High-Risk Hepatocellular Carcinoma: Hepatic Arterial Infusion Chemotherapy versus Transarterial Chemoembolization

Figures & data

Table 1 Baseline Characteristics of the Patients with HCC Who Received TACE and HAIC Therapy Before and After PSM

Characteristic	Before PSM			After PSM
	TACE (N=507)	HAIC (N=426)	P-value	TACE (N=222)	HAIC (N=222)	P-value
Age Median age, mean ± SD	54.00±12.02	51.71±11.90	0.004	52.79±11.71	52.27±11.72	0.644
≤65	414 (81.7%)	368 (86.4%)	0.062	189 (85.1%)	191 (86.0%)	0.893
>65	93 (18.3%)	58 (13.6%)		33 (14.9%)	31 (14.0%)
Sex
Female	57 (11.2%)	43 (10.1%)	0.646	19 (8.6%)	23 (10.4%)	0.627
Male	450 (88.8%)	383 (89.9%)		203 (91.4%)	199 (89.6%)
ECOG
0	489 (96.4%)	388 (91.1%)	<0.001	210 (94.6%)	211 (95.0%)	1
1	18 (3.6%)	38 (8.9%)		12 (5.4%)	11 (5.0%)
Complication(DM/HT)
Absence	470 (92.7%)	368 (86.4%)	0.002	199 (89.6%)	199 (89.6%)	1
Presence	37 (7.3%)	58 (13.6%)		23 (10.4%)	23 (10.4%)
Hepatitis
Non-viral	30 (5.9%)	32 (7.5%)	0.622	14 (6.3%)	21 (9.5%)	0.415
HBV	472 (93.1%)	390 (91.5%)		206 (92.8%)	198 (89.2%)
HCV	5 (1.0%)	4 (0.9%)		2 (0.9%)	3 (1.4%)
Cirrhosis
No	0 (0%)	26 (6.1%)	<0.001	0 (0%)	1 (0.5%)	1
Yes	507 (100%)	400 (93.9%)		222 (100%)	221 (99.5%)
Laboratory tests
ALB, g/L	38.43±5.50	39.29±4.39	0.009	39.53±5.24	39.59±4.41	0.897
ALT, U/L	73.74±138.88	60.87±47.14	0.051	69.38±95.25	61.79±51.16	0.296
AST, U/L	110.71±168.95	104.10±88.28	0.445	69.38±95.25	61.79±51.16	0.296
TBIL, μmol/L	20.91±27.44	19.04±13.02	0.173	17.59±11.03	19.92±16.15	0.076
PLT, 10^9/L	89.05±56.50	257.87±126.12	0.000	88.40±46.58	251.34±105.62	0.000
AFP, ng/mL	28619.75±120, 587.91	34,110.22±50,359.67	0.393	18,998.83±79,102.96	27,679.10±44,491.13	0.169
Child-Pugh class
A	485 (95.7%)	414 (97.2%)	0.289	216 (97.3%)	217 (97.7%)	1
B	22 (4.3%)	12 (2.8%)		6 (2.7%)	5 (2.3%)
Maximum tumor size, cm
≤5	11 (2.2%)	5 (1.2%)	<0.001	6 (2.7%)	5 (2.3%)	0.75
5~10	151 (29.8%)	79 (18.5%)		57 (25.7%)	51 (23.0%)
>10	345 (68.0%)	342 (80.3%)		159 (71.6%)	166 (74.8%)
Number of HCC foci
≤5	244 (48.1%)	168 (39.4%)	0.0094	89 (40.1%)	94 (42.3%)	0.7
>5	263 (51.9%)	258 (60.6%)		133 (59.9%)	128 (57.7%)
Microvascular invasion
Absence	218 (43.0%)	162 (38.0%)	0.141	140 (63.1%)	139 (62.6%)	1
Presence	289 (57.0%)	264 (62.0%)		82 (36.9%)	83 (37.4%)
Portal vein tumor thrombosis
Absence	218 (43.0%)	172 (40.4%)	<0.001	140 (63.1%)	139 (62.6%)	0.854
Vp1	0 (0%)	3 (0.7%)		0 (0%)	1 (0.5%)
Vp2	1 (0.2%)	58 (13.6%)		1 (0.5%)	1 (0.5%)
Vp3	2 (0.4%)	97 (22.8%)		2 (0.9%)	1 (0.5%)
Vp4	286 (56.4%)	96 (22.5%)		79 (35.6%)	80 (36.0%)
HVTT
Absence	502 (99.0%)	356 (83.6%)	<0.001	219 (98.6%)	218 (98.2%)	0.801
I	2 (0.4%)	41 (9.6%)		2 (0.9%)	2 (0.9%)
II	2 (0.4%)	7 (1.6%)		1 (0.5%)	1 (0.5%)
III	1 (0.2%)	22 (5.2%)		0 (0%)	1 (0.5%)
BCLC stages
A	81 (16.0%)	41 (9.6%)	0.009	36 (16.2%)	40 (18.0%)	0.799
B	79 (15.6%)	60 (14.1%)		56 (25.2%)	51 (23.0%)
C	347 (68.4%)	325 (76.3%)		130 (58.6%)	131 (59.0%)
Extrahepatic spread
Absence	353 (69.6%)	249 (58.5%)	<0.001	148 (66.7%)	146 (65.8%)	0.92
Presence	154 (30.4%)	177 (41.5%)		74 (33.3%)	76 (34.2%)

