\u003e\n\u003cp\u003eMedian OS was seven months in the sarcopenia group and 18 months in non-sarcopenia patients (p=0.031).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-2771181/v1/c9f43ad5b234557d73c5608f.jpg"},{"id":65627296,"identity":"b595a4bb-6294-4ea8-bd88-86f83b785cb6","added_by":"auto","created_at":"2024-09-30 16:14:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2383640,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2771181/v1/8fed8e2e-ed6e-467b-b68f-c87a56e45b16.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The impact of lenvatinib on sarcopenia in patients with advanced unresectable hepatocellular carcinoma","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third leading cause of cancer-related death worldwide. Despite recent advances in the systemic treatment of advanced HCC, the prognosis of HCC is still poor. Chronic viral hepatitis B/C, alcohol use disorder, metabolic liver disease (particularly nonalcoholic fatty liver disease) and aflatoxins are the most frequent risk factors for HCC. The molecular mechanisms of HCC progression have not yet been completely clarified [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe relevant parameters for determining prognosis and therapy of HCC are defined by the Barcelona Classification for Liver Cancer (BCLC). Further prognostic scores or parameters, such as ALBI, but also ECOG status and clinical symptoms, may be applied to predict HCC prognosis. HCC is often diagnosed at advanced stages (BCLC C). In this case and considering international guidelines, such as EASL or ESMO, first-line systemic therapy with atezolizumab (PD-L1 antibody) in combination with bevacizumab is recommended based on data from the phase III IMbrave150 trial. In case of toxicity or contraindications, oral therapy with sorafenib or lenvatinib is recommended [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e Lenvatinib was approved in 2018 for the treatment of advanced HCC as first-line therapy. Based on results from the randomized phase III REFLECT trial, lenvatinib was not inferior to sorafenib regarding overall survival (OS) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Side effects related to lenvatinib were manageable with dose modifications. In addition, it has been reported that high serum lenvatinib levels resulted in weight (muscle and fat) loss [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. However, weight loss did not serve as a good predictor of prognosis to lenvatinib therapy in contrast to muscle loss [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Sarcopenia defined as skeletal muscle mass loss and/or grip strength reduction can easily be measured using computed tomography (CT) or magnetic resonance imaging (MRI). We and others have shown that sarcopenia is common in patients with advanced liver disease or malignancies and that it represents a relevant independent prognostic factor in these patients [\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. For instance, measurement of muscle mass at the third lumbar vertebra (L3) using CT has been shown to be a strong independent predictor of mortality in patients with cirrhosis or HCC [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Furthermore, muscle depletion can lead to physical disability in patients with HCC resulting in reduced tolerability to chemotherapy and TKI [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Finally, it has been shown that several TKIs can aggravate patients' sarcopenia due to different mechanisms. Only few studies, mostly from Japan, have reported on the clinical impact of sarcopenia on patients with advanced HCC treated with lenvatinib. However, the data are very limited and controversial and do not show the effects of lenvatinib on muscle mass [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eBase line characteristics\u003c/h2\u003e \u003cp\u003eTwenty-five patients treated with lenvatinib were enrolled in the study between June 2018 and November 2020. The median observation period was seven months (range\u0026thinsp;=\u0026thinsp;0\u0026ndash;23 months). Base line characteristics of all patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Sixteen of the patients were male (64%) and median age was 67 (39\u0026ndash;81 years). At the start of lenvatinib therapy, 76% (19) of the patients presented an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (eight patients ECOG 0, 11 patients ECOG 1). All patients had advanced HCC corresponding to BCLC stage C, of whom 12 (48%) patients presented with macroscopic infiltration of the main portal vein and 19 patients (76%) with extrahepatic metastasis. In 48% (12) AFP level was \u0026ge;\u0026thinsp;200 ng/ml. The ALBI score was 1 in 36% (8), 2 in 14 patients (56%) and 3 in three patients (12%). Regarding comorbidities, 80% (20) had concomitant Child-Pugh A liver cirrhosis and 20% (5) Child-Pugh B liver cirrhosis (four patients with 7 points, one patient with 8 points). Among the causes of liver cirrhosis, the following were the most common: chronic hepatitis B 20% (5), chronic hepatitis C 12% (3), alcohol 24% (6) and NASH/NAFLD 24% (6). Regarding treatment characteristics, nine (36%) patients received 4 mg/day as starting dose of lenvatinib and 52% (13) received 8 mg/day. Only 12% (3) received a 100% lenvatinib dose of 12 mg/day as starting dose. Interestingly, five patients (20%) received lenvatinib as second-line treatment, 8% (2), 4% (1) as third-line, and 4% (1) as fourth- line and even fifth-line therapy. Further previous and follow-up therapies are documented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Regarding weight and muscle mass, 76% (19) of the patients weighed above 60 kg and 72% (14) were overweight with a BMI\u0026thinsp;\u0026gt;\u0026thinsp;25. Interestingly, from the diagnosis of HCC to the start of lenvatinib therapy, 52% (12) had already lost muscle mass.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline and therapy characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e All patients\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon muscle loss during 3 months lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;6 (%)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMuscle loss\u003c/p\u003e \u003cp\u003eduring 3 months lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;15 (%)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026lt;65\u003c/p\u003e\u003cp\u003e\u0026ge;65\u003c/p\u003e\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (48%)\u003c/p\u003e \u003cp\u003e13 (52%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (50%)\u003c/p\u003e \u003cp\u003e3 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (53.2%)\u003c/p\u003e \u003cp\u003e7 (46.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex\u003c/b\u003e\u003c/p\u003e \u003cp\u003emale\u003c/p\u003e \u003cp\u003efemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (64%)\u003c/p\u003e \u003cp\u003e9 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7%)\u003c/p\u003e \u003cp\u003e2 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10 (66.7%)\u003c/p\u003e \u003cp\u003e5 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eECOG\u003c/b\u003e\u003c/p\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003cp\u003e\u0026ge;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (76%)\u003c/p\u003e \u003cp\u003e6 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (83.3%)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (86.7%)\u003c/p\u003e \u003cp\u003e2 (13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9544\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEtiology\u003c/b\u003e\u003c/p\u003e \u003cp\u003eHBV\u003c/p\u003e \u003cp\u003eHCV\u003c/p\u003e \u003cp\u003eAlcohol\u003c/p\u003e \u003cp\u003eNASH/NAFLD\u003c/p\u003e \u003cp\u003eOther/unknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003cp\u003e6 (24%)\u003c/p\u003e \u003cp\u003e6 (24%)\u003c/p\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (33.3%)\u003c/p\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (13.3%)\u003c/p\u003e \u003cp\u003e2 (13.3%)\u003c/p\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003cp\u003e4 (26.7%)\u003c/p\u003e \u003cp\u003e4 (26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.911233\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eChild Pugh score\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA\u003c/p\u003e\u003cp\u003eB\u003c/p\u003e\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (80%)\u003c/p\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.6%)\u003c/p\u003e \u003cp\u003e2 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (86.5%)\u003c/p\u003e \u003cp\u003e2 (13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.543558\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMELD \u0026gt;6 Points\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (84%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (79.