Predictive value of neutrophil-lymphocyte ratio for prognosis in patients with advanced hepatocellular carcinoma treated with programmed cell death 1 inhibitors

Table 1 Comparison of baseline information between patients with good prognosis and poor prognosis, n (%)/mean ± SD

Variable	Good prognosis group (n = 126)	Poor prognosis group (n = 108)	t/χ2	P value
Gender			0.035	0.851
Male	105 (83.33)	89 (82.41)
Female	21 (16.67)	19 (17.59)
Age (years)	56.81 ± 5.15	57.49 ± 5.02	1.020	0.309
BMI (kg/m2)	22.46 ± 1.47	22.15 ± 1.59	1.536	0.126
History of smoking	58 (46.03)	55 (50.93)	0.558	0.455
History of alcohol consumption	52 (41.27)	49 (45.37)	0.399	0.528
Etiology			0.250	0.883
Hepatitis B	113 (89.68)	98 (90.74)
Hepatitis C	5 (3.97)	3 (2.78)
Others	8 (6.35)	7 (6.48)
BCLC stage			5.661	0.017
B	46 (36.51)	24 (22.22)
C	80 (63.49)	84 (77.78)
Child-Pugh grade			3.009	0.083
A	104 (82.54)	79 (73.15)
B	22 (17.46)	29 (26.85)
ECOG PS score			3.951	0.047
0	87 (69.05)	61 (56.48)
1	39 (30.95)	47 (43.52)
Maximum tumor diameter (cm)	7.61 ± 1.93	8.79 ± 2.21	4.350	< 0.001
Macrovascular invasion	57 (45.24)	67 (62.04)	6.588	0.010
Extrahepatic spread	81 (64.29)	84 (77.78)	5.091	0.024

BMI: Body mass index; BCLC: Barcelona Clinic Liver Cancer; ECOG PS: Eastern Cooperative Oncology Group Performance Status.

Table 2 Comparison of hematological parameters between patients with good prognosis and poor prognosis, mean ± SD

Variable	Good prognosis group (n = 126)	Poor prognosis group (n = 108)	t	P value
AFP (ng/mL)	585.42 ± 146.85	762.18 ± 176.41	8.248	< 0.001
NLR	2.85 ± 0.72	3.82 ± 1.02	8.296	< 0.001
ALT (U/L)	45.86 ± 10.48	48.17 ± 11.27	1.626	0.105
AST (U/L)	50.24 ± 12.31	54.39 ± 13.76	2.438	0.016
Total bilirubin (μmol/L)	18.86 ± 4.28	20.62 ± 4.92	2.943	0.004
Albumin (g/L)	38.42 ± 3.81	36.87 ± 3.94	3.046	0.003
International normalized ratio	1.11 ± 0.26	1.22 ± 0.27	2.928	0.004
Blood urea nitrogen (mmol/L)	5.27 ± 1.12	5.48 ± 1.26	1.345	0.180
Serum creatinine (μmol/L)	78.46 ± 15.23	81.34 ± 16.48	1.385	0.167

AFP: Alpha fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 3 Multivariate logistic regression analysis of factors influencing poor prognosis

Variable	Coefficient	SE	Wald stat	P value	OR	OR CI lower	OR CI upper
BCLC stage (C vs B)	0.849	0.429	1.978	0.048	2.336	1.008	5.413
Maximum tumor diameter (cm)	0.286	0.098	2.920	0.004	1.331	1.098	1.612
Macrovascular invasion (yes vs no)	0.452	0.391	1.156	0.248	1.572	0.730	3.382
Extrahepatic spread (yes vs no)	0.609	0.424	1.438	0.150	1.839	0.802	4.218
AFP (ng/mL)	0.006	0.001	4.668	< 0.001	1.006	1.004	1.009
NLR	1.474	0.273	5.402	< 0.001	4.365	2.557	7.451
AST (U/L)	0.038	0.015	2.523	0.012	1.039	1.008	1.070
Total bilirubin (μmol/L)	0.112	0.044	2.560	0.010	1.119	1.027	1.219
Albumin (g/L)	-0.127	0.050	-2.524	0.012	0.880	0.798	0.972
International normalized ratio	0.438	0.723	0.605	0.545	1.549	0.375	6.390

BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; AST: Aspartate aminotransferase; CI: Confidence interval; OR: Odds ratio.

