Limited Generalizability of Retrospective Single-Center Cohort Study in Comparison to Multicenter Cohort Study on Prognosis of Hepatocellular Carcinoma

Figures & data

Figure 1 Patient flowchart of the study population.

Abbreviations: AMC, Asan Medical Center; HCC, hepatocellular carcinoma; KPLCR, Korean Primary Liver Cancer Registry.

Table 1 Baseline Characteristics of the Study Populations^a

Variable	Single-Center Cohort (n=15,655)	Multicenter Cohort (n=16,443)	P-value
Age (years)	57.7 ± 10.4	61.1 ± 11.5	<0.001
Male	12,690 (81.1%)	13,045 (79.3%)	<0.001
Body mass index (kg/m^2)	24.3 ± 3.3	24.0 ± 3.4	<0.001
Diabetes mellitus	3314 (22.0%)	5779 (40.0%)	<0.001
Hypertension	4564 (30.2%)	4347 (33.4%)	<0.001
Hepatitis B^b	10,622 (73.1%)	9879 (62.3%)	<0.001
Hepatitis C^c	1410 (10.4%)	1883 (12.7%)	<0.001
mUICC staging			<0.001
Stage I	2626 (16.8%)	2532 (15.4%)
Stage II	6176 (39.5%)	6168 (37.6%)
Stage III	4712 (30.1%)	4147 (25.3%)
Stage IVA	1291 (8.3%)	1920 (11.7%)
Stage IVB	850 (5.4%)	1627 (9.9%)
BCLC staging			<0.001
Stage 0	2572 (16.4%)	1312 (9.3%)
Stage A	6719 (42.9%)	3655 (25.9%)
Stage B	2293 (14.7%)	2722 (19.3%)
Stage C	3563 (22.8%)	5402 (38.3%)
Stage D	508 (3.2%)	1013 (7.2%)
Child-Pugh class			<0.001
Class A	12,126 (78.0%)	11,476 (73.1%)
Class B	2904 (18.7%)	3469 (22.1%)
Class C	510 (3.3%)	747 (4.8%)
MELD score	8 (7–10)	8 (7–11)	<0.001
Type of initial treatment			<0.001
Curative^d	6586 (42.1%)	5282 (32.1%)
Non-curative^e	7626 (48.7%)	8070 (49.1%)
Best supportive care	1443 (9.2%)	3091 (18.8%)
Initial treatment modality			<0.001
Surgical resection	5162 (33.0%)	3304 (20.1%)
Liver transplantation	211 (1.3%)	156 (0.9%)
LAT	1213 (7.7%)	1822 (11.1%)
TACE/TARE	6825 (43.6%)	6839 (41.6%)
Radiotherapy	186 (1.2%)	245 (1.5%)
Systemic therapy	615 (3.9%)	986 (6.0%)
Best supportive care	1443 (9.2%)	3091 (18.8%)

Notes: Data are presented as mean ± standard deviation, median (interquartile range), or frequency (proportion). ^aMissing data was excluded from the analysis. ^bHepatitis B was defined as any of the following: positive hepatitis B surface antigen, positive viral titer, or previous history of antiviral therapy. ^cHepatitis C was defined as any of the following: positive hepatitis C antibody, positive viral titer, or previous history of antiviral therapy. ^dCurative treatment was defined as surgical resection, liver transplantation, and local ablation therapy. ^eNon-curative treatment was defined as TACE/TARE, radiotherapy, and systemic therapy.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; LAT, local ablation therapy; MELD, Model for End-stage Liver Disease; mUICC, modified Union for International Cancer Control; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Table 2 Cox Regression Analysis of Factors Associated with Mortality in the Entire Cohorts^a