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBCLC C\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMacroscopic MVP infiltration\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (48%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (26.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtrahepatic metastasis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (59.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAFP (ng/ml)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026lt;\u0026thinsp;200\u003c/p\u003e \u003cp\u003e\u0026ge;\u0026thinsp;200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (52%)\u003c/p\u003e \u003cp\u003e12 (48%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.6%)\u003c/p\u003e \u003cp\u003e2 (33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7 (46.6%)\u003c/p\u003e \u003cp\u003e8 (53.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.634617\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eALBI\u003c/b\u003e\u003c/p\u003e \u003cp\u003eGrade 1\u003c/p\u003e\u003cp\u003eGrade 2\u003c/p\u003e\u003cp\u003eGrade 3\u003c/p\u003e\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (36%)\u003c/p\u003e \u003cp\u003e14 (56%)\u003c/p\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (49.9%)\u003c/p\u003e \u003cp\u003e3 (49.9%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (26.6%)\u003c/p\u003e \u003cp\u003e8 (53.2%)\u003c/p\u003e \u003cp\u003e3 (19.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0,446579\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;18.5\u003c/p\u003e\u003cp\u003e\u0026gt;\u0026thinsp;18.5 - \u0026le;25\u003c/p\u003e\u003cp\u003e\u0026gt;\u0026thinsp;25\u003c/p\u003e\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003cp\u003e8 (20%)\u003c/p\u003e \u003cp\u003e14 (72%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003cp\u003e2 (33.3%)\u003c/p\u003e \u003cp\u003e3 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (6.6%)\u003c/p\u003e \u003cp\u003e6 (39.9%)\u003c/p\u003e \u003cp\u003e8 (53.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight (Kg)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e\u0026le;\u0026thinsp;60\u003c/p\u003e \u003cp\u003e\u0026gt;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (24%)\u003c/p\u003e \u003cp\u003e19 (76%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003cp\u003e5 (83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (26.6%)\u003c/p\u003e \u003cp\u003e11 (73.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMuscle mass assesment at beginning /during 3 months lenvatinib therapy\u003c/b\u003e\u003c/p\u003e \u003cp\u003eNon-sarcopenia\u003c/p\u003e \u003cp\u003eSarcopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14(56%)\u003c/p\u003e \u003cp\u003e11(44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(13.3%)\u003c/p\u003e \u003cp\u003e4(26.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9(59.9%)\u003c/p\u003e \u003cp\u003e6(40%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.361303\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrevious therapy\u003c/b\u003e\u003c/p\u003e \u003cp\u003eLiver transplantation\u003c/p\u003e \u003cp\u003eRFA Resection TACE SIRT Radiation Sorafenib Regorafenib PD-1 antibody Ramucimumab Cabozantinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003cp\u003e12 (48%)\u003c/p\u003e \u003cp\u003e11 (44%)\u003c/p\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003cp\u003e6 (100%)\u003c/p\u003e \u003cp\u003e4 (66.7%)\u003c/p\u003e \u003cp\u003e2 (33.3%)\u003c/p\u003e \u003cp\u003e1 (16.6%)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (13.3%)\u003c/p\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003cp\u003e4 (26.6%)\u003c/p\u003e \u003cp\u003e6 (40%)\u003c/p\u003e \u003cp\u003e2 (13.3%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003cp\u003e1 (6.7%)\u003c/p\u003e \u003cp\u003e1 (6.7%)\u003c/p\u003e \u003cp\u003e1 (6.7%)\u003c/p\u003e \u003cp\u003e1 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.873678\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eStart dosis lenvatinib (mg/d)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e4 8 12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (36%)\u003c/p\u003e \u003cp\u003e13 (52%)\u003c/p\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.6%)\u003c/p\u003e \u003cp\u003e5 (83.3%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5 (33.3%)\u003c/p\u003e \u003cp\u003e7 (46.7%)\u003c/p\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.443842\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLenvatinib\u003c/b\u003e first line \u0026ge;second line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (80%)\u003c/p\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (83.3%)\u003c/p\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (80%)\u003c/p\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTherapy after lenvatinib\u003c/b\u003e Sorafenib Pembrolizumab Pembrolizumab\u0026thinsp;+\u0026thinsp;Lenvatinib Ramucimumab Cabozantinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(24%)\u003c/p\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003cp\u003e2(8%)\u003c/p\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(40%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.061203\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eBaseline characteristics of patients at the beginning of lenvatinib and three months after lenvatinib therapy.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eNumbers are presented as n (%)\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eAbbreviations: ECOG, Eastern Cooperative Oncology Group performance status; BCLC, Barcelona Clinic Liver Cancer;\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003eAFP, alpha-fetoprotein; BMI, body mass index; ALBI, albumin-bilirubin score; MVP, main portal vein; NASH, non-alcoholic steatohepatitis; NAFLD, non-alcoholic fatty liver disease ; HBV, hepatitis B virus; HCV, hepatitis C virus; SIRT, selective internal radiotherapy; TACE, transarterial chemoembolization; MELD, Model of End Stage Liver Disease; PD-1, programmed cell death protein 1\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cb\u003e* Only 21 patients were evaluated, since four patients died before first CT-staging.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eMuscle development during lenvatinib therapy\u003c/h3\u003e\n\u003cp\u003eFor the present study, 150 CT imaging data were evaluated at different time-points as described in the methods section. Three months after onset of therapy with lenvatinib, development of muscle mass in 21 patients could be evaluated. Four patients died before first CT staging and had to be ruled out from analysis. Of the remaining 21 patients, 15 patients lost muscle mass during the first three months of treatment with lenvatinib (p\u0026thinsp;=\u0026thinsp;0.035) as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Interestingly, in our cohort, patients developing muscle loss during the first three months of lenvatinib intake (n\u0026thinsp;=\u0026thinsp;15) showed similar baseline and therapy characteristics when compared to patients without muscle loss (n\u0026thinsp;=\u0026thinsp;6) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In particular, no differences were detected in performance status according to ECOG score (p\u0026thinsp;=\u0026thinsp;0.9544). Of note, regarding liver function, 33.3% (2) in the non-sarcopenia group presented with worse liver function at onset of lenvatinib therapy vs. two patients (13.3%) in the sarcopenia group (p\u0026thinsp;=\u0026thinsp;0.5436).\u003c/p\u003e \u003cp\u003eIn the non-sarcopenia group, no patients with Albi grade 3 were observed, while in the sarcopenia group, 19.9% (3) featured an ALBI grade 3 (p\u0026thinsp;=\u0026thinsp;0.4466).