Efficacy and safety of adjuvant targeted immunotherapy for hepatocellular carcinoma with high recurrence risks after hepatectomy

Table 1 Patterns of initial recurrence and subsequent management strategies following surgery, n (%)

	Total (n = 109)	ATG (n = 47)	SG (n = 62)	P value
Recurrence site				0.790
Intrahepatic	98 (89.9)	42 (89.4)	56 (90.3)
Extrahepatic	5 (4.6)	3 (6.4)	2 (3.2)
Intrahepatic + extrahepatic	6 (5.5)	2 (4.3)	4 (6.5)
Post relapse treatment				0.475
Re-hepatectomy	30 (27.5)	11 (23.4)	19 (30.6)
Local + systemic treatment	18 (16.5)	7 (14.9)	11 (17.7)
Local therapy + radiofrequency ablation + systemic therapy	18 (16.5)	8 (17.0)	10 (16.1)
Radiofrequency ablation + systemic therapy	14 (12.8)	7 (14.9)	7 (11.3)
Local treatment	9 (8.3)	2 (4.3)	7 (11.3)
Radiofrequency ablation	8 (7.3)	6 (12.8)	2 (3.2)
Systemic therapy	6 (5.5)	4 (8.5)	2 (3.2)
Resection of extrahepatic metastases	5 (4.6)	2 (4.3)	3 (4.8)
Liver transplant	1 (0.9)	0 (0.0)	1 (1.6)

ATG: Adjuvant therapy group; SG: Surgery-alone group.

Table 2 Adjuvant therapy regimen details, n (%)/mean ± SD

Adjunctive treatment modalities	Adjuvant therapy group (n = 88)
Targeted therapy only
No	44 (50.0)
Yes	44 (50.0)
Immunotherapy only
No	71 (80.7)
Yes	17 (19.3)
Combination of targeted and immunotherapy
No	61 (69.3)
Yes	27 (30.7)
Time to initiation of adjuvant therapy, mouths	2.2 ± 1.2
Treatment duration, mouths	12.7 ± 7.0

Table 3 Recurrence-free and overall survival rates before and after propensity score matching

	PSM before			PSM after
	ATG (n = 88)	SG (n = 284)	P value	ATG (n = 88)	SG (n = 88)	P value
Median recurrence-free survival (months)	26.0	16.0	0.038	26.0	14.0	0.028
1-year recurrence-free survival rate (%)	79.5	63.7	0.006	79.5	62.3	0.013
Number of deaths (n)	3	12		3	6
Median overall survival, months			1.000			1.000
1-year overall survival rate (%)	100.0	100.0	1.000	100.0	100.0	1.000
Overall survival rate (%)	96.6	95.8	0.976	96.6	93.3	0.494

PSM: Propensity score matching; ATG: Adjuvant therapy group; SG: Surgery-alone group.

Table 4 Overview of treatment-related adverse event, n (%)

	0	1-2	3-4
Hypertensive	65 (73.80)	23 (26.13)	0 (0.00)
ALT/AST elevated	60 (68.18)	25 (28.41)	3 (3.41)
Leukopenia	86 (97.73)	2 (2.27)	0 (0.00)
Thrombocytopenia	84 (95.45)	3 (3.41)	1 (1.14)
Neutropenia	86 (97.73)	2 (2.27)	0 (0.00)
Anemic	86 (97.73)	2 (2.27)	0 (0.00)
Elevated creatinine	85 (96.59)	3 (3.41)	0 (0.00)
TSH elevated	84 (95.45)	4 (4.55)	0 (0.00)
Vomiting	86 (97.73)	2 (2.27)	0 (0.00)
Constipation	68 (77.27)	20 (22.73)	0 (0.00)
Anorexia	84 (95.45)	4 (4.55)	0 (0.00)
Dermatitis or rash	66 (75.00)	22 (25.00)	0 (0.00)
Fatigue	85 (96.59)	3 (3.41)	0 (0.00)

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; TSH: Thyroid-stimulating hormone.

