Comparison of liver resection and radiofrequency ablation in long-term survival among patients with early-stage hepatocellular carcinoma: a meta-analysis of randomized trials and high-quality propensity score-matched studies

Owing to its noticeable incidence, hepatocellular carcinoma (HCC) has markedly attracted clinicians’ attention [1]. A remarkable number of early-stage HCC (ES-HCC) cases were detected because of the regular surveillance for HCC recommended by the guidelines in Western countries [2, 3]. At present, liver transplantation is an ideal treatment for ES-HCC, which could satisfy the Milan criteria with a high 5-year survival rate [4]. Nevertheless, the shortage of liver donation and the high cost of liver transplantation restrict its widespread utilization. Thus, liver resection is recommended by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases for ES-HCC [2, 3]. However, most patients who are eligible for resection are also candidates for thermal ablation. Radiofrequency ablation (RFA) is a less morbid procedure, and long-term outcomes may be similar to resection, particularly for tumors with a size of < 2 cm. Therefore, RFA has been particularly recommended to treat ES-HCC [5‐8].

Many retrospective studies demonstrated that RFA and LR had similar survival benefits for ES-HCC patients [9‐19]. However, this conclusion is controversial. A noticeable number of retrospective studies indicated that LR could prolong the overall survival (OS) and disease-free survival (DFS) for ES-HCC compared with RFA [20‐24]. The benefit of RFA over LR for treating potentially resectable HCC has been studied in several RCTs conducted in China, Japan, and Hong Kong [25‐30]. However, these studies had mixed results; some concluded that LR is superior, while others noted that both yielded similar outcomes. Besides, the criteria differentiating tumor characteristics were consistent among RCTs [31]. Hence, whether RFA can be the primary treatment for ES-HCC remains controversial.

Hence, we conducted the present meta-analysis of RCTs and high-quality propensity score-matched (PSM) studies to elucidate the comparative survival benefits and detrimental influences of LR versus RFA for ES-HCC.

In this meta-analysis, meta-analysis showed that ES-HCC patients undergoing LR had better OS and DFS than those undergoing RFA. However, ES-HCC is a complex conceptual set of HCC with different diameters (0–5 cm) and different numbers (1–3 tumors). Additionally, details related to hepatectomy (including anatomic hepatectomy, laparoscopic hepatectomy, tumor resection margin) and radiofrequency ablation (including radiofrequency ablation guidance, ablation margin, and ablation equipment) will affect the survival of patients with HCC. Subgroup analysis showed that RFA and LR can provide similar OS and RFS for very early stage HCC (single tumor and the diameter less or equal to 2 cm). Additionally, when the tumor was single and less or equal to 3 cm, or the ablation margin wa larger than 1 cm, the OS provided by RFA and LR was similar, although the RFS was still better in LR. The incidence of postoperative complications was significantly lower, and hospitalization was significantly shorter among ES-HCC patients undergoing RFA.

The primary advantage of RFA over LR is less invasiveness. RFA causes minor damage to the surrounding healthy liver parenchyma, thus maximally preserving the liver remnant [37]. As a result, the complication rates were much lower, and the length of hospital stay was much shorter.

The main reason for the inferiority of RFA to LR in long-term survival is the higher local recurrence rate related to incomplete ablation [38]. The efficacy of RFA could be affected by several factors, including tumor number, tumor size, tumor location, RFA mode, RFA method, the level of regional medical care, and the experience of doctors [6, 39‐42]. The insufficient ablation led to a high local recurrence rate [39]. On the other hand, LR could remove both the tumor and its micro neoplastic embolus by radically resecting primary cancer and adjacent liver parenchymal to guarantee a negative margin [43, 44]. In the subgroup analysis, we found that RFA can achieve similar OS to LR when the ablation margin was lager than 1 cm. Hence, the complete removal of the primary tumor and potential micrometastasis by LR might explain cothe superior long-term prognosis of early-stage HCC patients in the LR group.

Several meta-analyses have been available to compare the effects of RFA versus LR for HCC. Xu et al. performed a meta-analysis of five RCTs comparing survival outcomes of patients with small HCC who underwent LR or RFA [31]. RFA led to decreased overall survival compared with LR at 5 years, but the trial sequential analysis indicated that additional trials were necessary to confirm this conclusion. Additionally, time-to-event outcomes are most appropriately analyzed using HR [34]. Another recently published network meta-analysis by Zhang et al., which included RCTs and PSM studies, showed that LR is superior to RFA in OS and DFS [45]. The results are consistent with ours. However, their meta-analysis did not include one RCT and several PSM studies newly published in 2022. As far as we know, our meta-analysis is the most updated, with a maximum number of high-quality studies being included. More than 11,000 ES-HCC patients from 5 countries in the east and west were included to make the results more reliable and clinically meaningful. Moreover, sensitivity, subgroup, and meta-regression analyses provided ample evidence supporting our conclusion. The most important is that we focused on special subgroups which previous meta-analysis not did, including tumor number, tumor size, surgical margin, ablation margin, and even different guidance for RFA. Recently, a study based on Surveillance, Epidemiology, and End Results Program (SEER) database promped that RFA is an inferior option for solitary hepatocellular carcinoma ≤ 5 cm without cirrhosis [46]. This is an interesting and important finding because it lets us know that for HCC patients without cirrhosis, surgery is far a more suitable treatment than RFA. Because of insufficient data of liver cirrhosis in most of included studies and the proportion of liver cirrhosis of those studies reported, this data ranged from 2.2 to 94.1%, and we cannot confirm this view of the recent study. More well-designed studies are needed to verify this conclusion.

It should be noted that there are limitations for this study. First, we included both RCTs and PSM studies. Although the propensity score matching method could reduce baseline differences between groups, the deviations could not be eliminated compared with RCTs. Second, tumor heterogeneity could not be avoided. Although all the cases were ES-HCC, tumor number and size varied among patients in the included studies. Hence, we conducted a subgroup analysis; however, we found no significant difference between the two groups in OS among patients with a single tumor size of < 3 cm. However, extended subgroup analysis based on tumor number and tumor size is limited due to limited data. Third, the proportion of open LR or LH, anatomic or non-anatomic LR, are also inconsistent among included articles. Furthermore, with the development of RFA technology, various RFA techniques were used in different studies at different times. The influence of such heterogeneity has not been determined.

In conclusion, this meta-analysis showed that LR provided better OS and DFS for patients with early-stage HCC. However, RFA and LR probably had similar effects on OS in patients with solitary HCC less than 3 cm or when the ablation margin was larger than 1 cm which need more studies to confirm. The effects of different modalities of RFA on long-term survival are needed for further assessment.