Hepatocellular carcinoma (HCC) ranks as the sixth most common cancer globally and stands as the third leading cause of cancer-related mortality (Sung et al., 2021). Due to its highly asymptomatic nature, over 60% of cases progress to an advanced stage upon diagnosis, precluding curative interventions (Cappuyns et al., 2024). The prognosis for these patients is exceedingly grim, with a median overall survival (OS) of approximately 2.7–4.0 months in the absence of treatment (Lu et al., 2019). Consequently, there is a pressing need for potent therapies that can significantly extend survival.

The Barcelona Clinic Liver Cancer (BCLC) staging system recommends systemic therapy involving targeted therapy and immunotherapy for advanced HCC patients at BCLC stage C (Reig et al., 2022). Based on the promising outcomes from the IMbrave150 trial, guidelines now advocate for atezolizumab-bevacizumab combination therapy as the first-line treatment choice for advanced HCC patients. However, multi-tyrosine kinase inhibitors (TKIs) such as lenvatinib and sorafenib remain viable options if the combination therapy is contraindicated (Trevisani et al., 2024).

In addition to systemic therapies, FOLFOX-based hepatic arterial infusion chemotherapy (HAIC) has demonstrated superior outcomes compared to sorafenib for advanced HCC (Lyu et al., 2022). HAIC delivers a concentrated dose of medication directly to liver tumors, resulting in a significant local antitumor effect, and has been widely used in primary and metastatic hepatic malignant tumors (Sidaway, 2022a). According to Chinese and Japanese guidelines, HAIC is the recommended treatment for advanced HCC, particularly in patients with major portal vein tumor thrombosis (PVTT) (Chen et al., 2020). While a phase III trial has reported survival benefits from combining sorafenib with HAIC using a modified FOLFOX regimen compared to sorafenib monotherapy, the outcomes of HAIC plus TKIs versus HAIC monotherapy remain unexplored (He et al., 2019).

In this retrospective study, we aimed to investigate the efficacy of combined HAIC and TKIs compared to HAIC monotherapy in advanced HCC patients.

This multicenter retrospective study demonstrated an association between HAIC plus TKIs and extended OS by 9.2 months compared with HAIC monotherapy among patients with advanced HCC. These results were consistent across all subgroup analyses. The combination therapy was also associated with a significant improvement in overall tumor response and PFS compared with HAIC monotherapy. Additionally, more patients in the combination therapy group were able to undergo salvage liver resection after tumor regression or necrosis, with 68.2% of patients achieving pCR. Both HAIC combined with sorafenib or HAIC monotherapy demonstrated acceptable safety profiles. These results demonstrate that HAIC combined with TKIs is superior to HAIC monotherapy in the treatment of advanced HCC.

Controversy persists between Western and Eastern approaches to treating advanced HCC patients. While systemic therapies are recommended as the first-line option in the West, locoregional options such as transarterial chemoembolization (TACE), HAIC, and even surgical resection have been adopted in the East, particularly in China (Lu et al., 2019). The primary reason lies in the high tumor burden observed in Chinese patients, a characteristic consistent with our study. These patients require rapid control, which locoregional approaches can provide. HAIC, delivering high doses of chemotherapy directly through the hepatic artery to the tumor, has demonstrated superior outcomes compared to both TACE and sorafenib in China, elevating its status as a more ambitious treatment option (Li et al., 2022; Lyu et al., 2022). Consequently, Chinese guidelines recommend HAIC as a first-line option for advanced HCC patients, especially those with substantial tumor burden (Sun et al., 2022; Yau et al., 2022; Xie et al., 2023; Zhao et al., 2024). Furthermore, previous studies have highlighted the promising antitumor activity of HAIC combined with sorafenib, surpassing sorafenib monotherapy (He et al., 2019; Zheng et al., 2022). Thus, the combination therapy of HAIC with antiangiogenic agents emerges as a novel treatment strategy for patients with advanced HCC.