Notes: Data are number of patients; data in parentheses are percentage unless otherwise indicated. Data in bracket was percent of patients. The quantitative data with mean± standard deviation or median with interquartile range (IQR) were compared by the Kruskal–Wallis test. The qualitative data in two groups were compared by using the Chi square test. P value < 0.05 suggest statistically significant differences. The variables matched included age.

Abbreviations: HCC, hepatocellular carcinoma; HAIC, hepatic arterial infusion chemotherapy; TACE, transcatheter arterial chemoembolization; PSM, propensity score match; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis type B viral; HCV, hepatitis type C viral; DM, diabetes mellitus; HT, hypertension; HVTT, hepatic vein tumor thrombosis; BCLC, Barcelona Clinic Liver Cancer.

Figure 1 Enrollment pathway of patients with high-risk hepatocellular carcinoma(hHCC) who underwent HAIC and TACE therapy. *High risk: patients with Vp4 portal vein tumor thrombosis (PVTT), bile duct invasion, or a tumor infiltration volume of more than 50%.

Abbreviations: HCC, hepatocellular carcinoma; HAIC, hepatic arterial infusion chemotherapy; TACE, transarterial chemoembolization.

Figure 2 Comparison of survival between patients who received HAIC and TACE. Kaplan–Meier curves for the progression-free survival(PFS) and overall survival(OS) before and after propensity score matching (PSM).PFS before PSM (a), OS before PSM (b); PFS after PSM (c), OS after PSM (d).

Abbreviations: HAIC, hepatic arterial infusion chemotherapy; TACE, transarterial chemoembolization.

Table 2 Summary of Best Overall Response Before and After PSM

Best Overall Response n(%)	Before PSM			After PSM
	TACE (n=222)	HAIC (n=222)	P-value	TACE (n=507)	HAIC (n=426)	P-value
ORR	26 (11.7)	55 (24.8)	0.000	82 (16.2)	89 (20.9)	0.064
DCR	128 (57.7)	186 (83.8)	0.000	309 (60.9)	335 (78.6)	0.000
CSR	18 (8.1)	33 (14.9)	0.026	45 (8.9)	66 (15.5)	0.002
CR	1 (0.5)	2 (0.9)		3 (0.6)	2 (0.5)
PR	25 (11.3)	53 (23.9)		79 (15.6)	87 (20.4)
SD	102 (45.9)	131 (59.0)		227 (44.8)	246 (57.7)
PD	94 (42.8)	36 (16.2)		198 (39.1)	91 (21.4)

Notes: Data are number of patients; data in parentheses are percentage unless otherwise indicated and data in bracket was percent of patients. P value < 0.05 suggest statistically significant differences.