\u003c/p\u003e \u003cp\u003eThe remaining parameters (e.g. age, sex, etiology of HCC or previous treatments) were similar between the two patient groups. Mainly, there was no difference between BMI and muscle mass status during the three months of lenvatinib therapy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eEfficacy of lenvatinib in all patients and influence of sarcopenia on OS, PFS and ORR\u003c/h3\u003e\n\u003cp\u003eEfficacy of lenvatinib in our cohort of patients was similar to published data from randomized trials and other retrospective analyses. The estimated median OS and median PFS for all patients (n\u0026thinsp;=\u0026thinsp;25) were 18.0 months (95%CI:0.42,35.58) and 8.0 months (95%CI:3.52,12.48), respectively (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). There were no complete responses (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), while 16% (4) achieved partial remission (PR) as best response to lenvatinib and 20% (5) stable disease (SD). The objective response rate (ORR) was 16% and the disease control rate (DCR) was 36%.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eObjective response rate and disease control rate\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAll patients\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25 (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon muscle loss during 3 months Lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;6 (%)*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMuscle loss\u003c/p\u003e \u003cp\u003eduring 3 months lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;15 (%)*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (53.3%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (6.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eunknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (20%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (26.7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eNumbers are presented as n (%)\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003eAbbreviations: HCC, hepatocellular carcinoma; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ORR, objective response rate; DCR, disease control rate\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cb\u003e* Only 21 patients were evaluated, since four patients died before first CT staging.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding efficacy of lenvatinib in patients who developed muscle loss in the first three months of lenvatinib, the sarcopenia group showed similar OS of 18.0 months (95%CI:2.12, 33.89) compared to all patients and PFS of 13.0 months (95%CI 7.14, 18.86). Compared to the non-sarcopenia group, OS and PFS in patients of the sarcopenia group did not differ significantly (p\u0026thinsp;=\u0026thinsp;0.783 and p\u0026thinsp;=\u0026thinsp;0.396, respectively), (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). ORR was 16.7% in the non-sarcopenia group and 20% in the sarcopenia group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) (p\u0026thinsp;=\u0026thinsp;1). Partial response was observed in 1 patient (16.7%) in the non-sarcopenia group vs. in three patients (20%) in the sarcopenia group. DCR was 26.7% in the sarcopenia group vs. 66.7% in the non-sarcopenia group.\u003c/p\u003e\n\u003ch3\u003eAnalysis of factors potentially associated with OS\u003c/h3\u003e\n\u003cp\u003eMuscle status before start of lenvatinib therapy was also evaluated. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, 44% (11) of all patients (n\u0026thinsp;=\u0026thinsp;25) presented muscle loss at baseline. Patients suffering from muscle loss before starting lenvatinib therapy seem to have shorter survival in terms of OS and PFS than patients without sarcopenia (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) (P\u0026thinsp;=\u0026thinsp;0.031).\u003c/p\u003e \u003cp\u003eTo further clarify the role of muscle loss before and during lenvatinib therapy, univariate analysis, including prognostic parameters, such as age, ALBI, Child-Pugh, ECOG, serum AFP\u0026thinsp;\u0026ge;\u0026thinsp;200 ng/ml and portal vein infiltration, were included together with muscle loss before and during lenvatinib therapy. As shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e4\u003c/span\u003e, in the univariate analysis, Child-Pugh score was identified as predictor of survival (HR 2.47, 95% CI 1.217, 5.012). However, presence of sarcopenia at onset of lenvatinib therapy was not found to be a negative predictor of survival. Decreasing SMI during the first three months of lenvatinib therapy was not identified as a poor prognostic factor. Multivariate analysis was not applicable due to small sample size.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate Regression Analysis of factors associated with OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e95%-CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALBI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.056\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChild-Turcotte-Pugh score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.472\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.217\u0026ndash;5.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum AFP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePortal Vein Infiltration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.095\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle Loss before Lenva\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle Loss under Lenva 3M\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.675\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003en\u0026thinsp;=\u0026thinsp;21 only patients with 3 months FU\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviation: ECOG, Eastern Cooperative Oncology Group performance status; ALBI, albumin-bilirubin score; AFP, alpha-fetoprotein\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eToxicity\u003c/h3\u003e\n\u003cp\u003eIn Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003e, all adverse effects (AEs) are documented. In all patients, AEs were observed during the observation period as follows: 40% (10), 16% (4), 12% (3) and 4% (1) discontinued lenvatinib therapy because of disease progression (PD), deterioration in liver function, serious adverse events, or intolerance, respectively. Three patients (12%) completed the therapy during two years. The most common adverse effects in all patients were fatigue, decreased weight, mucositis, diarrhea, hypertension, and decreased appetite. In 60% of patients (15), grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events were documented.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events during lenvatinib therapy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grades\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eAny grades\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003egrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e(all patients,\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e(all patients\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;25)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNon muscle loss during 3 months lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;6*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003emuscle loss during 3 months lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;15*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNon muscle loss during 3 months lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;6*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003emuscle loss during 3 months lenvatinib\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;15*\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eany grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003egrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal treatment related AEs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6(100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15(100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5(83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0635\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5(83.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7(46.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.1778\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.2857\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4(26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.2807\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucositis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (32%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4(66.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.2857\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5(93.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1?