Abstract
Objective
Microvascular invasion (MVI) is a risk factor for disease recurrence and worse survival in hepatocellular carcinoma (HCC) patients after radical resection. This study aimed to investigate the efficacy of prophylactic transarterial chemoembolization (TACE) after R0 resection in HCC patients with MVI.
Methods
A total of 130 HCC patients with MVI who received R0 resection were retrospectively analyzed, and categorized into TACE (n = 73) and non-TACE (n = 57) groups according to whether prophylactic TACE after R0 resection was performed or not. Tumor recurrence, death, recurrence-free survival (RFS), and overall survival (OS) were evaluated.
Results
Tumor grading (P = 0.001), minor axis of tumor (P = 0.017), neutrophil (P = 0.029), and aspartate aminotransferase (P = 0.014) were higher in TACE group compared to non-TACE group at baseline, indicating a worse baseline disease condition in TACE group. During the follow up, tumor recurrence rate (56.2% versus 61.4%, P = 0.548), mortality rate (37.0% vs. 43.9%, P = 0.427), RFS (median: 44.0 versus 37.0 months, P = 0.325), and OS (median not reached in both groups, P = 0.355) were not different between TACE and non-TACE groups. Considering the worse baseline disease condition in TACE group versus non-TACE group as confounding factor, that affects the evaluation of efficacy; the multivariable Cox regression analyses were performed for adjustment, which revealed that group (TACE versus non-TACE) was independently correlated with prolonged RFS (P = 0.007, HR = 0.447, 95% CI: 0.248–0.804) and OS (P = 0.001, HR = 0.260, 95% CI: 0.116–0.583).
Conclusion
Prophylactic TACE after R0 resection is beneficial to improve the prognosis in HCC patients with MVI. However, further large-scale, randomized, controlled studies are needed for verification.
Keywords: Hepatocellular carcinoma, Microvascular invasion, Prophylactic transarterial chemoembolization, Recurrence-free survival, Overall survival
Introduction
Liver cancer ranks as the sixth of new cancer cases and third of cancer-caused deaths globally, which affects approximately 865 thousand new cases and causes 757 thousand deaths per years [1]. Especially in China, liver cancer ranks as the fourth of new cancer cases and second of cancer-caused deaths, which accounts for approximately 368 thousand new cases and 317 thousand deaths annually [2]. Hepatocellular carcinoma (HCC) is the major type of liver cancer, with an unsatisfied prognosis generally [3–5]. The radical resection remains the priority and the cornerstone for HCC treatment [6]; however, post-operative patients are still facing high risk of disease recurrence [7, 8], particularly in those patients with high recurrent risk such as patients with microvascular invasion (MVI) [9–11]. Therefore, adjuvant therapies are recommended to reduce the recurrent risk and improve the prognosis in these patients [12].
Transarterial chemoembolization (TACE), injecting a mixture of chemotherapeutic drugs and embolization agents to the target tumor-feeding artery to realize its anti-tumor effect, has been recommended and widely applied to treat the intermediate-to-advanced stage HCC patients [13–15]. Benefiting from the superior anti-tumor efficacy and acceptable tolerance, prophylactic TACE after tumor resection is recently proposed to be applied in HCC patients, intending to decrease the risk of recurrence and increase the overall survival (OS); however, the findings are not consistent [16, 17]. For instance, a previous study revealed that prophylactic TACE after tumor resection decreased 1-year, 2-year, and 3-year recurrent rate and increased 1-year, 2-year, and 3-year survival rate in HCC patients; but the median OS was not improved statistically [16]. Another study reported that prophylactic TACE after tumor resection did not statistically improve the recurrence-free survival (RFS) and OS in HCC patients; while after adjustment, prophylactic TACE independently related to prolonged RFS and OS [17]. The inconsistence of the benefits about prophylactic TACE after tumor resection may result from the patients’ features and heterogeneity; afterwards, a few recent studies divided HCC patients into different risk stratifications based on key prognostic factors such as MVI, neutrophil to lymphocyte ratio, and tumor size, and discovered that prophylactic TACE after tumor resection improved RFS and OS in HCC patients with high-risk stratification, but had a weaker effect in HCC patients with low or intermediate risk stratification (not statistically) [18, 19].
Based on the above information, this study hypothesized that prophylactic TACE after tumor resection was beneficial for HCC with MVI. Therefore, this study aimed to compare the efficacy of prophylactic TACE compared to no prophylactic TACE after R0 resection in HCC patients with MVI.