Abbreviations: PSM, propensity score match; ORR, objective response rate; DCR, Disease control rate; CSR, conversion surgery rate; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.

Table 3 Univariate and Multivariate Analysis of Risk Factors for Progression-Free Survival and Overall Survival After Matching

	Univariable Analysis		Multivariable Analysis
	Hazard Ratio (95% CI)	p-value	Hazard Ratio (95% CI)	P-value
PFS analyses
Age (≤65 vs >65)	0.64 (0.47–0.87)	0.004	0.73 (0.53–1.00)	0.052
Sex (Female vs Male)	1.05 (0.73–1.51)	0.797
Hepatitis (Absence vs Presence)	1.14 (0.82–1.60)	0.439
ECOG (0 vs 1)	0.38 (0.22–0.66)	0.001	0.48 (0.27–0.85)	0.011
Child-Pugh (A vs B)	1.00 (0.51–1.94)	0.994
BCLC stage (A vs B vs C)	1.28 (1.11–1.47)	0.001	1.13 (0.96–1.34)	0.141
Complication (Absence vs Presence)	0.60 (0.42–0.86)	0.006	0.77 (0.53–1.13)	0.179
Maximum tumor size-cm (≤5 vs 5~10 vs >10)	1.13 (0.91–1.40)	0.260
HVTT/IVCTT (Absence vs I–III)	0.72 (0.32–1.61)	0.417
MVI (Absence vs Presence)	1.13 (0.91–1.40)	0.280
Number of HCC foci (≤5 vs >5)	1.22 (0.98–1.51)	0.070
PVTT (Absence vs Vp1-Vp3 vs Vp4)	1.03 (0.98–1.09)	0.272
Extrahepatic spread (Absence vs Presence)	1.49 (1.20–1.86)	<0.001	1.20 (0.93–1.56)	0.166
Treatment (TACE vs HAIC)	0.64 (0.52–0.79)	<0.001	0.61 (0.49–0.75)	<0.001
OS analyses
Age (≤65 vs >65)	0.628 (0.463–0.851)	0.003	0.75 (0.55–1.03)	0.073
Sex (Female vs Male)	1.07 (0.75–1.52)	0.711
Hepatitis (Absence vs Presence)	1.15 (0.81–1.64)	0.426
ECOG (0 vs 1)	0.75 (0.47–1.19)	0.218
Child-Pugh (A vs B)	1.67 (0.89–3.14)	0.112
BCLC stages (A vs B vs C)	1.33 (1.16–1.53)	<0.001	1.00 (0.78–1.28)	0.997
Complication (Absence vs Presence)	0.56 (0.39–0.81)	0.002	0.63 (0.43–0.92)	0.016
Maximum tumor size-cm (≤5 vs 5~10 vs >10)	1.16 (0.95–1.42)	0.152
HVTT/IVCTT (Absence vs I–III)	0.67 (0.38–1.15)	0.145
MVI (Absence vs Presence)	1.41 (1.15–1.74)	0.001	1.02 (0.28–3.71)	0.975
Number of HCC foci (≤5 vs >5)	1.39 (1.13–1.72)	0.002	1.25 (0.99–1.58)	0.061
PVTT (Absence vs Vp1-Vp3 vs Vp4)	1.09 (1.04–1.15)	0.001	1.08 (0.78–1.49)	0.661
Extrahepatic spread (Absence vs Presence)	1.41 (1.14–1.74)	0.002	1.31 (0.97–1.78)	0.08
Treatment (TACE vs HAIC)	0.90 (0.73–1.10)	0.3

Note: The multivariable analysis includes the variables with P-value ≤0.1 from the univariable analysis.

