Immune checkpoint inhibitors plus anti-angiogenesis in patients with resected high-risk hepatitis B virus-associated hepatocellular carcinoma

Table 1 Baseline characteristics of patients before and after propensity score matching or inverse probability of treatment weighting, n (%)

	Total (n =150)	Before PSM and IPTW, PCT (n = 30)	Before PSM and IPTW, non-PCT (n = 120)	Before PSM and IPTW, P value	After PSM, PCT (n = 29)	After PSM, non-PCT (n = 29)	After PSM, P value	After IPTW, PCT (134.1)	After IPTW, non-PCT (150.8)	After IPTW, P value
Sex, male	124 (82.7)	24 (80)	100 (83.3)	0.666	23 (79.3)	25 (86.2)	0.487	107.9 (80.4)	125.1 (83.0)	0.752
Age, ≤ 57 years	76 (50.7)	18 (60)	58 (48.3)	0.253	17 (58.6)	14 (48.3)	0.43	85.3 (63.6)	74.7 (49.5)	0.195
BMI, ≤ 23.9 kg/m²	87 (58)	16 (53.3)	71 (59.2)	0.563	16 (55.2)	19 (65.5)	0.421	70.6 (52.6)	90.5 (60.0)	0.501
TACE	61 (40.7)	7 (23.3)	54 (45)	0.031	7 (24.1)	7 (24.1)	1	46.5 (34.6)	60.8 (40.3)	0.622
Extent of resection, major	29 (19.3)	6 (20)	23 (19.2)	0.918	6 (20.7)	5 (17.2)	0.738	28.0 (20.9)	28.5 (18.9)	0.819
Cirrhosis	126 (84)	27 (90)	99 (82.5)	0.412	27 (93.1)	27 (93.1)	1	124.6 (92.9)	124.3 (82.4)	0.153
Number, solitary	142 (94.7)	29 (96.7)	113 (94.2)	1	28 (96.6)	27 (93.1)	1	131.2 (97.8)	141.1 (93.6)	0.276
Maximum diameter, > 5 cm	73 (48.7)	16 (53.3)	57 (47.5)	0.567	15 (51.7)	12 (41.4)	0.43	59.8 (44.6)	73.2 (48.5)	0.717
Vascular invasion	100 (66.7)	23 (76.7)	77 (64.2)	0.194	22 (75.9)	21 (72.4)	0.764	96.8 (72.2)	100.9 (66.9)	0.615
Edmondson-Steiner, III-IV	79 (52.7)	16 (53.3)	63 (52.5)	0.935	15 (51.7)	18 (62.1)	0.426	79.3 (59.1)	80.7 (53.5)	0.608
Satellite nodules	30 (20)	7 (23.3)	23 (19.2)	0.61	6 (20.7)	6 (20.7)	1	25.9 (19.3)	30.1 (20.0)	0.939
Margin, narrow	92 (61.3)	21 (70)	71 (59.2)	0.276	20 (69)	15 (51.7)	0.18	100 (74.6)	89.9 (59.6)	0.149
Necrosis	48 (32)	9 (30)	39 (32.5)	0.793	8 (27.6)	6 (20.7)	0.539	42.3 (31.6)	49.5 (32.8)	0.906
BCLC stage, A	130 (86.7)	24 (80)	106 (88.3)	0.272	23 (79.3)	27 (93.1)	0.194	99.8 (74.4)	133.0 (88.2)	0.05
Child-Pugh, A	145 (96.7)	28 (93.3)	117 (97.5)	0.261	27 (93.1)	27 (93.1)	1	6.6 (4.9)	3.9 (2.6)	0.474
Antiviral treatment	115 (76.7)	26 (86.7)	89 (74.2)	0.148	25 (86.2)	27 (93.1)	0.67	115.3 (86.0)	116.1 (77.0)	0.306
HBV-DNA, ≥ 2000 IU/mL	50 (33.3)	10 (33.3)	40 (33.3)	1	10 (34.5)	10 (34.5)	1	39.4 (29.4)	49.8 (33.0)	0.715
HBsAg, ≥ 250 IU/mL	96 (64)	20 (66.7)	76 (63.3)	0.734	19 (65.5)	20 (69)	0.78	85.1 (63.5)	96.1 (63.7)	0.979
HBeAg, positive	18 (12)	4 (13.3)	14 (11.7)	0.759	4 (13.8)	4 (13.8)	1	17.7 (13.2)	18.4 (12.2)	0.889
AFP, ≥ 400 ng/mL	52 (34.7)	7 (23.3)	45 (37.5)	0.145	7 (24.1)	11 (37.9)	0.256	33.8 (25.2)	58.3 (38.7)	0.214
ALT, IU/L	32.00 (21.00, 52.75)	32.00 (25.25, 77.25)	31.50 (19.52, 48.00)	0.174	32.00 (25.00, 81.00)	32.00 (16.00, 54.00)	0.199	55.99 (44.63)	47.10 (61.55)	0.415
AST, IU/L	34.00 (24.18, 52.75)	34.10 (28.00, 58.50)	34.00 (24.00, 52.00)	0.431	34.00 (28.00, 60.00)	34.00 (24.00, 46.00)	0.597	47.23 (28.58)	47.87 (47.64)	0.926
GGT, IU/L	38.00 (25.00, 98.50)	47.15 (31.15, 105.25)	36.00 (23.00, 96.75)	0.185	46.00 (31.00, 97.00)	26.00 (19.00, 133.00)	0.305	73.69 (73.31)	88.28 (128.05)	0.404
ALP, IU/L	85.50 (72.00, 113.75)	101.50 (83.25, 136.25)	83.50 (70.00, 109.50)	0.014	100.00 (83.00, 128.00)	87.00 (66.00, 113.00)	0.159	105.55 (34.27)	96.81 (44.53)	0.26
ALB, g/L	41.53 (4.31)	40.69 (5.13)	41.74 (4.08)	0.302	40.87 (5.12)	39.90 (3.92)	0.424	41.35 (5.22)	41.83 (4.10)	0.661
TBIL, µmol/L	15.90 (11.62, 20.10)	13.95 (11.53, 17.95)	16.45 (11.67, 20.30)	0.169	13.80 (11.40, 16.90)	17.80 (11.10, 25.20)	0.084	14.91 (7.10)	17.27 (7.38)	0.132

