Current research status and future directions of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma

Abstract

The rapid evolution of systemic therapies for hepatocellular carcinoma (HCC), one of the most common types of liver cancer, has attracted significant attention especially to hepatic arterial infusion chemotherapy (HAIC) as a highly promising treatment approach. This method, which delivers chemotherapy directly into the liver's arterial supply, is designed to maximize the concentration of anti-cancer drugs at the tumor site while minimizing systemic side effects. Despite the potential and the encouraging results observed in various studies, HAIC has not yet achieved widespread acceptance and utilization. Sorafenib is a widely used systemic therapy that targets multiple pathways involved in tumor growth and angiogenesis, while transarterial chemoembolization (TACE) is a locoregional therapy that combines arterial embolization with chemotherapy. These treatments have been the mainstay of HCC management, yet they have limitations that HAIC may potentially overcome. This article specifically comments on the network meta-analysis that examined the current research status of HAIC, highlighting its effectiveness and safety profile in comparison to established standard treatments such as Sorafenib and TACE. Through an extensive review of existing studies, the authors conclude that patients receiving HAIC often experience better survival rates and longer periods without disease progression compared to those receiving Sorafenib or TACE.

Key Words: Hepatic arterial infusion chemotherapy; Hepatocellular carcinoma; Network meta-analysis; Interventional therapy; Systemic treatment

Core Tip: Hepatic arterial infusion chemotherapy (HAIC) has been shown to offer significantly superior efficacy and safety compared to traditional treatments such as Sorafenib and transarterial chemoembolization for patients suffering from advanced hepatocellular carcinoma. By directly delivering high concentrations of chemotherapeutic agents to the liver tumor through the hepatic artery, HAIC maximizes tumoricidal effects while minimizing systemic side effects. This article underscores the promising clinical outcomes associated with HAIC. Through continued investigation and validation, HAIC has the potential to become a cornerstone in the treatment paradigm for advanced hepatocellular carcinoma, providing patients with a more effective and safer therapeutic option.

TO THE EDITOR

Primary liver cancer, particularly hepatocellular carcinoma (HCC), is a leading cause of cancer-related mortality worldwide, ranking as the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer deaths[1]. The chief cause of HCC is liver cirrhosis, including alcoholic cirrhosis, virus-associated cirrhosis, and cryptogenic cirrhosis[2]. The primary treatments for early-stage HCC typically include surgical resection, liver transplantation, and ablation. Surgical resection involves the removal of the tumor from the liver, while liver transplantation replaces the diseased liver with a healthy donor liver. Ablation refers to procedures that destroy cancer cells, such as radiofrequency ablation or microwave ablation. Each of these treatment options aims to effectively manage the cancer itself and improve patient outcomes. However, most patients are diagnosed at an advanced stage, rendering them ineligible for surgical options and resulting in unsatisfactory outcomes with a 5-year survival rate of only 5% to 36%[3].

Hepatic arterial infusion chemotherapy (HAIC) has emerged as a notable therapeutic strategy, particularly in Japan, where it is recommended as a first-line treatment for patients with advanced HCC and portal vein thrombosis[4]. HAIC influences the blood supply characteristics of the liver and HCC cells to deliver high concentrations of chemotherapeutic drugs directly to the tumor, minimizing systemic side effects and sparing healthy liver tissues[5]. Despite its potential, HAIC has not gained widespread acceptance in Western countries, largely due to insufficient phase 3 randomized controlled trials validating its efficacy.

This article focuses on the network meta-analysis by Zhou et al[6] that aims to assess the current research status of HAIC, compare its efficacy and safety with other treatments such as Sorafenib and transarterial chemoembolization (TACE), and explore future directions that could enhance its clinical application and acceptance globally.

Efficacy and safety of HAIC

Recent studies have demonstrated the superior efficacy and safety of HAIC compared to Sorafenib and TACE. A network meta-analysis including 9 randomized controlled trials and 35 cohort studies highlighted the advantages of HAIC in terms of overall survival (OS) and progression-free survival (PFS). HAIC outperformed Sorafenib in several metrics, including hazard ratios (HR) for OS (0.55) and PFS (0.51), and odds ratios (OR) for tumor response and adverse events. Similarly, HAIC demonstrated better outcomes compared to TACE, with HRs and ORs consistently favoring HAIC across various efficacy and safety measures[7].