Materials and methods
Patients
The clinical data of 130 HCC patients with MVI who received R0 resections from January 2017 to January 2020 were retrospectively analyzed. The inclusion criteria contained: (a) pathologically diagnosed with HCC with MVI; (b) received R0 resections; (c) aged over 18 years old; (d) Barcelona Clinic Liver Cancer (BCLC) stage of 0-A; (e) had complete clinical data for study use. The exclusion criteria contained: (a) had severe coronary heart diseases or malignancies; (b) had documented liver abscess, intra-abdominal infection, biliary fistula, or intra-abdominal bleeding; (c) were pregnant or during lactation. The study had the approval of the Ethics Committee of Baoji Central Hospital with the approval number of BZYL2024-25. Each patient or the family member offered informed consent. This study was performed in the accordance with the Declaration of Helsinki.
Data collection and groupings
The study collected clinical characteristics of patients. In brief, age, sex, Child-Pugh score, tumor location, hepatitis B surface antigen (HbsAg), liver cirrhosis, ascites were recorded pro-surgery; tumor grading and diameter were recorder during or post-surgery; laboratory indexes were recorded pro-TACE; moreover, recurrence and survival information were also recorded during follow ups. The cohort was divided into 2 groups based on whether the patients received prophylactic TACE after surgery: non-TACE group (N = 57) and TACE group (N = 73).
TACE procedures
Prophylactic TACE was performed at two weeks to one month after resection. Briefly, TACE was performed through the femoral artery using the Seldinger technique. A 5-F catheter or microcatheter was selectively inserted into the appropriate hepatic artery under digital subtraction angiography (DSA) guidance. A suspension of iodized oil with epirubicin (20 mg) was slowly injected in a 3–5 mL dosage until the blood flow in the tumor-supplying artery slowed down. The amount of iodine oil used depended on the size and number of tumors and the abundance of arterial blood supply and was usually not more than 20 mL in a single dose. Subsequently, chemotherapeutic agents were infused using 200 mg of oxaliplatin.
Statistics
Clinical characteristics and laboratory indexes were compared between the non-TACE and TACE groups using Student's t-test, Chi-square test, Fisher's exact test, or Wilcoxon rank sum test, as appropriate. Recurrence rate and death rate were compared using the Chi-square test. RFS and OS were compared using a log-rank test and shown using Kaplan-Meier curves. The RFS was defined as the time from surgery to recurrence, death, or the last follow-up. The OS was defined as the time from surgery to death or the last follow-up. The correlation of factors including treatment groups, clinical characteristics, and laboratory indexes with RFS and OS were firstly analyzed by univariate Cox regression analysis. Then, the independent association of treatment groups with RFS and OS were identified using multivariable Cox regression analysis with enter mode for the adjustment of clinical characteristics and laboratory indexes. P < 0.05 was considered significant.
Results
Baseline characteristics
A total of 73 patients with age at 55.5 ± 10.3 years, consisting of 72.6% males, were analyzed in the TACE group; while a total of 57 patients with age at 56.1 ± 10.4 years, consisting of 82.5% males, were analyzed in the non-TACE group. By comparison, tumor grading was worse (P = 0.001), minor axis of tumor was larger (P = 0.017), but liver cirrhosis rate was lower (P = 0.049), in the TACE group compared with non-TACE group. In addition, other clinical characteristics were not different between the TACE group and non-TACE group (Table 1).
Table 1.
Clinical characteristics
| Items | Non-TACE (N = 57) | TACE (N = 73) | P value |
|---|---|---|---|
| Age (yeas), mean±SD | 56.1 ± 10.4 | 55.5 ± 10.3 | 0.770 |
| Male, n (%) | 47 (82.5) | 53 (72.6) | 0.186 |
| Child-Pugh stage, n (%) | 1.000 | ||
| A | 52 (91.2) | 67 (91.8) | |
| B | 5 (8.8) | 6 (8.2) | |
| Location, n (%) | 0.388 | ||
| Left lobe of liver | 21 (36.8) | 20 (27.4) | |
| Right lobe of liver | 36 (63.2) | 52 (71.2) | |
| Caudate lobe of liver | 0 (0.0) | 1 (1.4) | |
| Tumor grading*, n (%) | 0.001 | ||
| Poor differentiation | 6 (10.5) | 15 (20.8) | |
| Poor-moderate differentiation | 7 (12.3) | 27 (37.5) | |
| Moderate differentiation | 27 (47.4) | 22 (30.6) | |
| Moderate-high differentiation | 7 (12.3) | 2 (2.8) | |
| High differentiation | 10 (17.5) | 6 (8.3) | |
| Maximum diameter of tumor (cm), mean±SD | 6.3 ± 2.5 | 7.2 ± 2.8 | 0.073 |
| Minor axis of tumor (cm), mean±SD | 4.8 ± 1.8 | 5.7 ± 2.1 | 0.017 |
| HbsAg, n (%) | 52 (91.2) | 60 (82.2) | 0.139 |
| Liver cirrhosis, n (%) | 45 (78.9) | 46 (63.0) | 0.049 |
| Ascites, n (%) | 3 (5.3) | 7 (9.6) | 0.512 |
*a patient in with TACE group was not evaluated for tumor grading, and was diagnosed as a specific subtype of clear cell hepatocellular carcinoma.
