Comparative prognostic performance of staging systems for hepatocellular carcinoma: Evidence from a Vietnamese cohort study

Table 1 Patient characteristics and tumor profiles in our cohort grouped by hepatitis B virus and hepatitis C virus status

Feature of interest	Study population, n = 987	HBV-HCV infection status				Intergroup statistical significance
		HBV, n = 446, 45.2%	HCV, n = 308, 31.2%	Non-B-non-C, n = 213, 21.6%	Co-infected HBV + HCV, n = 20, 2.0%
Demographic features
Male sex, n (%)	789 (79.9)	368 (82)	246 (80)	161 (76)	15 (75)	NS (χ²)
Age in years, mean	62.28 ± 11.05	59.10 ± 11.21	65.11 ± 8.77	64.91 ± 11.85	61.40 ± 11.95	< 0.001 (A)
Clinical features
Size of tumor in cm (IQR)	4.8 (2.8-8.2)	5.0 (2.8-8.8)	4.0 (2.6-6.85)	6.0 (3.0-10.0)	3.85 (2.5-6.65)	< 0.001 (K-W)
Number of tumors, n (%)						NS (χ²)
1	584 (59.2)	261 (58.5)	177 (57.5)	134 (62.9)	12 (60.0)
2	151 (15.3)	69 (15.5)	56 (18.2)	24 (11.3)	2 (10.0)
≥ 3	252 (25.5)	116 (26.0)	75 (24.4)	55 (25.8)	6 (30.0)
Solidity, n (%)						NS (χ²)
Infiltrative	67 (6.8)	30 (6.7)	17 (5.5)	20 (9.4)	0 (0.0)
Solid	920 (93.2)	416 (93.3)	291 (94.5)	193 (90.6)	20 (100.0)
Intrahepatic vascular invasion, n (%)	17 (1.7)	5 (1.1)	7 (2.3)	4 (1.9)	1 (5.0)	NS (χ²)
Portal thrombosis, n (%)	156 (15.8)	53 (11.9)	50 (16.2)	50 (23.5)	3 (15.0)	0.002 (χ²)
Metastasis, n (%)						NS (χ²)
No metastasis	893 (90.5)	401 (89.9)	283 (91.9)	190 (89.2)	19 (95.0)
Lymph nodes	70 (7.1)	35 (7.8)	22 (7.1)	12 (5.6)	1 (5.0)
Lung	10 (1.0)	5 (1.1)	1 (0.3)	4 (1.9)	0 (0.0)
Lymph nodes + Lung	2 (0.2)	0 (0.0)	0 (0.0)	2 (0.9)	0 (0.0)
Other sites	12 (1.2)	5 (1.1)	2 (0.6)	5 (2.3)	0 (0.0)
Ascites, n (%)	216 (21.9)	91 (20.4)	61 (19.8)	60 (28.2)	4 (20.0)	NS (χ²)
Cirrhosis, n (%)	612 (62.0)	253 (56.7)	208 (67.5)	136 (63.8)	15 (75.0)	0.012 (χ²)
Tumor rupture, n (%)	55 (5.6)	26 (5.8)	14 (4.5)	15 (7.0)	0 (0.0)	NS (χ²)
ECOG performance status, n (%)						0.001 (χ²)
0: Normal activity	655 (66.4)	311 (69.7)	214 (69.5)	118 (55.4)	12 (60.0)
1: Mildly restricted	271 (27.5)	114 (25.6)	69 (22.4)	80 (37.6)	8 (40.0)
≥ 2: Significantly restricted	61 (6.2)	21 (4.7)	25 (8.1)	15 (7.0)	0 (0.0)
Laboratory examinations
AFP in ng/mL	27.7 (5.9-767.3)	36.55 (5.9-1000.0)	27.45 (6.8-334.0)	16.50 (4.3-471.8)	65.70 (12.95-902.65)	0.049 (K-W)
PT as %	79.54 ± 16.16	79.98 ± 15.80	79.82 ± 16.18	78.59 ± 16.82	75.69 ± 17.09	NS (A)
INR	1.11 (1.00-1.23)	1.11 (1.00-1.23)	1.11 (1.00-1.24)	1.09 (1.00-1.23)	1.13 (1.01-1.27)	NS (K-W)
AST in U/L	58.5 (38.0-105.0)	56.85 (38.6-99.0)	68.2 (36.75-107.25)	52.0 (35.4-101.0)	77.15 (41.2-141.0)	NS (K-W)
ALT in U/L	44.7 (28.0-74.1)	44.35 (29.2-66.9)	46.5 (27.7-88.95)	40.0 (25.3-70.0)	55.65 (35.75-86.25)	NS (K-W)
Albumin in g/L	36.53 ± 6.52	37.15 ± 6.28	36.23 ± 6.73	35.60 ± 6.68	37.45 ± 5.45	0.024 (A)
Total bilirubin in μmol/L	16.0 (11.5-23.7)	14.9 (11.3-22.2)	17.15 (12.0-25.15)	16.2 (11.0-24.5)	17.3 (13.75-24.05)	NS (K-W)
Creatinine in μmol/L	90.03 ± 26.91	87.21 ± 21.92	89.65 ± 26.03	96.73 ± 35.84	87.25 ± 18.41	< 0.001 (A)
Platelet as 109/L1	186.18 ± 95.99	192.72 ± 96.99	159.71 ± 75.65	213.90 ± 109.61	152.70 ± 95.51	< 0.001 (A)
Treatment
First choice of treatment, n (%)						< 0.001 (χ²)
RFA/WMA	102 (10.3)	42 (9.4)	39 (12.7)	17 (8.0)	4 (20.0)
Surgery	123 (12.5)	70 (15.7)	34 (11.0)	19 (8.9)	0 (0.0)
TACE	458 (46.4)	218 (48.9)	153 (49.7)	76 (35.7)	11 (55.0)
Chemotherapy	50 (5.1)	22 (4.9)	10 (3.2)	18 (8.5)	0 (0.0)
Palliative Care	254 (25.7)	94 (21.1)	72 (23.4)	83 (39.0)	5 (25.0)
Prognosis
Survival status, n (%)						0.02 (χ²)
Alive	731 (74.1)	346 (77.6)	230 (74.7)	142 (66.7)	13 (65.0)
Deceased	256 (25.9)	100 (22.4)	78 (25.3)	71 (33.3)	7 (35.0)
Survival time, month	15 (4-35)	15 (4-36)	21.5 (7-40)	9 (1.5-22)	18.5 (6.5-44)	< 0.001 (K-W)

