Hepatocellular carcinoma (HCC) remains the most common primary liver tumor and the fourth most common cause of cancer-related death worldwide; with a 5-year survival rate of 18%, it remains the second most lethal cancer after pancreatic cancer.¹ Surgical resection, liver transplantation, and local ablative therapy are the curative treatments of choice to provide long-term survival, and these modalities are suitable for early, resectable HCC cases according to current practice guidelines.^2–5 Additionally, transarterial chemoembolization (TACE) is a technique that can promote tumor necrosis. TACE involves an intra-arterial infusion of chemotherapy such as doxorubicin, mitomycin C, or cisplatin, emulsified in the oily radio-opaque agent Lipiodol^® with arterial feeding embolization,^6–9 and it is reserved for the treatment of intermediate HCC (Barcelona Clinic Liver Cancer Staging [BCLC] stage B) and as bridging therapy for patients on the liver transplant waiting list.^5,10,11 Nevertheless, TACE can be utilized as a neoadjuvant treatment prior to surgical resection in resectable HCC cases (BCLC 0-A)² to reduce the tumor size; these procedures may increase resectability or even prevent cancer cell dissemination, thereby improving disease-free survival (DFS),^12–17 on the contrary, several studies have reported no benefits of preoperative TACE in improving survival rates and even an increase in perioperative morbidity, for which reason it has been argued that preoperative TACE should be avoided.^18–21 This study aimed to clarify the benefits of preoperative TACE in patients with resectable HCC. The primary outcomes were resectability rate and short-term adverse events (within 30 days postoperatively), and the secondary outcomes were DFS and overall survival (OS) rates.

Patient characteristics and study design

This study was approved by ethical review board of the Phramongkutklao Hospital (approval number: IRBRTA 180/66). The requirement for written informed consent from each patient was waived owing to the retrospective design of the study. All data were retrospectively collected from patient records, and a 1:1 propensity-matched case-control study was conducted using a logistic regression model that included the following covariates: sex, age, model for end-stage liver disease (MELD) score, and number and size of tumors. A total of 160 patients with resectable HCC who underwent treatment at our institution between January 2010 and December 2015 were included. The inclusion criteria were as follows: (1) patients diagnosed with HCC, with the diagnosis confirmed by a diagnostic radiologist (based on the classic dynamic radiological features of HCC are contrast uptake in the arterial phase and wash-out in the venous/late phase) or by a pathologist for patients who underwent liver biopsy; (2) patients exhibiting tumor resectability (ability to remove the tumor with a negative margin, a suitable future liver remnant volume, and patency of the portal and hepatic veins); and (3) patients with a single tumor (no upper limit on size) or tumor smaller than 3 cm with no more than three nodules (BCLC 0-A). The exclusion criteria were as follows: (1) patients with extrahepatic metastasis; (2) patients with portal hypertension; (3) patients willing to undergo liver transplantation; and (4) patients with vascular invasion. Candidates for TACE before surgery were determined based on the surgeon’s preference, which included (1) a large tumor (> 5 cm), (2) individuals in whom hepatectomy could not be performed within 1 month due to the operation schedule, and (3) patients with active medical problems that needed to be resolved prior to hepatectomy. Preoperative TACE patients were fully informed of the risks and benefits of the procedure before deciding whether to undergo it.

Definitions

The liver resection (LR) group included patients who underwent upfront LR, and the TACE-LR group included patients who underwent TACE prior to LR. Major hepatectomy was defined as resection of more than two liver segments.²² Morbidity was classified using the Clavien-Demartines-Dindo system;²³ postoperative liver failure,²⁴ post-hepatectomy hemorrhage,²⁵ and biliary leakage²⁶ were defined according to the International Study Group criteria, and perioperative mortality was defined as all-cause death within 30 days of surgery.

Surgical procedures

Surgical resection was performed under general anesthesia with low central venous pressure. A right subcostal incision with a midline extension or inverted-L incision was made, and anatomical hepatectomy was performed with a resection margin of at least 1 cm over the tumor. Intraoperative ultrasonography was routinely performed to estimate the number, size, location, and feeding vessels of tumors, and a marginal line was marked with an electronic scalpel on the liver surface under intraoperative ultrasonographic guidance. Complete anatomical resection could be performed according to the area of discoloration after ligation of the feeding vessels. The Cavitron ultrasonic aspiration (CUSA; Valleylab Inc.) or clamp-crushing techniques were used to dissect the liver parenchyma, and hemostasis was achieved with electric coagulation, argon units, titanium clips, and suturing. The Pringle maneuver was routinely performed, with clamping and unclamping times of 15 and 5 minutes, respectively. Patients stayed at the hospital until their liver function approached a healthy level and adverse reactions and complications had disappeared.