Variable	Univariate Analysis		Multivariable Analysis with Multiple Imputation
	HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Cohort
Single-center	1 (reference)		1 (reference)
Multicenter	1.55 (1.50–1.59)	<0.001	1.16 (1.13–1.20)	<0.001
Age ≥ 60 years	1.22 (1.19–1.26)	<0.001	1.13 (1.10–1.17)	<0.001
Female (vs Male)	0.83 (0.80–0.87)	<0.001	0.93 (0.89–0.96)	<0.001
Hepatitis B^b	0.77 (0.75–0.80)	<0.001	0.95 (0.91–0.98)	0.003
Hepatitis C^c	1.18 (1.13–1.24)	<0.001	1.06 (1.00–1.11)	0.04
mUICC staging
Stage I	1 (reference)		1 (reference)
Stage II	1.56 (1.47–1.65)	<0.001	1.50 (1.42–1.58)	<0.001
Stage III	3.81 (3.60–4.03)	<0.001	2.78 (2.62–2.94)	<0.001
Stage IVA	9.32 (8.76–9.92)	<0.001	5.55 (5.20–5.92)	<0.001
Stage IVB	14.59 (13.67–15.58)	<0.001	8.07 (7.54–8.63)	<0.001
Child-Pugh class
Class A	1 (reference)		1 (reference)
Class B	3.09 (2.99–3.20)	<0.001	1.94 (1.87–2.01)	<0.001
Class C	5.05 (4.74–5.37)	<0.001	3.12 (2.92–3.34)	<0.001
Type of initial treatment
Curative^d	1 (reference)		1 (reference)
Non-curative^e	3.64 (3.50–3.78)	<0.001	2.39 (2.30–2.49)	<0.001
Best supportive care	12.89 (12.31–13.50)	<0.001	5.71 (5.42–6.01)	<0.001
Initial treatment modality
Surgical resection	1 (reference)
Liver transplantation	0.76 (0.61–0.95)	0.02
LAT	1.43 (1.33–1.54)	<0.001
TACE/TARE	3.55 (3.39–3.72)	<0.001
Radiotherapy	8.75 (7.83–9.78)	<0.001
Systemic therapy	14.82 (13.85–15.85)	<0.001
Best supportive care	14.70 (13.95–15.50)	<0.001

Notes: ^aMissing data was imputed. ^bHepatitis B was defined as any of the following: positive hepatitis B surface antigen, positive viral titer, or previous history of antiviral therapy. ^cHepatitis C was defined as any of the following: positive hepatitis C antibody, positive viral titer, or previous history of antiviral therapy. ^dCurative treatment was defined as surgical resection, liver transplantation, and local ablation therapy. ^eNon-curative treatment was defined as TACE/TARE, radiotherapy, and systemic therapy.

Abbreviations: CI, confidence interval; HR, hazard ratio; LAT, local ablation therapy; mUICC, modified Union for International Cancer Control; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Figure 2 Kaplan–Meier estimates of overall survival in the two cohorts.

Table 3 Cox Regression Analysis of Risk of Mortality by Initial Treatment in the Entire Cohorts^a

Initial Treatment Modality	Univariate Analysis		Multivariable Analysis with Multiple Imputation^b
	HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Surgical resection
Single-center (n=5162)	1 (reference)		1 (reference)
Multicenter (n=3304)	1.38 (1.27–1.50)	<0.001	1.32 (1.22–1.44)	<0.001
Liver transplantation
Single-center (n=211)	1 (reference)		1 (reference)
Multicenter (n=156)	2.22 (1.41–3.51)	<0.001	2.10 (1.30–3.38)	0.002
LAT
Single-center (n=1213)	1 (reference)		1 (reference)
Multicenter (n=1822)	1.64 (1.45–1.87)	<0.001	1.50 (1.32–1.71)	<0.001
TACE/TARE
Single-center (n=6825)	1 (reference)		1 (reference)
Multicenter (n=6839)	1.25 (1.20–1.31)	<0.001	1.24 (1.19–1.29)	<0.001
Radiotherapy
Single-center (n=186)	1 (reference)		1 (reference)
Multicenter (n=245)	1.16 (0.94–1.43)	0.16	1.14 (0.91–1.42)	0.25
Systemic therapy
Single-center (n=615)	1 (reference)		1 (reference)
Multicenter (n=986)	0.86 (0.78–0.96)	0.007	0.83 (0.74–0.92)	0.001
Curative treatment^c
Single-center (n=6586)	1 (reference)		1 (reference)
Multicenter (n=5282)	1.54 (1.44–1.65)	<0.001	1.48 (1.39–1.59)	<0.001
Non-curative treatment^d
Single-center (n=7626)	1 (reference)		1 (reference)
Multicenter (n=8070)	1.28 (1.23–1.33)	<0.001	1.22 (1.17–1.27)	<0.001
Best supportive care
Single-center (n=1443)	1 (reference)		1 (reference)
Multicenter (n=3091)	0.85 (0.80–0.91)	<0.001	0.85 (0.79–0.91)	<0.001

Notes: ^aMissing data was imputed. ^bAdjusted for sex, age, hepatitis B, hepatitis C, Child-Pugh class, and modified Union for International Cancer Control (mUICC) staging. ^cCurative treatment was defined as surgical resection, liver transplantation, and local ablation therapy. ^dNon-curative treatment was defined as TACE/TARE, radiotherapy, and systemic therapy.

Abbreviations: CI, confidence interval; HR, hazard ratio; LAT, local ablation therapy ablation; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.

