Hepatic arterial infusion chemotherapy with anti-angiogenesis agents and immune checkpoint inhibitors for unresectable hepatocellular carcinoma and meta-analysis

Table 1 P value of different interventions

Intervention	OR	Intervention	HR
HAIC	0.9520107	HAIC + Sorafenib	0.03757857
HAIC + Sorafenib	0.9420071	HAIC	0.09333929
SIRT	0.8131607	TACE + Lenvatinib	0.098075
TACE + Lenvatinib	0.8014429	Sintilimab + Bevacizumabbiosimila	0.24973929
Sintilimab + Bevacizumabbiosimila	0.6559643	Camrelizumab + Rivoceranib	0.30909286
Lenvatinib + Pembrolizumab	0.5922857	Atezolizumab + Bevacizumab	0.35838929
Camrelizumab + Rivoceranib	0.5853643	Lenvatinib + Pembrolizumab	0.51200714
Durvalumab + Tremelimumab	0.523425	Durvalumab + Tremelimumab	0.52634286
Durvalumab	0.3891893	Donafenib	0.62278571
Atezolizumab + Bevacizumab	0.3369036	Tislelizumab	0.66164643
Lenvatinib	0.3254286	Nivolumab	0.67260357
Tislelizumab	0.2732107	Durvalumab	0.68975714
Nivolumab	0.1859964	Lenvatinib	0.78121071
Donafenib	0.1165357	Sorafenib	0.9135
Sorafenib	0.007075	SIRT	0.97393214

HAIC: Hepatic arterial infusion chemotherapy; TACE: Transcatheter arterial chemoembolization; SIRT: Selective internal radiation therapy; HR: Hazard ratio; OR: Odds ratio.

Table 2 Baseline characteristics before or after propensity score matching, n (%)

Variable	Prior to PSM			Following PSM
	Triple therapy (n = 324)	AIPB (n = 118)	P value	Triple therapy (n = 88)	AIPB (n = 88)	P value
Age
Mean (SD)	50.2 (11.2)	55.4 (11.6)	< 0.001	54.2 (10.8)	53.9 (11.2)	0.859
Median [Min, Max]	51.0 [23.0, 80.0]	56.5 [23.0, 82.0]		55.0 [26.0, 78.0]	55.0 [23.0, 74.0]
Sex
Female	36 (11.1)	8 (6.8)	0.244	11 (12.5)	6 (6.8)	0.307
Male	288 (88.9)	110 (93.2)		77 (87.5)	82 (93.2)
ECOG PS
0	318 (98.1)	106 (89.8)	< 0.001	85 (96.6)	85 (96.6)	1
1	6 (1.9)	11 (9.3)		3 (3.4)	3 (3.4)
2	0 (0)	1 (0.8)		0 (0)	0 (0)
Hepatitis virus
Negative	27 (8.3)	15 (12.7)	0.228	11 (12.5)	12 (13.6)	1
Positive	297 (91.7)	103 (87.3)		77 (87.5)	76 (86.4)
ALT
mean (SD)	62.4 (72.8)	53.6 (34.9)	0.0894	58.4 (60.5)	53.2 (36.1)	0.489
Median [Min, Max]	44.6 [8.90, 930]	45.4 [6.10, 196]		41.1 [8.90, 448]	44.6 [6.10, 196]
AST
mean (SD)	92.5 (83.1)	88.3 (78.5)	0.627	82.0 (65.3)	87.1 (84.9)	0.657
Median [Min, Max]	66.2 [13.5, 702]	66.8 [11.1, 470]		58.7 [13.5, 327]	63.7 [11.1, 470]
Child-Pugh class
A	296 (91.4)	94 (79.7)	0.00133	75 (85.2)	77 (87.5)	0.826
B	28 (8.6)	24 (20.3)		13 (14.8)	11 (12.5)
AFP > 400 ng/mL
No	142 (43.8)	60 (50.8)	0.229	45 (51.1)	42 (47.7)	0.763
Yes	182 (56.2)	58 (49.2)		43 (48.9)	46 (52.3)
Maximum diameter of tumor/cm
mean (SD)	10.5 (4.25)	9.38 (4.75)	0.0291	9.86 (4.07)	9.57 (4.83)	0.668
Median [Min, Max]	10.3 [1.90, 23.5]	9.25 [1.10, 21.0]		10.0 [2.10, 19.2]	9.10 [1.10, 20.5]
Tumor number
Single	122 (37.7)	19 (16.1)	< 0.001	21 (23.9)	19 (21.6)	0.857
Multiple	202 (62.3)	99 (83.9)		67 (76.1)	69 (78.4)
Vascular invasion
No	78 (24.1)	42 (35.6)	0.0221	25 (28.4)	30 (34.1)	0.515
Yes	246 (75.9)	76 (64.4)		63 (71.6)	58 (65.9)
Extrahepatic metastasis
No	171 (52.8)	45 (38.1)	0.00888	34 (38.6)	38 (43.2)	0.646
Yes	153 (47.2)	73 (61.9)		54 (61.4)	50 (56.8)
BCLC
A	0 (0)	2 (1.7)	0.0632	0 (0)	2 (2.3)	0.309
B	30 (9.3)	11 (9.3)		7 (8.0)	9 (10.2)
C	294 (90.7)	105 (89.0)		81 (92.0)	77 (87.5)

AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; AIPB: Angiogenesis inhibitors and programmed cell death protein 1/programmed cell death ligand 1 blockers; triple therapy: Hepatic arterial infusion chemotherapy plus angiogenesis inhibitors and programmed cell death protein 1/programmed cell death ligand 1 blockers; PSM: Propensity score matching; BCLC: Barcelona Clinic Liver Cancer; ECOG PS: Eastern Cooperative Oncology Group performance status.

Table 3 Summary of adverse events, n (%)

	Before PSM				After PSM
	Triple therapy group (n = 324)		AIPB group (n = 118)		Triple therapy group (n = 88)		AIPB group (n = 88)
	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4	Grade 1-2	Grade 3-4
Fever	67 (20.7)	23 (7.1)	4 (3.4)	2 (1.7)	20 (22.7)	8 (9.1)	4 (4.5)	0 (0)
Nausea	100 (30.9)	0 (0)	6 (5.1)	0 (0)	24 (27.3)	0 (0)	5 (5.7)	0 (0)
Vomit	32 (9.9)	15 (4.6)	7 (5.9)	6 (5.1)	7 (8.0)	3 (3.4)	6 (6.8)	4 (4.5)
Abdominal pain	97 (29.9)	162 (50.0)	18 (15.3)	18 (15.3)	24 (27.3)	44 (50.0)	15 (17.0)	13 (14.8)
ALT increased	79 (24.4)	125 (38.6)	32 (27.1)	39 (33.1)	27 (30.4)	33 (37.5)	22 (25.0)	29 (33.0)
AST increased	130 (40.1)	161 (49.7)	36 (30.5)	44 (37.3)	40 (45.5)	49 (55.7)	26 (29.5)	34 (38.6)
Hyperbilirubinemia	37 (11.4)	7 (2.2)	7 (5.9)	11 (9.3)	10 (11.4)	0 (0)	4 (4.5)	8 (9.1)
Anemia	37 (11.4)	8 (2.5)	7 (5.9)	4 (3.4)	11 (12.5)	1 (1.1)	5 (5.7)	3 (3.4)
Neutropenia	86 (26.5)	20 (6.2)	9 (7.6)	12 (10.2)	29 (33.0)	5 (5.7)	5 (5.7)	9 (10.2)
Thrombocytopenia	103 (31.8)	90 (27.8)	27 (22.9)	20 (16.9)	24 (27.3)	16 (18.2)	20 (22.7)	13 (14.8)
Bleeding	48 (14.8)	3 (0.9)	1 (0.8)	1 (0.8)	12 (13.6)	1 (1.1)	1 (1.1)	1 (1.1)
Diarrhea	62 (19.1)	60 (18.5)	22 (18.6)	3 (2.5)	17 (19.3)	5 (5.7)	17 (19.3)	3 (3.4)
Hoarseness	80 (24.7)	0 (0)	13 (11.0)	0 (0)	21 (23.9)	0 (0)	10 (11.4)	0 (0)
Rash	92 (28.4)	4 (1.2)	28 (23.7)	4 (3.4)	24 (27.3)	0 (0)	20 (22.7)	3 (3.4)
HFS	69 (21.3)	9 (2.8)	19 (16.1)	18 (15.3)	18 (20.5)	1 (1.1)	14 (15.9)	11 (12.5)
Hypertension	76 (23.5)	11 (3.4)	31 (26.3)	34 (28.8)	22 (25.0)	3 (3.4)	23 (26.1)	27 (30.7)
RCCEP	42 (13.0)	14 (4.3)	16 (13.6)	6 (5.1)	11 (12.5)	5 (5.7)	13 (14.8)	6 (6.8)
Hypothyroidism	64 (19.8)	8 (2.5)	2 (1.7)	0 (0)	18 (20.5)	2 (2.3)	0 (0)	0 (0)
Fatigue	32 (9.9)	31 (9.6)	4 (3.4)	4 (3.4)	6 (6.8)	8 (9.1)	3 (3.4)	2 (2.3)
Hepatitis	10 (3.1)	1 (0.3)	0 (0)	0 (0)	5 (5.7)	1 (1.1)	0 (0)	0 (0)
Coma	0 (0)	2 (0.6)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)

AFP: Alpha-fetoprotein; AIPB: Angiogenesis inhibitors and programmed cell death protein 1/programmed cell death ligand 1 blockers; triple therapy: Hepatic arterial infusion chemotherapy plus angiogenesis inhibitors and programmed cell death protein 1/programmed cell death ligand 1 blockers; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HFS: Hand-foot syndrome; RCCEP: Reactive cutaneous capillary endothelial proliferation.