Liver resection for hepatocellular carcinoma larger than 10 cm: A multi-institution long-term observational study

Table 1 Demographic data (categorical) of hepatocellular carcinoma patients undergoing liver resection, n (%), n = 3985

Variables		Total	S-HCC, < 10 cm	L-HCC, ≥ 10 cm	P value
Number1		3985 (100)	3559 (89)	426 (11)
Gender	Male	3061 (77)	2716 (76)	345 (81)	0.031
Age	≤ 20	9 (< 1)	4 (< 1)	5 (1)	< 0.001
	21-40	292 (7)	240 (7)	52 (12)
	41-60	1668 (42)	1478 (42)	190 (45)
	≥ 61	2016 (51)	1837 (52)	179 (42)
Diabetes	Yes	831 (21)	764 (21)	67 (16)	0.006
Hypertension	Yes	1172 (29)	1053 (30)	119 (28)	0.480
HBV surface antigen	Positive	2074 (52)	1849 (52)	225 (53)	0.740
Anti-HCV antibody	Positive	1135 (28)	1091 (31)	44 (10)	< 0.001
Non-HBV non-HCV	Yes	986 (25)	815 (23)	171 (40)	< 0.001
Cigarette smoking	Yes	380 (10)	330 (9)	50 (12)	0.100
Alcohol consumption	Yes	322 (8)	277 (8)	45 (11)	0.047
Betel nut	Yes	109 (3)	93 (3)	16 (4)	0.170
AJCC 6th (2002-2009)		1771	1577	194
	Stage I	1035 (58)	973 (62)	62 (32)	< 0.001
	Stage II	347 (20)	307 (19)	40 (21)
	Stage III	364 (21)	279 (18)	85 (44)
	Stage IV	25 (1)	18 (1)	7 (4)
AJCC 7th (2010-2015)		2214	1982	232
	Stage I	1064 (48)	1031(52)	33 (14)	< 0.001
	Stage II	783 (35)	717 (36)	66 (28)
	Stage III	341 (15)	220 (11)	121 (52)
	Stage IV	26 (1)	14 (1)	12 (5)

¹Number excluded surgical mortality (30-d mortality).

AJCC: American Joint Committee on Cancer; HBV: Hepatitis B virus; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; L-HCC: Hepatocellular carcinoma ≥ 10 cm; S-HCC: Hepatocellular carcinoma < 10 cm.

Table 2 Demographic data (continuous) of hepatocellular carcinoma patients undergoing liver resection, n = 3985

Variables		Total	S-HCC, < 10 cm	L-HCC, > 10 cm	P value
		Mean ± SD	Mean ± SD	Mean ± SD
Tumor size	cm	4.41 ± 3.98	3.36 ± 2.14	13.14 ± 4.95	< 0.001
Age	yr	58.7 ± 12.4	59.1 ± 12.1	55.7 ± 14.3	< 0.001
Alpha-fetoprotein	ng/mL	6156.3 ± 60012	2400.7 ± 19087	40531.8 ± 178925	< 0.001
Albumin	g/dL	3.8 ± 0.6	3.8 ± 0.6	3.5 ± 0.7	< 0.001
Alkaline phosphatase	U/L	97.9 ± 104.4	90.1 ± 75.6	161.1 ± 221.4	< 0.001
AST	U/L	81.3 ± 158.1	76.4 ± 140.0	121.8 ± 261.2	< 0.001
ALT	U/L	85.1 ± 144.8	84.2 ± 133.5	92.2 ± 217.0	0.290
Bilirubin-direct	mg/dL	0.4 ± 0.8	0.4 ± 0.8	0.4 ± 0.6	0.400
Bilirubin-total	mg/dL	1.1 ± 1.3	1.1 ± 1.4	1.1 ± 1.0	0.680
ICG-15	%	9.7 ± 7.9	9.9 ± 8.1	8.0 ± 5.8	< 0.001
PT	seconds	11.8 ± 2.1	11.7 ± 2.0	12.0 ± 2.6	0.019

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; HCC: Hepatocellular carcinoma; ICG-15: Indocyanine green retention test at 15 minutes; L-HCC: Hepatocellular carcinoma ≥ 10 cm; PT: Prothrombin time; SD: Standard deviation; S-HCC: Hepatocellular carcinoma < 10 cm.

