Advanced hepatocellular carcinoma treatment strategies: Are transarterial approaches leading the way?

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with advanced stages posing significant treatment challenges. Although hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising modality for treating advanced HCC, particularly in Asian clinical practice, its adoption in Western medicine remains limited due to a lack of large-scale randomized controlled trials. This editorial reviews and comments on the meta-analysis conducted by Zhou et al, which evaluates the efficacy and safety of HAIC and its combination strategies for advanced HCC. The authors performed a comprehensive meta-analysis of various clinical trials and cohort studies comparing HAIC and its combinations to other first-line treatments, such as sorafenib and transarterial chemoembolization (TACE). In this work, HAIC showed significantly better results regarding overall survival and progression-free survival compared to sorafenib or TACE alone and their combination. HAIC in combination with lenvatinib, ablation, programmed cell death 1 inhibitors, and radiotherapy further enhanced patient outcomes, indicating a synergistic effect. This editorial focuses on the critical role of multimodal treatment strategies in managing advanced HCC. It advocates for a paradigm shift towards integrated treatment approaches to enhance survival rates and improve the quality of life in patients with advanced HCC.

Key Words: Hepatocellular carcinoma; Hepatic arterial infusion chemotherapy; Transarterial chemoembolization; Sorafenib; Combined therapy

Core Tip: The treatment landscape for hepatocellular carcinoma (HCC) is various, including surgical resection, ablation, transplantation, transarterial, and systemic therapies. Each modality is selected based on tumor characteristics, liver function, and patient performance status. This editorial explores the role of hepatic arterial infusion chemotherapy and its combination strategies for advanced HCC, highlighting its potential advantages and advocating for its broader acceptance based on recent meta-analysis findings.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and the fourth leading cause of mortality in cancer patients worldwide[1]. Five-year survival of HCC is approximately 18%[2]. Only 20%-30% of HCC patients are eligible for curative treatment. For the remaining majority, the prognosis remains poor, particularly when HCC is diagnosed at an advanced stage, where curative options such as surgical resection, liver transplantation, or ablation are no longer feasible. Advanced HCC typically consists of extensive liver involvement, vascular invasion, and distant metastases, making treatment especially challenging[1].

Different treatment options have been described for patients affected by HCC depending on tumor stage with/without vascular invasion, number and size of the lesions, underlying liver function (Child-Pugh, model for end-stage liver disease score), and patient performance status (ECOG PS 0-4).

According to the Barcelona Clinic Liver Cancer (BCLC) organization, patients with very early stage (0) and early stage (A) HCC can be treated with surgical resection, ablation, or liver transplantation[3,4].

According to the European Association for the Study of the Liver (EASL) guidelines, surgical resection is the preferred treatment for patients with single tumors larger than 2 cm, preserved liver function (Child-Pugh A or B), good performance status (PS 1-2), and an adequate volume of remaining liver. Depending on the tumor size (< 5 cm) and liver function (Child-Pugh A), the 5- and 10-year survival rates after resection are favorable at 70% and 35%, respectively. However, the 5-year recurrence rate remains high at 70%[5,6].

The advancement of minimally invasive surgery, which is associated with fewer postoperative complications and a potentially minimal impact on liver function[7-10], supports the consideration of resection for patients who would initially have been chosen for ablation. This is particularly relevant for patients with peripheral tumors where ablation might be contraindicated due to risks like tract seeding or damage to neighboring organs[7].

For patients classified as BCLC 0-A who do not qualify for surgical resection or liver transplantation, ablation can be a viable alternative.

Ablation techniques include radiofrequency ablation (RFA), microwave ablation, and the injection of chemical agents (such as ethanol, boiling saline, and acetic acid), as well as laser therapy and cryotherapy. Microwave ablation has shown promise with favorable response rates for tumors ranging from 3 to 5 cm in size and those near blood vessels or the gallbladder[11]. It generally requires fewer sessions and provides survival rates comparable to those achieved with RFA. For very early HCCs (≤ 2 cm), ablation can offer similar survival outcomes to resection but with better cost-effectiveness[11-13]. However, for single, larger early-stage HCCs, surgical resection remains the preferred approach due to its superior survival rates[13,14].

Liver transplantation is the best treatment for patients who meet the Milan criteria (single nodule ≤ 5 cm in diameter or up to three nodules, each ≤ 3 cm, without macrovascular invasion or extrahepatic spread) or extended liver transplant criteria. By eliminating both the tumor(s) and the underlying cirrhosis, this approach offers 5-year and 10-year survival rates of approximately 60%-80% and 50%, respectively. Additionally, the recurrence rate of HCC post-transplantation is under 15%, which is better than the recurrence rate following surgical resection[15].