Apart from sorafenib, lenvatinib has demonstrated comparable tumor response and survival outcomes in patients with advanced HCC (Vogel et al., 2021). Notably, a recent phase III clinical trial (LANUCH) reported that TACE combined with lenvatinib significantly improved survival compared to lenvatinib monotherapy (Peng et al., 2023). This finding suggests a synergistic antitumor effect between locoregional therapy and lenvatinib. However, the efficacy of lenvatinib in combination with HAIC remains uncertain. In our study, more than 60% of patients in the HT group received lenvatinib plus HAIC, and the outcomes, including OS and PFS, were comparable to those of sorafenib plus HAIC, thus validating the synergistic effect of these two treatment regimens. Additionally, it is important to note that the current study population might have worse basic characteristics than that of the IMbrave 150 trial (Finn et al., 2020), as all patients included in our study were classified as BCLC C stage with high tumor burden. Further studies are needed to compare bevacizumab plus atezolizumab and HAIC combined with TKIs as the first-line treatment for advanced HCC.

A previous study demonstrated that FOLFOX-HAIC yields a favorable tumor response in advanced HCC patients with PVTT (Yuan et al., 2023). On the contrary, it may be not an appropriate choice for treating advanced HCC patients with extrahepatic metastases, as its effect in controlling extrahepatic lesions is limited. However, according to some previous studies, patients with extrahepatic metastases demonstrated inferior tumor response and survival outcomes compared to those without distant metastases, but no statistical difference was observed (Lyu et al., 2019; Ueshima et al., 2020). Besides, numerous research studies and case reports have indicated long-term overall survival (OS) benefits following HAIC therapy in advanced HCC patients with extrahepatic metastases (Kogure et al., 2007; Yoshida et al., 2014). The specific mechanisms underlying these favorable outcomes remain unclear. One speculated reason is that after HAIC treatment, certain chemotherapy drugs enter the bloodstream, thereby reaching distant metastatic lesions and exerting anti-tumor effects (Gao et al., 2018). Moreover, it is widely agreed that the primary causes of death in most HCC patients include liver function failure, upper gastrointestinal bleeding, and progression of intrahepatic lesions. Consequently, controlling extrahepatic lesions has minimal impact on patient survival prognosis. Additionally, in cases where patients experience progression of distant extrahepatic lesions, sequential administration of systemic therapeutic drugs can be employed for their control. Therefore, some patients receiving initial HAIC monotherapy were included in this study as the control group. While in the multivariate analysis, it still revealed that extrahepatic metastases were the sole independent prognostic factors for both OS and PFS. As a systemic therapy option, TKIs exert antitumor effects on both intrahepatic and extrahepatic tumors. Furthermore, TKIs are multi-kinase inhibitors with antiproliferative and antiangiogenic activities, countering hypoxia-induced angiogenesis induced by HAIC (Sidaway, 2022b). Consequently, patients with extrahepatic metastases are more likely to benefit from combination therapy.

In this study, we opted for HAIC combined TKIs as a potent approach to rapidly reduce tumor burden. Previous reports have indicated that TACE combined with HAIC may lead to better OS and a higher conversion rate than TACE monotherapy for advanced HCC patients (Li et al., 2021). Although TACE plus HAIC has been reported as superior to TACE monotherapy in retrospective studies (Li et al., 2021; Yuan et al., 2023), whether this combination provides survival benefits compared to HAIC alone remains unclear—especially considering that HAIC has already demonstrated significant OS improvement over TACE in HCC patients with high tumor burden (Li et al., 2022). Additionally, the impact of TACE-induced vascular embolism on HAIC’s ability to deliver chemotherapeutic drugs through tumor-associated arterial branches remains unknown, necessitating further investigation. Furthermore, the incidence of grade 3–4 AEs and overall AEs was higher with TACE than with HAIC (Li et al., 2022), and the addition of TKIs would likely further increase AE incidence. In the absence of evidence supporting the superiority and safety of TACE combined with HAIC, this combination therapy should be cautiously considered for advanced HCC patients.