¹Among the 987 patients, with platelet values missing for 21 cases (2.1%).

HBV: Hepatitis B virus; HCV: Hepatitis C virus; AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ECOG: Eastern cooperative oncology group; INR: International normalized ratio; IQR: Interquartile range; NS: Not significant; PT: Prothrombin time; RFA: Radio frequency ablation; TACE: Transarterial chemoembolization; WMA: Warm microwave ablation; A: ANOVA test; K-W: Kruskal Wallis test.

Table 2 Univariate and multivariate Cox regression analysis of prognostic factors in the entire cohort and hepatitis B virus-hepatitis C virus infection status subgroups

Variables	Univariate HR (95%CI)	Univariate P	Multivariate HR (95%CI)	Multivariate P value
Demographic features
Sex	1.208	0.243
Age	1.001	0.851
Clinical features
Tumor size	1.130	< 0.001	1.059 (1.024-1.094)	0.001
Tumor number
1		< 0.001
2	0.426	< 0.001
≥ 3	0.407	< 0.001
Ruptured tumor	3.233	< 0.001
Solid tumor	0.342	< 0.001
Intrahepatic vascular invasion	3.295	0.001
Extrahepatic vascular invasion	9.860	0.023
Portal thrombosis	4.305	< 0.001	1.905 (1.393-2.608)	< 0.001
Metastasis	1.493	< 0.001	1.270 (1.069-1.509)	0.007
Ascites	3.406	< 0.001	1.560 (1.166-2.084)	0.003
Portal hypertension	1.316	0.036
Cirrhosis	1.938	< 0.001
ECOG score	3.731	< 0.001	2.801 (2.308-3.401)	< 0.001
HBV-HCV infection status		0.002
HCV	0.571	< 0.001
Non-B-non-C	0.589	0.001
Co-infected	0.818	0.611
Laboratory examinations
AFP	1.001	< 0.001	1.000 (1.000-1.000)	0.020
ALT	1.000	0.538
AST	1.002	< 0.001	1.001 (1.000-1.002)	0.021
Albumin	0.917	< 0.001	0.956 (0.936-0.977)	< 0.001
PT	0.982	< 0.001
INR	0.923	0.632
Platelet count	1.003	< 0.001
Total bilirubin	1.005	< 0.001
Creatinine	1.003	0.113
Treatment
RFA/WMA		< 0.001
Surgery	0.064	< 0.001
TACE	0.051	< 0.001
Chemotherapy	0.123	< 0.001
Palliative care	0.119	< 0.001

