Advancing hepatocellular carcinoma treatment with hepatic arterial infusion chemotherapy

Abstract

Hepatocellular carcinoma (HCC) remains a major challenge in oncology, being a leading cause of cancer-related mortality worldwide. Early-stage HCC is typically treated with surgical resection, transplantation, or ablation, while advanced-stage HCC relies on systemic therapies like sorafenib and newer combinations such as atezolizumab-bevacizumab. Despite these advancements, there is still a need for effective treatments for unresectable HCC, especially in cases with macroscopic vascular invasion. Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising outcomes in Asia for the treatment of unresectable HCC, yet its application in Western countries has been relatively limited. This letter reviews the recent meta-analysis by Zhou et al published in the World Journal of Gastrointestinal Oncology, which demonstrates the efficacy and safety of HAIC vs sorafenib. The analysis includes 9 randomized controlled trials and 35 cohort studies, highlighting significant improvements in overall survival, progression-free survival, and objective response rates with HAIC and its combinations. The editorial explores the reasons behind the limited use of HAIC in Western countries. It underscores the potential of HAIC to enhance treatment outcomes for advanced HCC and calls for more research and broader adoption of HAIC in clinical practice globally.

Key Words: Hepatocellular carcinoma; Hepatic arterial infusion chemotherapy; Tyrosine kinase inhibitors; Immunotherapy; Survival

Core Tip: Hepatic arterial infusion chemotherapy (HAIC) is shown to be a highly effective and safer treatment for advanced hepatocellular carcinoma. Despite its success in Asia, HAIC is underutilized in western countries. Further research and clinical trials in diverse populations are essential to validate HAIC’s benefits and integrate it into global oncology practices.

TO THE EDITOR

Hepatocellular carcinoma (HCC) remains a formidable challenge in oncology, representing the sixth most commonly diagnosed cancer and the fourth leading cause of cancer-related mortality globally[1]. In the early stages, curative approaches such as surgical resection, transplantation, and ablation are treatment options depending on the patient’s status. For intermediate-stage HCC, locoregional treatment approaches like transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) are prioritized. In advanced-stage HCC, systemic therapies are the first choice of treatment, as recommended by international guidelines[2]. Recently, there have been significant advancements in the treatment of unresectable HCC. The evolution of systemic therapy that began with sorafenib has led to a considerable improvement in HCC survival outcomes with the introduction of combination regimens such as atezolizumab-bevacizumab, and durvalumab-tremelimumab. However, there remains an unmet need to optimize treatment for unresectable HCC with macroscopic vascular invasion.

Hepatic arterial infusion chemotherapy (HAIC) has recently emerged as a prominent treatment method for unresectable HCC, particularly in Asia. Although it has not yet been included in European and American guidelines, it is recognized in Japanese guideline as a treatment option for HCC with portal vein thrombosis that is unsuitable for other local treatments[3]. HAIC delivers chemotherapeutic agents directly into the hepatic artery, which supplies blood to the liver and, more importantly, to the HCC tumors. Since HCC tumors derive their blood supply predominantly from the hepatic artery (as opposed to the portal vein, which supplies most of the normal liver), HAIC ensures that a high concentration of the drug reaches the tumor with minimal exposure to the rest of the liver and systemic circulation. This method enhances the effectiveness of the chemotherapy while reducing systemic side effects[4].

This letter aims to provide a critical and comprehensive overview of the recent meta-analysis by Zhou et al[5] on the efficacy of HAIC for advanced HCC. The editorial seeks to highlight the significant findings of the study, discuss the potential benefits and drawbacks of HAIC, and explore the reasons behind its limited adoption in western countries despite its demonstrated success in Asia.

HAIC AND COMBINATION THERAPY STRATEGIES

HAIC can be administered as monotherapy or in combination with other treatment modalities. While it is most commonly combined with systemic therapies, there are also examples in the literature where it is used in combination with other locoregional therapies. Among combination therapies, studies evaluating concomitant use with sorafenib are predominant.