Transarterial chemoembolization

TACE was performed through a catheter inserted via the right common femoral artery with a 5 Fr sheath in a retrograde manner. Selective catheterization of the celiac artery and super-selective catheterization of the branch of the right or left hepatic artery were conducted, and an arteriogram was performed using a microcatheter. After the hypervascular tumor was identified by arteriography, chemoembolization was performed using a mixture of an average of 12 mg (range of 8–15 mg according to the patient’s body surface area) of mitomycin-C and 10 mL of Lipiodol^® (Guerbet LLC), and completed by embolization of the feeding artery by gel foam until a slow flow of contrast was observed. The endpoint of TACE was considered as no viable tumor (no arterial enhancement in the tumor with completed Lipiodol^® staining) at a 1-month follow-up on magnetic resonance imaging (MRI) and non-contrast multidetector computed tomography (MDCT). The mean duration between TACE and resection was 115.6 days. Of the 37 patients who received preoperative TACE, 19 had post-embolization syndrome, 10 (27%) had temporary fever, 4 (10.8%) had nonspecific right upper abdominal pain, and none had major morbidities or mortality.

Postoperative management and follow-up

Patients were required to return to our department for follow-up every 3–6 months after treatment, except for those who died or lost contact. The serum alpha-fetoprotein (AFP) level was measured, and ultrasonography and MDCT or MRI were performed at each visit. Chest computed tomography and bone scintigraphy were performed in cases of suspected extrahepatic recurrence. Once recurrence was confirmed, a second treatment approach was proposed through multidisciplinary team discussions, including surgeons, medical oncologists, pathologists, and radiologists; however, the patient's opinion was conclusive. The therapies included repeat LR, local ablative therapies (radiofrequency ablation or microwave ablation), percutaneous ethanol injection, transcatheter hepatic arterial chemoembolization, or targeted therapy. All examinations and treatments were performed at the authors’ hospital.

Statistical analyses

Continuous variables were compared using the Student t-test or the nonparametric Mann–Whitney test as appropriate, and are presented as mean ± standard deviation and median (interquartile range) for non-normally distributed data. Categorical variables were compared using the chi-square test or Fisher exact test, as appropriate, and are presented as number (percentage). OS was calculated from the date of surgery to the date of death, and DFS was calculated from the date of surgery to the date of the first recurrence at any site. Survival rates were calculated using the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals for risk factors associated with DFS and OS. Propensity scores were estimated using a logistic regression model that included the following covariates: sex, age, MELD score, and number and size of tumors. A ratio of 1:1 was used for propensity matching. All statistical analyses were performed using STATA/IC 14.0 (Stata Corp.). Statistical significance was set at P < 0.05. The data of patients who were lost to follow-up or who discontinued participation were treated as censored.

The patients’ demographic data and characteristics are presented in Table 1. Of 160 patients, 37 and 123 patients were included in the TACE-LR and LR groups, with a mean age of 56.3 and 60.3 years, respectively. After 1:1 propensity score matching in the LR-matching group (n = 37), no significant between-group differences were observed in baseline parameters (TACE-LR vs. LR-matching). Furthermore, the number of major hepatectomies was not significantly different between the two groups (TACE-LR vs. LR-matching, 16 vs. 12, P = 0.338).

Table 1 . Patient Demographics, Characteristics, and Perioperative Data.

Perioperative data	TACE-LR (n = 37)	LR (n = 123)	LR-matching (n = 37)	P-value
				TACE-LR vs. LR	TACE-LR vs. LR-matching
Age (yr)	56.27 ± 10.8	60.26 ± 11.15	51.59 ± 10.76	0.056	0.066†
Gender, man	32 (86.49)	101 (82.11)	33 (89.19)	0.534	1.000*
MELD score	8.11 ± 2.58	8.14 ± 3.07	8.16 ± 3.12	0.96	0.94
T staging (AJCC, 8th edition)				0.71	0.61
T1a	7	24	2
T1b	21	81	21
T2	8	15	11
T3	1	3	3
Location of the tumor				0.65	0.61
Right lobe	24	69	24
Left lobe	7	38	9
Bi lobe	6	16	4
Number of tumors	1.30 ± 0.57	1.16 ± 0.43	1.43 ± 0.65	0.11	0.34
Size of the tumor	5.10 ± 3.41	4.21 ± 3.2	6.18 ± 4.49	0.14	0.25
Major hepatectomy	16 (43.24)	21 (17.07)	12 (32.43)	0.001	0.338
Length of hospital stay (median, IQR)	8 (7–11)	7 (6–9)	7 (6–9)	0.005‡	0.017‡
Operative time (median, IQR)	300 (255–360)	285 (240–360)	290 (270–405)	0.176‡	0.824‡
Blood loss (median, IQR)	800 (500–1,200)	500 (200–1,000)	500 (300–1,000)	0.013‡	0.148‡
LPPRC transfusion	16 (43.24)	38 (30.89)	11 (29.73)	0.164	0.227
FFP transfusion	8 (21.62)	22 (17.89)	8 (21.62)	0.610	1.000
PLT transfusion	4 (10.81)	8 (6.50)	3 (8.11)	0.475*	1.000*
Complications	9 (24.32)	17 (13.82)	5 (13.51)	0.129	0.235
Major morbidity (CD grade III/IV)	4 (10.81)	4 (3.25)	2 (5.41)	0.084*	0.674*
Mortality	1 (2.70)	1 (0.81)	0 (0.00)	0.410*	1.000*
Positive R1 status	3 (8.11)	8 (6.50)	3 (8.11)	0.717*	1.000*