HR: Hazard ratio; 95%CI: 95% confidence interval; HBV: Hepatitis B virus; HCV: Hepatitis C virus; AFP: Alpha-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ECOG: Eastern Cooperative Oncology group; INR: International normalized ratio; PT: Prothrombin time; RFA: Radio frequency ablation; TACE: Transarterial chemoembolization; WMA: Warm microwave ablation.

Table 3 Distribution of follow-up status at key time points in the entire cohort and patients categorized by hepatitis B virus and hepatitis C virus infection status

Group	Status	12 months	36 months	60 months
Entire cohort	Deceased	202	241	253
	Lost to follow-up	237	509	661
	Under follow-up	548	237	73
HBV	Deceased	80	93	99
	Lost to follow-up	126	243	313
	Under follow-up	240	110	34
HCV	Deceased	57	72	77
	Lost to follow-up	47	148	199
	Under follow-up	204	88	32
Non-B-Non-C	Deceased	59	70	70
	Lost to follow-up	62	113	138
	Under follow-up	92	30	5

HBV: Hepatitis B virus; HCV: Hepatitis C virus.

Table 4 Comparison of prognostic and calibration performance of scoring systems at 12 months and 36 months after initial treatment

Score	Time in months	C-index	AUC	χ2	HL P value	LRT P value	AIC	Mean error	90% quantile
BCLC	12	0.769	0.815	254.43	< 0.05	< 10-46	3024.30	0.063	0.280
	36	0.765	0.838	1280.44	< 0.05	< 10-46	2774.41	0.072	0.128
HKLC_9	12	0.794	0.834	451.70	< 0.05	< 10-53	2992.47	0.103	0.183
	36	0.798	0.859	7218.33	< 0.05	< 10-51	2750.78	0.104	0.141
HKLC_5	12	0.793	0.830	372.81	< 0.05	< 10-51	3002.21	0.116	0.175
	36	0.795	0.859	4017.61	< 0.05	< 10-50	2758.09	0.102	0.166
CLIP	12	0.756	0.792	379.93	< 0.05	< 10-49	3010.61	0.068	0.128
	36	0.749	0.809	2490.52	< 0.05	< 10-44	2785.58	0.002	0.005
ITA.LI.CA	12	0.757	0.795	300.31	< 0.05	< 10-45	3025.01	0.067	0.119
	36	0.764	0.814	1741.14	< 0.05	< 10-44	2786.67	0.057	0.074
JIS	12	0.683	0.712	221.52	< 0.05	< 10-25	3116.60	0.064	0.118
	36	0.683	0.721	765.66	< 0.05	< 10-25	2871.86	0.008	0.018
Tokyo	12	0.748	0.781	293.75	< 0.05	< 10-41	3045.51	0.063	0.118
	36	0.755	0.811	1733.23	< 0.05	< 10-41	2797.68	0.010	0.024
MESIAH_GROUP	12	0.739	0.765	242.39	< 0.05	< 10-34	3078.19	0.095	0.234
	36	0.744	0.802	968.24	< 0.05	< 10-38	2812.91	0.143	0.214

C-index: Concordance index; AUC: Area under the curve; HL: Hosmer-Lemeshow test; LRT: Likelihood ratio test; AIC: Akaike information criterion; BCLC: Barcelona Clinic Liver Cancer; HKLC: Hong Kong Liver Cancer; CLIP: Cancer of the Liver Italian Program; ITA.LI.CA: Italian Liver Cancer; JIS: Japan Integrated staging; MESIAH: Model to estimate survival in ambulatory hepatocellular carcinoma patients.