\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4(26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDecreased appetite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3(20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.5975\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolyneuropathy/\u003c/p\u003e \u003cp\u003eTremor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4(26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.5439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVertigo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(16.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4(26.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.2807\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProteinuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (16%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.5439\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver funtion disorder Elevated AST/ALT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDyspnoe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.2857\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edecreased platelet count\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1(16.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.500\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArterial lung embolie\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.0714\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0.0714\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleura effusion/\u003c/p\u003e \u003cp\u003eedema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2(13.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstipation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand-Foot Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePruritus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ehepatic encephalopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncreased Bilirubin/INR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1(6.7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1(6.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003eNumbers are presented as n (%)\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003eThe table includes treatment-related adverse events (AEs) of any grades and grade\u0026thinsp;\u0026ge;\u0026thinsp;3, observed during treatment with lenvatinib\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003e\u003cb\u003e* Only 21 patients were evaluated, since four patients died before first CT staging.\u003c/b\u003e\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eInterestingly, patients developing muscle loss had fewer severe adverse effects. However, reduced rate of side effects was not significantly different compared to the patients without muscle loss (p\u0026thinsp;=\u0026thinsp;0.06).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we analyzed the effect of lenvatinib on muscle loss development in a non-selected real-life cohort of patients with advanced HCC. The majority of the patients significantly developed progressive muscle loss during the first three months of lenvatinib therapy. Outcome of all patients in terms of OS, PFS and ORR was similar to the published data in the pivotal prospective randomized phase III trial [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite muscle loss, patients benefitted from the therapy with lenvatinib since outcomes and toxicity were similar to the outcome of patients without muscle loss.\u003c/p\u003e\n\u003cp\u003eHCC occurs mostly as a consequence of liver cirrhosis and chronic pre-existing liver diseases, such as viral hepatitis C or B, alcohol abuse and non-alcoholic steatohepatitis. As a result of these comorbidities, decreased physical activity and nutritional deficiencies are very common in these patients, causing loss in weight and muscle volume. Especially sarcopenia, which is defined as a significant loss of skeletal muscle mass, quality and/or function seemed to have a relevant prognostic role in these patients. In recent works, we and others elucidated the role of sarcopenia in the outcome of patients with liver cirrhosis [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]. In the last decade, previous studies reported on the prognostic value of sarcopenia also in solid tumors. Shachar et al. described in a meta-analysis that up to 74% of patients with advanced tumors were sarcopenic and that sarcopenia has a significant impact on cancer outcomes including OS and PFS [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. Sarcopenia is also not a rare finding in patients with HCC. Moreover, several tyrosine kinase inhibitors (TKI), including sorafenib and lenvatinib, may increase sarcopenia. In patients with advanced HCC and treated with sorafenib, sarcopenia seems to be a prognostic factor for mortality and an independent factor for early dose-limiting sorafenib toxicities [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eLenvatinib has been approved since 2018 for first-line therapy of advanced HCC based on the results of the phase III REFLECT trial. Although sarcopenia as a possible prognostic parameter before and during therapy with lenvatinib was not analyzed in the REFLECT trial [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e], the high frequency of patients with loss of appetite and weight reported during the therapy with lenvatinib, suggests a possible role in sarcopenia development which can influence on the outcome of patients [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e]. How far lenvatinib influences the development of muscle mass and not only weight loss is unclear to date. Regarding the role of sarcopenia in patients with advanced HCC and treated with lenvatinib, only limited data, mostly from Japan, have been published to date. Confirming our hypothesis, in our cohort of patients from Germany, we detected a significant decrease of muscle loss (-6.5% \u0026plusmn; 3.3%; p\u0026thinsp;=\u0026thinsp;0.035) in the first three months of lenvatinib therapy in the majority of patients (60%). Moreover, this effect was observed not only in patients with previous muscle loss but also in patients without previous muscle loss. It has been described that several multikinase inhibitors, mainly targeting vascular endothelial growth factor (VEGFR/VEGF) signal cascade, are suspected of inducing muscle mass loss. VEGF seems to promote the proliferation of myogenic fibers. Thus, the effect of TKI could inhibit muscle growth due to this mechanism, exacerbating the muscle mass loss and inducing sarcopenia. Lenvatinib may inhibit tumor cell proliferation by downstream downregulation of PI3K, AKT and mTOR. The suppression of the AKT/mTOR pathway has also been described as being involved in muscle atrophy and may further explain the effects of lenvatinib on muscle mass. However, not all molecular pathways involved in sarcopenia have been fully elucidated to date. Further mechanisms, such as increased systemic inflammatory response and decreased protein synthesis due to chronic liver disease and cancer, are also involved in the aggravation of muscle mass loss in these patients [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eDespite the significant muscle loss in our cohort of unselected patients, we observed a benefit in terms of mOS of 18.00 months (95%CI: 0.42, 35.58), PFS of 8.00 months (95%CI:3.52,12.48) and ORR of 16% due to systemic therapy with lenvatinib. In the REFLECT study, lenvatinib showed an OS of 13.6 months (95% CI: 12.1,14.9). The achieved ORR was 24.1% and PFS was 7.4 months (95% CI: 6.9 to 8.8 months). Regarding toxicity, grade\u0026thinsp;\u0026ge;\u0026thinsp;3 adverse events occurred in 60.0% of patients in our cohort during lenvatinib therapy, which is higher than the results of the REFLECT trial, where serious adverse events were observed in 43.1% of patients. Similar to the REFLECT trial, the most common adverse events found in our cohort were decreased weight in four patients (16%), mucositis in eight (32%), hypertension in seven (28%), diarrhea in seven (28%) and decreased appetite in seven patients (28%). Analyzing the base line characteristics of patients included in the REFLECT study, we found several differences compared to the characteristics of our cohort of patients. For instance, in the REFLECT trial, patients had BCLC stage B or C, Child-Pugh class A cirrhosis and ECOG score of 0 or 1. Additionally, patients with 50% or more liver occupation and/or bile duct or main portal vein invasion were excluded. Our real-life cohort of patients included 20% with Child Pugh B liver cirrhosis, 24% had ECOG\u0026thinsp;\u0026ge;\u0026thinsp;2 and 48% main infiltration of the portal vein, which were not included in the REFLECT study. Moreover, 