In this study, we assessed change in SMV in patients with HCC who were treated with LEN. We found that SMV decreased during the administration period and that change in SMV mass during the administration period was significantly associated with poor prognosis in these patients.
Sarcopenia is associated with poor prognosis in patients with cirrhosis or HCC, independent of liver function reserve.9–14 Patients with HCC receive various treatments, along with assessment of both TNM stage and liver function reserve. In terms of treatment of HCC, sarcopenia is associated with a negative impact in HCC patients who undergo curative treatments such as hepatectomy and radiofrequency ablation.18 Most of these previous studies assessed SMV prior to initiation of treatment. Other non-curative treatment is often continued or repeated until response failure or intolerance to treatment occurs. The results of the present study suggest that because SMV can change during non-curative treatment (Fig. 1), the impact of SMV may be less at the start of non-curative treatment compared with its impact during curative treatment. Several studies have reported no significant association between sorafenib and hepatic intra-arterial therapy with SMV loss at baseline or OS, but identified change in SMV during these treatments as a significant prognostic factor for OS.15, 16 In contrast, Imai et al reported an association of SMV loss with poor prognosis, both at baseline and during treatment.12 These findings imply that change in SMV during treatment may be a useful predictor of prognosis in patients with HCC receiving non-curative treatment, including LEN.
Several studies have identified change in SMV during treatment as an impact factor in HCC patients with treated with MTAs.12, 15 However, these reports did not consider the impact of long-term change in SMV. In the present study, the median administration period of LEN was 7.7 months, and the impact of long-term change in SMV over at least 6 months was investigated in more than half of the enrolled patients.
In patients with HCC, SMV is affected by both liver function reserve and tumor-related factors in addition to age or sex.19 In fact, in the present study, median PMI-Pre, PMI-1st, and PMI-Post were 5.63, 5.62, and 4.97 cm2/m2, respectively, and SMV had decreased significantly between Pre and Post. Furthermore, there was no significant difference in ΔPMI/m between the low and normal PMI groups. Similarly, Uchikawa et al reported a significant decrease in SMV during administration of MTAs, with or without muscle volume loss at baseline.20 In the present study, liver function reserve was worse and ChE and albumin levels were lower in the severe atrophy group than in the mild atrophy group (Table 4). These results suggest that maintaining nutritional status and hepatic reserve prevents SMV loss. Takada et al reported that branch-chain amino acids (BCAAs) were useful for maintaining the serum albumin level, which helped to avoid early discontinuance of sorafenib therapy.21 Another study reported that in HCC patients treated with LEN, there was significant correlation between the plasma acyl carnitine-to-free carnitine ratio and change in the Brief Fatigue Inventory score, and mentioned that LEN affected carnitine insufficiency and fatigue.22 Accordingly, we should consider the early introduction of nutrition therapy, including BCAAs and levocarnitine, in HCC patients treated with MTAs.
In this study, non-mALBI 1 or 2a at the start of LEN was a significant risk factor for OS (Table 3). Furthermore, the median ALBI score at baseline was –2.48 (mALBI grade 2a) in patients with mild atrophy and –2.31 (mALBI grade 2b) in those with severe atrophy (Table 4). Hiraoka et al reported that mALBI grade 1 or 2a were better prognostic factors in LEN treatment 23, and similar results were obtained in this study. The above findings suggest that a decrease in hepatic reserve leads to a rapid decrease in SMV, leading to a worsening of prognosis.
In the present patients with hypertension, severe AEs (grade 3 or worse) occurred more frequently in those in the mild than those in the severe atrophy group (Table S2), despite no significant difference in any grade of hypertension between the two groups. It is possible that blood pressure control was originally worse in more of the patients in the mild atrophy group compared with the severe atrophy group. There was no significant difference in any of the other AEs that affect patients’ nutritional status such as diarrhea, anorexia, or body weight loss between either of the low and normal PMI groups or the severe and mild atrophy groups. Uojima et al have reported low SMV as a risk factor associated with severe AEs in patients treated with LEN, and that SMV was more important than body weight in those patients.14 In the present study, the initial dose of LEN was reduced as appropriate at the discretion of each researcher, and accordingly, AEs were unlikely to occur. However, doses of LEN were less reduced in patients in the severe atrophy group compared with those in the mild atrophy group. This result suggests that continued administration of excessive amounts of LEN may result in decreased hepatic reserve and SMV. A reduction in the dose of LEN should be considered in treatment of patients with SMV loss, even if AEs are mild. Furthermore, Hiraoka et al reported that the AE of appetite loss was more frequent in patients with lower BMI when a set dose was used and suggested that there might be a risk of LEN overdose in these patients even with a set dose.24 In the present study, lower BMI was not a risk factor for OS (Table 3) and there was no significant difference in BMI in terms of the severity of AEs. However, BMI was lower in the present patients with severe atrophy than in those with mild atrophy (Table 4). Furthermore, the Pre values of ChE were lower in the severe atrophy group than in the mild atrophy group. These results suggest that patients with low BMI or poor nutritional status may be at risk of overdose, even with standard doses of LEN.
In the present study, we calculated SMV according to the simple method specified in the JSH guidelines for sarcopenia in liver disease.17 The JSH guidelines define SMI as the cross-sectional area of skeletal muscle at the level of L3 divided by height squared on CT.17 However, there is a demand for a simple screening method for sarcopenia that is more suitable for use in clinical practice, such as that described in the present study. In recent years, various researchers have proposed screening methods for sarcopenia using arm circumference, calf circumference, and body mass index.25–27 These simple methods are useful for evaluating changes in SMV during the treatment period for HCC and CLD.
The present study had several limitations in addition to its retrospective design and small sample size. First, as markers of muscular strength such as hand grip strength and walking speed were not evaluated, a diagnosis of sarcopenia was impossible according to the JSH guidelines. Second, we measured PMI by manual tracing on the CT images, which could have introduced errors due to inconsistency among the researchers. Third, we evaluated nutritional status only with respect to albumin, sugar metabolism, lipid metabolism and ChE. Sano et al have reported a significant association of BCAA levels with sarcopenia, and a significant correlation of Δleucine with ΔSMI (R = 0.256, P < 0.001).28 Okubo et al have reported that sarcopenia was diagnosed significantly more frequently in patients with vitamin D deficiency compared with those without vitamin D deficiency.29 In addition, we did not evaluate liver fibrosis by hyaluronic acid, Mac-2 binding protein glycosylated isomer, or elastography (e.g., transient elastography, magnetic resonance). To prevent sarcopenia and thus improve prognosis in HCC patients treated with LEN, prospective large-scale and interventional studies are needed to overcome the above-mentioned limitations.
In conclusion, progressive loss of SMV was associated with OS in patients with HCC during administration of LEN. Prevention of SMV loss, including nutrition therapy, is essential for improving prognosis in HCC patients treated with LEN.