There are five randomized controlled trials (RCT) comparing the outcomes of sorafenib with sorafenib + HAIC combination therapy. Among these, only two are phase 3 RCT, and their results are inconsistent. Kudo et al[6] conducted a study across 31 centers in Japan, in which adding HAIC to sorafenib treatment showed an effect on progression-free survival (PFS) and objective response rate (ORR) but not on medical overall survival (mOS) [mOS: 11.8 months vs 11.5 months; hazard ratio (HR) = 1.009; P = 0.9][6]. Conversely, He et al[7] carried out a study in five centers from China, and adding HAIC to sorafenib treatment significantly increased mOS (mOS: 13.3 months vs 7.1 months; HR = 0.35; P < 0.001). This study also found statistically significant improvements in ORR and medical PFS (mPFS) with the HAIC + sorafenib combination[7]. The discrepancies between these two studies could be attributed to differences in HCC etiology and the chemotherapy regimens used in HAIC. The Japanese study included approximately 50% of patients with hepatitis C virus (HCV)-related HCC and 20% with hepatitis B virus (HBV)-related HCC, while the Chinese study had 80% of patients with HBV-related HCC. Pooled analyses of two phase 3 studies evaluating the efficacy of sorafenib indicate that sorafenib is more effective in HCV-related HCC[8]. Additionally, the chemotherapy protocols utilized in HAIC exhibited notable differences. The Japanese study employed a low-dose 5-fluorouracil (5-FU)-cisplatin[6], whereas the Chinese study utilized the FOLFOX regimen[7].

HAIC is being utilized in numerous medical centers employing a multitude of chemotherapy regimens, including low-dose cisplatin, low-dose cisplatin-5-FU, high-dose cisplatin-5-FU, and 5-FU-oxaliplatin(FOLFOX)[9]. Cisplatin-based chemotherapy regimens are frequently utilized in HAIC treatments. In a phase 2 study by Ikeda et al[10], patients with advanced-stage HCC were treated with either sorafenib monotherapy or a combination of sorafenib and HAIC with cisplatin. The combination therapy achieved an overall response rate of approximately 20%[10]. The primary advantage of cisplatin monotherapy is the absence of a need for catheter placement. Due to the synergistic antitumoral effects of cisplatin and 5-FU, they have been tested together in HAIC applications across different dose combinations. Although the use of low-dose cisplatin with 5-FU (FP) is quite heterogeneous, the weekly cisplatin dose is generally 10-20 mg/m², and the 5-FU dose is 200-300 mg/m² for five days each week[9]. In a retrospective study, Nouso et al[11] compared HCC patients treated with low-dose FP to those monitored with best supportive care and reported significantly longer survival in the group receiving low-dose FP with HAIC (mOS: 14 months vs 5.2 months; P < 0.0001)[11]. In one of the few phase 3 trials in this field, Kudo et al[6] also used low-dose FP in their study of HAIC + sorafenib. Although no survival difference was demonstrated in the overall population, the subgroup with portal trunk invasion showed better survival compared to sorafenib alone (mOS: 11.7 months vs 6.5 months)[6]. Additionally, the Korean Liver Cancer Study Group compared low-dose FP with high-dose FP, finding better ORR rates with the high-dose regimen (16.7% vs 0%). The high-dose FP regimen consisted of 60 mg/m² cisplatin and 500 mg/m² 5-FU administered on days 1-3 every four weeks, approximately two to three times the dose used in the low-dose FP regimen[12].

All HAIC studies conducted with the FOLFOX regimen have met their primary endpoints[7,13,14]. In phase 3 randomized trial conducted in patients with intermediate-stage HCC, FOLFOX HAIC was compared with TACE, and it demonstrated superiority in both OS (mOS: 23.1 months vs 16.1 months; HR = 0.58; P < 0.001) and PFS (mPFS: 9.6 months vs 5.4 months; HR = 0.57; P < 0.001)[13]. ORRs as high as 50% have been achieved with FOLFOX-HAIC[13,14]. Despite the absence of direct comparisons between different chemotherapy regimens utilized in HAIC, the FOLFOX regimen has exhibited the most favorable outcomes so far, thereby becoming the most widely adopted regimen in clinical practice in Asia.

One of the major drawbacks of HAIC is the lack of a well-established, standardized protocol for its application. Additionally, the need for catheter placement introduces risks of catheter-related infections and thrombosis. The overall frequency of catheter-related complications is reported to be between 5% and 15%[9]. On the other hand, side effects associated with cytotoxic chemotherapy are also observed. The most common adverse events include bone marrow suppression, hypoalbuminemia, anorexia, hyperbilirubinemia, and elevated transaminase levels[15].