Table 4 Cox Regression Analysis of Risk of Mortality by Initial Treatment in BCLC-Guided Subcohorts^a

Initial Treatment Modality	Univariate Analysis		Multivariable Analysis with Multiple Imputation^b
	HR (95% CI)	P-value	Adjusted HR (95% CI)	P-value
Surgical resection
Single-center (n=3771)	1 (reference)		1 (reference)
Multicenter (n=1481)	1.10 (0.96–1.26)	0.17	1.07 (0.93–1.23)	0.33
Liver transplantation
Single-center (n=146)	1 (reference)		1 (reference)
Multicenter (n=90)	1.35 (0.69–2.66)	0.38	1.30 (0.65–2.60)	0.45
LAT
Single-center (n=280)	1 (reference)		1 (reference)
Multicenter (n=346)	1.42 (1.07–1.90)	0.02	1.44 (1.08–1.92)	0.01
TACE
Single-center (n=661)	1 (reference)		1 (reference)
Multicenter (n=366)	1.74 (1.50–2.02)	<0.001	1.72 (1.48–2.00)	<0.001
Systemic therapy
Single-center (n=293)	1 (reference)		1 (reference)
Multicenter (n=514)	0.93 (0.80–1.08)	0.33	0.94 (0.81–1.10)	0.44

Notes: ^aMissing data was imputed. ^bAdjusted for sex, age, hepatitis B, hepatitis C, Child-Pugh class, and modified Union for International Cancer Control (mUICC) staging.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; CI, confidence interval; HR, hazard ratio; LAT, local ablation therapy; TACE, transarterial chemoembolization.

Figure 3 Kaplan–Meier estimates of overall survival of patients who received (A) surgical resection, (B) liver transplants, (C) LAT, (D) TACE, and (E) systemic therapy according to the treatment indications*.

Notes: *Treatment indications: patients of BCLC stage 0 or A, single tumor: surgical resection, BCLC stage A with 3 or less nodules each up to 3 cm: LAT, BCLC stage B: TACE, BCLC stage C:systemic therapy, and patients with any degree of liver function who meet the Milan’s criteria: liver transplantation.

Abbreviations: BCLC, Barcelona Clinic Liver Cancer; LAT, local ablation therapy; TACE, transarterial chemoembolization.

Table 5 Subgroup Analysis^a

Subgroup	Single-Center Cohort		Multicenter Cohort
	Cases	Events (%)	Cases	Events (%)	Crude HR (95% CI)^b	P-value	P for interaction
Sex							0.013
Male	12,690	6126 (48.3%)	13,045	8893 (68.2%)	1.52 (1.48–1.58)	<0.001
Female	2965	1190 (40.1%)	3398	2142 (63.0%)	1.68 (1.57–1.81)	<0.001
mUICC staging							<0.001
Stage I	2626	527 (20.1%)	2532	1058 (41.8%)	2.13 (1.91–2.36)	<0.001
Stage II	6176	1991 (32.2%)	6168	3273 (53.1%)	1.65 (1.56–1.74)	<0.001
Stage III	4712	2954 (62.7%)	4147	3267 (78.8%)	1.29 (1.23–1.36)	<0.001
Stage IVA	1291	1100 (85.2%)	1920	1807 (94.1%)	1.32 (1.23–1.42)	<0.001
Stage IVB	850	744 (87.5%)	1627	1586 (97.5%)	1.34 (1.23–1.46)	<0.001
Child-Pugh class							<0.001
Class A	12,126	4738 (39.1%)	11,476	6717 (58.5%)	1.55 (1.49–1.61)	<0.001
Class B	2904	2156 (74.2%)	3469	3039 (87.6%)	1.26 (1.19–1.33)	<0.001
Class C	510	391 (76.7%)	747	686 (91.8%)	1.53 (1.35–1.73)	<0.001
Type of initial treatment							<0.001
Curative^c	6586	1523 (23.1%)	5282	1945 (36.8%)	1.58 (1.47–1.67)	<0.001
Non-curative^d	7626	4533 (59.4%)	8070	6222 (77.1%)	1.27 (1.22–1.32)	<0.001
Best supportive care	1443	1260 (87.3%)	3091	2868 (92.8%)	0.75 (0.70–0.80)	<0.001

Notes: ^aMissing data was imputed. ^bCrude hazard ratio for multicenter vs single-center cohort. ^cCurative treatment was defined as surgical resection, liver transplantation, and local ablation therapy. ^dNon-curative treatment was defined as TACE/TARE, radiotherapy, and systemic therapy.

Abbreviations: CI, confidence interval; HR, hazard ratio; mUICC, modified Union for International Cancer Control.