TACE transcatheter arterial chemoembolization, SD standard deviation, HbsAg hepatitis B surface antigen
Regarding laboratory characteristics, the levels of neutrophil (P = 0.029) and AST (P = 0.014) were higher in the TACE group compared with non-TACE group. However, no difference was observed in other laboratory test indexes between the TACE group and non-TACE group (Table 2).
Table 2.
Laboratory characteristics
| Items | Non-TACE (N = 57) | TACE (N = 73) | P value |
|---|---|---|---|
| HBV-DNA (IU/mL), median (IQR) | 100.0 (100.0–32275.0) | 100.0 (100.0–12625.0) | 0.395 |
| Neutrophil (10^9/L), median (IQR) | 2.4 (1.9–3.2) | 3.0 (2.2–4.0) | 0.029 |
| Lymphocyte (10^9/L), median (IQR) | 1.7 (1.2–2.1) | 1.5 (1.2–2.1) | 0.168 |
| Platelet (10^9/L), median (IQR) | 132.0 (99.5–183.5) | 149.0 (119.0–195.5) | 0.128 |
| Albumin (g/L), median (IQR) | 38.6 (35.0–40.8) | 39.4 (35.8–41.5) | 0.360 |
| AST (U/L), median (IQR) | 27.3 (21.3–39.9) | 35.4 (26.6–47.4) | 0.014 |
| ALT (U/L), median (IQR) | 33.8 (21.6–52.4) | 37.0 (24.5–51.9) | 0.593 |
| Creatinine (μmol/L), median (IQR) | 65.1 (57.8–75.8) | 65.1 (56.5–71.0) | 0.446 |
| Total bilirubin (μmol/L), median (IQR) | 16.7 (12.2–23.0) | 16.5 (13.0–20.7) | 0.970 |
| AFP (ng/mL), median (IQR) | 96.3 (5.7–874.0) | 68.5 (6.3–1210.0) | 0.505 |
| Prothrombin time (s), median (IQR) | 12.4 (11.9–13.8) | 12.3 (11.5–13.2) | 0.496 |
| International normalized ratio, median (IQR) | 1.1 (1.0–1.1) | 1.1 (1.0–1.1) | 0.356 |
TACE transcatheter arterial chemoembolization, HBV-DNA hepatitis B virus deoxyribonucleic acid, IQR interquartile range, AFP alpha fetoprotein, AST aspartate aminotransferase, ALT alanine aminotransferase
Efficacy assessment
Tumor recurrence rate was not different between the TACE group and non-TACE group (56.2% vs. 61.4%, P = 0.548) (Fig. 1A). The mortality was not different between the TACE group and non-TACE group (37.0% vs. 43.9%, P = 0.427), either (Fig. 1B).
Fig. 1.
Recurrence and mortality rate. Comparison of recurrence rate (A) and mortality rate (B) between the TACE group and non-TACE group
Via Kaplan-Meier curves, the median (95% CI) of RFS was 44.0 (29.8–58.2) months in the TACE group, and was 37.0 (28.0–46.0) months in the non-TACE group. Even though a numerically longer RFS was reported in the TACE group, no statistical difference in RFS was observed between the TACE group and non-TACE group (P = 0.325) (Fig. 2A). Regarding OS information, the median OS was not reached in both groups. By comparison, no difference in OS was discovered between the TACE group and non-TACE group, either (P = 0.355) (Fig. 2B).
Fig. 2.
