Supplementary Fig. 1. Patient flow diagram. HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; BCLC, Barcelona Clinic Liver Cancer.
Supplementary Material (exclusion of BCLC stage 0 or stage A)
Supplementary Fig. 2. ROC curves and equations of the multivariable logistic regression of the TACE refractoriness (n=99). AUC, area under the curve; ROC, receiver operating characteristic; TACE, transarterial chemoembolization.
Supplementary Fig. 3. Total bilirubin ROC curves of the univariable logistic regression of liver function deterioration (n=99). AUC, area under the curve; ROC, receiver operating characteristic.
25.5%
Time from first TACE (month)
Supplementary Fig. 4. Kaplan-Meier survival curves of 27 patients (TACE refractoriness and liver function deterioration) vs. 94 patients (except 27 patients who were refractory to TACE and exhibited liver function deterioration). TACE, transarterial chemoembolization.
Supplementary Table 1. Baseline Characteristics (n=99) (Exclusion of BCLC Stage 0 or Stage A)
Variable Value
Mean age (years) 65.0 (56.0-73.0)
Male 75 (75.8)
Diabetes mellitus 37 (37.4)
BMI (kg/m2) 23.1 (20.7-26.2)
Alcohol intake (g/day) 14.1 (0.0-54.0)
Etiology of HCC
HBV 54 (54.5)
HCV 17 (17.2)
Alcohol 20 (20.2)
Other 8 (8.1)
Final follow-up state
Death 22 (22.2)
Ongoing follow-up 46 (46.5)
Lost to follow-up 31 (31.3)
Tumor size (cm) 3.2 (1.8-5.8)
Number of tumors 2.0 (1.0-3.0)
Portal vein thrombosis 8 (8.1)
Liver cirrhosis 91 (91.9)
Platelet (×103/µL) 129.0 (88.0-164.0)
Albumin (g/dL) 3.7 (3.3-4.1)
Total bilirubin (mg/dL) 0.9 (0.6-1.2)
AST (U/L) 50.0 (35.0-68.0)
ALT (U/L) 35.0 (22.0-50.0)
BUN (mg/dL) 14.6 (12.5-17.6)
Creatinine (mg/dL) 0.9 (0.7-1.0)
Na (mmol/L) 138.0 (136.0-140.0)
Prothrombin time (INR) 1.1 (1.0-1.2)
AFP (ng/mL) 12.1 (5.8-160.3)
PIVKA II (mAU/mL) 73.0 (24.0-429.1)
MELD score 8.0 (7.0-10.0)
Modified UICC stage
Stage I 13 (13.1)
Stage II 35 (35.4)
Stage III 33 (33.3)
Stage IV 18 (18.2)
BCLC stage
Intermediate stage (B) 25 (25.3)
Advanced stage (C) 72 (72.7)
Terminal sate (D) 4 (2.0)
Child-Pugh
Score 5 58 (58.6)
Score 6 41 (41.4)
Values are presented as median (range) or n (%).
BCLC, Barcelona Clinic Liver Cancer; BMI, body mass index; HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen;
Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II; MELD, model for end-stage liver disease; UICC, Union for International Cancer Control.
Supplementary Table 2. Comparison of the Characteristics between Patients with TACE Response and without TACE Response (n=99)
Variable TACE response (n=39) Without TACE response (n=60) p-value
Age (years) 65.0 (62.0-69.0) 62.5 (56.0-76.0) 0.619
Male 29 (74.4) 46 (76.7) 0.793
BMI (kg/m2) 24.2 (22.0-26.4) 22.4 (20.6-25.8) 0.114
Tumor size (cm) 2.7 (1.5-3.9) 3.7 (2.0-6.7) 0.044
Number of tumors 1.0 (1.0-2.0) 2.0 (1.0-6.0) 0.001
Diabetes mellitus 14 (35.9) 23 (38.3) 0.807
Alcohol (g/day) 14.4 (0.0-54.0) 10.8 (0.0-54.0) 0.673
Portal vein thrombosis 1 (2.6) 7 (11.7) 0.142
Liver cirrhosis 36 (92.3) 55 (91.7) 1.000
Platelet (×103/µL) 131.0 (96.0-154.0) 121.5 (76.3-168.8) 0.618
Albumin (g/dL) 3.9 (3.6-4.3) 3.6 (3.2-4.1) 0.017
Total bilirubin (mg/dL) 0.9 (0.6-1.1) 0.9 (0.6-1.3) 0.596
AST (U/L) 45.0 (32.0-68.0) 51.5 (36.3-69.3) 0.427
ALT (U/L) 30.0 (22.0-51.0) 36.5 (22.0-48.5) 0.931
BUN (mg/dL) 14.5 (12.5-16.3) 15.2 (12.5-18.0) 0.348
Creatinine (mg/dL) 0.9 (0.7-1.0) 0.9 (0.7-1.0) 0.975
Na (mmol/L) 138.0 (137.0-140.0) 138.5 (136.0-140.8) 0.732
Prothrombin time (INR) 1.1 (1.0-1.1) 1.1 (1.0-1.2) 0.116
AFP (ng/mL) 7.8 (4.3-25.7) 27.4 (8.6-397.7) 0.002
PIVKA II (mAU/mL) 38.7 (23.0-184.2) 143.4 (24.1-863.3) 0.065
MELD score 8.0 (7.0-9.0) 8.5 (7.0-10.0) 0.120
Modified UICC 0.014
Stage I 8 (20.5) 5 (8.3)
Stage II 15 (38.5) 20 (33.3)
Stage III 13 (33.3) 20 (33.3)
Stage IV 3 (7.7) 15 (25.0)
BCLC stage 0.979
Intermediate stage (B) 11 (28.2) 14 (23.3)
Advanced stage (C) 26 (66.7) 46 (76.7)
Terminal sate (D) 2 (5.1) 0 (0.0)
Child-Pugh 0.083
Score 5 27 (69.2) 31 (51.7)
Score 6 12 (30.8) 29 (48.3)
Values are presented as median (range) or n (%).
