Primary hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system. According to the latest statistical data, liver cancer ranks sixth in the incidence of malignant tumors and third in mortality [1]. East Asia and Africa have the highest incidence and mortality, while parts of Europe and the USA have an increasingly higher incidence [2,3]. As for larger HCC, liver resection is the preferred treatment according to the previous guideline [4–6]. And according to Barcelona Clinic Liver Cancer (BCLC) classification [7], HCCs beyond 5 cm still qualify as early-stage eligible for SR. However, the prerequisites for resection are based on liver function, portal hypertension, and the extent of hepatectomy and surgical invasiveness according to the EASL guideline [4]. The principle of TACE is to inject chemotherapeutic drugs and embolization agents into the supplying arteries of the tumor, resulting in ischemia and hypoxia of the tumor cells, thereby promoting apoptosis and necrosis [8]. TACE has been a significant non-surgical treatment for hepatocellular carcinoma in recent years [5,9,10], which has less trauma and definite curative effect so that some HCC patients who are not suitable for surgical resection can also get the chance of TACE [11].

In patients with large HCC (lesion> 5 cm), previous studies and guidelines have focused on HCC in the early stage of BCLC (single lesion>5 cm, or 2–3 nodules ≤3 cm), which recommends that SR should be the optimal treatment. TACE should be the treatment of choice for HCC patients with the BCLC B stage [12,13]. However, recent studies have indicated that in patients with multiple large HCCs, surgical resection has better overall survival than TACE [14–18]. A meta-analysis of 2619 patients also indicates that SR had better overall survival than TACE with intermediate HCC [19]. The previous analysis concentrating on solitary large hepatocellular carcinoma indicated that SR resulted in greater survivability and time to disease progression than TACE [20]. However, the number of included samples is small, and there is some heterogeneity in the paper. And the article focused on large solitary HCC. Recently, more studies have been published on SR and TACE in the treatment of large HCC, and most of them have conducted propensity-matching studies [14,15,18,21,22].

So, we do this meta-analysis to compare the survival of patients with primary large hepatocellular carcinoma treated with SR and TACE.

This systemic review meta-analysis compared the effectiveness of SR and TACE based on 14 studies that included 3609 patients and demonstrated that SR is associated with improved overall survival when compared with TACE for patients with large HCC. The results were consistent after PSM analysis. Subgroup analysis suggests that SR is superior to TACE regardless of tumor size and tumor numbers. In patients with large HCC, the SR group shows better PFS than the TACE group.

Previous guidelines did not have a significant classification of large HCC. According to the BCLC algorithm, solitary large HCC > 5 cm was defined as stage A, and hepatic resection should be the optimal treatment [7]. As for BCLC stage B, EASL and AASLD guidelines recommended TACE as the treatment of choice [4,5]. The role of SR for large HCC remains controversial. According to previous guidelines, SR is not indicated for BCLC B stage HCC patients because of poor overall survival. On the other hand, strict surgical guidelines preclude most patients from surgical treatment. The previous selection criteria for SR presented in the previous (EASL)/(EORTC) Clinical Practice Guidelines in 2012 were solitary tumors and very well-preserved liver function, hepatic vein to portal system gradient lower than 10 mmHg or platelet count ≥100,000/ml [32]. However, many studies have shown that in selected patients with intermediate-stage BCLC HCC, SR can give better survival than TACE [16,30,33]. A meta-analysis of 9 studies with 2619 patients indicated that SR had better overall survival than TACE for patients with intermediate-stage HCC [19]. Our meta-analysis focused on large HCC, which is not limited to the BCLC stage, and indicated that SR was superior to TACE. The crude 1-year, 3- year, and 5-year overall survival rate in the SR group and TACE group was 83.3% vs. 65.8, 63.2% vs. 40.0%, and 53.2% vs. 30.9%. The previous study shows that the early stage of HCC may achieve 70% 5-year survival rates [7]. Our research included large HCC combined early stage and intermediate stage, and the overall survival was lower than it. Stevens et al. included four studies on large HCC and found that cumulative overall survival rates in the SR group and TACE at 1, 3, and 5 years were 85% vs. 75%, 72% vs. 54%, and 61% vs. 36%, which was consistent with our results.

