Int J Gastrointest Interv 2023; 12(4): 169-175
Published online October 31, 2023 https://doi.org/10.18528/ijgii230025
Copyright © International Journal of Gastrointestinal Intervention.
Division of Hepato-Pancreato-Biliary Surgery, Department of Surgery, Phramongkutklao Hospital, Bangkok, Thailand
Correspondence to:*Division of Hepato-Pancreato-Biliary Surgery, Department of Surgery, Phramongkutklao Hospital, Thung Phaya Thai, Ratchathewi, Bangkok 10400, Thailand.
E-mail address: firstname.lastname@example.org (P. Burasakarn).
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background: Transarterial chemoembolization (TACE) is reserved for the treatment of intermediate hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer stage B); however, it can also be utilized as a neoadjuvant treatment prior to surgical resection in resectable HCC cases. This study aimed to clarify the benefits of TACE in patients with resectable HCC.
Methods: Data were retrospectively collected from patients with resectable HCC who had undergone hepatectomy between January 2010 and December 2015. 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 score, and the number and size of tumors.
Results: Of 160 patients, 37 and 123 were included in the TACE before liver resection (TACE-LR) and upfront LR groups, respectively. After 1:1 propensity score matching in the LR-matched group (n = 37), no significant differences in baseline parameters were found between the TACE-LR and LR-matched groups. Moreover, there were no significant differences in short-term outcomes, including intraoperative blood loss (800 mL vs. 500 mL, P = 0.148), operative time (300 min vs. 290 min, P = 0.824), and overall morbidity (24.3% vs. 13.51%, P = 0.235) between the TACE-LR and LR-matched groups. As long-term outcomes, no significant between-group differences were found in the 5-year disease-free survival rate (TACE-LR, 38%; LR, 58%; P = 0.89) or the 5-year overall survival rate (TACE-LR, 80.9%; LR, 80.8%; P = 0.72).
Conclusion: The short- and long-term outcomes were not significantly different between preoperative TACE and LR for resectable HCC.
Keywords: Carcinoma, hepatocellular, Chemoembolization, therapeutic, General surgery, Survival, Treatment outcome
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.
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.
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 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.
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.
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.
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
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 (
Table 1 . Patient Demographics, Characteristics, and Perioperative Data.
|Perioperative data||TACE-LR (||LR (||LR-matching (|
|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|
|Location of the tumor||0.65||0.61|
|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*|
No statistically significant differences were found in operative time (TACE-LR vs. LR-matching groups, 300 min vs. 290 min,
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;
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|
|HR (95% CI)||Adjusted-HR (95% CI)||HR (95% CI)||Adjusted-HR|
|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|
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 flow40,41 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.
The data are available from the corresponding author upon reasonable request.
No potential conflict of interest relevant to this article was reported.
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