TACE, transarterial chemoembolization; BMI, body mass index; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II; MELD, model for end-stage liver disease; UICC, Union for International Cancer Control; BCLC, Barcelona Clinic Liver Cancer.
Supplementary Table 3. Multivariate Logistic Regression of the TACE Refractoriness
Characteristics Univariable OR (95% CI) p-value Multivariable OR (95% CI) B p-value
Tumor size (cm) 1.177 (1.014-1.366) 0.032
Number of tumors 1.563 (1.160-2.105) 0.003 1.558 (1.159-2.094) 0.444 0.003
Albumin 0.363 (0.154-0.854) 0.020 0.353 (0.143-0.870) -1.042 0.024
AFP 1.000 (1.000-1.001) 0.286
TACE, transarterial chemoembolization; OR, odds ratio; CI, confidence interval; B, beta coefficient; AFP, alpha-fetoprotein.
Supplementary Table 4. Risk Factors for Liver Function Deterioration after TACE without Response in Child-Pugh Class A HCC Patients Variable Remained in Child-Pugh class A (n=35) Worsened to Child-Pugh class B or C (n=25) p-value
Age (years) 64.0 (58.0-75.0) 61.0 (50.0-76.0) 0.334
Male 28 (80.0) 18 (72.0) 0.470
Diabetes mellitus 14 (40.0) 9 (36.0) 0.753
BMI (kg/m2) 23.0 (20.8-26.5) 21.3 (19.6-24.6) 0.118
Alcohol (g/day) 0.0 (0.0-43.2) 39.6 (0.0-90.0) 0.034
Tumor size (cm) 3.4 (2.2-6.0) 4.4 (1.6-9.7) 0.845
Number of tumors 2.0 (1.0-6.0) 3.0 (1.5-5.0) 0.613
Portal vein thrombosis 4 (11.4) 3 (12.0) 1.000
Liver cirrhosis 31 (88.6) 24 (96.0) 0.390
Platelet (x103/µL) 127.0 (77.0-162.0) 101.0 (74.5-174.0) 0.702
Albumin (g/dL) 3.7 (3.3-4.1) 3.5 (3.01-4.1) 0.311
Total bilirubin (mg/dL) 0.7 (0.5-1.0) 1.1 (0.9-1.4) 0.002
AST (U/L) 43.0 (36.0-60.0) 59.0 (37.0-88.5) 0.172
ALT (U/L) 35.0 (22.0-42.0) 39.0 (24.0-58.5) 0.261
BUN (mg/dL) 16.4 (13.4-18.3) 13.3 (11.2-18.0) 0.105
Creatinine (mg/dL) 0.9 (0.8-1.1) 0.9 (0.6-1.0) 0.342
Na (mmol/L) 138.0 (136.0-140.0) 139.0 (136.0-141.0) 0.177
Prothrombin time (INR) 1.1 (1.0-1.2) 1.2 (1.0-1.3) 0.028
AFP (ng/mL) 21.0 (9.0-286.7) 57.6 (6.5-712.4) 0.476
PIVKA II (mAU/mL) 121.0 (24.3-599.0) 180.0 (23.0-2955.8) 0.472
MELD score 8.0 (7.0-9.0) 9.0 (7.5-11.0) 0.051
Modified UICC 0.556
Stage I 2 (5.7) 3 (12.0)
Stage II 11 (31.4) 9 (36.0)
Stage III 14 (40.0) 6 (24.0)
Stage IV 8 (22.9) 7 (28.0)
BCLC stage 0.606
Intermediate stage (B) 9 (25.7) 5 (20.0)
Advanced stage (C) 26 (74.3) 20 (80.0)
Child-Pugh 0.126
Score 5 21 (60.0) 10 (40.0)
Score 6 14 (40.0) 15 (60.0)
Values are presented as median (range) or n (%).
TACE, transarterial chemoembolization; HCC, hepatocellular carcinoma; BMI, body mass index; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II; MELD, model for end-stage liver disease; UICC, Union for International Cancer Control; BCLC, Barcelona Clinic Liver Cancer.