RFS and OS. Comparison of RFS (A) and OS (B) between the TACE group and non-TACE group
Adjustment by multivariable analyses
Considering the difference of baseline characteristics between the TACE group and non-TACE group that may greatly affect the evaluation of efficacy as confounding factors, univariate and multivariable Cox regressions were performed to evaluate the RFS and OS.
Univariate Cox regression analysis revealed that Group (TACE vs. non-TACE) was not correlated with RFS (P = 0.332, HR = 0.802, 95% CI: 0.514–1.252). Importantly, after adjustment by multivariable Cox regression analysis, Group (TACE vs. non-TACE) was independently correlated with prolonged RFS (P = 0.007, HR = 0.447, 95% CI: 0.248–0.804) (Table 3); moreover, platelet level was also independently associated with better RFS (P = 0.022, HR = 0.993, 95% CI: 0.987–0.999), but maximum diameter of tumor was independently associated with worse RFS (P < 0.001, HR = 1.814, 95% CI: 1.430–2.300).
Table 3.
Univariate and multivariate Cox regression analyses for RFS
| Items | Univariate Cox regression | Multivariate Cox regression | ||||
|---|---|---|---|---|---|---|
| P value | HR | 95% CI of HR | P value | HR | 95% CI of HR | |
| Group (TACE vs. non-TACE) | 0.332 | 0.802 | 0.514–1.252 | 0.007 | 0.447 | 0.248–0.804 |
| Age (per year) | 0.729 | 0.996 | 0.976–1.017 | 0.534 | 1.009 | 0.981–1.038 |
| Sex (male vs. female) | 0.280 | 1.364 | 0.776–2.398 | 0.638 | 1.237 | 0.510–3.000 |
| Tumor grading (per grade) | 0.219 | 0.892 | 0.743–1.070 | 0.082 | 0.789 | 0.603–1.031 |
| Child-Pugh stage (B vs. A) | 0.022 | 2.177 | 1.120–4.235 | 0.101 | 2.786 | 0.819–9.482 |
| Location (right or caudate lobe vs. left lobe) | 0.902 | 1.031 | 0.637–1.667 | 0.534 | 1.216 | 0.656–2.253 |
| Maximum diameter of tumor (per cm) | < 0.001 | 1.479 | 1.353–1.617 | < 0.001 | 1.814 | 1.430–2.300 |
| minor axis of tumor (per cm) | < 0.001 | 1.488 | 1.332–1.662 | 0.909 | 1.017 | 0.762–1.357 |
| HbsAg (yes vs. no) | 0.931 | 1.030 | 0.530–2.001 | 0.842 | 1.090 | 0.467–2.543 |
| Liver cirrhosis (yes vs. no) | 0.898 | 0.969 | 0.595–1.576 | 0.367 | 0.713 | 0.342–1.486 |
| Ascites (yes vs. no) | 0.885 | 0.940 | 0.409–2.163 | 0.196 | 0.439 | 0.126–1.528 |
| Neutrophil (per 10^9/L) | 0.142 | 1.130 | 0.960–1.330 | 0.434 | 0.897 | 0.683–1.178 |
| Lymphocyte (per 10^9/L) | 0.911 | 0.980 | 0.686–1.400 | 0.150 | 1.458 | 0.872–2.439 |
| Platelet (per 10^9/L) | 0.574 | 1.001 | 0.998–1.004 | 0.022 | 0.993 | 0.987–0.999 |
| Albumin (per g/L) | 0.076 | 0.954 | 0.906–1.005 | 0.705 | 0.984 | 0.905–1.070 |
| AST (per U/L) | 0.002 | 1.010 | 1.004–1.017 | 0.541 | 0.994 | 0.977–1.012 |
| ALT (per U/L) | 0.162 | 1.003 | 0.999–1.007 | 0.262 | 1.007 | 0.995–1.020 |
| Creatinine (per μmol/L) | 0.728 | 1.003 | 0.985–1.021 | 0.764 | 1.004 | 0.980–1.028 |
| Total bilirubin (per μmol/L) | 0.604 | 1.003 | 0.993–1.013 | 0.305 | 0.989 | 0.969–1.010 |
| AFP (per ng/mL) | 0.087 | 1.000 | 1.000–1.001 | 0.229 | 1.000 | 1.000–1.001 |
| Prothrombin time (per s) | 0.689 | 1.027 | 0.901–1.170 | 0.278 | 1.128 | 0.908–1.401 |
| International normalized ratio (per ratio) | 0.881 | 1.191 | 0.122–11.638 | 0.476 | 0.218 | 0.003–14.332 |
HBV-DNA was not included in this analysis due to multicollinearity.