Data are presented as hazard ratios (95% confidence intervals). A narrow margin is defined as a tumor < 1 cm from the resection margin. The major extent of resection is defined as the resection of three or more liver segments. PCT: Postoperative combined therapy; PSM: Propensity score matching; IPTW: Inverse probability of treatment weighting; BMI: Body mass index; TACE: Transcatheter arterial chemoembolization; BCLC: Barcelona Clinical Liver Cancer; HBeAg: Hepatitis B e antigen; HBV-DNA: Hepatitis B virus-deoxyribonucleic acid; HBsAg: Hepatitis B surface antigen; AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransaminase; GGT: Gamma glutamyl transferase; ALP: Alkaline phosphatase; ALB: Albumin; TBIL: Total bilirubin.

Table 2 Comparison of survival outcomes with or without postoperative combined therapy

Duration (months)	Non-PCT, %	PCT, %	P of log-rank	HR (95%CI), P value	Adjusted HR (95%CI), P value
RFS before PSM and IPTW
6	81.7 (75.0, 88.9)	93.3 (84.8, 100.0)	0.119	0.33 (0.08-1.42), 0.138	0.17 (0.04-0.78), 0.022
12	67.9 (60.0, 76.9)	79.3 (65.8, 95.6)	0.183	0.56 (0.24-1.33), 0.188	0.32 (0.12-0.80), 0.015
18	59.8 (51.1, 69.9)	59.8 (42.8, 83.7)	0.590	0.83 (0.42-1.64), 0.590	0.48 (0.22-1.02), 0.055
24	49.7 (40.1, 61.7)	53.2 (35.4, 79.9)	0.567	0.83 (0.43-1.59), 0.567	0.50 (0.24-1.03), 0.061
RFS after PSM
6	79.3 (65.9, 95.5)	96.6 (90.1, 100.0)	0.041	0.15 (0.02-1.24), 0.078
12	72.1 (57.3, 90.6)	82.0 (68.9, 97.7)	0.322	0.57 (0.19-1.75), 0.328
18	62.7 (46.5, 84.6)	61.9 (44.6, 86.0)	0.855	0.92 (0.37-2.27), 0.855
24	55.8 (38.2, 81.4)	55.0 (36.8, 82.2)	0.908	0.95 (0.40-2.25), 0.908
RFS after IPTW
6	81.4 (74.5, 88.8)	92.1 (80.5, 100.0)	0.095	0.38 (0.07-1.96), 0.249
12	67.3 (59.2, 76.6)	78.6 (63.6, 97.3)	0.161	0.57 (0.23-1.44), 0.236
18	59.6 (50.8, 69.9)	65.0 (47.7, 88.5)	0.375	0.73 (0.34-1.55), 0.411
24	49.3 (39.5, 61.5)	56.9 (38.0, 85.3)	0.386	0.75 (0.37-1.51), 0.418
OS before PSM and IPTW
6	95.0 (91.2, 99.0)	100.0 (100.0, 100.0)	0.216	0.00 (0.00-Inf), 0.998	0.00 (0.00-Inf), 0.999
12	88.8 (83.2, 94.7)	96.7 (90.5, 100.0)	0.224	0.30 (0.04-2.33), 0.252	0.21 (0.03-1.71), 0.143
18	85.7 (79.4, 92.5)	96.7 (90.5, 100.0)	0.149	0.25 (0.03-1.90), 0.182	0.19 (0.02-1.49), 0.113
24	82.5 (75.2, 90.5)	89.2 (75.2, 100.0)	0.280	0.46 (0.11-1.97), 0.292	0.30 (0.06-1.41), 0.127
OS after PSM
6	93.1 (84.3, 100.0)	100.0 (100.0, 100.0)	0.154	0.00 (0.00-Inf), 0.999
12	89.7 (79.2, 100.0)	96.6 (90.1, 100.0)	0.300	0.32 (0.03-3.09), 0.326
18	89.7 (79.2, 100.0)	96.6 (90.1, 100.0)	0.300	0.32 (0.03-3.09), 0.326
24	83.3 (68.8, 100.0)	89.1 (75.1, 100.0)	0.463	0.53 (0.10-2.93), 0.470
OS after IPTW
6	95.1 (91.3, 99.0)	100.0 (100.0, 100.0)	0.016	0.00 (0.00-0.00), P < 0.001
12	88.3 (82.4, 94.6)	96.7 (90.5, 100.0)	0.083	0.29 (0.04-2.22), 0.233
18	85.4 (78.9, 92.5)	96.7 (90.5, 100.0)	0.036	0.25 (0.03-1.85), 0.174
24	82.4 (75.0, 90.5)	90.0 (76.8, 100.0)	0.133	0.41 (0.09-1.81), 0.242

