Preoperative transcatheter arterial chemoembolization and prognosis of patients with solitary large hepatocellular carcinomas (≥5 cm): Multicenter retrospective study

Abstract Objectives Large hepatocellular carcinoma (LHCC) is prone to short‐term recurrence and poor long‐term survival after hepatectomy, and there is still a lack of effective neoadjuvant treatments to improve recurrence‐free survival (RFS) and overall survival (OS). We retrospectively analyzed the efficacy of preoperative transcatheter arterial chemoembolization (TACE) in solitary LHCC (≥5 cm). Materials and Methods A multicenter medical database was used to analyze preoperative TACE's effects on RFS, OS, and perioperative complications in patients with solitary LHCC who received surgical treatment from January 2005 to December 2015. The patients were divided into Group A (5.0–9.9 cm) and Group B (≥10 cm), with 10 cm as the critical value, and the effect of preoperative TACE on RFS, OS and perioperative complications was assessed in each subgroup. Results In the overall population, patients with preoperative TACE had better RFS and OS than those without preoperative TACE. However, after stratifying the patients into the two HCC groups, preoperative TACE only improved the survival outcomes of patients with Group B (≥10 cm). Multivariate Cox‐regression analysis showed that lack of preoperative TACE was an independent risk factor for RFS and OS in the overall population and in Group B but not in Group A. Conclusions Preoperative TACE is beneficial for patients with solitary HCC (≥10 cm).


| INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and the third leading cause of cancer-related death. 1 For HCC with a relatively early stage of disease, hepatectomy has been considered a radical treatment that can achieve a good survival prognosis. [2][3][4] However, the tumor is highly prone to recurrence after hepatectomy, resulting in the patient's death, particularly in HCC patients with larger tumor diameters and microvascular invasion (MVI). [5][6][7] Therefore, we should take appropriate measures to reduce recurrence and improve the overall survival (OS) of patients. 8 Transcatheter arterial chemoembolization (TACE), as an effective local treatment, can improve the OS of patients with unresectable HCC, and thus is often used for the treatment of advanced HCC. [9][10][11][12][13] A large number of studies in the past have confirmed that postoperative TACE can reduce recurrence and prolong OS of patients, [14][15][16][17] and can TACE also be used as a neoadjuvant treatment for HCC? There is still controversy on the benefits of using TACE as a neoadjuvant therapy.  Some scholars have proposed that preoperative TACE is not beneficial for all of patients with HCC, and whether it can improve the long-term survival mainly depends on the diameter of the tumor. 17,18,20,25,27 To explore whether the efficacy of preoperative TACE depends on the tumor diameter, we used a multicenter database to stratify patients according to tumor diameter and, for the first time, explored the efficacy of preoperative TACE in patients with large hepatocellular carcinoma (LHCC) in different tumor diameter groups.  (4) no radiologic evidence of invasion into the major portal/hepatic vein branches; (5) radical resection of HCC (R0), that is, no residual tumor tissue under direct observation or microscopy; (6) no previous treatment of HCC. Exclusion criteria: (1) younger than 18 years old; (2) poor liver function with Pugh-Child Class C; (3) missing prognosis and follow-up information. The ethics committees of the six medical centers approved the study, and the study complied with the Helsinki Declaration and local laws.

| Data collection
All patients underwent contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), or chest X-ray scanning upon admission to the hospital. Preoperative Information on baseline patient characteristics includes age, sex, diabetes mellitus, etiology of liver diseases, cirrhosis, Child-Pugh grade, platelets count, international normalized ratio (INR), alpha-fetoprotein (AFP) level, the presence or absence of postoperative adjuvant TACE, maximum tumor size, MVI, satellite nodules, tumor differentiation, and tumor capsule. Continuous variables, such as age, are transformed into binary variables according to recognized cut-off values or upper and lower lines of normal values. 8,18,42 Anatomic resection refers to the resection of one or more adjacent hepatic sections along the hepatic vasculature and includes segmentectomy, subsegmentectomy, sectionctomy, and hemihepatectomy. Non-anatomic resection is defined as local resection or enucleation regardless of the anatomical segment or section of the lobar anatomy. 43,44

| Preoperative TACE
Considering that this was a retrospective study, the decision to use TACE prior to surgery was left to the analysis showed that lack of preoperative TACE was an independent risk factor for RFS and OS in the overall population and in Group B but not in Group A. Preoperative TACE is beneficial for patients with solitary HCC   (≥10 cm).