Except for in combination of HAIC and TKI, several clinical studies are investigating the efficacy of HAIC combined with TKI and ICI in HCC. Preliminary results indicate that this combination shows promise in improving ORR and OS, comparing with monotherapy or dual combination therapy. For instance, the combination of HAIC with apatinib and camrelizumab has demonstrated good efficacy and tolerability in some patients (Zhang TQ. et al., 2023). Combining HAIC with TKI and ICI can produce a synergistic effect, enhancing overall antitumor efficacy. HAIC reduces tumor burden, TKI inhibits tumor growth, and ICI boosts the immune response against cancer cells. This combination targets the tumor through multiple mechanisms, reducing the likelihood of resistance and tumor escape (Llovet et al., 2022). However, given that most of these studies were retrospective or small-sample phase II clinical trials, the efficacy and safety need to be further validated by large-sample prospective clinical studies. Besides, during our study period, most ICIs were not approved for HCC and thus were not covered by medical insurance in China, which resulted in increasing the financial burden on patients, leading them to refuse immunotherapy. Therefore, ICI was not chosen as a first-line treatment option for patients in this study.

In our retrospective study, we employed PSM to mitigate group differences. However, in the matched cohort of this study, although PFS was longer in the HT group compared to the HA group, there was no statistically significant difference between the two groups. One possible explanation is that combination therapy may rapidly reduce tumor burden but has a limited role in preventing tumor progression and metastasis. This suggests that further refinement of combination therapy is necessary. Regarding subgroup analyses, notably, the integration of TKIs with HAIC demonstrated significantly improved OS and PFS outcomes compared to HAIC monotherapy. These benefits were observed regardless of tumor size, tumor number, or the presence of vascular invasion or extrahepatic metastasis. These findings suggest that combining HAIC with TKIs could offer a superior therapeutic approach for advanced HCC, irrespective of tumor burden. However, it is worth noting that within the female and no-hepatitis subgroups, the combination group did not achieve superior survival outcomes, possibly due to the small sample size. Validation in a larger cohort is warranted for further confirmation.

A previous study has reported that HAIC exhibits a higher ORR compared to TACE based on RECIST 1.1 criteria, resulting in a higher conversion rate for unresectable HCC patients (Deng et al., 2023a). Recent research has highlighted that combination therapy can significantly enhance the likelihood of converting to liver resection after reducing tumor burden resulting in a relatively high rate of pCR (Zhu et al., 2021; Zhang W. et al., 2023; Deng et al., 2023b; Kudo et al., 2023; Vitale et al., 2023; Trevisani et al., 2024). Notably, the conversion rate is closely tied to the ORR within a relatively short timeframe (Chen et al., 2024). In our study, the ORR was markedly higher in the HT group, which also exhibited a greater rate of conversion to liver resection and pCR. These findings suggest that combination therapy may facilitate curative treatment for a larger proportion of patients.

In addition to favorable outcomes, combination therapy led to a moderate increase in the incidence of AEs. Notably, there was a higher occurrence of AEs related to TKIs, consistent with findings from previous trials involving sorafenib and lenvatinib (Llovet et al., 2008; Cheng et al., 2009; Kudo et al., 2018). Fortunately, these AEs were generally manageable with appropriate supportive medications and did not exacerbate the disease or necessitate discontinuation of therapy. Interestingly, the incidence of AEs in the HT group was higher than that observed in patients treated with HAIC plus sorafenib in a previous study (He et al., 2019). This discrepancy might be attributed to the fact that our enrolled patients had more advanced disease and worse baseline characteristics. Another notable HAIC-specific AE was abdominal pain, resulting from arteria vasospasm during oxaliplatin infusion. Unfortunately, there are currently no foolproof methods to completely alleviate this specific pain. However, prescribing pain relief and spasm-relieving medications or adjusting the infusion rate of oxaliplatin may help mitigate the discomfort (Lv et al., 2016; Wu et al., 2021). In summary, the combination of HAIC with TKIs demonstrated a safe and tolerable profile.

Our study has several potential limitations that warrant consideration. First, as a retrospective study, inherent selection bias is unavoidable. Therefore, we employed PSM and subgroup analysis to minimize differences between the two groups. Second, it is essential to emphasize that our study was conducted in China, where HCC patients are predominantly influenced by the HBV. Consequently, our findings may have limitations when extrapolated to HCC patients with different etiologies. Finally, given that our study involved multiple centers, variations in the criteria for HAIC may exist among different institutions.

In conclusion, when compared to HAIC monotherapy, combination therapy involving HAIC combined with TKIs yielded favorable tumor responses and improved long-term survival outcomes for patients with advanced HCC. Importantly, a substantial number of patients achieved curative liver resection following successful conversion. Consequently, combination therapy emerges as a promising treatment strategy for advanced HCC patients.