Table 4 Receiver operating characteristic analysis of factors influencing poor prognosis

Variable	Best_threshold	Sensitivities	Specificities	AUC	Youden_index	F1_score
BCLC stage	0.5	0.778	0.357	0.567	0.135	0.615
Maximum tumor diameter (cm)	9.165	0.444	0.825	0.657	0.269	0.539
AFP (ng/mL)	673.855	0.694	0.746	0.778	0.44	0.698
NLR	3.165	0.759	0.69	0.785	0.449	0.716
AST (U/L)	57.64	0.398	0.778	0.586	0.176	0.48
Total bilirubin (μmol/L)	19.57	0.583	0.603	0.598	0.186	0.57
Albumin (g/L)	37.695	0.611	0.587	0.607	0.198	0.375

BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; AST: Aspartate aminotransferase; AUC: Area under the curve.

Table 5 Comparison of baseline characteristics between patients with low neutrophil-to-lymphocyte ratio and high neutrophil-to-lymphocyte ratio, n (%)/mean ± SD

Variable	Low NLR group (n = 129)	High NLR group (n = 105)	t/χ2	P value
Gender			0.513	0.474
Male	109 (84.50)	85 (80.95)
Female	20 (15.50)	20 (19.05)
Age (years)	56.98 ± 5.12	57.65 ± 5.05	1.007	0.315
BMI (kg/m2)	22.44 ± 1.49	22.19 ± 1.58	1.218	0.224
History of smoking	58 (44.96)	55 (52.38)	1.276	0.259
History of alcohol consumption	52 (40.31)	49 (46.67)	0.953	0.329
Etiology			0.197	0.906
Hepatitis B	116 (89.92)	95 (90.48)
Hepatitis C	5 (3.88)	3 (2.86)
Others	8 (6.20)	7 (6.67)
BCLC stage			5.828	0.016
B	47 (36.43)	23 (21.90)
C	82 (63.57)	82 (78.10)
Child-Pugh grade			3.790	0.052
A	107 (82.95)	76 (72.38)
B	22 (17.05)	29 (27.62)
ECOG PS score			4.081	0.043
0	89 (68.99)	59 (56.19)
1	40 (31.01)	46 (43.81)
Maximum tumor diameter (cm)	7.52 ± 1.84	8.76 ± 2.12	4.800	< 0.001
Macrovascular invasion	56 (43.41)	68 (64.76)	10.593	0.001
Extrahepatic spread	82 (63.57)	83 (79.05)	6.673	0.010

NLR: Neutrophil-to-lymphocyte ratio; BMI: Body mass index; BCLC: Barcelona Clinic Liver Cancer; ECOG PS: Eastern Cooperative Oncology Group Performance Status.

Table 6 Comparison of hematological parameters between patients with low neutrophil-to-lymphocyte ratio and high neutrophil-to-lymphocyte ratio

Variable	Low NLR group (n = 129)	High NLR group (n = 105)	t	P value
AFP (ng/mL)	568.35 ± 125.63	783.27 ± 182.29	10.26	< 0.001
ALT (U/L)	45.92 ± 10.45	48.08 ± 11.32	1.516	0.131
AST (U/L)	49.98 ± 12.25	54.78 ± 13.82	2.812	0.005
Total bilirubin (μmol/L)	18.95 ± 4.25	20.74 ± 4.95	2.983	0.003
Albumin (g/L)	38.34 ± 3.79	36.77 ± 3.97	3.099	0.002
International normalized ratio	1.10 ± 0.27	1.22 ± 0.28	3.472	< 0.001
Blood urea nitrogen (mmol/L)	5.25 ± 1.11	5.51 ± 1.27	1.687	0.093
Serum creatinine (μmol/L)	78.49 ± 15.31	81.32 ± 16.54	1.357	0.176

NLR: Neutrophil-to-lymphocyte ratio; AFP: Alpha fetoprotein; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

Table 7 Comparison of efficacy between patients with low neutrophil-to-lymphocyte ratio and high neutrophil-to-lymphocyte ratio, n (%)

Variable	Low NLR group (n = 129)	High NLR group (n = 105)	χ2	P value
CR	21 (16.28)	8 (7.62)
PR	25 (19.38)	9 (8.57)
SD	46 (35.66)	43 (40.95)
PD	37 (28.68)	45 (42.86)
ORR	46 (35.66)	17 (16.19)	10.386	0.001
DCR	92 (71.32)	60 (57.14)	5.110	0.024

NLR: Neutrophil-to-lymphocyte ratio; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate.