Table 5 Baseline characteristics of 372 participants on follow-up, n (%)/mean ± SD

	PSM before (n = 372)			PSM after (n = 176)
	ATG (n = 88)	SG (n = 284)	P value	ATG (n = 88)	SG (n = 88)	P value
Diabetes			0.111			0.294
No	82 (93.2)	247 (87.0)		82 (93.2)	78 (88.6)
Yes	6 (6.8)	37 (13.0)		6 (6.8)	10 (11.4)
ECOG PS			0.089			0.064
0	69 (78.4)	196 (69.0)		69 (78.4)	58 (65.9)
1	19 (21.6)	88 (31.0)		19 (21.6)	30 (34.1)
BMI (kg/m2)	22.5 ± 2.7	22.8 ± 2.7	0.386	22.5 ± 2.7	22.8 ± 2.7	0.520
Age (years)			0.678			0.639
> 60	31 (35.2)	107 (37.7)		31 (35.2)	34 (38.6)
≤ 60	57 (64.8)	177 (62.3)		57 (64.8)	54 (61.4)
Sex			0.625			0.799
Female	8 (9.1)	31 (10.9)		8 (9.1)	9 (10.2)
Male	80 (90.9)	253 (89.1)		80 (90.9)	79 (89.8)
HBsAg			0.505			0.245
Negative	29 (33.0)	83 (29.2)		29 (33.0)	22 (25.0)
Positive	59 (67.0)	201 (70.8)		59 (67.0)	66 (75.0)
HBsAb			0.882			0.528
Negative	33 (37.5)	109 (38.4)		33 (37.5)	29 (33.0)
Positive	55 (62.5)	175 (61.6)		55 (62.5)	59 (67.0)
HCV			0.536			1.000
Negative	86 (97.7)	271 (95.4)		86 (97.7)	87 (98.9)
Positive	2 (2.3)	13 (4.6)		2 (2.3)	1 (1.1)
HBV-DNA (IU/mL)			0.777			0.546
> 2000	39 (44.3)	121 (42.6)		39 (44.3)	43 (48.9)
≤ 2000	49 (55.7)	163 (57.4)		49 (55.7)	45 (51.1)
AFP (μg/L)			0.006			0.525
> 400	32 (36.4)	62 (21.8)		32 (36.4)	28 (31.8)
≤ 400	56 (63.6)	222 (78.2)		56 (63.6)	60 (68.2)
ALBI score			0.589			1.000
1	25 (28.4)	97 (34.2)		25 (28.4)	25 (28.4)
2	61 (69.3)	182 (64.1)		61 (69.3)	62 (70.5)
3	2 (2.3)	5 (1.8)		2 (2.3)	1 (1.1)
WBC (× 109/L)	6.7 ± 2.4	6.4 ± 2.4	0.255	6.7 ± 2.4	6.7 ± 3.1	0.924
RBC (× 1012/L)	4.6 ± 0.7	4.6 ± 0.6	0.539	4.6 ± 0.7	4.6 ± 0.6	0.882
Hb (g/L)	135.0 ± 20.6	137.9 ± 18.9	0.214	135.0 ± 20.6	138.9 ± 16.5	0.173
PLT (× 109/L)	216.0 ± 80.6	199.0 ± 83.7	0.095	216.0 ± 80.6	207.2 ± 80.6	0.471
ALP (umol/L)	102.0 ± 68.5	100.9 ± 60.8	0.888	102.0 ± 68.5	99.5 ± 45.0	0.772
AST (U/L)	52.7 ± 59.8	61.8 ± 95.8	0.405	52.7 ± 59.8	59.6 ± 82.6	0.527
ALT (U/L)	53.3 ± 75.0	59.4 ± 87.6	0.558	53.3 ± 75.0	59.4 ± 79.7	0.601
Hydroperitoneum			0.257			0.353
No	57 (64.8)	202 (71.1)		57 (64.8)	51 (58.0)
Yes	31 (35.2)	82 (28.9)		31 (35.2)	37 (42.0)
Child-Pugh grade			0.656			0.755
A	83 (94.3)	264 (93.0)		83 (94.3)	82 (93.2)
B	5 (5.7)	20 (7.0)		5 (5.7)	6 (6.8)
Number of tumors			0.710			0.479
≥ 2	23 (26.1)	80 (28.2)		23 (26.1)	19 (21.6)
1	65 (73.9)	204 (71.8)		65 (73.9)	69 (78.4)
Maximum tumor diameter (mm)	72.6 ± 37.9	64.6 ± 35.0	0.067	72.6 ± 37.9	63.9 ± 35.9	0.119
Cirrhosis			0.070			0.226
No	44 (50.0)	111 (39.1)		44 (50.0)	36 (40.9)
Yes	44 (50.0)	173 (60.9)		44 (50.0)	52 (59.1)
PVTT			0.601			0.245
0	71 (80.7)	243 (85.6)		71 (80.7)	80 (90.9)
1	5 (5.7)	14 (4.9)		5 (5.7)	3 (3.4)
2	8 (9.1)	16 (5.6)		8 (9.1)	3 (3.4)
3	4 (4.5)	11 (3.9)		4 (4.5)	2 (2.3)
HVTT			1.000			1.000
No	84 (95.5)	272 (95.8)		84 (95.5)	83 (94.3)
Yes	4 (4.5)	12 (4.2)		4 (4.5)	5 (5.7)

