Recurrence after resection is the main obstacle for hepatocellular carcinoma (HCC) patients and limits surgical efficacy (1, 2). Many adjunctive therapies have been used to reduce the risk of recurrence and metastasis after liver resection (3–5).

Transarterial chemoembolization (TACE) has been the most widely used treatment for intermediate-stage HCC and preoperative downstaging treatment (2, 6–8). Preventively, adjuvant TACE has been used to reduce the risk of recurrence and prolong survival for HCC patients after hepatectomy (9). And it is usually performed approximately 4 weeks after hepatectomy.

However, it remains controversial whether adjuvant TACE can benefit HCC patients after hepatectomy (10, 11). A growing amount of supporting evidence has confirmed that, for the high-risk recurrence population (tumor size > 5 cm, multiple nodules, circulating tumor cells, microvascular invasion (MVI) and macrovascular invasion), adjuvant TACE can significantly reduce the recurrence rate and prolong long-term survival (5, 12–18). The procedure might improve the prognosis by eliminating residual cancer cells. Interestingly, for HCC patients with a low risk of recurrence (tumor size ≤ 5 cm, single nodule, MVI-negative and no macrovascular invasions), it is unclear whether adjuvant TACE could provide benefits after hepatectomy.

Here, focusing on HCC patients with a low risk of recurrence, we reassessed whether adjuvant TACE could benefit prognosis in these patients after hepatectomy with a propensity score matching (PSM) analysis from two independent cancer centers.

Patients diagnosed with HCC who underwent hepatectomy between March 2015 and September 2019 at Shanghai Cancer Center (SHCC) in Shanghai, China, and patients diagnosed between December 2009 and June 2010 who underwent hepatectomy at the Eastern Hepatobiliary Surgery Hospital (EHBH) in Shanghai, China, were retrospectively reviewed.

The inclusion criteria were as follows: (1) HCC was diagnosed pathologically after hepatectomy; (2) single nodule; (3) diameter ≤ 5 cm; (4) Child–Pugh A or B liver function; and (5) adjuvant TACE adopted within 2 months after hepatectomy. The exclusion criteria were as follows: (1) recurrent HCC; (2) patients with microvascular or macrovascular invasions or satellites; (3) patients with extrahepatic metastasis; (4) a previous history of treatment of malignancy; (5) recurrence before or at adjuvant TACE; (6) perioperative mortality; and (6) incomplete data.

Data were extracted from medical records, cross-checked and statistically analyzed. The following clinicopathological parameters were extracted and analyzed statistically: sex, age, chronic hepatitis B/C virus (HBV/HCV) infection, transfusion, albumin (ALB), total bilirubin (TBIL), alanine transaminase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), alpha-fetoprotein (AFP), carbohydrate antigen 19-9 (CA19-9), prothrombin time (PT), platelet count, tumor size, differentiation of tumor cells and liver cirrhosis.

The chemotherapeutic regimens used in adjuvant TACE included hydroxycamptothecin, pirarubicin (THP) and floxuridine (FUDR) in the SHCC cohorts and doxorubicin hydrochloride, TPH and epirubicin in the EHBH cohorts. The dosages of these chemotherapeutic drugs and lipiodol were determined by body surface area and liver function.

This study was approved by the Clinical Research Ethics Committee of EHBH and the Institutional Review Board and the Ethics Committee of SHCC. Written informed consent was obtained from all subjects before the operation and (or) TACE. The consent was also obtained for participation in our study.

Postoperative recurrence is the main obstacle to improving surgical efficacy in HCC (23). Increasing supporting evidence has confirmed that adjuvant TACE can benefit the high-risk recurrence population (4, 5, 12–18). However, it remains unclear whether adjuvant TACE can benefit patients with a low risk of recurrence after hepatectomy. In our study, PSM analysis revealed that patients receiving adjuvant TACE had significantly shorter RFS than those who did not, and that adjuvant TACE could not prolong the OS for patients with a low risk of recurrence after hepatectomy.

As early as 2004, Ren reported that in HCC patients with risk factors (tumors with a size greater than 5 cm, multiple nodules, and vascular invasion) for residual tumors after hepatectomy, adjuvant TACE could prolong survival but not in patients without risk factors for residual tumors (9). Since then, clinical studies have begun to pay attention to the relationship between adjuvant TACE and postoperative recurrence risk (13, 24–28). They also reported that adjuvant TACE can significantly reduce recurrence risk and prolong RFS and OS in HBV-related HCC patients with intermediate (a single tumor > 5 cm without MVI) or high risk of recurrence (single tumor with MVI or 2 or 3 tumors). However, patients with a low recurrence risk (single tumor ≤ 5 cm without MVI) were not included (13).