Table 8 Multivariate logistic regression analysis of factors influencing objective response rate

Variable	Coefficient	SE	Wald stat	P value	OR	OR CI lower	OR CI upper
NLR (high vs low)	-1.045	0.336	-3.112	0.002	0.352	0.182	0.680
BCLC stage (C vs B)	-0.222	0.369	-0.602	0.552	0.801	0.387	1.656
Maximum tumor diameter (cm)	-0.132	0.080	-1.649	0.102	0.877	0.749	1.027
Macrovascular invasion (yes vs no)	-0.068	0.332	-0.206	0.838	0.934	0.483	1.805
Extrahepatic spread (yes vs no)	-0.327	0.340	-0.963	0.334	0.721	0.371	1.402

NLR: Neutrophil-to-lymphocyte ratio; BCLC: Barcelona Clinic Liver Cancer; OR: Odds ratio; CI: Confidence interval.

Table 9 Cox proportional hazards regression analysis of factors influencing progression-free survival in patients with advanced hepatocellular carcinoma treated with programmed cell death protein 1 inhibitors

Variable	Univariate		Multivariate
	HR (95%CI)	P value	HR (95%CI)	P value
BCLC stage (C vs B)	1.824 (1.254-2.652)	0.002	1.512 (1.021-2.239)	0.040
Child-Pugh grade (B vs A)	1.521 (1.088-2.124)	0.014	1.281 (0.904-1.814)	0.165
Maximum tumor diameter (per 1 cm increase)	1.283 (1.163-1.414)	< 0.001	1.191 (1.074-1.321)	0.001
Macrovascular invasion (yes vs no)	1.654 (1.208-2.254)	0.002	1.322 (0.952-1.834)	0.096
Extrahepatic spread (yes vs no)	1.584 (1.142-2.194)	0.006	1.263 (0.894-1.783)	0.188
AFP (≥ 400 ng/mL vs < 400 ng/mL)	1.962 (1.432-2.688)	< 0.001	1.623 (1.164-2.263)	0.004
NLR (high vs low)	2.451 (1.782-3.371)	< 0.001	2.084 (1.494-2.904)	< 0.001
AST (≥ 40 U/L vs < 40 U/L)	1.421 (1.039-1.943)	0.028	1.247 (0.902-1.725)	0.184
Total bilirubin (≥ 20 μmol/L vs < 20 μmol/L)	1.378 (1.008-1.883)	0.045	1.176 (0.851-1.625)	0.325
Albumin (≥ 35 g/L vs < 35 g/L)	0.721 (0.526-0.988)	0.042	0.814 (0.587-1.128)	0.216

BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; AST: Aspartate aminotransferase; HR: Hazard ratio; CI: Confidence interval.

Table 10 Cox proportional hazards regression analysis of factors influencing overall survival in patients with advanced hepatocellular carcinoma treated with programmed cell death protein 1 inhibitors

Variable	Univariate		Multivariate
	HR (95%CI)	P value	HR (95%CI)	P value
BCLC stage (C vs B)	2.148 (1.421-3.255)	< 0.001	1.763 (1.144-2.715)	0.010
Child-Pugh grade (B vs A)	1.681 (1.171-2.413)	0.005	1.405 (0.963-2.051)	0.077
Maximum tumor diameter (per 1 cm increase)	1.352 (1.207-1.514)	< 0.001	1.241 (1.102-1.398)	< 0.001
Macrovascular invasion (yes vs no)	1.892 (1.347-2.654)	< 0.001	1.475 (1.034-2.105)	0.032
Extrahepatic spread (yes vs no)	1.821 (1.271-2.607)	0.001	1.521 (1.044-2.216)	0.029
AFP (≥ 400 ng/mL vs < 400 ng/mL)	2.241 (1.578-3.183)	< 0.001	1.847 (1.281-2.663)	0.001
NLR (high vs low)	2.861 (2.001-4.091)	< 0.001	2.421 (1.667-3.516)	< 0.001
AST (≥ 40 U/L vs < 40 U/L)	1.578 (1.121-2.225)	0.009	1.318 (0.924-1.889)	0.128
Total bilirubin (≥ 20 μmol/L vs < 20 μmol/L)	1.518 (1.082-2.139)	0.016	1.261 (0.884-1.799)	0.202
Albumin (≥ 35 g/L vs < 35 g/L)	0.652 (0.461-0.923)	0.016	0.745 (0.521-1.067)	0.108

BCLC: Barcelona Clinic Liver Cancer; AFP: Alpha fetoprotein; NLR: Neutrophil-to-lymphocyte ratio; AST: Aspartate aminotransferase; HR: Hazard ratio; CI: Confidence interval.