Transarterial treatments are an option for patients with BCLC stage 0-A who have failed first-line therapies and are considered standard care for those with BCLC intermediate stage (B) disease. This includes patients with multinodular HCC that have no vascular invasion or extrahepatic spread, preserved portal flow, good liver function (Child A-B), and a favorable performance status (PS 0). The main transarterial treatments are transarterial chemoembolization (TACE), hepatic arterial infusion chemotherapy (HAIC), and selective internal radiation therapy (SIRT). These approaches take advantage of the fact that while normal liver tissue receives over 75% of its blood supply from the portal vein, liver tumors receive approximately 80% of their blood from the hepatic artery.

TACE, introduced in the 1970s for unresectable HCC, remains the standard treatment for intermediate-stage HCC with relatively preserved liver function. The TACE procedure involves intra-arterial injection of a cytotoxic agent followed by embolization of the tumor-feeding artery, combining the effects of targeted tumor ischemia and chemotherapy. After undergoing TACE, overall survival rates of 70.3%, 40.4%, and 32.4% were reported at 1, 3, and 5 years, respectively[16]. Combining TACE with sorafenib has shown improved progression-free survival (PFS) compared to TACE alone. While the role of TACE as a bridge to liver transplantation is not yet well-defined, it can be effective in downstaging patients with advanced HCC[17].

SIRT (also known as TARE) involves the intra-arterial infusion of yttrium-90 microspheres and is considered for patients with BCLC intermediate stage (B). It has demonstrated comparable results to TACE and can be considered for patients with single nodules ≤ 8 cm[18]. When used as a bridge to transplantation, SIRT shows similar outcomes to RFA and TACE[17].

Systemic therapy encompasses the adoption of multikinase inhibitors like sorafenib and lenvatinib and immunotherapy. Sorafenib, approved in 2007, targets pathways involved in cell proliferation and angiogenesis. It benefits HCC patients with Child-Pugh A or B7 liver function. Lenvatinib, approved in 2018, demonstrated non-inferiority to sorafenib. Lenvatinib is used globally, but sorafenib is less favored in Asia due to its lower efficacy in hepatitis B virus (HBV)-HCC patients[19]. Immune checkpoint inhibitors (ICIs) have enriched the panel of advanced HCC treatments. For example, pembrolizumab, targeting programmed cell death 1, was approved in the United States as a second-line treatment after sorafenib failure[20].

THE ROLE OF HAIC

HAIC is a locoregional treatment that utilizes a catheter technique to directly and continuously deliver high doses of anti-cancer drugs to liver tumors. This approach increases the local concentration of drugs within the tumor while minimizing systemic side effects. HAIC typically involves the implantation of a catheter and port system, enabling repeated administration of chemotherapeutic agents.

HAIC treatment is currently not included in the guidelines of the American Association for the Study of Liver Diseases, the EASL, or the Asian Pacific Association for the Study of the Liver, due to insufficient clinical evidence to make strong recommendations. Despite this, HAIC has been utilized in Asia, especially in Japan and South Korea, to enhance the prognosis of advanced HCC and has been incorporated into treatment guidelines[21]. The potential of HAIC may be underestimated due to the small sample sizes in previous studies and the lack of larger randomized trials.

Recently, the Japanese Society of Implantable Port Assisted Treatment has proposed clinical practice guidelines for HAIC with a port system, which could facilitate broader adoption of this treatment[22,23].

The primary advantage of HAIC compared to other systemic treatments is its substantial increase in local drug concentration due to the higher first-pass effect in the liver. This results in enhanced antitumor efficacy while minimizing systemic toxicity. In this regard, most studies on HAIC have reported a zero rate of treatment discontinuation due to infusion-related complications. Another significant advantage of HAIC lies in its application for patients with portal vein tumor thrombus. Most guidelines consider unresectable HCC with significant portal vein tumor thrombosis unsuitable for TACE, with sorafenib being the standard recommended treatment. However, before sorafenib approval for advanced HCC, HAIC was already routinely used in the Asian region, particularly in Japan and Korea, demonstrating promising results and likely surpassing the outcomes achieved with sorafenib alone. These findings prompted the design of trials comparing various HAIC regimens (such as cisplatin and 5-FU based) with sorafenib alone and their combinations[24]. While cisplatin and 5-FU based HAIC are the most commonly used regimens in Japan, they do not appear to outperform TACE in combination therapy. On the other hand, more aggressive HAIC regimens, such as 5-FU, leucovorin, and oxaliplatin (FOLFOX)-HAIC, have shown a distinct advantage over TACE in terms of both efficacy and safety[25].

