Prognostic Effect of Sarcopenia in Hepatocellular Carcinoma Patients Targeted with Interventional Therapy Combined with Immunotherapy and Targeted Therapy

Figures & data

Figure 1 Flow chart of research design.

Figure 2 Computed tomographic scans showing areas of skeletal muscle (red, green, and blue), visceral adipose tissue (yellow), and subcutaneous adipose tissue (purple) in patients with sarcopenia (A) and without sarcopenia (B).

Table 1 The baseline characteristics of all included patients

Characteristics	Low SMI (n=47)	High SMI (n=49)	Total (n=96)	p value
Sex				1.000
Male	43 (44.79%)	44 (45.83%)	87 (90.63%)
Female	4(4.17%)	5(5.21%)	9(9.38%)
Age				0.205
Mean±SD	58.36±9.11	55.78±10.65	57.04±9.96
Median[min-max]	59.00[40.00,79.00]	57.00[31.00,77.00]	57.00[31.00,79.00]
Lesions				0.195
Solitary	9(9.38%)	15 (15.63%)	24 (25.00%)
Multiple	38 (39.58%)	34 (35.42%)	72 (75.00%)
Maximum tumor dimension (cm)				0.003
Mean±SD	8.90±4.95	5.94±3.67	7.39±4.57
Median[min-max]	9.80[0.50,18.20]	6.00[0.60,14.20]	7.00[0.50,18.20]
Macrovascular invasion				0.962
No	29 (30.21%)	30 (31.25%)	59 (61.46%)
Yes	18 (18.75%)	19 (19.79%)	37 (38.54%)
Extrahepatic metastasis				0.544
No	36 (37.50%)	40 (41.67%)	76 (79.17%)
Yes	11 (11.46%)	9(9.38%)	20 (20.83%)
BCLC stage				0.863
B	20 (20.83%)	20 (20.83%)	40 (41.67%)
C	27 (28.13%)	29 (30.21%)	56 (58.33%)
SMI (cm^2/m^2)				<0.01
Mean±SD	40.35±3.07	50.54±5.52	45.55±6.79
Median[min-max]	40.71[33.09,44.96]	50.20[36.33,63.33]	44.82[33.09,63.33]
BMI (kg/m^2)				<0.01
Mean±SD	21.54±2.89	24.66±2.84	22.75±3.54
Median[min-max]	22.23[15.67,26.89]	24.49[18.81,30.41]	23.25[12.54,30.41]
Visceral adipose tissue (cm^2)				<0.01
Mean±SD	120.65±59.06	163.73±84.61	142.64±75.99
Median[min-max]	120.11[5.74,229.72]	145.44[27.98,376.32]	128.97[5.74,376.32]
Subcutaneous adipose tissue (cm^2)				<0.01
Mean±SD	106.42±50.44	149.68±58.09	128.50±58.39
Median[min-max]	106.59[3.36,213.92]	145.63[42.01,349.48]	123.03[3.36,349.48]
Interventional therapy cycle
Mean±SD	2.96±1.87	3.47±2.76	3.22±2.37	0.292
Median[min-max]	2.00[1.00,8.00]	3.00[1.00,13.00]	2.00[1.00,13.00]
Targeted and immunotherapy cycle
Mean±SD	8.50±4.93	9.43±6.05	8.98±5.52	0.416
Median[min-max]	8.00[1.00,24.00]	8.00[3.00,26.00]	8.00[1.00,26.00]
Hepatitis				0.234
No	5(5.21%)	3(3.13%)	8(8.33%)
HBV	38 (39.58%)	45 (46.88%)	83 (86.46%)
HCV	4(4.17%)	1(1.04%)	5(5.21%)
Cirrhosis				0.126
No	3(3.13%)	8(8.33%)	11 (11.46%)
Yes	44 (45.83%)	41 (42.71%)	85 (88.54%)
AFP (ng/ml)				0.065
AFP < 400	25 (26.04%)	35 (36.46%)	60 (62.50%)
AFP ≥ 400	22 (22.92%)	14 (14.58%)	36 (37.50%)
WBC				0.302
Mean±SD	6.19±1.87	5.81±1.72	6.00±1.80
