Patient characteristics
A total of 124 consecutive patients with HCC admitted to Dr. Sardjito Hospital were identified during the study period. Twenty-four patients were excluded because CT scan imaging data and/or required clinical/laboratory data were missing or because of concomitant malignancies. Therefore, 100 HCC patients were included in the final analyses. There were 74 men (74%), and the mean ± standard deviation age was 55.03 ± 11.20 years. The most common cause of HCC was hepatitis B infection (58%). Non-B non-C type (NBNC) HCC, which tests negative for HBV and HCV markers, ranked second (34%).
All enrolled patients initially presented to the hospital after the onset of symptoms. The most common clinical signs or symptoms were malaise and nausea (76%), abdominal pain (68%), weight loss (80%), and hepatomegaly (92%); jaundice, ascites, splenomegaly, and hematemesis/melena were observed in 25%, 32%, 30%, and 11% of patients, respectively. The BCLC stage distribution and JIS score data suggested that most the patients were diagnosed at an intermediate to advanced stage (BCLC stage C, 59%; JIS score 3, 31%) and had relatively large tumours (mean diameter, 12.05 ± 4.97 cm). Interpretation of the CT scan indicated that the most common tumour types in Indonesian HCC patients were multiple (70%) and nodular (65%) types.
Because of the advanced-stage presentation, all patients were given only palliative (transarterial chemoembolisation [TACE]) or supportive treatment (end-stage life support). Some patients did not undergo TACE because of the long waiting list or died while waiting for TACE. Treatment with radiofrequency ablation (RFA) and the use of sorafenib were limited because of their high costs and lack of coverage by the national health insurance. The rate of alcohol consumption was low (only 8%) among these patients presumably because of religious practices and the limited availability of alcohol in the public market. Complete baseline characteristics are summarised in Table 1.
Association between sarcopenia and HCC survival
Of the 100 patients included in the final analysis, 31 were diagnosed with sarcopenia (L3 SMI value ≤36.2 cm2/m2 for men and ≤29.6 cm2/m2 for women), of which 23 (75%) were men. At baseline, the median L3 SMI value was 39.94 ± 8.03 cm2/m2 in men and 32.53 ± 5.23 cm2/m2 in women. Inter-observer concordance on the L3 SMI value and mean muscle attenuation was >95%.
The median survival of HCC patients was 92 ± 8.5 days. The Kaplan–Meier curves showed that median survival was shorter in patients with sarcopenia than in patients with high SMI/non-sarcopenia (29.0 ± 6.68 versus 133 ± 34.70 days, P < 0.0001), as shown in Figure 1. The Cox regression model indicated that sarcopenia was associated with poor prognosis, with a mean 3-month overall survival rate of 26 ± 8%, and a poor prognosis (HR, 1.921; 95% CI, 1.129–3.268; P = 0.016) in multivariate analysis (Table 2).
To examine the effects of sarcopenia on the prognosis of HCC patients, subgroup analyses were performed to compare survival between sarcopenia and non-sarcopenia patients grouped by gender, age, BCLC stage, and JIS score (Supplementary Figure). Sarcopenia remained an independent predictor of reduced survival in the following subgroups: men, patients aged ≥55 years, patients with BCLC stage C, and patients with JIS score 4 (log-rank P <0.0001, P <0.0001, P <0.0001, and P = 0.0028, respectively).
Baseline characteristics of the study population according to sarcopenic status are shown in Table 3. Sarcopenia was significantly associated with higher CP score, INR, and blood potassium level (P <0.001, P = 0.037, and P = 0.035, respectively), whereas albumin levels were lower in patients with sarcopenia than in patients without sarcopenia (P = 0.010).
Association between IMF deposition and HCC survival
As shown in Figure 1, patients with low MA and IMF deposition had a significantly shorter median survival than those with high MA (62.0 ± 13.82 versus 457 ± 77.13 days, P < 0.0001). In addition, the low MA group had a higher mortality rate (HR, 3.580; 95% CI, 1.895–6.764; P < 0.001) in multivariate analysis (Table 2), suggesting that IMF deposition is associated with the progression of liver disease. An MA value ≤44.4 HU for men or ≤39.3 HU for women was established as the threshold for IMF deposition, and there was no significant difference between the proportion of men and women with a low MA value (Table 3).
As summarised in Table 3, patients with IMF deposition had significantly higher AST and CRP levels, which indicate the presence of local and systemic inflammation. In addition, the IMF deposition group showed higher AFP, INR, and CP score, and lower sodium and albumin levels, which are markers of the severity of liver cancer. In subgroup analyses, IMF deposition was significantly associated with poor survival among patients of the same gender (male, log-rank P < 0.0001), same age group (age ≥ 55 years old, log-rank P < 0.0001), same BCLC stage (BCLC stage C, log-rank P = 0.0004) and same JIS score (JIS score 3, log-rank P = 0.0006). This suggested that IMF deposition is a robust predictor of HCC survival (Supplementary Figure).
HCC staging system and significant factors affecting survival
To identify the optimal staging system for predicting prognosis and survival in Indonesian patients, we evaluated methods based on the anatomical characteristics of the tumour (TNM classification) and methods that combine the anatomical features of the tumour with an integrated assessment of liver disease, such as the BCLC stage and JIS score. As depicted in Figure 2, BCLC stage and the JIS score were significantly associated with poor survival in the Kaplan–Meier analysis, showing superior predictive power. These two systems were identified as independent predictors of survival compared with other prognostic systems (LCSGJ TNM stage and AJCC TNM stage 8th edition) as shown in Table 2.
Univariate Cox analysis showed that the factors significantly associated with increased mortality were gender (P = 0.029; HR, 1.845), sarcopenia (P < 0.001; HR, 2.950), IMF deposition (P < 0.001; HR, 5.487), HBV infection (P = 0.002; HR, 2.326), CP class (P < 0.001; HR, 5.069 for class C), LCSGJ TNM stage (P < 0.001; HR, 3.308 for stage 4), AJCC 8th ed. TNM stage (P < 0.001; HR, 3.663 for stage 4), JIS score (P < 0.001; HR, 28.373 for score 5), BCLC stage (P < 0.001; HR, 65.958 for stage D), and AFP ≥200 ng/ml (P = 0.006; HR, 1.916). Multivariate analysis showed that gender (P < 0.001; HR, 3.211), sarcopenia (P = 0.016; HR, 1.921), IMF deposition (P < 0.001; HR, 3.580), JIS score (P = 0.020; HR, 2.067 for score 4), and BCLC stage (P = 0.003; HR, 6.131 for stage D) were independently and significantly associated with reduced survival. The detailed results of the univariate and multivariate analyses of liver-related mortality are shown in Table 2.