K E Y W O R D S
hepatectomy, hepatocellular carcinoma, recurrence survival, transcatheter arterial chemoembolization discretion of the treating surgeon and the patient at that time. The patient was placed supine, locally disinfected, draped, and given local anesthetized. The puncture site was chosen to be 2 cm below the inguinal ligament, and the catheter sheath was placed into the femoral artery using the Seldinger technique. First, the DSA technique helps with abdominal trunk and standard hepatic artery angiography to determine the tumor's location, size, and condition of the tumor. Once the tumor is understood, the catheter sheath is advanced deeper into the left or right hepatic artery or the vessel that feeds the tumor, 5-fluorouracil (500 mg/m 2 ) or oxaliplatin (100 mg/m 2 ) was injected into the proper hepatic artery, and embolization was performed using different embolization materials. The embolization materials used were iodized oil and gelatin sponge cubes, or iodized oil only, which was entirely mixed with these chemotherapeutic drugs as an emulsion and injected. Because TACE was performed at different hospitals, embolization materials varied.
Patients were asked to return to the hospital 4-8 weeks after embolization for follow-up investigations, including routine blood tests, liver, and kidney function, coagulation function, AFP, and imaging. Imaging included abdominal enhanced CT, MRI, or chest X-ray scans. The above procedures were performed by highly qualified attending physicians who received relevant interventional medicine training.

| Stratification according to the initial maximum diameter of the tumor
The maximum tumor diameters were measured by enhanced CT or MRI before surgical resection or preoperative TACE in all patients. According to the maximum tumor diameter, all HCC patients were divided into the 5-9.9 cm group and the ≥10 cm group, which were then defined as Group A and Group B, respectively. 18

| Postoperative follow-up and study endpoints
The reexamination frequency of all patients after the operation was once every 2-3 months in the first 6 months, once every 3-6 months in the following 18 months, and then once every 6-9 months if there was no recurrence. The postoperative follow-up included liver biochemistry, routine blood tests, coagulation function, AFP, chest X-ray or chest CT scans, abdominal B ultrasound, abdominal enhanced CT or MRI. Radiofrequency ablation, TACE, chemotherapy, molecular targeted therapy, surgical re-resection, or liver transplantation were performed according to the recurrence and the patient's wishes when the patient was diagnosed with recurrence. Life-supporting treatment was given to the end-stage patient.
Study endpoints included complications within 30 days, recurrence-free survival (RFS), and OS. Postoperative liver failure (PLF) was defined as serum TBIL >50 μoml/L and prothrombin activity (PTA) <50% on day 5 after hepatectomy, 45 postoperative bile leakage was defined as ≥3 days after surgery with a bilirubin concentration in the drain exceeding three times the normal bilirubin concentration in plasma. 46 OS was defined as the time from the date of surgery to the date of patient death or last follow-up, and RFS was defined as the time from the date of surgery to the date of first postoperative tumor recurrence or last follow-up. The cut-off last date was July 1, 2021.

| Statistical analysis
Continuous variables were expressed as median (range) or mean ± standard deviation (SD), categorical variables were reported as number (n) or percentages of patients (%). Continuous variables were compared by the Student's t-test or Mann-Whitney U-test. Categorical variables were compared by the χ 2 test or Fisher's exact test. The survival curves of RFS and OS of patients who received or did not receive TACE before surgery were generated by the Kaplan-Meier method, and the log-rank test was used to compare the differences. The Cox proportional hazard regression analyses were used to adjust for other prognostic factors associated with RFS and OS. All statistical analyses and visualizations of this study were obtained by R version 3.6.1 with the SVA. A p value <0.05 was considered statistically significant.

| Baseline clinicopathological and postoperative complications
During the study period, 2560 HCC patients underwent radical HCC resection, of which 556 solitary HCC patients with diameter ≥5 cm were included in the study cohort. The baseline characteristics, clinicopathological features, and postoperative complications of the entire population are presented in Table 1 surgery was 5 weeks (range 4-8), and for patients who had multiple preoperative TACE sessions, the median interval between the last TACE and surgery was 4 weeks (range 3-6). There were no significant differences in age, sex, cirrhosis, tumor diameter, Child-Pugh classification, MVI, pathological grade, postoperative complications, and other variables between the two groups (p > 0.05). The baseline characteristics, clinicopathological features, and postoperative complications of each subgroup are listed in Table 2.

| The effects of preoperative TACE on the prognosis of HCC in two groups
The median follow-up time of the overall HCC population was 41 months. The mortality (25.3% vs. 39.4%, p < 0.05) and recurrence (38.0% vs. 58.4%, p < 0.05) rates of patients undergoing surgical resection with TACE were lower than those without TACE, showing statistical differences. The median OS and RFS of patients with TACE before surgery were 76 months and 37 months, respectively, longer than those without TACE (73 months and 32 months, respectively, p = 0.044 and 0.025) ( Figure 1A,B). Then, we stratified according to the tumor diameter and found that there was no significant difference in OS and RFS between patients with TACE and those without TACE in Group A (p = 0.88 and p = 0.81, respectively) (Figure 2A,B). However, at Group B, the OS and RFS of patients with preoperative TACE were significantly better than those without preoperative TACE (p < 0.05 and p < 0.05, respectively) ( Figure 3A,B).