RFS recurrence-free survival, HR hazard ratio, CI confidence interval, TACE transcatheter arterial chemoembolization, HbsAg hepatitis B surface antigen, HBV-DNA hepatitis B virus deoxyribonucleic acid, AFP alpha fetoprotein, AST aspartate aminotransferase, ALT alanine aminotransferase
Univariate Cox regression analysis disclosed that Group (TACE vs. non-TACE) was not related to OS (P = 0.359, HR = 0.775, 95% CI: 0.450–1.336). Notably, after adjustment by multivariable Cox regression analysis, Group (TACE vs. non-TACE) was independently correlated with longer OS (P = 0.001, HR = 0.260, 95% CI: 0.116–0.583) (Table 4); however, Child-Pugh stage (P = 0.030, HR = 5.105, 95% CI: 1.175–22.174) and maximum diameter of tumor (P < 0.001, HR = 1.766, 95% CI: 1.370–2.278) were independently associated with shorter OS.
Table 4.
Univariate and multivariate Cox regression analyses for OS
| Items | Univariate Cox regression | Multivariate Cox regression | ||||
|---|---|---|---|---|---|---|
| P value | HR | 95% CI of HR | P value | HR | 95% CI of HR | |
| Group (TACE vs. non-TACE) | 0.359 | 0.775 | 0.450–1.336 | 0.001 | 0.260 | 0.116–0.583 |
| Age (per year) | 0.953 | 0.999 | 0.974–1.025 | 0.987 | 1.000 | 0.965–1.037 |
| Sex (male vs. female) | 0.960 | 0.984 | 0.516–1.876 | 0.332 | 0.631 | 0.249–1.599 |
| Tumor grading (per grade) | 0.593 | 0.941 | 0.752–1.176 | 0.089 | 0.742 | 0.527–1.046 |
| Child-Pugh stage (B vs. A) | 0.002 | 3.039 | 1.479–6.245 | 0.030 | 5.105 | 1.175–22.174 |
| Location (right or caudate lobe vs. left lobe) | 0.973 | 1.010 | 0.560–1.820 | 0.952 | 1.024 | 0.478–2.194 |
| Maximum diameter of tumor (per cm) | < 0.001 | 1.546 | 1.392–1.718 | < 0.001 | 1.766 | 1.370–2.278 |
| minor axis of tumor (per cm) | < 0.001 | 1.559 | 1.364–1.784 | 0.507 | 1.117 | 0.806–1.547 |
| HbsAg (yes vs. no) | 0.277 | 1.490 | 0.726–3.058 | 0.361 | 0.656 | 0.266–1.621 |
| Liver cirrhosis (yes vs. no) | 0.470 | 0.808 | 0.452–1.442 | 0.164 | 0.523 | 0.210–1.303 |
| Ascites (yes vs. no) | 0.182 | 0.560 | 0.239–1.311 | 0.313 | 0.463 | 0.104–2.064 |
| Neutrophil (per 10^9/L) | 0.113 | 1.172 | 0.963–1.428 | 0.282 | 0.836 | 0.603–1.159 |
| Lymphocyte (per 10^9/L) | 0.193 | 0.734 | 0.461–1.169 | 0.979 | 0.991 | 0.508–1.935 |
| Platelet (per 10^9/L) | 0.177 | 1.002 | 0.999–1.006 | 0.055 | 0.994 | 0.987–1.000 |
| Albumin (per g/L) | 0.073 | 0.945 | 0.889–1.005 | 0.533 | 0.967 | 0.869–1.075 |
| AST (per U/L) | 0.006 | 1.011 | 1.003–1.018 | 0.976 | 1.000 | 0.979–1.020 |
| ALT (per U/L) | 0.399 | 1.002 | 0.997–1.008 | 0.537 | 1.005 | 0.990–1.020 |
| Creatinine (per μmol/L) | 0.944 | 1.001 | 0.979–1.023 | 0.480 | 1.010 | 0.983–1.038 |
| Total bilirubin (per μmol/L) | 0.621 | 1.003 | 0.991–1.016 | 0.422 | 0.989 | 0.963–1.016 |
| AFP (per ng/mL) | 0.656 | 1.000 | 0.999–1.000 | 0.210 | 1.000 | 0.999–1.000 |
| Prothrombin time (per s) | 0.603 | 0.953 | 0.796–1.142 | 0.794 | 0.944 | 0.614–1.452 |
| International normalized ratio (per ratio) | 0.943 | 0.904 | 0.057–14.304 | 0.966 | 0.870 | 0.001–508.533 |
HBV-DNA was not included in this analysis due to multicollinearity.