ECOG PS: Eastern Cooperative Oncology Group Performance Status; BMI: Body mass index; HBsAg: Hepatitis B surface antigen; HBsAb: Hepatitis B surface antibody; HCV: Hepatitis C virus; HBV: Hepatitis B virus; AFP: Alpha-fetoprotein; ALBI: Albumin-bilirubin score; WBC: White blood cell; RBC: Red blood cell; Hb: Hemoglobin; PLT: Platelet; ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; PVTT: Portal vein tumor thrombus; HVTT: Hepatic vein tumor thrombus; PSM: Propensity score matching; ATG: Adjuvant therapy group; SG: Surgery-alone group.

Table 6 Surgical and perioperative data of 372 participants on follow-up, n (%)/mean ± SD/median (interquartile rage)

	PSM before (n = 372)			PSM after (n = 176)
	ATG (n = 88)	SG (n = 284)	P value	ATG (n = 88)	SG (n = 88)	P value
Surgical methods			0.544			0.114
Laparoscopy	16 (18.2)	58 (20.4)		16 (18.2)	23 (26.1)
Open	68 (77.3)	205 (72.2)		68 (77.3)	56 (63.6)
Anatomic resection			0.013			0.88
No	42 (47.7)	95 (33.5)		42 (47.7)	41 (46.6)
Yes	46 (52.3)	189 (66.5)		46 (52.3)	47 (53.4)
Tumor clinical typing			0.273			0.393
Nodular fusion	7 (8)	16 (5.6)		7 (8)	5 (5.7)
Nodular	48 (54.5)	179 (63)		48 (54.5)	58 (65.9)
Chunky	19 (21.6)	39 (13.7)		19 (21.6)	13 (14.8)
Lumpy	12 (13.6)	46 (16.2)		12 (13.6)	12 (13.6)
Diffuse	2 (2.3)	4 (1.4)		2 (2.3)	0 (0)
Tumor margin (cm)			0.339			0.344
< 1	34 (38.6)	94 (33.1)		34 (38.6)	28 (31.8)
≥ 1	54 (61.4)	190 (66.9)		54 (61.4)	60 (68.2)
Transfusion			0.112			0.202
No	72 (81.8)	251 (88.4)		72 (81.8)	78 (88.6)
Yes	16 (18.2)	33 (11.6)		16 (18.2)	10 (11.4)
Pringle maneuver application			0.945			0.289
No	52 (59.1)	169 (59.5)		52 (59.1)	45 (51.1)
Yes	36 (40.9)	115 (40.5)		36 (40.9)	43 (48.9)
Surgical time (minutes)	254.5 ± 110.2	265.3 ± 113.5	0.43	254.5 ± 110.2	276.8 ± 128.4	0.218
Day of hospitalization (days)	15.4 ± 4.7	15.7 ± 4.5	0.659	15.4 ± 4.5	15.7 ± 4.8	0.661
Blood loss (mL)	275.0 (200.0-500.0)	300.0 (187.5-500.0)	0.148	300.0 (187.5-500.0)	200.0 (100.0-425.0)	0.127
Red blood cell transfusion (mL)	0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.055	0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.176
Plasma transfusion (mL)	0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.253	0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.374
Number of Pringle maneuver time	0.0 (0.0-1.0)	0.0 (0.0-1.0)	0.828	0.0 (0.0-1.0)	0.0 (0.0-1.0)	0.42
Pringle maneuver time (minutes)	0.0 (0.0-20.0)	0.0 (0.0-15.0)	0.933	0.0 (0.0-20.0)	0.0 (0.0-20.2)	0.21

PSM: Propensity score matching; ATG: Adjuvant therapy group; SG: Surgery-alone group.