Median[min-max]	5.95[2.94,11.37]	5.73[2.67,9.85]	5.83[2.67,11.37]
Neut				0.109
Mean±SD	6.69±12.39	3.75±1.42	5.19±8.80
Median[min-max]	4.04[1.66,69.80]	3.47[1.60,7.34]	3.78[1.60,69.80]
Lymph				0.741
Mean±SD	1.49±0.58	1.52±0.49	1.50±0.53
Median[min-max]	1.40[0.51,2.99]	1.54[0.52,2.88]	1.46[0.51,2.99]
Mono				0.329
Mean±SD	0.58±1.13	0.42±0.18	0.49±0.80
Median[min-max]	0.38[0.09,8.00]	0.39[0.13,0.97]	0.38[0.09,8.00]
RBC				0.262
Mean±SD	4.70±0.82	4.78±0.49	4.74±0.67
Median[min-max]	4.64[3.23,7.18]	4.80[3.93,6.62]	4.75[3.23,7.18]
Hb				0.098
Mean±SD	141.54±29.79	149.02±14.69	145.36±23.51
Median[min-max]	143.00[4.38,202.00]	151.00[109.00,178.00]	148.50[4.38,202.00]
PLT				0.018
Mean±SD	203.36±89.19	163.06±69.46	182.79±81.85
Median[min-max]	210.00[65.00,521.00]	156.00[51.00,379.00]	175.00[51.00,521.00]
PT				0.148
Mean±SD	11.92±1.21	12.34±1.56	12.13±1.40
Median[min-max]	11.70[9.90,15.30]	12.00[10.40,20.20]	11.90[9.90,20.20]
INR				0.063
Mean±SD	1.04±0.10	1.08±0.13	1.06±0.12
Median[min-max]	1.03[0.87,1.33]	1.06[0.91,1.75]	1.04[0.87,1.75]
D-Dimer				0.926
Mean±SD	1.11±0.88	1.14±1.87	1.13±1.46
Median[min-max]	0.90[0.09,3.86]	0.47[0.05,10.98]	0.69[0.05,10.98]
ALT				0.615
Mean±SD	45.61±30.84	42.25±34.39	43.90±32.57
Median[min-max]	37.60[7.00,176.70]	39.00[11.60,243.80]	37.75[7.00,243.80]
AST				0.015
Mean±SD	67.32±40.39	51.49±32.14	59.24±37.08
Median[min-max]	55.70[12.00,174.40]	42.30[19.50,171.00]	51.10[12.00,174.40]
GGT				0.199
Mean±SD	160.74±100.86	127.89±143.60	143.98±124.97
Median[min-max]	150.10[17.80,524.50]	87.80[23.00,839.10]	111.20[17.80,839.10]
ALP				0.033
Mean±SD	143.44±57.70	120.23±51.82	131.59±55.72
Median[min-max]	124.40[64.30,282.90]	106.00[60.50,315.20]	114.65[60.50,315.20]
GLU				0.315
Mean±SD	5.51±1.21	5.82±1.76	5.67±1.52
Median[min-max]	5.36[3.52,9.52]	5.44[4.00,14.17]	5.38[3.52,14.17]
TBIL				0.751
Mean±SD	22.39±20.39	21.29±12.50	21.83±16.75
Median[min-max]	18.50[9.10,151.40]	18.10[5.40,77.00]	18.40[5.40,151.40]
DBIL				0.142
Mean±SD	6.91±10.42	5.73±5.44	6.31±8.24
Median[min-max]	5.30[1.60,72.10]	4.10[1.60,33.30]	4.30[1.60,72.10]
Cre				0.502
Mean±SD	68.44±13.95	70.39±14.42	69.44±14.15
Median[min-max]	68.00[45.90,112.90]	67.70[48.10,125.60]	67.85[45.90,125.60]
ALB				0.367
Mean±SD	40.11±5.23	40.72±4.53	40.42±4.87
Median[min-max]	40.50[27.10,53.80]	41.30[30.40,47.40]	40.90[27.10,53.80]
Child–Pugh class				0.351
A	44 (45.83%)	42 (43.75%)	86 (89.58%)
B	3(3.13%)	7(7.29%)	10 (10.42%)
Down-stage surgery				0.399
No	42 (43.75%)	47 (48.96%)	89 (92.71%)
Yes	5(5.21%)	2(2.08%)	7(7.29%)
Radiation Therapy				0.067
No	40 (41.67%)	34 (35.42%)	75 (78.13%)
Yes	7(7.29%)	15 (15.63%)	21 (21.88%)