Supplementary Table 5. Multivariate Logistic Regression of Liver Function Deterioration
Characteristics Univariable OR (95% CI) p-value Multivariable OR (95% CI) B p-value
Alcohol (g/day) 1.011 (0.999-1.024) 0.077
Total bilirubin 7.681 (1.866-31.611) 0.005 7.681 (1.866-31.611) 2.039 0.005
Prothrombin time (INR) 112.366 (1.480-8530.505) 0.033
OR, odds ratio; CI, confidence interval; B, beta coefficient; INR, international normalized ratio.
Supplementary Table 6. Baseline Characteristics (n=22) (BCLC Stage 0 or Stage A)
Variable Value
Mean age (years) 71.0 (63.0-75.3)
Male 9 (40.9)
Diabetes mellitus 8 (36.4)
BMI (kg/m2) 24.0 (21.0-26.0)
Alcohol intake (g/day) 0.0 (0-27.0)
Etiology of HCC
HBV 11 (50.0)
HCV 6 (27.3)
Alcohol 3 (13.6)
Other 2 (9.1)
Final follow-up state
Death 3 (13.6)
Ongoing follow-up 15 (68.2)
Lost to follow-up 4 (18.2)
Tumor size (cm) 1.9 (1.5-2.3)
Number of tumors 1.0 (1.0-2.0)
Portal vein thrombosis 0 (0.0)
Liver cirrhosis 22 (100.0)
Platelet (×103/µL) 138.0 (82.8-169.3)
Albumin (g/dL) 3.9 (3.5-4.2)
Total bilirubin (mg/dL) 0.9 (0.5-1.2)
AST (U/L) 47.5 (29.5-65.2)
ALT (U/L) 31.5 (18.8-40.3)
BUN (mg/dL) 14.2 (12.1-17.6)
Creatinine (mg/dL) 0.8 (0.7-0.9)
Na (mmol/L) 139.0 (137.0-141.0)
Prothrombin time (INR) 1.1 (1.0-1.1)
AFP (ng/mL) 16.0 (4.6-89.3)
PIVKA II (mAU/mL) 23.5 (17.1-92.8)
MELD score 8.0 (7.0-9.0)
Modified UICC stage
Stage I 9 (40.9)
Stage II 8 (36.4)
Stage III 5 (22.7)
Stage IV 0 (0.0)
BCLC stage
Very early stage (0) 8 (36.4)
Early stage (A) 14 (63.6)
Child-Pugh
Score 5 16 (72.7)
Score 6 6 (27.3)
Values are presented as median (range) or n (%).
BCLC, Barcelona Clinic Liver Cancer; BMI, body mass index; HCC, hepatocellular carcinoma; HBV, hepatitis B virus;
HCV, hepatitis C virus; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II; MELD, model for end-stage liver disease; UICC, Union for International Cancer Control.
Supplementary Material (BCLC stage 0-A and stage B)
Supplementary Table 7. Baseline Characteristics (n=25) (BCLC Stage B)
Variable Value
Mean age (years) 65.0 (56.0-74.0)
Male 20 (80.0)
Diabetes mellitus 8 (32.0)
BMI (kg/m2) 23.8 (20.3-26.6)
Alcohol intake (g/day) 0.0 (0.0-41.4)
Etiology of HCC
HBV 15 (60.0)
HCV 5 (20.0)
Alcohol 3 (12.0)
Other 2 (8.0)
Final follow-up state
Death 4 (16.0)
Ongoing follow-up 10 (40.0)
Lost to follow-up 11 (44.0)
Tumor size (cm) 4.5 (3.3-6.1)
Number of tumors 2.0 (1.0-3.5)
Portal vein thrombosis 1 (4.0)
Liver cirrhosis 21 (84.0)
Platelet (×103/µL) 140.0 (126.5-190.5)
Albumin (g/dL) 3.9 (3.4-4.2)
Total bilirubin (mg/dL) 0.8 (0.5-1.1)
AST (U/L) 47.0 (29.5-68.5)
ALT (U/L) 41.0 (22.0-62.5)
BUN (mg/dL) 15.2 (11.5-18.4)
Creatinine (mg/dL) 0.9 (0.7-1.0)
Na (mmol/L) 139.0 (137.0-140.5)
Prothrombin time (INR) 1.1 (1.0-1.1)
AFP (ng/mL) 11.3 (6.0-209.2)
PIVKA II (mAU/mL) 309.0 (44.3-724.2)
MELD score 7.0 (7.0-8.5)
Modified UICC stage
Stage I 0 (0.0)
Stage II 13 (52.0)
Stage III 12 (48.0)
Stage IV 0 (0.0)
Child-Pugh
Score 5 16 (64.0)
Score 6 9 (36.0)
Values are presented as median (range) or n (%).
TACE, transarterial chemoembolization; HCC, hepatocellular carcinoma; BMI, body mass index; AST, aspartate transaminase; ALT, alanine transaminase; BUN, blood urea nitrogen; Na, sodium; INR, international normalized ratio; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence-II; MELD, model for end-stage liver disease; UICC, Union for International Cancer Control; BCLC, Barcelona Clinic Liver Cancer.
