Skeletal Muscle Loss during Tyrosine Kinase Inhibitor Treatment for Advanced Hepatocellular Carcinoma Patients

Abstract

<b><i>Introduction:</i></b> The measurement of body composition such as the skeletal muscle index (SMI) has been reported to be useful for predicting prognosis in hepatocellular carcinoma (HCC). In this study, we analyzed skeletal muscle change during sorafenib and lenvatinib therapy and the association between SMI and prognosis. <b><i>Methods:</i></b> A total of 67 patients with advanced HCC and Child-Pugh grade A status treated with tyrosine kinase inhibitors (TKIs) at Hiroshima University between September 2009 and December 2018 were enrolled in this retrospective cohort study. Patients underwent computed tomography (CT) imaging before starting sorafenib treatment and 1–3 months after treatment initiation. <b><i>Results:</i></b> In all patients, the median SMI was 45.3 cm<sup>2</sup>/m<sup>2</sup> before TKI treatment and 42.1 cm<sup>2</sup>/m<sup>2</sup> after treatment; 54 of 67 (80.6%) patients experienced SMI loss. The median ΔSMI was –1.5 cm<sup>2</sup>/m<sup>2</sup>/months, and no difference in ΔSMI was observed between patients receiving sorafenib and lenvatinib. No significant differences were observed in median ΔSMI between patients with and without progressive disease (–2.35 and –1.1 cm<sup>2</sup>/m<sup>2</sup>/months, respectively), albumin-bilirubin grade 1 and 2 group disease (–1.7 and –1.5 cm<sup>2</sup>/m<sup>2</sup>/months, respectively), and relative dose intensity ≤80 and >80 (–1.8 and –1.2 cm<sup>2</sup>/m<sup>2</sup>/months, respectively). <b><i>Conclusion:</i></b> This report demonstrated that patients receiving TKI treatment experienced a significant loss of skeletal muscle mass regardless of disease progression, hepatic reserve, or which TKI (sorafenib or lenvatinib) they received.

Prognostic value of low skeletal muscle mass in hepatocellular carcinoma patients treated with sorafenib or lenvatinib: A meta-analysis

“…After being excluded by titles and abstracts, 29 full-text articles were assessed for eligibility. 18 records didn't meet the inclusion criteria and were discarded: 2 involving other kinase inhibitors (Nault et al, 2013[ 28 ], 2015[ 29 ]), 9 with overlapped patient data (Antonelli et al, 2018[ 2 ]; Gigante et al, 2015[ 13 ]; Hoshino et al, 2015[ 16 ]; Imai et al, 2015[ 17 ], 2019[ 19 ]; Labeur et al, 2018[ 23 ][ 24 ]; Okada et al, 2019[ 33 ]; Saeki et al, 2019[ 34 ]), 5 lacking HR and 95 % CI (Mir et al, 2012[ 26 ]; Okada et al, 2020[ 32 ]; Saeki et al, 2018[ 35 ]; Uchikawa et al, 2020[ 39 ]; Ueki et al, 2016[ 40 ]), 1 without any interesting outcome (Cheng et al, 2019[ 7 ]) and 1 with low quality and faulty data (Nishikawa et al, 2017[ 30 ]). Thus, 11 retrospective studies (Antonelli et al, 2018[ 3 ]; Endo et al, 2020[ 10 ]; Hiraoka et al, 2017[ 15 ]; Imai et al, 2020[ 18 ]; Labeur et al, 2019[ 25 ]; Naganuma et al, 2017[ 27 ]; Sawada et al, 2019[ 36 ]; Takada et al, 2018[ 38 ]; Uojima et al, 2020[ 41 ]; Wu et al, 2021[ 43 ]; Yamashima et al, 2017[ 45 ]) were included in this meta-analysis, comprising 1148 patients.…”

Skeletal Muscle Loss during Multikinase Inhibitors Therapy: Molecular Pathways, Clinical Implications, and Nutritional Challenges

“…Our search was conducted until July 2020. Table 1 detailed the results of the eleven studies [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ] assessing the effect of TKI treatment on skeletal muscle mass from computerized tomography (CT) scan at the third lumbar (L3) vertebra.…”

“…The mean SMI was reduced from 41.6 to 39.9 cm 2 /m 2 after 3–4 months of targeted therapy. Furthermore, Uchikawa et al evaluated 23 HCC patients treated with sorafenib and found a significant decrease in SMI between baseline and 1–3 months after starting treatment ( p < 0.01) [ 33 ]. To better investigate the role of the treatment itself in muscle wasting, a post hoc analysis of the Phase III DECISION trial study [ 32 ] compared SMI changes among 365 patients with advanced thyroid cancer in sorafenib vs. placebo groups between baseline and 6 months after starting sorafenib therapy.…”

“…However, Hiraoka et al used psoas muscle assessment, which is less precise and suitable to assess total muscle mass than skeletal muscle indexes such as SMI and skeletal muscle area (SMA) (see above). Recently, a subgroup analysis of the study of Uchikawa et al found in 8 patients (with advanced HCC and Child-Pugh grade A) treated with lenvatinib a significant decrease in SMI between baseline and 1–3 months after starting treatment ( p = 0.025) [ 33 ], independently with progression disease. Further studies with a larger sample size are needed to clarify the impact of lenvatinib on muscle mass.…”

“…Some studies [ 27 , 30 , 31 ] assessed SMA, evaluating all the cross-sectional skeletal muscle area at the third lumbar vertebra (bilateral rectus abdominis, external oblique, internal oblique, transverse abdominal, psoas, quadratus lumborum, and paraspinal muscle). Other studies calculated SMI by dividing SMA by the square of the height [ 26 , 29 , 33 , 34 , 36 ] or skeletal muscle density (SMD; in Hounsfield) [ 34 ] or LBM estimated from SMA as described by Mourtzakis et al [ 73 ]. One study [ 28 ] used the bilateral psoas index (PI; in cm 2 /m 2 ) by dividing psoas muscle area by the square of the height.…”