Combination strategies involving HAIC have also shown promise. For instance, HAIC combined with lenvatinib and ablation (HAIC + Lenv + A) exhibited the highest likelihood of favorable OS and PFS outcomes. Other combinations, such as HAIC with anti-programmed cell death 1 (PD-1) therapy and radiotherapy also indicated improved efficacy over HAIC monotherapy. These findings suggest integrating HAIC with other therapeutic modalities to enhance treatment outcomes for patients with advanced HCC[8].

Comparative studies and meta-analysis

A significant volume of research has focused on comparing HAIC with other treatment modalities. For example, a phase 3 trial demonstrated that HAIC resulted in longer OS and PFS compared to TACE, highlighting HAIC's potential as a superior treatment option for advanced HCC[9]. Additionally, combination therapies involving HAIC, such as HAIC + Sorafenib and HAIC + PD-1, have shown improved efficacy in clinical trials, further supporting the integration of HAIC into multimodal treatment strategies[10]. As shown in a randomized trial, Sorafenib plus 3cir-OFF HAIC was found to be better in patients with HCC and major portal vein tumor thrombosis due to improved survival as well as an acceptable safety profile[11]. The HAIC-Lenvatinib combination was found to significantly improve survival outcomes of patients with advanced HCC while demonstrating acceptable toxicity when compared to HAIC alone[12].

As shown in the network meta-analysis by Zhou et al[6], HAIC has demonstrated significantly greater effectiveness and a better safety profile compared to both Sorafenib and TACE. Moreover, when HAIC is combined with other therapeutic interventions, it shows even further improved efficacy compared to HAIC monotherapy. This enhanced performance of HAIC in combination treatments has been consistently observed in various treatment ranking analyses, indicating its potential as a more comprehensive and powerful approach for managing HCC.

Despite these promising results, HAIC's acceptance in Western clinical practice remains limited. This is primarily due to the lack of large-scale randomized controlled trials validating its efficacy and safety in diverse patient populations. To address this gap, further research is needed to establish standardized protocols for HAIC administration and to evaluate its long-term outcomes in comparison to other established treatments.

Future directions

Emerging research trends in HAIC are focusing on optimizing combination therapies and identifying biomarkers that can predict treatment response. The integration of HAIC with novel systemic therapies, such as immune checkpoint inhibitors and targeted therapies, is a particularly promising area of investigation. These combination strategies aim to enhance the anti-tumor immune response and improve overall treatment efficacy.

One of the most promising areas of research is the combination of HAIC with immunotherapy. Preliminary studies have shown that HAIC combined with anti-PD-1 therapy can significantly improve treatment outcomes by influencing the immune system's ability to target and destroy cancer cells[13]. Similarly, combining HAIC with targeted therapies, such as tyrosine kinase inhibitors, may enhance the therapeutic effects and provide more durable responses[14].

To establish HAIC as a standard treatment for advanced HCC, large-scale clinical trials are necessary. These trials should aim to evaluate the efficacy and safety of HAIC in diverse patient populations, including those with different stages of HCC and varying degrees of liver function. Additionally, research should focus on identifying optimal dosing regimens and treatment schedules to maximize HAIC's therapeutic potential[15].

Future research should also explore the development of personalized treatment approaches based on individual patient characteristics and tumor biology. By tailoring HAIC and its combination strategies to the specific needs of each patient, it may be possible to achieve better treatment outcomes and improve OS rates in advanced HCC[16].

CONCLUSION

The network meta-analysis by Zhou et al[6] concludes that HAIC has significant potential as a treatment for advanced HCC, offering superior efficacy and safety compared to traditional therapies such as Sorafenib and TACE. The integration of HAIC with other therapeutic modalities, such as immunotherapy and targeted therapies, holds promise for enhancing treatment outcomes and providing more durable responses.

Despite these promising findings, further research is needed to establish HAIC as a standard treatment in Western clinical practice. Large-scale randomized controlled trials and the development of standardized protocols for HAIC administration are essential to validate its efficacy and safety and to ensure its widespread adoption. In conclusion, HAIC represents a promising advancement in the treatment of advanced HCC. By continuing to explore its potential through rigorous research and clinical trials, more effective and personalized treatment strategies can be devised that will improve patient outcomes and advance the field of HCC treatment.