Table 3 Surgical and oncological outcome of patients with hepatocellular carcinoma, n (%)

	S-HCC, < 10 cm		L-HCC, ≥ 10 cm		P-value
Surgical mortality at 30-d	25 (0.7)		9 (2.1)		0.003
Patient number1	3559 (100)		426 (100)
Follow-up times in d, mean ± SD	1733.1 ± 1071.5		1175.3 ± 1034.2		< 0.001
Recurrence status					< 0.001
Yes	1568 (44.1)		256 (60.1)
No	1735 (48.7)		101 (23.7)
Never disease free	256 (7.2)		69 (16.2)
Recurrence pattern					< 0.001
Local2	1109 (70.7)		131 (51.2)
Regional3	88 (5.6)		10 (3.9)
Combined4	63 (4.0)		36 (14.1)
Distant	87 (5.5)		47 (18.4)
Death without recurrence	221 (14.1)		32 (12.5)
Disease free survival in d, median (IQR)	1024 (413-1907)		329 (121-1244)		< 0.001
1-yr DFS rate	2585 (78.3)		173 (48.5)		< 0.001
3-yr DFS rate	2037 (61.7)		129 (36.1)		< 0.001
5-yr DFS rate	1828 (55.3)		111 (31.1)		< 0.001
Final status					< 0.001
Alive	2424 (68.1)		175 (41.1)
Death - liver cause	795 (22.3)		195 (45.8)
Death - other cause	340 (9.6)		56 (13.1)
Overall survival (d) [median (IQR)]	1579 (871-2455)		801.5 (362-1818)		< 0.001
1-yr OS rate	3354 (94.2)		323 (75.8)		< 0.001
3-yr OS rate	2954 (83.0)		227 (53.3)		< 0.001
5-yr OS rate	2689 (75.6)		197 (46.2)		< 0.001

¹Number excluded surgical mortality (30-d mortality).

²Local recurrence include resection margin/remnant liver or trocar site.

³Regional recurrence include adjacent organs/regional LNs, or both.

⁴Combined recurrence include local and regional recurrence.

DFS: Disease-free survival; HCC: Hepatocellular carcinoma; IQR: Interquartile range; L-HCC: Hepatocellular carcinoma ≥ 10 cm; OS: Overall survival; SD: Standard deviation; S-HCC: Hepatocellular carcinoma < 10 cm.

Table 4 Analyses of survival outcome with and without IPTW between the two groups: HCC ≥ 10 cm vs < 10 cm

	Without IPTW				With IPTW
	Unadjusted		Adjusted		Unadjusted		Adjusted
	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
Recurrence
Entire cohort	2.24 (1.96-2.56)	< 0.001	1.85 (1.60-2.13)	< 0.001	1.60 (1.28-2.01)	< 0.001	1.73 (1.40-2.15)	< 0.001
Within stage I					1.43 (0.87-2.37)	< 0.001	1.62 (1.02-2.56)	0.042
Within stage II					1.64 (1.23-2.20)	0.160	1.70 (1.28-2.27)	< 0.001
Within stage III					1.98 (1.61-2.43)	0.001	2.14 (1.74-2.63)	< 0.001
Within stage IV					1.46 (0.56-3.83)	< 0.001	1.93 (0.63-5.91)	0.251
All-cause mortality
Entire cohort	2.70 (2.36-3.10)	< 0.001	1.95 (1.68-2.26)	< 0.001	1.99 (1.59-2.48)	< 0.001	2.07 (1.70-2.51)	< 0.001
Within stage I					2.34 (1.49-3.67)	< 0.001	2.47 (1.64-3.74)	< 0.001
Within stage II					1.81 (1.22-2.69)	0.003	1.80 (1.31-2.49)	< 0.001
Within stage III					1.78 (1.44-2.20)	< 0.001	1.89 (1.52-2.35)	< 0.001
Within stage IV					0.71 (0.27-1.86)	0.490	1.31 (0.58-2.96)	0.510
Liver-cause mortality
Entire cohort	3.16 (2.70-3.70)	< 0.001	2.16 (1.82-2.56)	< 0.001	2.09 (1.61-2.72)	< 0.001	2.15 (1.73-2.67)	< 0.001
Within stage I					2.36 (1.31-4.26)	0.004	2.15 (1.43-3.24)	< 0.001
Within stage II					1.95 (1.21-3.15)	0.006	1.88 (1.29-2.72)	0.001
Within stage III					2.00 (1.58-2.55)	< 0.001	2.12 (1.67-2.69)	< 0.001
Within stage IV					0.67 (0.24-1.92)	0.460	0.96 (0.37-2.48)	0.932

CI: Confidence interval; HCC: Hepatocellular carcinoma; IPTW: Inverse-probability of treatment weighting.

