Landscape of transarterial chemoembolization represented interventional therapy for hepatocellular carcinoma

Abstract

This article discusses the article written by Tan et al. Transarterial chemoembolization (TACE) is one of the main treatment methods for advanced hepatocellular carcinoma (HCC). There are other vascular interventional therapies, including drug-eluting bead TACE, transarterial radioembolization, and hepatic arterial infusion chemotherapy. TACE combined with anti-angiogenesis therapy may improve tumor control and prolong progression free survival. The combination therapy of TACE and immunotherapy may improve the clinical efficacy of HCC. In future research, more basic and clinical studies are needed to explore the immunogenic intervention therapy.

Key Words: Transarterial chemoembolization; Interventional therapy; Hepatocellular carcinoma; Anti-angiogenesis; Immunotherapy; Programmed cell death 1

Core Tip: The continuous development of transarterial chemoembolization represented interventional therapy technology and the constant updating of systemic drugs such as molecular targeted drugs and immune checkpoint inhibitors are changing the treatment pattern of primary hepatocellular carcinoma (HCC). The combination of interventional therapy and systemic therapy will become a new dawn for HCC treatment.

TO THE EDITOR

Primary liver cancer is one of the most common malignant tumors, and its mortality rate has risen to the fourth highest among cancer-related deaths worldwide[1]. In clinical practice, hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer[2]. HCC, mainly caused by viral hepatitis, has exhibited high degree of malignancy[3]. HCC not only has a very insidious onset, but also lacks corresponding clinical symptoms in the early stage, making it difficult to diagnose early[4]. Moreover, HCC progresses rapidly with poor prognosis, seriously threatening people's health and life[5].

Interventional therapy, defined as a treatment method directly targeting tumors under imaging guidance, plays a dominant role in the treatment of HCC[6]. It is estimated that about half of HCC patients worldwide require interventional therapy[7]. Radiofrequency ablation is the main method of local ablation for early HCC, while transarterial chemoembolization (TACE) and systemic anti-tumor therapy are the main treatment methods for advanced HCC[8].

VASCULAR INTERVENTIONAL THERAPY

In the past few years, some new methods and technologies have been introduced to improve the performance of TACE[9]. There are several vascular interventional therapies.

The introduction of embolization drug elution beads provides an alternative solution for iodinated oil based TACE, called drug-eluting bead TACE (DEB-TACE)[10]. DEB-TACE may reduce drug-related adverse reactions due to improved pharmacokinetics[11]. However, with the development of specialized mixing and injection systems as well as new catheter technologies, traditional TACE has also made substantial progress. Traditional TACE and DEB-TACE have shown similar survival benefits and are therefore often replaced in clinical practice.

Over the past 20 years, transarterial radioembolization (TARE) has been a continuously evolving form of arterial therapy[12]. Of note, there are several areas of concern, including comparison with TACE, criteria for downgrading to resection or transplantation, and safety or efficacy in advanced HCC with large vessel invasion.

Hepatic arterial infusion chemotherapy (HAIC) can increase tumor response rate and reduce systemic toxicity by increasing local chemotherapy drug concentration in tumor tissue, and has been recommended as one of the main treatment options for advanced HCC patients in Asia[13]. FOLFOX-HAIC (HAIC with infusional fluorouracil, leucovorin, and oxaliplatin) improved overall survival over TACE in patients with unresectable large HCC[14].

TACE COMBINED WITH ANTI-ANGIOGENESIS THERAPY

TACE can cause tumor necrosis by embolization of the tumor's blood supply artery and the cytotoxicity of chemotherapy drugs. However, embolization can easily lead to hypoxia inside the tumor and stimulate the generation of tumor blood vessels, which can easily induce tumor recurrence. Therefore, single TACE treatment still cannot effectively improve HCC prognosis[15]. Anti angiogenic drugs may inhibit TACE caused tumor recurrence by normalizing blood vessels and improving the hypoxic microenvironment of tumors. The latest TACTICS trial compared the efficacy and safety of TACE combined with sorafenib and TACE linear therapy for unresectable liver cancer[16]. The updated research results indicate that TACE combined with sorafenib can significantly prolong the specific progression free survival of HCC patients, but cannot improve the overall survival. TACE combined with sequential lenvatinib can improve tumor control and prolong patient survival in HCC with high tumor burden[17]. Overall, there is currently no advanced evidence to support the clinical efficacy of combining anti angiogenic drugs with TACE.

TACE COMBINED WITH IMMUNOTHERAPY

TACE can effectively reduce tumor burden and activate the immune system by releasing tumor neoantigens and immune related inflammatory factors, thereby enhancing immune anti-tumor response[18]. The continuous development of systemic therapies such as molecular targeted drugs and immune checkpoint inhibitors is changing the treatment prospects of unresectable HCC[19]. Recently, immunotherapy based on programmed death ligand 1 inhibitors has made breakthroughs in the treatment of advanced HCC, demonstrating stronger anti-tumor activity and superior survival benefits compared to traditional monotherapy[20]. The patient selection criteria or different subgroups of HCC patients might receive different benefits from this combined approach. These results indicate a new era of TACE combined immunotherapy for HCC[21]. There are currently multiple Phase III clinical trials underway for the combination therapy of TACE and programmed cell death 1 (PD-1) inhibitors (NCT03778957, NCT04268888, NCT04246177, NCT04340193), which confirm the clinical efficacy of TACE combined with PD-1 inhibitors in the treatment of HCC[22].

CLINICAL IMPLICATIONS

The continuous development of TACE represented interventional therapy technology and the constant updating of systemic drugs such as molecular targeted drugs and immune checkpoint inhibitors are changing the treatment pattern of primary HCC. The decision-making process for choosing between these therapies is personalized. Clear criteria for therapy applicability depending on HCC staging will help clarify clinical decision-making processes. The combination of interventional therapy and systemic therapy will become a new dawn for HCC treatment. A multidisciplinary approach with different specialists including surgeons, oncologists, and radiologists in deciding and administering these therapies in managing HCC is of importance. In future research, we need to conduct more basic and clinical studies to explore the immunogenic intervention therapy[23].

CONCLUSION

TACE is one of the main treatment methods for advanced HCC. There are other vascular interventional therapies, including DEB-TACE, TARE, and HAIC. The development of TACE represented interventional therapy and systemic drugs such as molecular targeted drugs and immune checkpoint inhibitors are changing the treatment pattern of primary HCC. TACE combined with anti-angiogenesis therapy may improve tumor control and prolong progression free survival. The combination therapy of TACE and immunotherapy may improve the clinical efficacy of HCC.