Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, ranked as the sixth most common neoplasm and the third leading cause of cancer-related mortality worldwide (1). Advances in diagnostic imaging and widespread application of screening programs in high-risk populations have allowed detection of HCC at earlier stages, but some patients with HCC still continue to present in intermediate or even advanced stages. According to the Barcelona Clinic Liver Cancer (BCLC) algorithm for the treatment of HCC, intermediate-stage HCC (stage B) is defined as extensive multifocal disease without vascular invasion in patients with preserved liver function and the absence of cancer-related symptoms (2).

However, intermediate-stage HCC actually involves a heterogeneous group of patients, encompassing those with a wide range of tumor sizes (larger than 3 cm to over 10 cm) and numbers (2 to over 20), provided that patients have good liver function (Child-Pugh classes A or B) (3). Likewise, the prognosis of patients with intermediate-stage HCC varies (4). According to the BCLC algorithm, transarterial chemoembolization (TACE) is the recommended treatment for patients with intermediate-stage HCC (5). Whereas TACE has been reported to extend the survival of groups of patients with intermediate-stage HCC, the outcomes for individual patients treated with TACE for intermediate-stage HCC have remained mixed (6). At the present time, it remains controversial whether there is enough evidence supporting TACE, particularly relative to liver resection (LR), as the best treatment for patients with intermediate-stage HCC (7).

In fact, multiple recent reports have suggested that LR, when compared to TACE, might provide a survival benefit to patients with intermediate-stage HCC (8–10). Historically, LR has been reserved for the treatment of patients with early−stage HCC who have good liver function (11). Yet with improvements in surgical techniques and perioperative care, the surgical mortality rate for LR in patients with HCC has been reduced to less than 1% (12, 13). In addition, the complete surgical removal of the tumor may offer the best chance for long-term survival in patients with HCC. Nevertheless, patients who have LR for HCC larger than 5 cm often relapse after a short recurrence-free interval, especially those patients with huge (10 cm or larger) HCC (14, 15).

At the same time, TACE has been used successfully as a neoadjuvant therapy for large HCC prior to LR (16). A 2018 systematic review demonstrated that TACE can feasibly be combined with other modalities to improve the resectability rate for HCC (17). Along these lines, the use of preoperative TACE followed by LR has been shown to improve survival outcomes for some patients with large HCC (18).

Over the years, our Cancer Center has treated a relatively large population of patients with intermediate-stage HCC. Provided that liver function reserve was adequate and complete resection of the tumor appeared feasible, we offered LR to these patients. For some, we also recommended preoperative TACE, with the belief that this might potentially reduce postoperative recurrences and improve long-term survival. Our hypothesis has been that some patients with BCLC stage B may benefit from not only LR but also preoperative TACE. The aim of this retrospective study was to identify patients at our Cancer Center with intermediate-stage HCC who had LR and others who had TACE prior to LR, to compare the outcomes of each approach using survival rates, and to determine the prognostic factors for recurrence and death in these patients.

This study was conducted in accordance with the principles of the Declaration of Helsinki (19), and the study protocol was approved by the Ethics Committee of the Sun Yat-sen University Cancer Center.

Patients with intermediate-stage HCC have large and multifocal HCCs and do not have evidence of intrahepatic macrovascular invasion or extrahepatic metastases (25). Progression after treatment continues to be a substantial challenge in the clinical management of patients with large HCC and is associated with poor survival outcomes. Currently, the most common treatment for intermediate-stage HCC is TACE (26). TACE concludes with selective embolization of HCC tumors. However, before that, the procedure involves the intra-arterial infusion of a chemotherapy agent embedded in lipiodol, which tends to accumulate in the blood and lymph vessels of tumors, and serves as a vehicle for prolonging tumor exposure to the agent, yet does not adversely affect normal liver cells (8) (27).