OS overall survival, HR hazard ratio, CI confidence interval, TACE transcatheter arterial chemoembolization, HbsAg hepatitis B surface antigen, HBV-DNA hepatitis B virus deoxyribonucleic acid, AFP alpha fetoprotein, AST aspartate aminotransferase, ALT alanine aminotransferase
Discussion
TACE is the basis of treatment for HCC with intermediate or advanced stage [13]. A previous meta-analysis summarized 11 studies and approximately 13 thousand cases, and reported that TACE reduced mortality risk while elevated objective response rate (ORR) compared to transcatheter arterial chemotherapy infusion (another basis of treatment for HCC) in patients with intermediate or advanced HCC [20]. Moreover, based on the TACE treatment, the addition of targeted therapy can further improve the prognosis of HCC patients [21–23]. For instance, a meta-analysis pooled 23 studies with about 3.1 thousand cases, which reported that TACE combined with sorafenib promoted ORR, disease control rate (DCR), and time of disease progression (TTP) compared with TACE alone in patients with various-stage HCC [21]. Another meta-analysis collectively analyzed 17 studies engaging approximately 1.4 thousand cases, and revealed that TACE combined with camrelizumab improved complete response (CR), ORR, DCR, progression-free survival (PFS) and OS compared to other treatment regimens apart from TACE or camrelizumab in patients with unresectable or advanced HCC [22]. In addition, a recent review summarized 13 studies comprising about 1.3 thousand cases, and disclosed that TACE combined with lenvatinib plus PD-1 inhibitor increased ORR and DCR, as well as prolonged PFS and OS in patients with advanced HCC [23]. These evidences highlight the role of TACE as a cornerstone for intermediate or advanced staged HCC treatment.
TACE has also been used for prophylactic purpose after tumor resection in early-stage or resectable HCC patients, which intends to reduce post-operative recurrent risk and improve the prognosis [16–19, 24, 25]; however, the results are not consistent among studies. A previous study reported that 1-year, 2-year, and 3-year recurrent rate was reduced, 1-year, 2-year, and 3-year survival rate was elevated, but OS was not different by prophylactic TACE compared to non-TACE after tumor resection in HCC patients [16]. Another study disclosed that RFS and OS were not improved by prophylactic TACE compared to non-TACE after tumor resection in HCC patients, but the improvement was identified after propensity scoring match [17]. This inspires us the patients’ features may be different between prophylactic TACE and non-TACE treated patients, which serve as confounding factors for efficacy assessment. In this present study, the baseline characteristics were also different between the TACE and non-TACE groups, which disclosed that tumor grading, minor axis of tumor and AST were higher in the TACE group compared to the non-TACE group, indicating patients with more severe disease condition received prophylactic TACE after R0 resection in HCC patients, which were in line with previous studies [16, 17].
Interestingly, investigations are also carried out to identify specific types of HCC patients who can benefit more from prophylactic TACE after tumor resection [18, 19, 25]. A previous study stratified HCC patients into low-risk, intermediate-risk, and high-risk subgroups based on alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), tumor diameter, and MVI, and observed that prophylactic TACE after tumor resection promoted OS in the high-risk subgroup, but not in the low-risk or intermediate-risk subgroups [18]. Another study stratified HCC patients into low-risk and high-risk subgroups based on NLR, tumor amount, tumor maximum size, histological grade, positive resection margin, MVI, and antivirus therapy, which reported that prophylactic TACE after tumor resection extended the OS in the high-risk subgroup but not in the low-risk subgroup [19]. In addition, a study stratified HCC patients as presenting MVI subgroup and non-MVI subgroup, then revealed that prophylactic TACE after tumor resection decreased 1-year, 2-year, and 3-year recurrent rates and mortality rates in subgroup presenting MVI but not in non-MVI subgroup [25].