100% of our patients had BCLC C, while only 78.2% of patients in the REFLECT trial were BCLC C. Finally, 24% of our patients received lenvatinib after at least one prior systemic therapy. Thus, our findings showed that lenvatinib was beneficial and safe in a European unselected cohort of patients with advanced HCC in daily clinical practice, confirming the data from other real-life cohorts of patients from Asia published to date. [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eMost importantly, in this study, treatment with lenvatinib in patients developing muscle loss was also found to be beneficial in terms of OS and PFS. The mOS of the patients with muscle loss was 18.00 months (95%CI: 2.12, 33.89) and the PFS 13.0 months (95%CI 7.14, 18.86). This was not significantly different compared to the patients without muscle loss development (p\u0026thinsp;=\u0026thinsp;0.783 and p\u0026thinsp;=\u0026thinsp;0.396, respectively). ORR was comparable between the two groups. Partial response was observed in 16.7% (1) in the non-sarcopenia group vs. 20% (3) in the sarcopenia group. In the non-sarcopenia group, 50% (3) achieved SD. Regarding toxicity, there was no significant increase in side effects in patients who developed muscle loss during lenvatinib therapy. Indeed, patients developing muscle loss had fewer severe adverse effects, including less worsening of liver function.\u003c/p\u003e\n\u003cp\u003eThe presence of presarcopenia or sarcopenia before intake of lenvatinib was found to be a significant prognostic factor and a predictive marker for tolerability to lenvatinib in patients with advanced HCC and treated with lenvatinib in several studies published to date (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e) [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. We also analyzed the impact of previous muscle loss on survival in patients treated with lenvatinib and found that suffering from previous sarcopenia before starting lenvatinib therapy (44%) showed that in these patients, survival in terms of OS and PFS was shorter than in patients without previous sarcopenia. However, in the univariate analysis, presence of muscle loss at onset of lenvatinib therapy and the development of muscle loss were not found to be negative predictors of survival.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003cstrong\u003e\u003cstrong\u003eTable 5: \u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eTrials evaluating the effect of sarcopenia in\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003epatients with advanced HCC and treated with lenvatinib\u003c/strong\u003e\u003c/strong\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"781\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst Author/ \u0026nbsp;Year\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCountry\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy desing\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003epatients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMethodes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime of muscle\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eassesment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCut off value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eComparison\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePraktiknjo,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;et al,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2022\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGermany\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonocentric,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRetrospective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e25\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT scan: L3 SMI?\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ees\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAt the beginning and 3 months after lenvatinib treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMI:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eM:\u0026lt; 42 cm\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003cstrong\u003e/m\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eW: \u0026lt;38 cm\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003cstrong\u003e/m\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSarcopenia vs. Non-Sarcopenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ep=0.783\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ep=0.396\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eDong et al,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2022 [33]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eChina\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonocentric\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eretrospective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e40\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT scan: L3 SMI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1month prior to\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ethe initiation of lenvatinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMI:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eM:\u0026lt; 42 cm\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003cstrong\u003e/m\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eW: \u0026lt;38 cm\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003cstrong\u003e/m\u003c/strong\u003e\u003cstrong\u003e\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003esarcopenia patients vs. non-sarcopenia patients\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.024\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.044\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHiraoka et al,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2021 [25]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eJapan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMulticentric\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRetrospecive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e151\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT scan: L3- PSI\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1 month before and 4 weeks after\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003estarting lenvatinib treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMI:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eM: 4.24 cm\u0026sup2;/m\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eW: 2.50 cm\u0026sup2;/m\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre-sarcopenia vs non pre-sarcopenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001 \u0026nbsp; \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.025\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eKotoh et al,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2020\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[37]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eJapan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonocentric, Retrospective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e53\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT scan: L3-\u003c/strong\u003e\u003cstrong\u003eSMI \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHGS: \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eGS dynamometer\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore receiving lenvatinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMI:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eM:\u0026lt; 42 cm\u0026sup2;/m\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eW: \u0026lt;38 cm\u0026sup2;/m\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eHGS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eM:\u0026lt;26 kg\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eW:\u0026lt;18 kg\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eHGS\u003c/strong\u003e\u003cstrong\u003e: Low vs. \u0026nbsp; \u0026nbsp; High\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMuscle depletion vs. Non-Muscle depletion\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSarcopenia \u0026nbsp;vs. non- Sarcopenia\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eTTF\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.036\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndo et al,\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2020\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e[34]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eJapan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMonocentric\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRetrospective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e63\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT