Compared with sorafenib, HAIC shows a better therapeutic effect and a lower incidence of adverse events (AEs) in the treatment of advanced or unresectable HCC [27-29]. HAIC has been widely used in Japan [12]. For TACE-refractory HCC, HAIC presents a satisfactory therapeutic effect[19, 20]. Sorafenib, as the first-line drug for advanced HCC, also has good efficacy in the treatment of TACE-refractory HCC[24, 30, 31]. As far as we know, this study is the first systematic review and meta-analysis to evaluate the efficacy of HAIC and sorafenib in the treatment of TACE-refractory HCC.
Through systematic literature retrieval, a total of 5 articles were included in this study. Different from the conclusion of previous systematic reviews [27-29], the study showed that sorafenib could prolong the overall survival of patients with TACE-refractory HCC compared with HAIC (HR = 1.69, 95% CI [1.09, 2.62], p=0.018). Although the ORR of the HAIC group was significantly higher than that of the sorafenib group (RR = 3.08, 95%CI [1.38, 6.87], p=0.006), the DCR between the HAIC group and the sorafenib group was not significantly different (RR = 0.94, 95%CI [0.60, 1.48], p=0.798). As we know, TACE blocks the hepatic artery blood supply of liver cancer and plays an anti-cancer role by inducing tumor ischemia, hypoxia, and necrosis. Hypoxia can up-regulate hypoxia-inducing factor 1 and then up-regulate vascular endothelial growth factor (VEGF) to promote tumor angiogenesis, which is related to tumor refractory to TACE [32-36]. Furthermore, when TACE is not completely effective, it may induce a significant angiogenesis reaction[37]. Sorafenib is a multi-kinase inhibitor of VEGF and platelet-derived growth factor (PDGF) receptors[38]. The better effectiveness of sorafenib in patients with TACE-refractory HCC may be related to its inhibition of tumor angiogenesis[16, 39, 40].
All of the patients in 4 studies[20, 23-25] had no extrahepatic metastasis, while Moriya et al. included patients with extrahepatic metastasis. And the proportion of patients with extrahepatic metastasis included in Moriya et al.' s study[26] was significantly different between the two groups (5% vs. 80%, p<0.01). The prognosis of HCC patients with extrahepatic metastasis was significantly worse than that of HCC patients without extrahepatic metastasis [11, 12, 26]. When the study of Moriya et al. was excluded, the results of the meta-analysis in OS did not change significantly (HR = 1.841, 95% CI [1.12, 3.03], p=0.016), which means that Moriya et al.' s study did not have a significant influence on the research results. When excluding other studies one by one, the results of the meta-analysis in OS are still stable.
Previous studies suggest that compared with sorafenib, patients in the HAIC group have a lower incidence of AEs in the treatment process and higher safety, especially when HCC is combined with portal vein tumor thrombosis [12, 27, 41]. Both the HAIC group and the sorafenib group, there were cases of discontinuation of treatment due to AEs. Ikeda et al. [24] showed that 9.1% of patients in the HAIC group were discontinued due to AEs, and 14% of patients in the sorafenib group were discontinued due to AEs. The study of Kondo et al. [20] suggested that the rate of discontinuation of treatment due to severe AEs in the sorafenib group was up to 32.5%, while the rate of discontinuation due to AEs in the HAIC group was only 2.3%. It should be noted that HAIC has specific operational difficulties and the risk of infection of the injection device [23], while oral sorafenib is convenient, and patient compliance may be better. And compared with HAIC, sorafenib prolong the overall survive (HR = 1.69, 95% CI [1.09, 2.62], p=0.018). Discontinuation of sorafenib therapy due to AEs may not wholly offset the survival benefits of sorafenib compared with HAIC for TACE-refractory HCC. Sorafenib may be more suitable for the treatment of TACE- refractory HCC.
The study has several limitations. First, all the studies included in this study were retrospective studies, and no high-quality randomized controlled trials were included. Second, the small number of studies included, and the small sample size included in each study, may overestimate the efficacy of the treatment. Third, baseline characteristics and treatments were not identical between studies, which may introduce heterogeneity. And due to the small number of studies, it is currently impossible to perform Meta-regression to determine the source of heterogeneity. Finally, the included studies were all from Japan, and most included patients without extrahepatic metastasis [20, 23-25], the generalization of the results may be limited to some extent. In the case of limited clinical evidence, the results of this meta-analysis can provide references for clinicians. Sure, large-scale, high-quality, randomized controlled trials are needed.