Short-term outcomes

No statistically significant differences were found in operative time (TACE-LR vs. LR-matching groups, 300 min vs. 290 min, P = 0.824), intraoperative blood loss (800 mL vs. 500 mL, P = 0.148), or the intraoperative requirement for blood components between the two groups. Similarly, no significant between-group differences were observed in overall morbidity (24.3% vs. 13.51%, P = 0.235), major morbidity (10.81 vs. 5.41, P = 0.674), and mortality. The morbidities in the entire series included bile leakage in 5 (3.1%) patients, pulmonary complications in 8 (5%), wound complications in 4 (2.5%), hemorrhage in 1 (0.6%), bowel complications in 3 (1.8%), fever in 3 (1.8%), and liver failure in 1 (0.6%). The frequency of a microscopic positive margin (R1) resection was also not significantly different between the two groups (Table 1). However, the length of hospital stay was significantly longer in the TACE-LR group than in the LR-matched group (8 vs. 7 days, P = 0.017).

Long-term outcomes

The median survival of the two groups (TACE-LR and LR-matching) was not reached; however, the median time to recurrence was 2.77 months in the TACE-LR group, which did not show a statistically significant difference from that in the LR-matching group (5.84 months; P = 0.08). There were no statistically significant differences in the 5-year DFS rate (38% in TACE-LR and 58% in LR-matching, P = 0.89) (Fig. 1) or 5-year OS rate (80.9% in TACE-LR and 80.8% in LR-matching, P = 0.72) (Fig. 2). Univariate and multivariate HR analyses of risk factors for DFS and OS are presented in Table 2. The presence of more than one tumor (HR = 1.67, P = 0.034), a serum AFP level > 200 ng/mL (HR = 1.69, P = 0.004), intraoperative blood loss > 500 mL (HR = 1.75, P = 0.047), and intraoperative fresh frozen plasma (FFP) transfusion (HR = 1.91, P = 0.039) were significant risk factors predicting adverse DFS, while the presence of more than one tumor (HR = 3.53, P = 0.002), intraoperative blood loss > 500 mL (HR = 4.87, P = 0.014), and intraoperative FFP transfusion (HR = 3.38, P = 0.012) were significant risk factors predicting adverse OS.

Table 2 . Cox Proportional-Hazard Analysis of the Risk Factors for Adverse Disease-Free Survival and Overall Survival Outcomes.

Factor	Disease-free survival						Overall survival
	Univariate			Multivariate			Univariate			Multivariate
	HR (95% CI)	P-value		Adjusted-HR (95% CI)	P-value		HR (95% CI)	P-value		Adjusted-HR (95% CI)	P-value
LR (vs. TACE-LR)	1.03 (0.60–1.79)	0.904		1.19 (0.66–2.12)	0.568		1.22 (0.45–3.33)	0.692		1.60 (0.56–4.54)	0.380
Number of tumors	1.55 (0.96–2.51)	0.074		1.67 (1.04–2.7)	0.034		2.42 (1.2–4.88)	0.013		3.53 (1.60–7.79)	0.002
Size of tumor	1.05 (0.98–1.13)	1.183					1.09 (1.00–1.20)	0.053
MELD score	1.03 (0.94–1.13)	0.553					0.92 (0.74–1.15)	0.489
AFP > 200 (vs. < 200)	1.86 (1.14–3.03)	0.012		1.69 (1.02–2.79)	0.04		2.23 (0.96–5.18)	0.062
Major hepatectomy (vs. minor)	0.84 (0.48–1.48)	0.549					2.08 (0.89–4.87)	0.093
Operative time ≥ 360 min (vs. < 360)	1.53 (0.92–0.56)	0.103					1.42 (0.55–3.63)	0.469
Blood loss ≥ 500 mL (vs. < 500)	1.83 (1.11–3.01)	0.018		1.75 (1.01–3.04)	0.047		4.74 (1.40–16.04)	0.012		4.87 (1.37–17.30)	0.014
LPPRC transfusion intraoperatively	2.05 (1.27–3.30)	0.003		1.78 (0.21–6.53)	0.844		1.21 (0.69–2.11)	0.512
FFP transfusion intraoperatively	2.46 (1.41–4.28)	0.001		1.91 (1.03–3.52)	0.039		3.35 (1.40–8.01)	0.007		3.38 (1.31–8.72)	0.012
Postoperative complications (vs. no complication)	1.2 (0.63–2.29)	0.575					2.44 (0.99–5.99)	0.052
Biliary leakage/fistula	2.22 (0.81–6.12)	0.122					2.67 (0.78–9.15)	0.119
Grade of differentiation; poorly differentiation (vs. well/moderate)	1.33 (0.78–2.27)	0.294					2.00 (0.83–4.83)	0.121
Lymphovascular invasion	1.02 (0.32–3.25)	0.978					0.89 (0.21–3.84)	0.881