scan: L3-\u003c/strong\u003e\u003cstrong\u003eSMI \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eGS: \u0026nbsp; \u0026nbsp; measurement complies with the established\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eguideline (JSH)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eBefore receiving lenvatinib\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGS:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eM:\u0026lt;26 Kg \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eW: \u0026lt; 18 Kg\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSMI:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; M:\u0026lt;42 cm\u0026sup2;/m\u0026sup2;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;W: \u0026lt;38 cm\u0026sup2;/m\u0026sup2;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;GS: Normal vs. decreased\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eSMI\u003c/strong\u003e\u003cstrong\u003e: Normal SMI vs decreased SMI,\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePPS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.9\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eUojima et al,\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2020 [35]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eJapan\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMulticentric\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRetrospective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e100\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT scan: L3-SMI\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ebefore treatment initiation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMI:\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eM: \u0026lt; 42 cm\u0026sup2;/m\u0026sup2;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eW: \u0026lt; 38 cm\u0026sup2;/m\u0026sup2;:\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMI\u003c/strong\u003e\u003cstrong\u003e: low vs high\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTTF\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e0.021\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.435897435897436%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRinninella et al,\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e2019 [26]\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.3076923076923075%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eItaly\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.179487179487179%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTwo case\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eReports\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eRetrospective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.461538461538462%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e2\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.76923076923077%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCT scan: L3- SMA\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.333333333333334%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAt baseline and at 24 months after lenvatinib skeletal muscle area\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003etreatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.743589743589743%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.025641025641026%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSMA\u003c/strong\u003e\u003cstrong\u003e, Baseline vs. 24 months after the start of lenvatinib therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.0256410256410255%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOS\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePFS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.717948717948717%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e-\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: SM, skeletal muscle; SMI, skeletal muscle index , calculated as skeletal muscle mass divided by height squared (cm\u0026sup2;/m\u0026sup2;); HGS, handgrip strength; L3, \u0026nbsp;third lumbar vertebra level; OS, Overall survival; MST, median survival time; n.s., non significant; PFS, progression free survival; PPS, post- progression survival; SMA, skeletal mass area; PSI, psoas muscle area index \u0026nbsp;(muscle area at level of middle of third lumbar vertebra (cm\u0026sup2;)/height (m\u0026sup2;); TTF, time to treatment failure\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComparing our study to data published to date, ours is one of the first analyses on skeletal muscle evolution during lenvatinib therapy in patients with advanced HCC from a European cohort of patients (Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Only one report including two cases of patients from the REFLECT study from Italy has been published from Europe to date. In these two patients, muscle mass loss was studied over 24 months. Contrary to our findings, only a minimal reduction of muscle mass was detected in the two patients (2.13% and 10.83%), while 60% (15) in our cohort showed significant muscle mass loss (-6.5% \u0026plusmn; 3.3%, p\u0026thinsp;=\u0026thinsp;0.035) already after three months of lenvatinib therapy. OS of the two Italian patients (34 and 42 months) and duration of lenvatinib therapy (25 and 32 months) were longer than other cases reported to date [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. Further monocentric and multicentric studies published to date are reporting on data from Asia (Japan, China). They also reported on the role of sarcopenia in patients with advanced HCC treated with lenvatinib. However, these studies focused on the impact of sarcopenia before therapy with lenvatinib on outcome and tolerability to lenvatinib and not on the impact of lenvatinib on sarcopenia during the treatment. For instance, in the study presented by Uojima et al. 2020 with 100 patients from Japan, decreased muscle mass was shown to be associated with increased severe AEs and reduced OS [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e]. In this study, the majority of patients were ECOG 0 and 49% with BCLC B, while our patients were mostly ECOG 1 or higher and all patients presented with tumor stage BCLC C. Muscle mass assessment was performed only before lenvatinib therapy and defined as skeletal muscle index (SMI). In line with our data, sarcopenia before lenvatinib therapy was associated with reduced survival and PFS. In another large retrospective trial presented by Hiraoka et al. 2021 from Japan with 151 patients, presarcopenia before onset of therapy with lenvatinib was shown to be a significant prognostic factor for survival (HR 1.652, p\u0026thinsp;=\u0026thinsp;0.042) [\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, no longitudinal analysis of the effects of lenvatinib on sarcopenia were presented in these studies.\u003c/p\u003e\n\u003cp\u003eIn our study, CT imaging was selected to quantify muscle mass. This non-invasive method allows correlation with the whole-body mass. Moreover, we and other have already shown that this muscle mass measurement is a strong predictor for mortality in patients with cirrhosis and HCC (32\u0026ndash;33). However, some of the studies with HCC patients treated with lenvatinib published to date (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e) showed the effect of handgrip strength rather than skeletal muscle mass as a negative predictor of survival. For instance, in the 2020 retrospective analysis by Endo K et al., 63 patients with advanced HCC and treated with lenvatinib were analyzed. A decreased grip strength (GS) and decreased skeletal muscle mass index (SMI) were found in 33.3% and 34.9% of the patients, respectively. In this study, only GS seemed to have an impact on survival, since OS of the normal GS group was significantly higher than of the decreased GS group, while that of the normal and decreased SMI groups did not significantly differ, indicating that muscle strength and not just muscle mass alone may be also relevant as a prognostic marker [\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eSince all published studies to date included only patients from Asia, mostly from Japan, and quantitative and qualitative assessments of sarcopenia with different cut-off values among the published studies were presented, further direct comparisons among the studies are difficult. Nutritional habits and body composition may differ considerably between Japan and Europe with different impact on the effects of muscle mass during therapy with lenvatinib. To date, there are limited comparable data available including patients from outside Asia. Contrary to our findings, the analysis of two Italian patients published by Rinninella et al. showed only a minimal loss of muscle mass during therapy with lenvatinib [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eMore data from other cohorts of patients are warranted to clarify the role of sarcopenia in the treatment of patients with advanced HCC. Moreover, preventive and therapeutic interventions to avoid or to reduce sarcopenia, as already indicated [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e], should be included and investigated in clinical studies in more detail.