These previous studies all implied MVI presentation as a sign for prophylactic TACE after tumor resection in HCC patients [18, 19, 25]. Therefore, this present study intended to investigate this topic, and found that the tumor recurrence rate, mortality rate, RFS, and OS were all not different between the TACE group and non-TACE group by direct comparison, suggesting prophylactic TACE after R0 resection may not be beneficial in HCC patients with MVI. However, considering the difference of baseline characteristics between the TACE group and non-TACE group that may greatly affect the evaluation of efficacy as confounding factors, multivariable Cox regressions were performed. Subsequently, this study observed that prophylactic TACE after R0 resection was independently correlated with long RFS and OS after adjustment by multivariable regression in HCC patients with MVI, which fitted our hypothesis. The possible explanations for this may be as follows: (1) More severe disease condition was found in TACE group compared to non-TACE group, limiting the difference of prognosis in these two groups; then after adjustment by the baseline characteristics, the superiority of prophylactic TACE after R0 resection was identified in the HCC patients with MVI. (2) prophylactic TACE could reduce the proliferating, resident or difficult-to-find tumor cells via its direct embolism and targeted chemotherapy, to attenuate the risk of recurrence and prolong the survival [26, 27].
Apart from the interesting findings of this study, some limitations should be proposed as well. Firstly, the retrospective nature of this study restricted the generalizability of the findings. Secondly, the baseline characteristics were not comparable between the TACE and non-TACE group that might affect the findings; therefore, multivariate analyses were applied in this study for adjustment to compare the main outcomes (RFS and OS). Thirdly, the follow-up duration was not long enough, which could be lengthened to further evaluate the efficacy of prophylactic TACE. Fourthly, this study finding was restricted to the resectable patients at early stage who were analyzed in this study, while for other resectable or potentially resectable patients at intermediate stage, the feasibility of the finding needed further validation.
Conclusion
In conclusion, prophylactic TACE after R0 resection improves RFS and OS in HCC patients with MVI, implying its benefits for prognosis. However, further large-scale, randomized, controlled studies are needed for verification.
Acknowledgements
Not applicable.
Author contributions
Wenjie Sun and Jinbao Li contributed to the study conception and design. Material preparation and data collection were performed by Haozhe Fu and Jiangze Li. Data analysis was performed by Wenjie Sun, Yafang Li and Jinbao Li. All authors contributed the manuscript written and revision. All authors read and approved the final manuscript.
Funding
This study was supported by the 2024 Annual Research Project Approval Plan of the Baoji Municipal Health Commission (2024-027).
Data availability
The data used to support the findings of this study are available on request from the corresponding author.
Declarations
Ethics approval and consent to participate
The study had the approval of the Ethics Committee with the approval number of BZYL2024-25. Each patient or the family member offered informed consent.
Consent for publication
Not applicable.
Conflict of interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–63. [DOI] [PubMed] [Google Scholar]
- 2.Han B, Zheng R, Zeng H, et al. Cancer incidence and mortality in China, 2022. J Natl Cancer Cent. 2024;4(1):47–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Vogel A, Meyer T, Sapisochin G, et al. Hepatocellular carcinoma. Lancet. 2022;400(10360):1345–62. [DOI] [PubMed] [Google Scholar]
- 4.Wang QB, Li J, Zhang ZJ, et al. The effectiveness and safety of therapies for hepatocellular carcinoma with tumor thrombus in the hepatic vein, inferior vena cave and/or right atrium: a systematic review and single-arm meta-analysis. Expert Rev Anticancer Ther. 2025;25(5):561–70. [DOI] [PubMed] [Google Scholar]
- 5.Li YK, Wu S, Wu YS, et al. Portal venous and hepatic arterial coefficients predict post-hepatectomy overall and recurrence-free survival in patients with hepatocellular carcinoma: a retrospective study. J Hepatocell Carcinoma. 2024;11:1389–402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Xie DY, Zhu K, Ren ZG, et al. A review of 2022 Chinese clinical guidelines on the management of hepatocellular carcinoma: updates and insights. Hepatob Surg Nutr. 2023;12(2):216–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Li J, Liang YB, Wang QB, et al. Tumor-associated lymphatic vessel density is a postoperative prognostic biomarker of hepatobiliary cancers: a systematic review and meta-analysis. Front Immunol. 2024;15:1519999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Li J, Wang QB, Liang YB, et al. Tumor-associated lymphatic vessel density is a reliable biomarker for prognosis of esophageal cancer after radical resection: a systemic review and meta-analysis. Front Immunol. 2024;15:1453482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Tabrizian P, Jibara G, Shrager B, et al. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg. 2015;261(5):947–55. [DOI] [PubMed] [Google Scholar]
- 10.Nevola R, Ruocco R, Criscuolo L, et al. Predictors of early and late hepatocellular carcinoma recurrence. W J Gastroenterol. 2023;29(8):1243–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Li J, Su X, Xu X, et al. Preoperative prediction and risk assessment of microvascular invasion in hepatocellular carcinoma. Crit Rev Oncol Hematol. 2023;190:104107. [DOI] [PubMed] [Google Scholar]
- 12.Crook CJ, Li D. Adjuvant and neoadjuvant treatments for resectable hepatocellular carcinoma. Curr Oncol Rep. 2023;25(10):1191–201. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Chang Y, Jeong SW, Young Jang J, et al. Recent updates of transarterial chemoembolilzation in hepatocellular carcinoma. Int J Mol Sci. 2020;21(21): [DOI] [PMC free article] [PubMed]
- 14.Chen LT, Martinelli E, Cheng AL, et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with intermediate and advanced/relapsed hepatocellular carcinoma: a TOS-ESMO initiative endorsed by CSCO, ISMPO, JSMO, KSMO MOS and SSO. Ann Oncol. 2020;31(3):334–51. [DOI] [PubMed] [Google Scholar]
- 15.Department of Medical Administration NHCotPsRoC. Clinical practice guideline for primary liver cancer (2024 Edition). Med J Pek Union Med Coll Hosp. 2014;15(3):532–58.