Some researchers suggest that the evidence supporting TACE as first-line treatment for intermediate-stage HCC may not be strong enough, and they suggest that because LR may result in better outcomes than TACE, it should be considered first-line treatment for most patients with intermediate-stage disease (28). Others have echoed this, suggesting that treatments more aggressive than TACE, such as LR or energy ablation, should be considered first-line treatment for intermediate-stage HCC (29, 30). Some may argue that the high number and large size of tumors in some patients with intermediate-stage HCC make LR an inferior option. However, several large studies have demonstrated that the number and size of HCC tumors should not be used as a selection criterion for LR, provided that tumor location and liver function would otherwise allow resection (31–34). The results of these studies suggest that patients with multiple HCCs and Child-Pugh classes A or B should be considered for LR. Furthermore, recent advances in surgical technique, perioperative care, and accurate patient selection have gradually reduced the morbidity and mortality of LR, and encouraging postoperative results and oncological outcomes are being reported in patients with intermediate-stage HCC (10, 35, 36).

In this retrospective clinical study, we looked not only at 256 patients who had received LR for intermediate-stage HCC but also at 223 patients who underwent LR preceded by TACE, over a 9-year period, with a mean duration of follow-up of 40.2 months. When we compared the 2 groups in the study, we found them to be well-matched, with no significant differences in demographic or preoperative clinical characteristics (including tumor size or number, as well as baseline hepatitis, comorbidity, or AFP levels), or in type of hepatectomy performed, histopathological evidence of cirrhosis, or postoperative complications.

However, we did find that relative to the group that underwent LR alone, a significantly higher proportion of patients in the group that received TACE+LR had intraoperative findings of narrow resection margins, and a significantly lower proportion in that group had postoperative histopathological evidence of microvascular invasion. These observations suggest that by exposing the disease to cytotoxic agents and then blocking tumor vessels, TACE may have created a strong cytotoxic effect and caused substantial tumor necrosis prior to surgery, resulting in tumor contraction, narrower margins, and eradication of some of the microvascular invasion. These findings and potential mechanisms are consistent with those reported by others (24). They conflict with a 1995 study from Wu et al., which suggested that TACE should be avoided prior to LR because it did not provide complete necrosis in large tumors (though it did result in a mean 42.8% reduction in tumor volume) and it resulted in delayed surgery (37). However, their study differed from ours in that most of their patients in the TACE+LR group had multiple TACE treatments, administered every 4 to 6 weeks, and the overall survival for their patients who received TACE+LR was worse than for those who received only LR.

When we compared survival outcomes, patients having TACE+LR showed significantly longer OS and RFS than those having only LR. For example, the 5-year OS rate for the TACE+LR group was 52.9%, whereas that for the LR group was 33.8%. Likewise, the 3-year RFS rate for the TACE+LR group was 36.3%, whereas that for the LR group was 26.3%. Our OS and RFS results for patients having TACE+LR were markedly better than those reported by Zhao et al. for patients with intermediate-stage HCC having TACE alone. The 5-year OS rate was 12% and the 3-year RFS rate was 25% for the patients treated with only TACE, despite the vast majority of their patients having only a solitary tumor (8). Taken together, these observations and our results suggest that the combination of TACE and LR could offer more effective tumor eradication than either TACE or LR alone for patients with intermediate-stage HCC, particularly among those with multifocal HCC.

As noted above, some authors in the past have suggested that doing TACE before LR may increase the risk of perioperative morbidity. However, in our study there was no significant difference in the proportion of patients having postoperative complications, when comparing those having LR with those having TACE before LR. Similarly, Li et al. showed not only that the addition of preoperative TACE to LR for huge HCC (10 cm or larger) was associated with an improved OS and RFS, but also that this combination therapy did not increase perioperative morbidity or mortality (24).