\u003c/p\u003e\n\u003cp\u003eThe limitations of the present study include the relatively small number of patients and its retrospective design with patients of a single institution. Therefore, lack of significance between the patients without development of muscle loss and the patients with development of muscle loss could be related to the low number of patients. Moreover, four patients died before assessment of skeletal muscle mass three months after onset of lenvatinib therapy. Thus, sample selection may be biased. We evaluated only a quantitative parameter of skeletal muscle mass, but no quality parameters of the muscle mass, such as grip strength.\u003c/p\u003e\n\u003cp\u003eThe strengths of this trial are the inclusion of a European cohort of patients with different clinical body and nutritional features compared to patients from Japan and the assessment of sarcopenia not only at baseline but also over the course of therapy with lenvatinib.\u003c/p\u003e\n\u003cp\u003eIn summary, our study in an unselected European cohort of patients with advanced HCC and treated with lenvatinib showed similar outcome in terms of OS, PFS and ORR to published data in the pivotal prospective randomized phase III trial (REFLECT). Three months after starting lenvatinib therapy, most patients experienced a significant loss of skeletal muscle mass. However, despite of developing muscle loss, patients benefitted from the therapy with lenvatinib. No significant difference in OS and PFS between the group of patients developing muscle loss and the non-muscle loss group was found.\u003c/p\u003e\n\u003cp\u003eFurther studies are necessary to elucidate the role of muscle loss in patients with advanced HCC treated with lenvatinib. Since several studies showed a negative effect of sarcopenia on OS and tolerability to TKI in cancer patients, including HCC, sarcopenia assessment before and during lenvatinib should be taken into account and, if applicable, nutritional and sports measures should be started early on to prevent or improve sarcopenia both in clinical trials and in everyday practice in order to improve prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions \u0026nbsp;\u0026nbsp;\u003c/strong\u003eMP: \u0026nbsp; sarcopenia measurement, analysis and interpretation of data, drafting of the manuscript and statistical analysis; ASP: acquisition of data, creating and editing of Figures and Tables, drafting of the manuscript; FS\u003cstrong\u003e:\u0026nbsp;\u003c/strong\u003eanalysis and interpretation of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content; CM,TZ, RM, MBM, GF, PB, CB, AS, SM AMS, JL, SN, HM, SM, JCK and CPS: acquisition of data and critical revision of the manuscript for important intellectual content; TW, MS: critical \u0026nbsp;revision \u0026nbsp; of \u0026nbsp;the \u0026nbsp;statistical data and manuscript for important intellectual content; CM: acquisition of data, analysis and interpretation of computer tomography data and critical revision of the manuscript for important intellectual content; MG: acquisition of data, analysis and interpretation of data, drafting of the manuscript, study concept and design.\u003c/p\u003e\n\u003cp\u003eAll authors have read and agreed to the published version of the manuscript\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthic Statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll methods were carried out in accordance with relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003eThis retrospective \u0026nbsp; study \u0026nbsp;was \u0026nbsp;approved \u0026nbsp; by \u0026nbsp;the \u0026nbsp;Ethics \u0026nbsp; Committee \u0026nbsp;of \u0026nbsp;the \u0026nbsp; Medical \u0026nbsp;Faculty \u0026nbsp;of \u0026nbsp;the University of Bonn (No. 341/17).Written informed consent was obtained from all patients.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u0026nbsp;\u003c/strong\u003eThere are no conflicts of interest for any author involved in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eData availability\u003c/strong\u003e The data generated during this study are included in this article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eKudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. Mar 24; 391(10126):1163-1173, https://doi.org/10.1016/S0140-6736 (18)30207-1 (2018).\u003c/li\u003e\n \u003cli\u003eBray, F.et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Nov; 68(6):394-424, https://doi.org/10.3322/caac.21492 (2018).\u003c/li\u003e\n \u003cli\u003eKanneganti, M. Singal, A.G. INCIDENCE OF HEPATOCELLULAR CARCINOMA IN NONALCOHOLIC FATTY LIVER DISEASE. Gastroenterology. Feb 1:S0016-5085(22)00092-0, https://doi.org/10.1053/j.gastro.2022.01.037 (2022).\u003c/li\u003e\n \u003cli\u003eLlovet, J.M. et al. Hepatocellular carcinoma. Nat Rev Dis Primers. Jan 21; 7(1):6, https://doi.org/10.1038/s41572-020-00240-3 (2021).\u003c/li\u003e\n \u003cli\u003eVogel, A. Martinelli, E. ESMO Guidelines Committee. [email protected]; Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol. Jun;32(6):801-805, https://doi.org/10.1016/j.annonc.2021.02.014 (2021).\u003c/li\u003e\n \u003cli\u003eEuropean Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. Jul;69(1):182-236, https://doi.org/10.1016/j.jhep.2018.03.019 (2018).\u003c/li\u003e\n \u003cli\u003eIkeda, K. et al. Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. Apr;52((4)):512\u0026ndash;9, https://doi.org/10.1007/s00535-016-1263-4 (2017).\u003c/li\u003e\n \u003cli\u003eShachar, S.S. et al. Skeletal muscle measures as predictors of toxicity, hospitalization, and survival in patients with metastatic breast cancer receiving taxane-based chemotherapy. Clin Cancer Res. Feb;23((3)):658\u0026ndash;65, https://doi.org/10.1158/1078-0432.CCR-16-0940 (2017).\u003c/li\u003e\n \u003cli\u003ePraktiknjo, M. et al. Sarcopenia Is Associated With Development of Acute-on-Chronic Liver Failure in Decompensated Liver Cirrhosis Receiving Transjugular Intrahepatic Portosystemic Shunt. Clin Transl Gastroenterol. Apr;10(4):e00025, https://doi.org/10.14309/ctg.0000000000000025 (2019).\u003c/li\u003e\n \u003cli\u003ePraktiknjo, M. et al. Fat-free muscle mass in magnetic resonance imaging predicts acute-on-chronic liver failure and survival in decompensated cirrhosis. Hepatology. Mar;67(3):1014-1026, https://doi.org/10.1002/hep.29602 (2018).\u003c/li\u003e\n \u003cli\u003ePrado, C.M. et al. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. Jul;9: 629-35, https://doi.org/10.1016/S1470-2045(08)70153-0 (2008).\u003c/li\u003e\n \u003cli\u003eShachar, S.S., Williams, G. R., \u003csup\u003e\u0026nbsp;\u003c/sup\u003e Muss, H. B.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e, Nishijima, T. F.\u003csup\u003e\u0026nbsp;\u003c/sup\u003ePrognostic value of sarcopenia in adults with solid tumors: A meta-analysis and systematic review. European Journal of Cancer . Volume 57: 58-67, https://doi.org/10.1016/j.ejca.2015.12.030 (2016).\u003c/li\u003e\n \u003cli\u003eMeza-Junco, J. et al. Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma. J Clin Gastroenterol. Nov-Dec;47(10):861-70, https://doi.org/10.1097/MCG.0b013e318293a825 (2013).\u003c/li\u003e\n \u003cli\u003eHsu, C.S., Kao, J.H. Sarcopenia and chronic liver diseases. Expert Rev Gastroenterol Hepatol. Dec;12 (12):1229-1244, https://doi.org/10.1080/17474124.2018.1534586 (2018).\u003c/li\u003e\n \u003cli\u003eMarasco, G. et al. Clinical impact of sarcopenia assessment in patients with hepatocellular carcinoma undergoing treatments. J Gastroenterol. Oct;55(10):927-943, https://doi.org/10.1007/s00535-020-01711-w (2020).\u003c/li\u003e\n \u003cli\u003eHiraoka, A. et al. Real-life Practice Experts for HCC (RELPEC) Clinical importance of muscle volume in lenvatinib treatment for hepatocellular carcinoma: Analysis adjusted with inverse probability weighting. J Gastroenterol Hepatol. Jul; 36(7):1812-1819, https://doi.org/10.1111/jgh.15336 (2021).