Abbreviations: CI, confidence intervals; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; HVTT, hepatic vein Thrombosis; IVCTT, inferior vena cava tumor thrombus; MVI, microvascular invasion; PVTT, portal vein tumor thrombosis; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy.

Figure 3 Forest plot showing the subgroup analysis of progression-free survival (a) and overall survival (b).

Abbreviations: HCC, hepatocellular carcinoma; HAIC, hepatic arterial infusion chemotherapy; TACE, transarterial chemoembolization; HR, hazard ratio; ECOG, Eastern Cooperative Oncology Group; BCLC, Barcelona Clinic Liver Cancer; HVTT, hepatic vein thrombosis; MVI, microvascular invasion; PVTT, portal vein tumor thrombosis.

Table 4 Treatment-Related Adverse Events

Event, n (%)	TACE(n, 222)			HAIC (n, 222)			P values
	Any grade	Grade 1/2	Grade 3/4	Any grade	Grade 1/2	Grade 3/4	Any grade	Grade 1/2	Grade 3/4
Any TRAE	212(95.5)	208(93.7)	53(23.9)	190(85.6)	184(82.9)	18(8.1)	0.000	0.000	<0.001
Blood/bone marrow suppression
Leukopenia	9(4.1)	9(4.1)	0(0)	44(19.8)	33(14.9)	22(9.9)	<0.001	<0.001	<0.001
Neutropenia	5(2.3)	7(3.2)	2(0.9)	53(23.9)	33(14.9)	13(5.9)	0.000	<0.001	0.004
Reduced hemoglobin level	82(36.9)	87(39.2)	2(0.9)	24(10.8)	20(9.0)	4(1.8)	0.000	0.000	0.411
Thrombocytopenia	31(14.0)	37(16.7)	5(2.3)	55(24.8)	46(20.7)	11(5.0)	0.004	0.273	0.127
Constitutional symptom
Fever	82(36.9)	80(36.0)	3(1.4)	20(9.0)	20(9.0)	0(0)	0.000	0.000	0.082
Hepatic function
Elevated ALT level	129(58.1)	150(67.6)	31(14.0)	90(40.5)	90(40.5)	2(0.9)	<0.001	<0.001	<0.001
Elevated AST level	167(75.2)	129(58.1)	70(31.5)	125(56.3)	143(64.4)	7(3.2)	<0.001	0.173	0.000
Elevated total bilirubin level	65(29.3)	71(32.0)	20(9.0)	24(10.8)	24(10.8)	2(0.9)	<0.001	<0.001	<0.001
Hypoalbuminemia	80(36.0)	82(36.9)	2(0.9)	68(30.6)	59(26.6)	7(3.2)	0.227	0.019	0.092
Gastrointestinal events
Abdominal pain	95(42.8)	114(51.4)	29(13.1)	114(51.4)	114(51.4)	0(0)	0.071	>0.999	<0.001
Constipation	54(24.3)	54(24.3)	2(0.9)	66(29.7)	66(29.7)	0(0)	0.200	0.200	0.156
Diarrhea	13(5.9)	13(5.9)	2(0.9)	42(18.9)	42(18.9)	0(0)	<0.001	<0.001	0.156
Nausea	105(47.3)	105(47.3)	2(0.9)	46(20.7)	46(20.7)	0(0)	<0.001	<0.001	0.156
Vomiting	29(13.1)	31(14.0)	3(1.4)	20(9.0)	18(8.1)	15(6.8)	0.173	0.049	0.004

Notes: Data are number of patients; data in parentheses are percentage unless otherwise indicated. Data in bracket was percent of patients. The qualitative data in two groups were compared by using the Chi square test. P value < 0.001 suggest statistically significant differences.

Abbreviations: TRAE, treatment-related adverse events; HAIC, hepatic arterial infusion chemotherapy; TACE, transarterial chemoembolization.