Figure 1. The Kaplan-Meier survival curves of overall survival between TACE-LR and LR (A) TACE-LR and LR (matching) (B). TACE-LR, transarterial chemoembolization before liver resection; LR, liver resection.

Figure 2. The Kaplan-Meier survival curves of disease-free survival between TACE-LR and LR (A) TACE-LR and LR (matching) (B). TACE-LR, transarterial chemoembolization before liver resection; LR, liver resection.

Our study clearly indicates that TACE is not beneficial for patients with resectable HCC at presentation. Currently, TACE is recommended for the intermediate (B) stage according to the BCLC guidelines or in patients with multinodular HCC.^27–29 However, in general practice, TACE still plays a role in early-stage HCC, including as a treatment choice in patients whose tumors are not amenable to ablation/surgical resection or who are on the transplantation waiting list and require bridging therapy to maintain transplant candidacy.³⁰ Choi et al¹⁵ investigated the benefit of sequential TACE in patients with HCC requiring preoperative portal vein embolization (PVE) before surgery, and reported a significant survival benefit in patients receiving TACE-PVE compared to those receiving PVE alone when the tumor size was > 5 cm. Another benefit of TACE is that it can help induce a tumor necrosis rate of up to 80% in resected HCC specimens,^31,32 which is important because this can reduce the risk for intraoperative dissemination and facilitate the implantation of viable cells during surgical manipulation of the liver.³³ Kim et al³⁴ reported that a complete response after the initial TACE was the most robust predictor of long-term survival. Moreover, according to the results of a recent meta-analysis, TACE has been used as a neoadjuvant therapy for large HCC (≥ 5 cm) before hepatectomy³⁵ and can be combined with other modalities to improve the resectability rate for HCC.³⁶ Furthermore, the use of preoperative TACE followed by hepatectomy improves survival outcomes for patients with large HCC with portal vein invasion.³⁷

However, according to the results of this study, TACE does not help reduce immediate postoperative complications such as blood loss, intraoperative need for blood transfusion, operative time, or R1 resection. Furthermore, the long-term outcomes, including DFS and OS, were also not significantly different between patients who received preoperative TACE and those who underwent upfront surgery. Luo et al³⁸ reported that patients who received preoperative TACE showed more severe hepatic cirrhosis, longer operative times, and greater blood loss than those in the LR alone group. The authors concluded that preoperative TACE for resectable HCC increases surgical difficulty and risk, and should be carefully evaluated in individual patients. Sasaki et al²¹ reported that the 5-year OS rate after hepatectomy was significantly lower in patients who had received TACE before hepatectomy than in those who had undergone hepatectomy alone, suggesting that preoperative TACE should be avoided. Some limitations of TACE have been documented, particularly in well-differentiated tumors, cases of capsular and/or extracapsular tumor invasion, and microsatellite tumors, which usually have a dual blood supply and can survive embolization.^39,40 In addition, local tumor recurrence following TACE has been documented in cases of portal flow reversal through tumor drainage after blocking the hepatic arterial flow^40,41 and in cases of arterial collateral supply to tumors from collateral arteries.⁴² Moreover, the tumor-internal hypoxia caused by TACE promotes the production of vascular endothelial growth factor by surviving tumor cells, which can enhance tumor progression after TACE.^43,44 Surviving tumors can be supplied by the portal venous system if the arterial branches are significantly reduced by TACE.⁴⁵ These findings suggest that inadequate TACE can lead to uncontrolled tumor development.

The main limitation of this study was selection bias. Patients underwent preoperative TACE under less favorable conditions than those in the resection group—for instance, factors such as delayed surgery or a large tumor were more common in the TACE-LR group. Other limitations were its retrospective design and the fact that the study was performed at a single institution with a low volume of patients; the limited number of patients may have affected the multivariate analysis. Further well-designed, randomized studies are required.

In conclusion, short-term and long-term outcomes were not significantly different between preoperative TACE and upfront LR in patients with resectable HCC.

None.

The data are available from the corresponding author upon reasonable request.

No potential conflict of interest relevant to this article was reported.