\u003c/li\u003e\n \u003cli\u003eRinninella, E. et al. Minimal impact of lenvatinib (Lenvima\u0026reg;) on muscle mass in advanced hepatocellular carcinoma and implications for treatment duration. Two cases from the REFLECT study. European Review for Medical and Pharmacological Sciences.; 23: 10132-10138, https://doi.org/10.26355/eurrev_201911_19583 (2019).\u003c/li\u003e\n \u003cli\u003eNowak, S, Faron, A, Luetkens, JA. Fully Automated Segmentation of Connective Tissue Compartments for CT-Based Body Composition Analysis: A Deep Learning Approach. Investigative Radiology: June 2020 - Volume 55 - Issue 6 - p 357-366\u003c/li\u003e\n \u003cli\u003eLuetkens, J.A. et al. Opportunistic Computed Tomography Imaging for the Assessment of Fatty Muscle Fraction Predicts Outcome in Patients Undergoing Transcatheter Aortic Valve Replacement. Research Letter. \u0026copy; 2020 American Heart Association,Inc.Circulation. ; 141:234\u0026ndash;236, https://doi.org/10.1161/CIRCULATIONAHA.119.042927 (2020).\u003c/li\u003e\n \u003cli\u003eChang, K.V. et al. Association between loss of skeletal muscle mass and mortality and tumor recurrence in hepatocellular carcinoma: a systematic review and meta‐analysis. Liver Cancer; 7: 90‐103, https://doi.org/10.1159/000484950 (2018).\u003c/li\u003e\n \u003cli\u003eNishikawa, H. et al. Japan Society of Hepatology guidelines for sarcopenia in liver disease (1st edition): Recommendation from the working group for creation of sarcopenia assessment criteria. Hepatol Res. Sep;46(10):951-63, https://doi.org/10.1111/hepr.12774 (2016).\u003c/li\u003e\n \u003cli\u003eDong, D. et al. Prognostic significance of sarcopenia in patients with hepatocellular carcinoma treated with lenvatinib. Medicine (Baltimore). Feb 4; 101(5):e28680, https://doi.org/10.1097/MD.0000000000028680 (2022).\u003c/li\u003e\n \u003cli\u003eEndo, K. et al.Impact of Grip Strength in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib. Cancers (Basel). Aug 3; 12(8):2146, https://doi.org/10.3390/cancers12082146 (2020).\u003c/li\u003e\n \u003cli\u003eUojima, H. et al. Skeletal Muscle Mass Influences Tolerability and Prognosis in Hepatocellular Carcinoma Patients Treated with Lenvatinib. Liver Cancer. Apr;9(2):193-206, https://doi.org/10.1159/000504604 (2020).\u003c/li\u003e\n \u003cli\u003ePerisetti, A. et al. Sarcopenia in hepatocellular carcinoma: Current knowledge and future directions. World J Gastroenterol. Jan 28; 28(4):432-448, https://doi.org/10.3748/wjg.v28.i4.432 (2022).\u003c/li\u003e\n \u003cli\u003eKotoh, Y. et al. Effect of Handgrip Strength on Clinical Outcomes of Patients with Hepatocellular Carcinoma Treated with Lenvatinib. Applied Sciences. 10 (16):5403, https://doi.org/10.3390/app10165403 (2020).\u003c/li\u003e\n \u003cli\u003eMeza-Junco, J. et al. Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma. J Clin Gastroenterol; 47: 861-870, https://doi.org/10.1097/MCG.0b013e318293a825 (2013)\u003c/li\u003e\n \u003cli\u003eShimozato, N. et al. Efficacy and Safety of Lenvatinib for Patients with Advanced Hepatocellular Carcinoma: A Retrospective, Real-world Study Conducted in Japan. Anticancer Res. Jan; 42(1):173-183, https://doi.org/10.21873/anticanres.15471 (2022).\u003c/li\u003e\n \u003cli\u003eTsuchiya, K. et al, On Behalf Of Japanese Red Cross Liver Study Group. The Real-World Data in Japanese Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib from a Nationwide Multicenter Study. Cancers (Basel). May 26; 13(11):2608, https://doi.org/10.3390/cancers13112608 (2021).\u003c/li\u003e\n \u003cli\u003eGoh, M.J. et al. Efficacy and Safety of Lenvatinib Therapy for Unresectable Hepatocellular Carcinoma in a Real-World Practice in Korea. Liver Cancer. Feb; 10(1):52-62, https://doi.org/10.1159/000512239 (2021).\u003c/li\u003e\n \u003cli\u003eWang, D.X. et al. Efficacy and safety of lenvatinib for patients with advanced hepatocellular carcinoma: A retrospective, real-world study conducted in China. \u003cem\u003eWorld J Gastroenterol\u003c/em\u003e.; 26(30):4465-4478, https://doi.org/10.3748/wjg.v26.i30.4465 (2020).\u003c/li\u003e\n \u003cli\u003eFaron, A. et al. Combination of Fat-Free Muscle Index and Total Spontaneous Portosystemic Shunt Area Identifies High-Risk Cirrhosis Patients. Front Med (Lausanne). Apr 12; 9:831005, https://doi.org/10.3389/fmed.2022.831005 (2022).\u003c/li\u003e\n \u003cli\u003eTantai, X. et al. Effect of sarcopenia on survival in patients with cirrhosis: A meta-analysis. J Hepatol. Mar; 76(3):588-599, https://doi.org/10.1016/j.jhep.2021.11.006 (2022).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-2771181/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2771181/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLenvatinib is a multiple receptor tyrosine kinase inhibitor (TKI) approved for first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). TKI are suspected of exacerbating muscle wasting (sarcopenia) in patients with cancer. In this study, we analyze the role of sarcopenia in patients with advanced HCC treated with lenvatinib.\u003c/p\u003e \u003cp\u003eThis is a retrospective analysis of a real-life cohort of 25 patients with advanced HCC who were treated with lenvatinib from 2018 to November 2020 in Germany. Patients were stratified for loss of skeletal muscle index (SMI) during the first three months of lenvatinib therapy. Overall survival (OS), progression-free survival (PFS) and toxicity were analyzed for all patients, especially regarding development of sarcopenia before and during the first three months of therapy with lenvatinib.\u003c/p\u003e \u003cp\u003eThree months after beginning of therapy with lenvatinib, a significant reduction of muscle mass was observed in 60% of patients (p\u0026thinsp;=\u0026thinsp;0.035). Despite increase of sarcopenia, patients benefitted from lenvatinib in our cohort of patients in terms of OS and PFS and did not experience increased toxicity. Furthermore, muscle loss was not found to be a negative predictor of survival in the univariate analysis.\u003c/p\u003e \u003cp\u003ePatients with advanced hepatocellular carcinoma experience muscle wasting with lenvatinib therapy. However, despite progressive sarcopenia, patients benefit from a therapy with lenvatinib in terms of OS and PFS without increased toxicity. However, assessment and prophylaxis of skeletal muscle status should be recommended during a therapy with lenvatinib.\u003c/p\u003e","manuscriptTitle":"The impact of lenvatinib on sarcopenia in patients with advanced unresectable hepatocellular carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-04-27 22:07:48","doi":"10.21203/rs.3.rs-2771181/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2023-11-16T03:53:08+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-11-15T12:42:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"6794ce04-9b1c-4031-9df6-348cc74686a1","date":"2023-11-14T17:44:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-11-02T14:56:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"a13fb9ef-641c-47da-b945-ec4670425a00","date":"2023-09-26T14:14:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"5d27dcc7-7f31-4f39-8cb7-cc195eb011da","date":"2023-06-28T06:20:05+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-06-12T10:59:19+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-06-07T10:31:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-04-25T08:18:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-04-25T08:11:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2023-04-03T10:31:15+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6835abc4-adfe-48ec-a79e-978b02e976a5","owner":[],"postedDate":"April 27th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":20982122,"name":"Health sciences/Oncology/Cancer/Gastrointestinal cancer/Liver cancer/Hepatocellular carcinoma"},{"id":20982123,"name":"Biological sciences/Cancer/Cancer therapy/Chemotherapy"}],"tags":[],"updatedAt":"2024-09-30T16:05:28+00:00","versionOfRecord":{"articleIdentity":"rs-2771181","link":"https://doi.org/10.1038/s41598-024-66766-8","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-09-27 15:57:56","publishedOnDateReadable":"September 27th, 2024"},"versionCreatedAt":"2023-04-27 22:07:48","video":"","vorDoi":"10.1038/s41598-024-66766-8","vorDoiUrl":"https://doi.org/10.1038/s41598-024-66766-8","workflowStages":[]},"version":"v1","identity":"rs-2771181","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2771181","identity":"rs-2771181","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}