Abbreviations: SMI, skeletal muscle index; SD, standard deviation; BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, alpha-fetoprotein; WBC, white blood cell; Neut, neutrophils ; Lymph, lymphocyte; Mono, monocyte; RBC, red blood cell ; Hb, hemoglobin ; PLT, platelet; PT, prothrombin time; INR, international standardized ratio; ALT, glutamic-pyruvic transaminase; AST, glutamic oxaloacetic transaminase; GGT, γ glutamyl transpeptidase; ALP, alkaline phosphatase; GLU, glucose; TBIL, total bilirubin; DBIL, direct bilirubin; Cre, creatinine; ALB, albumin.

Table 2 Treatment-related adverse events for all grades

TRAEs, n (%)	Low-SMI	High-SMI	Total
Fatigue	14 (14.6%)	11 (11.5%)	25 (26.0%)
Decreased appetite	11 (11.5%)	10 (10.4%)	21 (21.9%)
Hypertension	9 (9.4%)	10 (10.4%)	19 (19.8%)
Abnormal liver function	7 (7.3%)	10 (10.4%)	17 (17.7%)
Weight decrease	5 (5.2%)	3 (3.1%)	8 (8.3%)
Hand-foot reaction	2 (2.1%)	5 (5.2%)	7 (7.3%)
Eczema	4 (4.2%)	3 (3.1%)	7 (7.3%)
Diarrhea	3 (3.1%)	3 (3.1%)	6 (6.3%)
Abdominal pain	2 (2.1%)	3 (3.1%)	5 (5.2%)
Oral mucositis	2 (2.1%)	1 (1.0%)	3 (3.1%)
Hyperbilirubinemia	1 (1.0%)	2 (2.1%)	3 (3.1%)
Immune-related adverse events	1 (1.0%)	2 (2.1%)	3 (3.1%)
Constipation	1 (1.0%)	1 (1.0%)	2 (2.1%)
Chest pain	1 (1.0%)	1 (1.0%)	2 (2.1%)
Proteinuria	1 (1.0%)	1 (1.0%)	2 (2.1%)
Limb edema	1 (1.0%)	1 (1.0%)	2 (2.1%)
Musculoskeletal pain	1 (1.0%)	1 (1.0%)	2 (2.1%)
Hypothyroidism	1 (1.0%)	1 (1.0%)	2 (2.1%)
Thrombocytopenia	1 (1.0%)	1 (1.0%)	2 (2.1%)
Pyrexia	1 (1.0%)	1 (1.0%)	2 (2.1%)
Gingival bleeding	1 (1.0%)	1 (1.0%)	2 (2.1%)
Headache	1 (1.0%)	1 (1.0%)	2 (2.1%)
Bone marrow suppression	0 (0%)	1 (1.0%)	1 (1.0%)

Abbreviations: TRAEs, treatment-related adverse events; SMI, skeletal muscle index.

Table 3 The correlation between SMI and BMI, maximum tumor dimension, the total cross-sectional areas of visceral adipose tissue and subcutaneous adipose tissue, PLT, AST, ALP

	BMI	Maximum Tumor Dimension	Areas of Visceral Adipose Tissue	Areas of Subcutaneous Adipose Tissue	PLT	AST	ALP
Correlation coefficient	0.502	-0.354	0.371	0.312	-0.312	-0.128	-0.205
p value	<0.001	<0.001	<0.001	0.002	0.002	0.213	0.046

Abbreviations: SMI, skeletal muscle index; BMI, body mass index; PLT, platelet; AST, glutamic oxaloacetic transaminase; ALP, alkaline phosphatase.