In addition, numerous meta-analyses have performed independent analyses of the risk factors for residual tumors (14, 16, 29–36). Among them, 5 studies performed subgroup analysis on the low risk of recurrence population (30–32, 34, 35). In 2014, Cheng reported that in HCC patients with a tumor size ≤ 5 cm, adjuvant TACE did not benefit disease-free survival (DFS) (30). Qi also found that in patients with small HCC (size ≤ 5 cm) or without vascular invasion, no significant differences existed in DFS and OS between the adjuvant TACE and adjuvant TACE groups (31). However, another study indicated that adjuvant TACE could benefit OS but not RFS in HCC patients with a tumor size < 5 cm (32). In addition, Huo also found that adjuvant TACE can significantly improve 1-year DFS and 5-year OS in HCC patients with a tumor size ≤ 5 cm and prolong 5-year DFS in patients without MVI but with OS (34). In contrast, Chen reported that in HCC patients with a tumor size ≤ 5 cm, a single tumor or MVI negativity, adjuvant TACE could not improve outcomes and could potentially promote recurrence after resection (35). The latest retrospective study also showed that adjuvant TACE might promote postoperative recurrence, especially for HCC patients without MVI, tumor size ≤ 5 cm and preoperative AFP < 400 ng/ml (37).

In our study, patients with a high risk of recurrence, such as those with multiple nodules, macrovascular invasion, microvascular invasion, satellites and larger tumor size (>5 cm), were excluded, and a total of 489 HCC patients (201 from SHCC and 288 from EHBH) were included. All patients had early-stage HCC (BCLC Stage 0 or A, Chinese Stage Ia and TNM Stage TIa or TIb; Tables 1 , 2 ). Comparatively, these patients have a lower risk of recurrence and longer long-term survival after hepatectomy. In the SHCC cohorts, 40 HCC patients (19.9%, 40/201) who received adjuvant TACE after hepatectomy had significantly shorter RFS than patients who did not receive adjuvant TACE ( Figure 1A , P=0.022). However, no significant difference existed in OS ( Figure 1C , P=0.568). The Cox proportional hazards multivariate analysis indicated that serum ALP and adjuvant TACE were both independent prognostic factors for recurrence ( Table 3 ). After PSM analysis to balance the differences between the adjuvant TACE and non-adjuvant TACE groups, the Kaplan–Meier curves showed a significant difference in RFS, but not in OS, between adjuvant TACE and non-adjuvant TACE patients after hepatectomy ( Figure 1B , P=0.035; Figure 1D , P=0.638). Multivariate analysis revealed that adjuvant TACE was the only independent prognostic factor for recurrence ( Table 3 ). Similar results were also acquired in the EHBH cohorts ( Figure 2 ; Table 3 ). The study also revealed that patients receiving TACE after hepatectomy had significantly shorter RFS before or after PSM, and adjuvant TACE was an independent prognostic factor for recurrence by multivariate analysis. It seems that in the low risk of recurrence population, adjuvant TACE could promote postoperative recurrence after hepatectomy but had no significant effect on OS. This outcome might be caused by liver function injury and immunological function damage induced by TACE (10, 11, 38). Recently, some models for predicting adjuvant TACE benefit in HCC patients have been proposed (39–42). They might constitute effective ways to select the population who can benefit from it.

There are several limitations of our study. First, it was a retrospective study with the inherent defects associated with such studies even after PSM, and a prospective study is required to validate the conclusions. Second, adjuvant TACE after resection usually required a comprehensive decision from the surgeon according to intraoperative and postoperative examinations. Because of selection bias, the recurrence risk of patients receiving adjuvant TACE may be higher than that of patients not receiving adjuvant TACE. Even if they received adjuvant TACE after resection, their outcomes may not be better than the outcomes of those who did not. Third, the cohorts come from two different institutions but were treated during different time periods (SHCC cohorts from March 2015 through September 2019; EHBH cohorts from December 2009 through June 2010). Treatment advances might have affected the prognoses of HCC patients and incurred recurrence and survivorship bias. Fourth, the mechanism for adjuvant TACE promoting postoperative recurrence need exploring.

In summary, we focused on HCC patients with a low risk of recurrence reassessed whether adjuvant TACE could benefit prognosis in these populations and found that adjuvant TACE may not improve long-term survival and might promote postoperative recurrence in HCC patients with a low risk of recurrence after hepatectomy. More clinical trials with higher levels of evidence are needed and could help clinicians perform better interventions for these patients after curative resection.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Clinical Research Ethics Committee of Eastern Hepatobiliary Surgery Hospital and Institutional Review Board and the Ethics Committee of Shanghai Cancer Center. The patients/participants provided their written informed consent to participate in this study.

Study concept and design (L-HF, Y-YZ, J-MZ, W-MC, HD, and LW), acquisition of data (J-MZ, MW, W-QX, TZ, and A-RM), analysis and interpretation of data (L-HF, Y-YZ, J-MZ, W-MC, HD, and LW), drafting of the manuscript (L-HF, Y-YZ, and J-MZ), critical revision of the manuscript for important intellectual content (W-MC, HD, and LW), administrative, technical, or material support (MW, W-QX, TZ, and A-RM), and study supervision (W-MC, HD, and LW). All authors contributed to the article and approved the submitted version.