| Univariable and multivariable analyses of OS and RFS
Results of univariate and multivariate analyses for the entire study cohort's overall and recurrence-free survivals are presented in Tables 3 and 4

| Comparison of the clinicopathological features between Group A and Group B
The comparison of clinicopathological features between Group A and Group B is shown in Table S4.

| DISCUSSION
Transcatheter arterial chemoembolization is one of the most widely used non-surgical therapeutic modalities for HCC. It mainly causes ischemic necrosis of the tumor by blocking the blood vessels feeding tumor, and at the same time delivers chemotherapy drugs through the artery to the target region to further promote tumor necrosis and tumor shrinkage. Recently, some researchers will consider it as a means of neoadjuvant therapy, the aim of which is *Those variables found significant at p < 0.05 in univariable analyses were entered into multivariable Cox-regression analyses.
Some reports suggest that preoperative TACE may only be significant in patients with an excessively large tumor diameter, [17][18][19][20][21]25,26 especially for patients with tumor diameter ≥10 cm. 18 We then divided the population into Groups A (5-9.9 cm) and B (≥10 cm) and explored the efficacy of preoperative TACE in each subgroup of the HCC population separately.
The results of this study showed that preoperative TACE benefited HCC patients and improved their RFS and OS in the overall population. However, after stratification, it was clear that the benefit was only significant for patients with tumor diameters ≥10 cm. In recent years, two studies on preoperative TACE from the same medical center, they just will be different in the setting of the inclusion criteria, and then the conclusion is different, and Zhou et al. included the inclusion criterion of tumor diameter ≥5 cm, which concluded that preoperative TACE had no effect on RFS and OS of patient. 39 Whereas, Li et al. set the cut-off value of tumor diameter at 10 cm, their conclusion was quite different. 18 This latter study illustrated that the benefit population of preoperative TACE might be patients with huge HCC (≥10 cm), which is consistent with our current results. We speculate that the possible reason for this stratification effect is that the corresponding tumor vascularization of Group B is more severe. Since the degree of tumor vascularization is positively correlated with the effectiveness of TACE, preoperative TACE could play a more critical role in Group B and ultimately benefit the survival of patients. 19,51,52 Second, as far as the tumor's biological characteristics are concerned, AFP level, MVI, and satellite nodules were higher in the Group B than in the Group A (p < 0.05), reflecting that the tumor biological characteristics of Group B were more aggressive. In other words, preoperative TACE could effectively inhibit the growth and proliferation of highly invasive HCC. Toshiya et al. suggested that preoperative TACE may be more suitable for more aggressive tumor populations. 22 In terms of perioperative complications and 30-day mortality, previous studies have shown that preoperative TACE could increase the intraoperative difficulty and perioperative complications. 26,36,38 In our study, this view is not tenable, which is consistent with the result of Li et al. 18,54 The surgical procedure does have a small portion of patients with necrosis tumors adherent to the surrounding tissues. But our chief surgeons are experienced and can completely overcome the adhesions caused by TACE. Again, it has been reported that as long as the interval between preoperative TACE and the operation is long enough, the negative impact of preoperative TACE on operation can be controllable. 18,54 In our study, the interval is at least 4 weeks. Therefore, as long as the patients are appropriately managed during perioperative period, the obstruction of TACE to surgery can be eliminated.
The results of this study revealed that tumor diameter ≥10 cm, AFP ≥ 400 μg/L, MVI, Edmondson grade, PLT level, and satellite nodules were independent risk factors for postoperative OS and RFS, which were also confirmed by previous studies. 18,[55][56][57][58][59][60][61][62] Our research has limitations. First, our study was a multicenter retrospective study that did not have a uniform standard for preoperative TACE. Second, considering that this study is a multi-center study, the embolic materials and chemotherapeutic drugs used in each center are different. Third, most of the people we include are infected with HBV, while the majority of HCC patients in western countries are caused by factors such as HCV or alcohol. This study may not be suitable for western populations.
In conclusion, our study demonstrated that preoperative TACE is a safe neoadjuvant that does not increase perioperative complications and mortality. There was a stratification effect on the efficacy of preoperative TACE, and the beneficiary population is HCC patients with tumor diameter ≥10 cm. This study provides further guidance for the treatment of patients with large and huge solitary HCC to avoid unnecessary preoperative TACE.

DATA AVAILABILITY STATEMENT
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

ETHICS STATEMENT
The ethics committees of the six medical centers approved the study, and the study complied with the Helsinki Declaration and local laws.