Hepatocellular carcinoma (HCC) is among the most common cancers with a high mortality rate globally (1, 2). Although curative surgical tumor resection is associated with a good HCC patient prognosis, most patients are diagnosed when the disease is relatively advanced, when liver reserve capacity is limited, or when liver transplantation is unavailable; therefore, only < 30% of patients undergo surgical treatment (3–5). For patients who cannot undergo curative surgery, various locoregional or systemic treatment strategies are instead used to prolong survival and improve quality of life (1, 2, 6).

The locoregional or systemic treatment strategies are usually chosen by the Barcelona Clinic Liver Cancer (BCLC) stages (3, 5). For BCLC stage C HCC, systematic therapy is regarded as the initial course of treatment (1, 2). Recently, combined systemic treatment based on tyrosine kinase inhibitors plus immune checkpoint inhibitors has become the most commonly used systematic treatment for HCC (3).

Locoregional approaches to inoperable HCC management include transarterial chemoembolization (TACE), percutaneous ablation (PA), and the insertion of ¹²⁵I seeds under computed tomography (CT) guidance (5, 7), with TACE being the most commonly implemented strategy. Furthermore, TACE can be used as a standard therapeutic intervention in BCLC stage A or B HCC patients (8), and has also been employed as a baseline treatment for HCC patients undergoing additional PA and ¹²⁵I seed insertion procedures (5, 7).

Recently, the transarterial radioembolization (TARE) technique has emerged as an alternative to TACE and utilizes ⁹⁰Y integrated into resin or glass matrix microspheres. Relative to TACE, TARE has many benefits including better patient quality of life, longer time-to-progression, higher antitumor activity of portal vein invasion cases, and the potential for neoadjuvant application before tumor resection (6, 9). However, the efficacy of TARE in treating HCC patients remains elusive.

Therefore, this meta-analysis aimed to compare the efficacy and safety of TARE and TACE in the management of inoperable HCC.

This meta-analysis was designed to evaluate the safety and clinical efficacy of TARE and TACE as treatment strategies to manage inoperable HCC based on treatment responses, complications, and survival outcomes for affected patients.

Treatment response rates are a key determinant of HCC patient prognosis, serving as an important short-term outcome for evaluating a therapeutic strategy. Pooled CR rates in the present meta-analysis were similar in the TARE and TACE patient groups, although the total response and disease control rates in the TARE group were higher than those in the TACE group. This suggests that TARE procedures performed using ⁹⁰Y can more readily take advantage of the vascular nature of HCC tumors to induce necrotic cell death upon ablation (19). These benefits may be attributed to the high dose of absorbed radiation, the state of the liver, the goals of each therapeutic approach, and the target volume for treated patients. The delivery of high radiation doses to the tumor capillary bed can more significantly induce necrosis following TARE than after TACE treatment (20, 21).

Compared to external radiation therapy, brachytherapy has various advantages due to the direct contact between the radiation source and internal tumor regions, enabling the persistent delivery of radiotherapy while minimizing off-target damage (21). Here, CR, total response, and disease control rates indicated low heterogeneity (I² = 0%), suggesting the credibility of these findings. Furthermore, the 89.5% pooled disease control role for the TARE group was also similar to the 91.1% rate reported previously in a meta-analysis comparing TACE and CT-guided ¹²⁵I seed insertion in HCC patients (22). Although CT-guided ¹²⁵I seed insertion has been employed as a brachytherapy-based approach to HCC patient treatment (7, 22), this technique carries a risk of hematoma and pneumothorax (22). TARE, however, is performed within tumor-feeding arteries and thus avoids the potential for such complications (16). TARE procedures can be implemented more easily than TACE or CT-guided ¹²⁵I seed insertion.

The present analyses revealed that TARE treatment was associated with lower pooled rates of fever and abdominal pain than TACE. TARE entails the injection of radioactive particles into a target artery in the liver without occluding that artery (23). Furthermore, this approach does not induce VEGF or HIF-1a overexpression, which can cause fever and pain in patients (12). This study also observed no differences in nausea/vomiting or fatigue between these groups, suggesting that TARE cannot abrogate gastrointestinal or hepatic toxicity associated with this locoregional treatment.

There were substantial variations in outcomes comparing OS durations were observed among studies, however, the pooled data suggested that TARE is associated with the significant prolongation of OS relative to TACE. The 1-year survival rate in the TARE group was also superior to that in the TACE group, which might be associated with the higher treatment response rate in this group. Whereas no significant differences were observed in pooled 3-year (21.9% vs. 22.0%) or 5-year (6.8% vs. 9.4%) OS rates between these groups. The low 3 and 5-year OS rates in both groups highlight the limitations of TARE and TACE to control HCC over extended periods.

There are some limitations to the present study. For one, this meta-analysis did not include any RCTs and the results are subject to a high risk of bias. In the future, appropriately designed prospective RCTs should be performed to validate the present results. Moreover, these studies did not employ uniform TACE protocols for the medication types or dosages, potentially contributing to further bias. Third, the numbers of patients in the TARE and TACE groups were not balanced, and there were variations in the etiological basis for HCC across the included studies. All of these factors may have further contributed to bias with respect to these results.

In summary, this meta-analysis showed that relative to TACE, TARE performed using ⁹⁰Y can achieve better treatment response rates and OS benefits in inoperable HCC patients while causing fewer side effects. However, this meta-analysis was conducted mainly based on the retrospective study. Therefore, the treatment effectiveness (such as treatment response, survival function, and safety) of TARE for inoperable HCC should be corroborated by future randomized controlled trials.