Compared to the group of patients in our study who had LR alone, those who received TACE before LR exhibited higher numerical mean volumes of intraoperative blood loss (652 mL vs. 567 mL) and intraoperative blood transfusion (177 mL vs. 149 mL), but these differences were not statistically significant. Some have suggested that patients with hepatitis who undergo preoperative TACE before LR might suffer more intraoperative bleeding and present more operative challenges than those who do not have TACE before LR (38). In our study, the proportion of patients with hepatitis in each group was not significantly different. This, combined with a lack of significant differences in blood loss and transfusion, may provide additional evidence that cirrhosis should not be considered a contraindication to TACE before LR. Some authors have reported that TACE had little influence on subsequent surgery if the interval between the last TACE and LR was long enough (39). The patients in our study who received preoperative TACE had an interval between the last TACE and LR of at least 4 weeks; this suggests the possibility that waiting at least 4 weeks between TACE and LR may result in a risk for bleeding and a need for transfusion that is closer to the risks for LR alone. Finally, the results of our study may provide some support for the proposal that the amount of intraoperative blood loss and blood transfusion during LR may more likely be a function of tumor size (40). The TACE+LR group in our study, which had numerically higher volumes of blood loss and transfusion, also had a higher proportion of patients with huge (10 cm or greater) HCC when compared to the LR group (28.2% vs. 24.9%, respectively), though once again these differences were not statistically significant.

On multivariate analyses, confirming our results based on Kaplan-Meier estimates, we observed that LR alone was independently associated with HCC recurrence and death. Furthermore, we observed that more than 3 HCC tumors, non-anatomical hepatectomy, microscopic vascular invasion, cirrhosis, and intraoperative blood transfusion were all independent predictors of poor OS. Most of these results echo the findings from several other studies of patients who have had LR for intermediate-stage HCC (1, 25, 41). However, the influence of intraoperative blood transfusion on post-LR outcomes continues to be debated. Several studies have observed that intraoperative transfusion had no influence on the OS of patients with HCC after LR (1, 24, 41). In contrast, Mori et al. reported that perioperative blood transfusion was an independent risk factor for poor prognosis after curative surgery for primary HCC in a multi−center study (42). Similarly, Maehara et al. reported that the presence of intraoperative transfusion was an independent poor prognostic factor for OS in patients having LR for HCC of 5 cm or larger (16). Our findings are in line with the studies from Mori et al. and Maehara et al.

This study has several limitations. First, this was a retrospective, single-center study that lacked randomization. The fact that the choice of treatment was made at the discretion of the treating physician may have introduced selection bias. Second, this study does not address which patients might benefit most from the addition of TACE prior to LR. It would be worthwhile to conduct an additional study to develop clinical prediction models (including with the possible use of radiomics) to identify the population that would be best served by the addition of TACE to LR for intermediate-stage HCC.

In this large retrospective study of patients with intermediate-stage HCC, the addition of TACE 1 to 3 months prior to LR resulted in significantly longer OS and RFS compared to LR alone. These results and comparisons with findings from other studies suggest that preoperative TACE with LR may result in better oncological outcomes than either TACE or LR alone, without a substantial increase in morbidity, and that this approach could be considered an effective combination treatment for intermediate-stage HCC.

All datasets presented in this study are included in the article/supplementary material.

The studies involving human participants were reviewed and approved by Ethics Committee of the Sun Yat-sen University Cancer Center. The patients/participants provided their written informed consent to participate in this study.

Conceptualization: MC, JH. Data curation: QZ, JW, ZH, FT. Formal analysis: QZ, XW, RL. Data analysis: RL, QZ. Funding acquisition: JH, QZ. Investigation: QZ, JW, ZH. Methodology: QZ, XW, ZH. Project administration: QZ, XW, JH, MC. Resources: QZ, MC, JH. Original draft: QZ, XW. Writing—review and editing: QZ, MC, JH. All authors contributed to the article and approved the submitted version.

This research was funded by the Chinese Postdoctoral Science Foundation (No. 2019M653203); National Natural Science Foundation of China (No. 81771955).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.