- 16.Li H, Liu Z, Han C. Clinical value of prophylactic transcatheter arterial chemoembolization treatment in patients with hepatocellular carcinoma. Am J Transl Res. 2022;14(5):3225–32. [PMC free article] [PubMed] [Google Scholar]
- 17.Wang L, Ke Q, Lin K, et al. Not all hepatocellular carcinoma patients with microvascular invasion after R0 resection could be benefited from prophylactic transarterial chemoembolization: a propensity score matching study. Cancer Manag Res. 2020;12:3815–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lin N, Wang L, Huang Q, et al. A simplified model for prophylactic transarterial chemoembolization after resection for patients with hepatocellular carcinoma. PLoS One. 2022;17(10): e0276627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.He S, Fan X, Ma H, et al. Effect of prophylactic TACE on 5-year survival of patients with hepatocellular carcinoma after hepatectomy. Oncol Lett. 2019;18(2):1824–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Liu X, Wang Z, Chen Z, et al. Efficacy and safety of transcatheter arterial chemoembolization and transcatheter arterial chemotherapy infusion in hepatocellular carcinoma: a systematic review and meta-analysis. Oncol Res. 2018;26(2):231–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Li D, Pang Y, Xu L, et al. Efficacy and safety of sorafenib combined with TACE in the treatment of advanced hepatocellular carcinoma: a meta-analysis. J Balkan Union Oncol. 2021;26(4):1355–64. [PubMed] [Google Scholar]
- 22.Xian F, Song XW, Bie J, et al. Efficacy and safety of camrelizumab combined with TACE for hepatocellular carcinoma: a systematic review and meta-analysis. Eur Rev Med Pharmacol Sci. 2024;28(2):687–701. [DOI] [PubMed] [Google Scholar]
- 23.Wang L, Lin L, Zhou W. Efficacy and safety of transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor in the treatment of advanced hepatocellular carcinoma: a meta-analysis. Pharmacol Therapeut. 2024;257:108634. [DOI] [PubMed] [Google Scholar]
- 24.Chen J, Zhang Y, Cai H, et al. Comparison of the effects of postoperative prophylactic transcatheter arterial chemoembolization (TACE) and transhepatic arterial infusion (TAI) after hepatectomy for primary liver cancer. J Balkan Union Oncol. 2018;23(3):629–34. [PubMed] [Google Scholar]
- 25.Li KY, Zhang SM, Shi CX, et al. Effect of prophylactic transcatheter arterial chemoembolization on hepatocellular carcinoma with microvascular invasion after R0 resection. A case-control study. Sao Paulo Med J. 2020;138(1):60–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Yan Q, Ni J, Zhang GL, et al. Efficacy of postoperative antiviral combined transcatheter arterial chemoembolization therapy in prevention of hepatitis B-related hepatocellular carcinoma recurrence. Chin Med J (Engl). 2013;126(5):855–9. [PubMed] [Google Scholar]
- 27.Cheng HY, Wang X, Chen D, et al. The value and limitation of transcatheter arterial chemoembolization in preventing recurrence of resected hepatocellular carcinoma. W J Gastroenterol. 2005;11(23):3644–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used to support the findings of this study are available on request from the corresponding author.