Prognostic impact of neoadjuvant therapy vs upfront surgery in patients with huge hepatocellular carcinoma undergoing curative resection

Table 1 Patient clinical characteristics, n (%)

Variable	Neoadjuvant therapy (n = 56)	Upfront surgery (n = 47)	P value
Age (year)			0.243
< 60	35 (62.5)	24 (51.1)
≥ 60	21 (37.5)	23 (48.9)
Sex
Male	47 (83.9)	41 (87.2)	0.636
Female	9 (16.1)	6 (12.8)
Hypertension			0.588
Absent	39 (69.6)	35 (74.5)
Present	17 (30.4)	12 (25.5)
Diabetes
Absent	50 (89.3)	44 (93.6)
Present	6 (10.7)	3 (6.4)
ASA			0.195
I	35 (62.5)	35 (75.5)
II	21 (37.5)	12 (25.5)
HBV			0.232
Absent	7 (12.5)	10 (21.3)
Present	49 (87.5)	37 (78.7)
HCV			0.238
Absent	52 (92.9)	46 (97.9)
Present	4 (7.1)	1 (2.1)
Hepatocirrhosis			0.662
Absent	10 (17.9)	10 (21.3)
Present	46 (82.1)	37 (78.7)
Tumor number			0.232
Multiple	11 (19.6)	14 (29.8)
Single	45 (80.4)	33 (70.2)
Vascular invasion			0.192
Absent	39 (69.6)	38 (80.9)
Present	17 (30.4)	9 (19.1)
PVTT			0.056
VP0	40 (71.4)	41 (87.1)
VP1	1 (1.8)	0 (0)
VP2	3 (5.4)	4 (8.5)
VP3	12 (21.4)	2 (4.3)
HVTT			0.823
Absent	48 (85.7)	41 (87.2)
Present	8 (14.3)	6 (12.8)
BCLC stage			0.232
A	31 (55.4)	28 (59.6)
B	7 (12.5)	10 (21.3)
C	18 (32.1)	9 (19.1)
HBeAg			0.703
Negative	48 (85.7)	39 (83)
Positive	8 (14.3)	8 (17)
AFP (ng/mL)			0.064
≤ 400	28 (50)	32 (68.1)
> 400	28 (50)	15 (31.9)
Anatomical resection			0.602
Absent	21 (37.5)	20 (42.6)
Present	35 (62.5)	27 (57.4)
Major liver resection			0.803
Absent	24 (42.9)	19 (40.4)
Present	32 (57.1)	28 (59.6)
Surgical method			0.736
Laparoscopy	15 (26.8)	14 (29.8)
Laparotomy	41 (73.2)	33 (70.2)
Adjuvant therapy			0.361
Absent	24 (42.9)	16 (34)
Present	32 (57.1)	31 (66)

ASA: American society of Aneshesiologists; HBV: Hepatitis B virus; HCV: Hepatitis C virus; PVTT: Portal vein tumor thrombosis; HVTT: Hepatic vein tumor thrombus; BCLC: Barcelona Clinic Liver Cancer; HBeAg: Hepatitis B e antigen; AFP: Alpha-fetoprotein.

Table 2 Intraoperative bleeding and postoperative hospital stay of patients, median (interquartile range)

Variable	Upfront surgery (n = 47)	Neoadjuvant therapy (n = 56)	P value
Blood loss (mL)	521.00 (200.00, 600.00)	421.00 (100.00, 600.00)	0.894
Operation time (minute)	258.00 (198.00, 311.00)	258.00 (191.50, 300.00)	0.625
Postoperative hospitalization time (day)	12.00 (7.00, 15.00)	9.00 (6.00, 11.00)	0.052
Intraoperative blood transfusion, n (%)	17 (36.2)	23 (41.1)	0.611

Table 3 Tumor response

mRECIST (n = 56)	n (%)
CR	7 (12.5)
PR	37 (66.1)
SD	11 (19.6)
PD	1 (1.8)
ORR	44 (78.6)
DCR	55 (98.2)

CR: Complete response; DCR: Disease control rate; ORR: Objective response rate; PD: Progressive disease; PR: Partial response; SD: Stable disease; mRECIST: Modified RECIST.

Table 4 Univariate and multivariate analyses of risk factors for recurrence-free survival