Table 4 Univariate and multivariate analyses of prognostic factors affecting overall survival

	Univariate Cox-Regression		Multivariate Cox-Regression
	HR (95% CI)	p value	HR (95% CI)	p value
Age (years)	1.010 (0.982-1.039)	0.470
Sex (male vs. female)	1.421 (0.638-3.165)	0.389
BMI (Kg/m^2)	0.900 (0.826-0.981)	0.017	0.955 (0.863-1.058)	0.249
SMI (cm^2/m^2)	0.933 (0.892-0.975)	0.002	0.945 (0.898-0.995)	0.031
Visceral adipose tissue (cm^2)	0.999 (0.995-1.002)	0.428
Subcutaneous adipose tissue (cm^2)	0.999 (0.994-1.004)	0.618
Lesion size (cm)	1.069 (1.007-1.136)	0.029	0.998 (0.933-1.067)	0.944
Cirrhosis (no vs. yes)	1.396 (0.554-3.520)	0.479
BCLC stage (B vs. C)	2.168 (1.181-3.983)	0.013	2.508 (1.307-4.633)	0.006
Child-Pugh stage (A vs. B)	1.358 (0.657-2.803)	0.409
AFP (ng/ml) (<400 vs. ≥400)	0.960 (0.538-1.712)	0.890
Downstage Surgery (no vs. yes)	1.203 (0.432-3.345)	0.724
Radiation therapy (no vs. yes)	1.561 (0.851-2.856)	0.150
Hepatitis
No Hepatitis	1.782 (0.755-4.206)	0.187
HBV	0.663 (0.309-1.422)	0.291
HCV	0.967 (0.234-4.002)	0.964
WBC	0.989 (0.849-1.152)	0.887
Neut	0.952 (0.868-1.044)	0.302
INR	0.502 (0.045-5.516)	0.573
Lymph	0.801 (0.475-1.350)	0.405
Mono	1.058 (0.818-1.368)	0.668
RBC	0.830 (0.523-1.317)	0.428
Hb	0.987 (0.974-1.001)	0.066	0.991 (0.978-1.005)	0.223
PLT	1.000 (0.997-1.003)	0.965
PT	0.933 (0.756-1.152)	0.521
D-Dimer	1.036 (0.889-1.207)	0.652
ALT	1.000 (0.993-1.008)	0.965
AST	1.002 (0.995-1.008)	0.662
GGT	1.001 (0.999-1.003)	0.272
ALP	1.003 (0.998-1.007)	0.261
GLU	0.883 (0.711-1.095)	0.257
TBIL	0.981 (0.955-1.009)	0.177
DBIL	0.979 (0.936-1.024)	0.347
Cre	1.009 (0.987-1.030)	0.437
ALB	0.971 (0.919-1.025)	0.289

Abbreviations: BMI, body mass index; SMI, skeletal muscle index; AFP, alpha-fetoprotein; HBV, hepatitis B virus; HCV, hepatitis C virus; WBC, white blood cell; Neut, neutrophils; INR, international standardized ratio; Lymph, lymphocyte; Mono, monocyte; RBC, red blood cell;Hb, hemoglobin ; PLT, platelet; PT, prothrombin time; ALT, glutamic-pyruvic transaminase; AST, glutamic oxaloacetic transaminase; GGT, γ glutamyl transpeptidase; ALP, alkaline phosphatase; GLU, glucose; TBIL, total bilirubin; DBIL, direct bilirubin; Cre, creatinine; ALB, albumin.

Figure 3 The overall survival (OS) of patients in high and low SMI groups. (A) The Kaplan-Meier curve showed that the OS of the high SMI group was significantly higher than the low SMI group (p < 0.05). (B) The survival heatmap exhibited that with the increase of SMI, the OS of patients is higher and the death is less.

Figure 4 When the optimal cutoff value was selected as the cutoff value for sarcopenia, the difference in overall survival between the high and low SMI groups.

Data Sharing Statement

The raw data supporting the conclusions of this article will be made available by Hongcai Yang and Tianhao Cong, without undue reservation.