Table 5 Comparison of prognostic accuracy of different scoring systems across groups according to hepatitis B virus and hepatitis C virus infection status at 12 months and 36 months after treatment

Infection status	Score	Time in months	AUC	χ2	LRT P value	AIC	Mean error	90% quantile
HBV	BCLC	12	0.821	88.70	4.60 10-21	279.18	0.272	0.514
		36	0.828	83.73	5.68 10-20	203.91	0.307	0.789
	HKLC_9	12	0.810	71.63	2.59 10-17	296.24	0.289	0.711
		36	0.809	63.58	1.54 10-15	224.05	0.358	0.723
	HKLC_5	12	0.806	68.18	1.49 10-16	299.69	0.294	0.641
		36	0.808	62.92	2.16 10-15	224.71	0.358	0.655
HCV	BCLC	12	0.831	72.13	2.01 10-17	206.34	0.246	0.614
		36	0.842	70.31	5.06 10-17	156.26	0.298	0.725
	HKLC_9	12	0.872	93.74	3.60 10-22	184.73	0.211	0.631
		36	0.885	85.92	1.87 10-20	140.66	0.271	0.769
	HKLC_5	12	0.875	94.19	2.87 10-22	184.28	0.213	0.687
		36	0.891	89.75	2.70 10-21	136.83	0.261	0.666
Non-B-Non-C	BCLC	12	0.751	35.75	2.24 10-9	174.21	0.372	0.732
		36	0.802	31.49	2.01 10-8	97.07	0.293	0.639
	HKLC_9	12	0.812	45.84	1.28 10-11	164.12	0.342	0.731
		36	0.878	45.90	1.25 10-11	82.66	0.256	0.669
	HKLC_5	12	0.797	41.21	1.36 10-10	168.74	0.355	0.750
		36	0.880	47.89	4.50 10-12	80.66	0.244	0.602

AUC: Area under the curve; AIC: Akaike information criterion; LRT: Likelihood ratio test; HBV: Hepatitis B virus; HCV: Hepatitis C virus; BCLC: Barcelona Clinic Liver Cancer; HKLC: Hong Kong Liver Cancer.

Table 6 Comparison of prognostic accuracy of different scoring systems across treatment modalities at 12 months and 36 months after initial treatment

Modality	Score	Time in months	AUC	χ2	LRT P value	AIC	Mean error	90% quantile
TACE	BCLC	12	0.8000	3.38	0.066	26.79	0.063	0.100
		36	0.7849	53.57	< 0.001	214.12	0.321	0.678
	HKLC_9	12	0.9078	3.45	0.063	26.72	0.061	0.047
		36	0.7702	44.33	< 0.001	223.36	0.343	0.702
	HKLC_5	12	0.9078	4.48	0.034	25.69	0.060	0.046
		36	0.7624	41.39	< 0.001	226.30	0.349	0.730
RFA	BCLC	12	0.8000	3.38	0.066	26.79	0.063	0.100
		36	0.7748	10.51	0.001	34.86	0.163	0.508
	HKLC_9	12	0.9078	3.45	0.063	26.72	0.061	0.047
		36	0.8214	6.15	0.013	39.22	0.192	0.632
	HKLC_5	12	0.9078	4.48	0.034	25.69	0.060	0.046
		36	0.8214	4.70	0.006	37.67	0.184	0.688
Surgery	BCLC	12	0.9140	16.44	< 0.001	27.05	0.078	0.238
		36	0.7882	9.69	0.002	36.04	0.222	0.565
	HKLC_9	12	0.8280	4.91	0.027	38.58	0.091	0.153
		36	0.7465	6.20	0.013	39.52	0.249	0.721
	HKLC_5	12	0.8120	4.63	0.031	38.86	0.091	0.183
		36	0.7292	4.50	0.034	41.23	0.264	0.758

RFA: Radiofrequency ablation; TACE: Transarterial chemoembolization; AUC: Area under the curve; AIC: Akaike information criterion; LRT: Likelihood ratio test; BCLC: Barcelona Clinic Liver Cancer; HKLC: Hong Kong Liver Cancer.