Variable	Univariate		Multivariate
	HR (95%CI)	P value	HR (95%CI)	P value
Treatment group (surgery vs NT)	1.577 (0.904-2.752)	0.109	2.167 (1.208-3.888)	0.010
Age (< 60 years vs ≥ 60 years)	1.072 (0.611-1.880)	0.808
Sex (male vs female)	1.335 (0.569-3.314)	0.506
Hypertension (absence vs presence)	2.248 (1.092-4.627)	0.028	2.163 (1.047-4.471)	0.037
Diabetes (absence vs presence)	1.007 (0.362-2.799)	0.989
ASA (I vs II)	1.720 (0.898-3.292)	0.102
Hepatitis B (absence vs presence)	0.558 (0.238-1.311)	0.181
Hepatitis C (absence vs presence)	3.289 (0.454-23.827)	0.239
Hepatocirrhosis (absence vs presence)	0.442 (0.188-1.039)	0.061
Tumor number (multiple vs single)	2.157 (1.205-3.860)	0.010	2.838 (1.549-5.200)	0.001
Vascular invasion (absence vs presence)	1.434 (0.717-2.867)	0.308
PVTT		0.114
0 vs 3	2.257 (0.810-6.289)
1 vs 3	11.709 (1.258-109.010)
2 vs 3	1.148 (0.210-6.269)
HVTT (absence vs presence)	1.152 (0.491-2.703)	0.746
BCLC stage		0.581
A vs C	1.228 (0.592-2.547)
B vs C	2.844 (1.256-6.439)
HBeAg (absence vs presence)	0.648 (0.324-1.298)	0.221
AFP group (< 400 ng/mL vs ≥ 400 ng/mL)	0.633 (0.381-1.156)	0.147
Anatomical resection (no vs yes)	0.791 (0.444-1.409)	0.426
Extensive liver resection (no vs yes)	0.600 (0.334-1.078)	0.088
Surgical method (scope vs octomy)	1.382 (0.760-2.512)	0.289
Adjuvant therapy (absence vs presence)	1.891(1.084-3.299)	0.025	2.540 (1.407-4.583)	0.002

NT: Neoadjuvant therapy; ASA: American society of Aneshesiologists; PVTT: Portal vein tumor thrombosis; HVTT: Hepatic vein tumor thrombus; BCLC: Barcelona Clinic Liver Cancer; HBeAg: Hepatitis B e antigen; AFP: Alpha-fetoprotein.

Table 5 Univariate and multivariate analyses of risk factors for overall survival

Variable	Univariate		Multivariate
	HR (95%CI)	P value	HR (95%CI)	P value
Treatment group (surgery vs NT)	2.334 (0.994-5.480)	0.052	2.860 (1.178-6.943)	0.020
Age (< 60 years vs ≥ 60 years)	0.794 (0.344-1.834)	0.589
Sex (male vs female)	0.946 (0.278-3.214)	0.929
Hypertension (absence vs presence)	1.334 (0.492-3.617)	0.571
Diabetes (absence vs presence)	2.466 (0.331-18.355)	0.378
ASA (I vs II)	1.002 (0.408-2.459)	0.997
Hepatitis B (absence vs presence)	0.258 (0.035-1.921)	0.186
Hepatitis C (absence vs presence)	21.789 (0.005-99916.054)	0.474
Hepatocirrhosis (absence vs presence)	0.392 (0.092-1.680)	0.207
Tumor number (multiple vs single)	1.823 (0.739-4.500)	0.193	1.866 (0.735-4.736)	0.190
Vascular invasion (absence vs presence)	0.910 (0.356-2.326)	0.843	0.828 (0.320-2.143)	0.697
PVTT		0.945
0 vs 3	1.002 (0.295-3.410)
1 vs 3	0.000 (0.000-)
2 vs 3	0.535 (0.055-5.159)
HVTT (absence vs presence)	0.713 (0.241-2.110)	0.541
BCLC stage		0.437
A vs C	0.836 (0.309-2.263)
B vs C	1.681 (0.509-5.558)
HBeAg (absence vs presence)	1.205 (0.356-4.074)	0.765
AFP group (< 400 ng/mL vs ≥ 400 ng/mL)	1.015 (0.434-2.376)	0.973
Anatomical resection (no vs yes)	0.991 (0.415-2.370)	0.984
Extensive liver resection (no vs yes)	0.600 (0.233-1.543)	0.289
Surgical method (scope vs octomy)	1.162 (0.451-2.992)	0.756
Adjuvant therapy (absence vs presence)	2.531 (1.081-5.926)	0.032	3.406 (1.400-8.284)	0.007

NT: Neoadjuvant therapy; ASA: American society of Aneshesiologists; PVTT: Portal vein tumor thrombosis; HVTT: Hepatic vein tumor thrombus; BCLC: Barcelona Clinic Liver Cancer; HBeAg: Hepatitis B e antigen; AFP: Alpha-fetoprotein.

Table 6 Postoperative morbidity and mortality after liver resection, n (%)

Variable	Neoadjuvant therapy (n = 56)	Upfront surgery (n = 47)	P value
Clavien-Dindo grade ≥ III	2 (3.6)	3 (6.4)	0.658
Post-hepatectomy liver failure	0 (0)	0 (0)	-1
Postoperative hemorrhage	5 (8.9)	6 (12.8)	0.543
Bile leakage	4 (7.1)	4 (8.5)	1.000
Fever	20 (35.7)	18 (38.3)	0.839
Pleural effusion	3 (5.4)	4 (8.5)	0.699
Ascites	8 (14.3)	6 (12.8)	1.000
Reoperation	0 (0)	0 (0)	-1
Hypoproteinemia	50 (89.3)	41 (87.2)	0.767
90-day mortality	0 (0)	2 (4.3)	0.206

¹Not calculated because no events occurred in either group.