Data are presented as rate (95% confidence interval) or hazard ratio (95% confidence interval). PCT: Postoperative combined therapy; CI: Confidence interval; HR: Hazard ratio; RFS: Recurrence-free survival; PSM: Propensity score matching; IPTW: Inverse probability of treatment weighting; OS: Overall survival.

Table 3 Adverse events of any grade occurring in ≥ 15% of patients according to Common Terminology Criteria for Adverse Events 5.0, n (%)

Adverse events	All grades	1	2	3-4
Hypertension	20 (66.7)	3 (10.0)	7 (23.3)	10 (33.3)
Platelet count decreased	14 (46.7)	6 (20.0)	5 (16.7)	3 (10.0)
Aspartate aminotransaminase increased	12 (40.0)	4 (13.3)	4 (13.3)	4 (13.3)
Total bilirubin increased	11 (36.7)	4 (13.3)	4 (13.3)	3 (10.0)
Proteinuria	11 (36.7)	2 (6.7)	8 (26.7)	1 (3.3)
Pain	10 (33.3)	4 (13.3)	5 (16.7)	1 (3.3)
Neutrophil count decreased	9 (30.0)	0	7 (23.3)	2 (6.7)
Alanine aminotransferase increased	9 (30.0)	4 (13.3)	4 (13.3)	1 (3.3)
Gamma glutamyl transferase increased	8 (26.7)	1 (3.3)	2 (6.7)	5 (16.7)
Diarrhea	7 (23.3)	3 (10.0)	3 (10.0)	1 (3.3)
Hypothyroidism	7 (23.3)	3 (10.0)	4 (13.3)	0
Hand-foot syndrome	7 (23.3)	1 (3.3)	4 (13.3)	2 (6.7)
Alkaline phosphatase increased	5 (16.7)	4 (13.3)	1 (3.3)	0
Hyperthyroidism	5 (16.7)	2 (6.7)	3 (10.0)	0
Rash	5 (16.7)	3 (10.0)	1 (3.3)	1 (3.3)
Weight loss	5 (16.7)	2 (6.7)	2 (6.7)	1 (3.3)

Table 4 Impact of hepatic impairment and medication use on recurrence-free survival and overall survival, n (%)

	Yes	No	OR (95%CI)	P value
RFS events occurred
Any degree of hepatic impairment			5.200 (1.068-25.309)	0.041
Yes	8 (26.7)	5 (16.7)
No	4 (13.3)	13 (43.3)
Medication interruption events for any reason			2.000 (0.440-9.096)	0.370
Yes	8 (26.7)	9 (30)
No	4 (13.3)	9 (30)
Medication duration less than median			0.571 (0.130-2.503)	0.458
Yes	7 (23.3)	8 (26.7)
No	5 (16.7)	10 (33.3)
OS events occurred
Any degree of hepatic impairment			2.909 (0.234-36.164)	0.406
Yes	2 (6.7)	11 (36.7)
No	1 (3.3)	16 (53.3)
Medication interruption events for any reason			1.600 (0.129-19.838)	0.714
Yes	2 (6.7)	15 (50.0)
No	1 (3.3)	12 (40.0)
Medication duration less than median			0.464 (0.037-5.749)	0.550
Yes	2 (6.7)	13 (43.3)
No	1 (3.3)	14 (46.7)

OR: Odds ratio; CI: Confidence interval; RFS: Recurrence-free survival; OS: Overall survival.