A meta-analysis comparing HAIC + sorafenib combination therapy with sorafenib alone in advanced HCC (including five RCTs and two observational studies) found that the combination therapy was associated with significantly better OS (HR = 0.56; P < 0.01), PFS (HR = 0.44; P < 0.01), and ORR (RR = 3.77; P < 0.01). However, grade 3/4 adverse events were more common in the combination arm[16]. Subgroup analysis showed that oxaliplatin-based HAIC resulted in better OS, PFS, and ORR compared to cisplatin-based HAIC, potentially due to oxaliplatin’s ability to induce immunogenic tumor cell death[17] and/or achieve higher concentrations in the tumor and its microenvironment[18].

The success of sorafenib + HAIC combination therapy may be attributed to sorafenib breaking the resistance to chemotherapeutic agents and creating a synergistic anticancer effect with HAIC[19]. Sorafenib may also enhance vascular permeability, increasing the concentration of locally administered chemotherapeutic agents[20]. In addition, HAIC administered prior to sorafenib treatment may reduce tumor burden, thereby increasing the efficacy of the drug[8].

In Zhou et al’s meta-analysis[5], the effectiveness of HAIC and its combination strategies in advanced HCC was investigated. This meta-analysis included studies on HAIC alone or in combination with other treatment strategies in unresectable HCC [according to the Barcelona Liver Clinic Cancer (BCLC) staging system, BCLC-B and BCLC-C] patients. A total of 9 RCTs and 35 cohort studies were included, comparing HAIC and combination therapies with Sorafenib in terms of OS, PFS, ORR (complete response and partial response), and adverse events. This meta-analysis encompassed a significantly larger number of studies compared to previous meta-analyses. While most included studies investigated HAIC + sorafenib combination therapy, the meta-analysis also evaluated combinations like HAIC + TACE and HAIC + ablation + lenvatinib. According to the meta-analysis, HAIC was deemed a better treatment option than TACE and sorafenib in terms of both efficacy and safety. Although combining HAIC with different treatment modalities appeared more effective than monotherapy, the improvement was marginal. Network meta-analysis of OS and PFS results indicated that HAIC with lenvatinib + ablation and HAIC + ablation combinations were associated with the best OS (HR = 0.12) and PFS (HR = 0.25) outcomes.

According to American and European guidelines, atezolizumab-bevacizumab or durvalumab-tremelimumab combinations are the standard first-line treatment for unresectable RCC. However, Eastern guidelines also include locoregional therapy in addition to systemic therapy. The addition of locoregional therapy to standard treatment for unresectable HCC remains an area of important research. A retrospective small-scale study in China evaluating the addition of HAIC to atezo-beva systemic therapy in advanced HCC reported impressive results with an ORR of 67% and mPFS of 10.3 months. Due to the short follow-up period, mOS was not reached[21]. In another study included in Zhou et al’s meta-analysis, the combination of HAIC and an anti-PD-1 inhibitor was compared to HAIC alone without specifying a particular anti-PD-1 inhibitor (90% of patients received toripolimab and sintilimab)[5]. The combination resulted in mOS of 18 months, compared to 14 months with HAIC monotherapy (P = 0.018; HR = 0.62). Disease control was also better with the combination (83% vs 66%; P = 0.006; HR = 0.62)[22]. A retrospective study by He et al[23] comparing the HAIC + toripalimab + lenvatinib triplet regimen with lenvatinib monotherapy found that the triplet regimen had superior OS (17.1 months vs 10.1 months; HR = 0.50; P = 0.005) and ORR (47.2% vs 9.2%; P < 0.001)[23].

All studies on HAIC are predominantly from East Asia, primarily China. Despite the promising outcomes observed in HAIC studies, the divergence in HCC projections between the East and West fuels skepticism toward HAIC in the western medical community. The etiology of HCC in the eastern population is largely attributed to HBV, with patients frequently diagnosed at advanced stages. In contrast, the west is characterized by a higher prevalence of alcohol- and HCV-related HCC, with patients typically diagnosed at earlier stages. The number of patients in western countries who are not able to undergo locoregional treatments such as TACE and TARE is quite limited.

CONCLUSION

HAIC holds significant potential for improving outcomes in advanced HCC. Continued research and efforts to overcome existing barriers will ensure that patients worldwide can benefit from this advanced treatment option. To facilitate broader adoption of HAIC, more large-scale clinical trials in diverse populations are necessary. These studies should aim to validate the benefits of HAIC and explore optimal combination strategies with other treatments. Additionally, increasing awareness and training in HAIC techniques among Western healthcare providers will be crucial for integrating this promising therapy into global oncology practices.