Besides, most studies included were retrospective cohort studies with PSM. Our results demonstrated that after PSM, in patients with large HCC, SR got better overall survival than TACE. Hyun et al. also compared the survival of 5,986 patients after SR and TACE; after PSM, both BCLC stage B and BCLC stage C patients showed significantly better OS for SR compared to TACE [34]. Both tumor size and tumor number influence operation. A previous study showed that from tumor sizes larger than 5 cm, the complete necrosis rate was all below 20%, which might weaken adhesiveness within the tumor, thus facilitating the invasion of HCC [35]. The overall survival of HCC larger than 10 cm treated by SR at five years ranged from 30.8% to 44.4%, according to previous studies [14,22]. Our analysis indicated that SR was the better treatment in both groups, which was consistent with previous studies [20,36]. Some studies indicated that pre-TACE could be beneficial for large HCCs while others got controversial results [9,10].

In patients with large liver cancer, due to the large mass, relatively complex tumor supplying arteries, and often accompanied by vascular invasion and portal vein tumor thrombus, TACE tumor necrosis rate was low and postoperative tumor angiogenesis was likely to lead to recurrence and metastasis, whereas the long-term prognosis was not ideal. A recent meta-analysis by Zhang et al. suggested that Resection might be a meaningful choice for hepatocellular carcinoma with portal vein thrombosis [37].

The majority of HCC in Asian countries is attributable to viral hepatitis, especially chronic HBV infection. In recent years, chronic HCV also contributed to HCC. In our meta-analysis, the percent of HBV-positive ranged from 36.8% to 98.9%, while the percent of cirrhosis ranged from 52.9% to 92.2%. The EASL guideline did not get a consensus on "criteria" for SR in cirrhosis, and the decision of SR should be influenced by liver function assessment, portal hypertension, and the extent of hepatectomy and surgical invasiveness [4]. The previous review suggested that in HCC with liver cirrhosis, SR was superior to TACE in 1-year and 3-year OS [38]. Previous studies showed that different surgical approaches affected the prognosis [39]. Liu et al. and Jabir MA et al. indicated that the anterior approach resulted in better operative and survival outcomes compared with the conventional approach, which was the preferred technique for major right hepatic resection for large HCC [40,41]. Deng et al. and Wang et al. showed that long-term survival after ALPPS was significantly better than that after TACE [15,18].

Other non-surgical may also gain an important role in the treatment of HCC; transarterial radioembolization (TARE) is increasingly used as an alternative to TACE for the treatment of HCC. A recent meta-analysis indicated that TARE provided significantly longer TTP than TACE but did not significantly differ in terms of OS [42]. Some studies also indicated that it was an important downstaging therapy for unresectable hepatocellular carcinoma prior to hepatic resection [43,44]. One study concentrated on the large HCC and found that in treating patients with BCLC-B2 substage HCC, TARE treatment could be a better choice than TACE, especially in those with a large tumor [45]. However, there was no comprehensive assessment of the effect of TARE vs. TACE vs. surgical resection, which may need further research.

Certainly, there are still some limitations underlying this meta-analysis. First of all, the enrolled studies are retrospective cohort researches, which relatively influence the accuracy of the study, and most studies have a bias in the selection of participants into the study, which may influence the results. However, PSM analysis partially attenuated the effects. Second, the number of surviving patients at each period is treated as a dichotomous variable with the number of survivors and total numbers of patients extracted from the included studies; OR value is used for analysis, and there is moderate heterogeneity in this article. However, PSM analysis showed no significant heterogeneity, which confirmed the conclusion. Third, most of the included studies are from Asian countries, lacking relevant studies from other countries, and the scope of the included studies is not wide enough. Fourth, there were only 2 or 3 related studies in partial subgroup analysis, which may affect the accuracy of the research results. Then, there was no definite classification of BCLC stages in most of the included studies, and the articles with classification included BCLC A/BCLC B stages. Different stages have a great impact on the prognosis of the disease. Finally, most of the studies did not mention if there were any follow treatments after primary therapy, which may have an effect on overall survival. Besides, TSA analysis is conducted in this study to meet the sample size required for the conclusion. And PSM analysis improves the quality of the articles included in the study.

This meta-analysis indicates that among patients with large primary hepatocellular carcinoma, the overall survival rate of patients undergoing surgical resection was higher than that of patients undergoing TACE. Further, more rigorous prospective controlled studies are needed to validate the results.

Luke Zhou: visualization, conceptualization, data curation, writing – original draft. Mao Zhang: data curation, formal analysis, supervision. Siyu Chen: visualization, conceptualization, formal analysis, supervision.

The study is funded by the Deyang Municipal Commission of Health and Family Planning (2018SZS078).

The data supporting this study's findings are available from references (including studies).