Table 5 Comparison of current study with our previous report

	Yeh etal[27]: 1st era	Current study: 2nd era
Number of HCC ≥ 10 cm	211	426
Study period	1982-2001	2002-2015
Study design	Retrospective	Institutional-based cohort with IPTW
Age in yr	47.8 ± 14.3	55.7 ± 14.3
Gender, male %	78%	81%
HBV infection, positive	81.9%	52.8%
HCV infection, positive	11.6%	10.3%
Size in cm	13.9 ± 3.4	13.14 ± 4.95
Surgical mortality at 30-d	4.3%	2.1%
1-yr DFS rate	32.9%	48.5%
3-yr DFS rate	18.8%	36.1%
5-yr DFS rate	12.7%	31.1%
1-yr OS rate	48.1%	75.8%
3-yr OS rate	24.0%	53.3%
5-yr OS rate	16.7%	46.2%

DFS: disease-free survival; HCC: Hepatocellular carcinoma; IPTW: Inverse-probability of treatment weighting; OS: Overall survival.

Table 6 Analyses of survival outcome with and without inverse-probability of treatment weighting between the two groups (hepatectomy vs transarterial chemoembolization) - TNM and Barcelona Clinic Liver Cancer stage

	Without IPTW				With IPTW
	Unadjusted		Adjusted		Unadjusted		Adjusted
	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value	Hazard ratio (95%CI)	P value
All-cause mortality
Entire cohort	0.33 (0.28-0.40)	< 0.001	0.46 (0.38-0.55)	< 0.001	0.49 (0.39-0.61)	< 0.001	0.46 (0.38-0.56)	< 0.001
Within stage I					0.39 (0.20-0.80)	0.009	0.37 (0.19-0.73)	0.004
Within stage II					0.30 (0.16-0.54)	< 0.001	0.24 (0.13-0.45)	< 0.001
Within stage III					0.50 (0.41-0.62)	< 0.001	0.50 (0.40-0.62)	< 0.001
Within stage IV					0.31 (0.14-0.67)	0.003	0.30 (0.09-0.93)	0.037
Liver-cause mortality
Entire cohort	0.32 (0.26-0.39)	< 0.001	0.45 (0.37-0.56)	< 0.001	0.48 (0.37-0.61)	< 0.001	0.46 (0.37-0.56)	< 0.001
Within stage I					0.33 (0.16-0.71)	0.004	0.27 (0.12-0.60)	0.001
Within stage II					0.30 (0.16-0.56)	< 0.001	0.22 (0.10-0.47)	< 0.001
Within stage III					0.50 (0.39-0.63)	< 0.001	0.50 (0.40-0.63)	< 0.001
Within stage IV					0.30 (0.13-0.70)	0.005	0.29 (0.09-1.00)	0.050
All-cause mortality
Entire cohort	0.33 (0.28-0.40)	< 0.001	0.37 (0.30-0.47)	< 0.001	0.38 (0.30-0.48)	< 0.001	0.38 (0.30-0.48)	< 0.001
BCLC stage A					NA	NA	NA	NA
BCLC stage B					0.33 (0.23-0.48)	< 0.001	0.30 (0.20-0.44)	< 0.001
BCLC stage C					0.40 (0.30-0.53)	< 0.001	0.41 (0.31-0.54)	< 0.001
BCLC stage D					NA	NA	NA	NA
Liver-cause mortality
Entire cohort	0.32 (0.26-0.39)	< 0.001	0.35 (0.27-0.44)	< 0.001	0.36 (0.28-0.45)	<0 .001	0.35 (0.28-0.45)	< 0.001
BCLC stage A					NA	NA	NA	NA
BCLC stage B					0.32 (0.21-0.47)	< 0.001	0.29 (0.19-0.43)	< 0.001
BCLC stage C					0.37 (0.27-0.49)	< 0.001	0.38 (0.28-0.51)	< 0.001
BCLC stage D					NA	NA	NA	NA

BCLC: Barcelona Clinic Liver Cancer; CI: Confidence interval; HCC: Hepatocellular carcinoma; IPTW: Inverse-probability of treatment weighting; NA: Not applicable; TACE: Transarterial chemoembolization.