Table 7 Univariate and multivariate Cox regression analysis of factors associated with recurrence-free survival

Cluster	PSM before				PSM after
	Univariate		Multifactor		Univariate		Multifactor
	P value	HR	95%CI	P value	P value	HR	95%CI	P value
Receiving adjuvant therapy (yes vs no)	0.042	0.717	0.521-0.988	0.01	0.031	0.659	0.450-0.964	0.005
diabetes (yes vs no)	0.758	0.94	0.633-1.395		0.315	0.761	0.447-1.295
ECOG score (0 vs 1)	0.891	0.98	0.740-1.299		0.9	0.975	0.653-1.454
Age (≤ 60 vs > 60)	0.401	0.893	0.685-1.164		0.632	0.91	0.618-1.339
Sex (male vs female)	0.681	0.914	0.594-1.405		0.721	1.12	0.600-2.090
HBsAg (positive vs negative)	0.603	0.928	0.700-1.230		0.077	0.679	0.441-1.043	0.13
HBsAb (positive vs negative)	0.662	1.06	0.815-1.379		0.949	1.013	0.686-1.495
AST, U/L (≤ 37 vs > 37)	0.005	0.686	0.527-0.893	0.23	0.035	0.655	0.443-0.970	0.13
ALT, U/L (≤ 40 vs > 40)	0.012	0.719	0.556-0.930	0.416	0.033	0.665	0.456-0.968	0.489
HCV DNA (positive vs negative)	0.274	0.723	0.404-1.293		0.697	0.757	0.187-3.072
HBV DNA, IU/mL (≤ 2000 vs > 2000)	0.677	1.057	0.814-1.373		0.225	0.792	0.543-1.154
AFP, μg/L (≤ 400 vs > 400)	0.058	1.358	0.990-1.862	0.026	0.206	1.309	0.863-1.985
ALBI score (1 vs 2/3)	0.021	0.714	0.537-0.950	0.119	0.077	0.668	0.427-1.045	0.155
Hydroperitoneum (yes vs no)	0.43	1.12	0.846-1.482		0.509	1.139	0.774-1.678
Child-Pugh grade (A vs B)	0.675	0.902	0.558-1.460		0.76	1.127	0.523-2.426
Number of tumors (1 vs ≥ 2)	0.208	0.833	0.627-1.107		0.094	0.692	0.450-1.065	0.07
Maximum tumor diameter (mm)	0.001	1.005	1.002-1.009	0.053	0.01	1.006	1.002-1.011	0.039
Cirrhosis (yes vs no)	0.588	1.075	0.828-1.395		0.21	1.276	0.872-1.867
PVTT (yes vs no)	0.156	0.779	0.552-1.100		0.518	1.46	0.463-4.607
HVTT (yes vs no)	0.077	0.614	0.358-1.055	0.126	0.615	0.822	0.382-1.768
Satellite node (yes vs no)	0.4	1.229	0.760-1.989		0.702	1.136	0.592-2.177
Peritoneal invasion or absence (yes vs no)	0.587	0.925	0.697-1.227		0.487	0.866	0.576-1.300
Tumor rupture (yes vs no)	0.885	1.029	0.697-1.519		0.894	0.966	0.583-1.602
CNLC staging (Ⅲ vs I/II)	0.132	0.769	0.547-1.082		0.323	1.354	0.743-2.469
Edmonson tumor grade (Ⅲ-IV vs I-II)	0.709	1.054	0.798-1.393		0.623	0.91	0.625-1.325
MVI (M1/M2 vs M0)	0.075	0.79	0.610-1.024	0.193	0.448	0.863	0.590-1.263
High recurrence risk factors (multiple vs single)	0.038	0.736	0.551-0.984	0.32	0.674	0.915	0.606-1.383
Surgical methods (open vs laparoscopy/robot)	0.469	0.896	0.666-1.206		0.337	0.81	0.527-1.245
Anatomic resection (yes vs no)	0.585	1.078	0.824-1.410		0.932	1.017	0.698-1.481
Tumor margin (< 1 cm vs ≥ 1 cm)	0.786	0.963	0.733-1.265		0.764	1.062	0.717-1.572
Blocking the hepatic portal (yes vs no)	0.925	1.013	0.779-1.317		0.63	0.911	0.625-1.330
Transfusion (yes vs no)	0.57	0.898	0.618-1.304		0.367	1.295	0.738-2.273

ECOG: Eastern Cooperative Oncology Group; HBsAg: Hepatitis B surface antigen; HBsAb: Hepatitis B surface antibody; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; HCV: Hepatitis C virus; HBV: Hepatitis B virus; AFP: Alpha-fetoprotein; ALBI: Albumin-bilirubin score; PVTT: Portal vein tumor thrombus; HVTT: Hepatic vein tumor thrombus; CNLC: China Liver Cancer; MVI: Microvascular invasion; PSM: Propensity score matching; HR: Hazard ratio; CI: Confidence interval.