The heterogeneity of the published studies and the different chemotherapy regimens used represent a jungle that is very difficult to navigate. A review of 1026 publications on HAIC for HCC reveals a significant increase in research output since 1990, with the most significant rise occurring in the past decade[26]. Notably, 83 studies were published in 2021, the highest number in the reviewed period. Regarding institutional and national contributions, Japan leads with 456 publications, followed by China (197), South Korea (96), and the United States (83). Overall, HAIC has gained prominence in HCC treatment, exploring its efficacy in combination with targeted and immunotherapy treatments.

The flip side of the coin is that several challenges hinder a clear evaluation of its efficacy. One of the key issues is the presence of too many variables across studies, making them difficult to compare. These variables include the size of the HCC, whether portal vein infiltration is present, and the degree of cirrhosis or hepatic arterialization. Additionally, the statistical analysis methods used in different studies vary, further complicating the comparison of results. Patient populations differ significantly, leading to heterogeneity in the outcomes. Furthermore, most of the studies come from Asia and this geographical dominance limits the global applicability of HAIC. To improve comparability, it would be crucial to establish global databases that classify patients into macro-categories based on factors such as HCC type, tumor size, liver function, and treatment line (first or second). This would enable the creation of a unified treatment strategy, allowing for more accurate comparisons. While HAIC shows generally favorable results, other studies suggest combining it with other treatments, indicating that HAIC alone might not be sufficient in most cases.

The meta-analysis conducted by Zhou et al[27] contributes to this context by seeking to organize and clarify the substantial heterogeneity present in the published studies[27].

The article is titled “Efficacy of HAIC and its combination strategies for advanced HCC: A network meta-analysis” and evaluates the effectiveness of HAIC both as a standalone treatment and in combination with other therapies for patients with advanced HCC. This meta-analysis offers a thorough comparison of HAIC with other first-line treatments, such as sorafenib and TACE, providing valuable insights into its potential advantages. The findings suggest that HAIC yields slightly better outcomes than both TACE and sorafenib in advanced HCC cases. Additionally, combined therapies (e.g., HAIC + TACE) showed modestly enhanced results in overall survival, PFS, complete response, partial response, overall response rate, and disease control rate compared to HAIC alone.

The analysis by Zhou et al[27] emphasizes the underutilization of HAIC in Western medical practice, primarily due to the lack of randomized controlled trials supporting its use. This meta-analysis, by integrating data from various randomized controlled trials and cohort studies, bridges this gap and advocates for broader acceptance of HAIC based on its demonstrated efficacy and safety. While challenges remain in its clinical integration, the compelling evidence presented in this study paves the way for renewed interest and further research in HAIC, promising improved outcomes for patients with advanced HCC.

THE EAST-WEST DIFFERENCE

The choice of treatment is governed by factors such as underlying comorbidities, the stage of the disease, liver function, and overall performance status. The management of HCC varies significantly between Eastern and Western countries due to differences in epidemiological and etiological factors. In Eastern countries, HCC is predominantly associated with HBV, hepatitis C virus, and aflatoxin exposure. Conversely, in Western countries, HCC is more commonly linked to metabolic syndrome and alcohol abuse. The prevalence of obesity, diabetes, and non-alcoholic fatty liver disease contributes significantly to HCC cases in these regions[28,29].

Guidelines for HCC differ between Western and Eastern countries. The Western guidelines (American Association for the Study of Liver Diseases, EASL-European Organization of Research and Treatment of Cancer) incorporate the BCLC staging classification in the therapeutic algorithm, leading to narrower resection indications (resection for non-cirrhotic livers, resection for a single tumor of any size or 2-3 nodules within 3 cm, no resection for vascular invasion). In contrast, eastern countries (China, Hong Kong, Japan, and Korea) do not have unified guidelines and do not use the BCLC in the therapeutic algorithm. For example, China and Japan consider resection for tumors of any size, including advanced stages with portal vein thrombi, if embolectomy through the portal vein can be attempted[30,31].

Western guidelines recommend TACE for BCLC stage B HCC, while Eastern guidelines may favor surgical resection if sufficient liver reserve is possible, even with portal vein involvement. In Western countries, macrovascular invasion is often managed with systemic therapies, while in Asia, TACE remains an option, and where expertise is available, HAIC serves as an alternative to TACE or initial systemic chemotherapy. The Japanese guideline recommended HAIC for HCC patients with more than four tumors, portal or macrovascular invasion, or those who have failed TACE[32].

The integration of local and systemic therapies in a multimodal approach ensures comprehensive tumor control. Local treatments such as HAIC and TACE deliver high concentrations of chemotherapeutic agents directly to the tumor site, achieving greater tumor shrinkage. When combined with systemic therapies, which address micrometastasis and circulating tumor cells, this approach maximizes tumor control and delays progression. One of the major challenges in advanced HCC treatment is the development of resistance to single-agent therapies. Multimodal approaches can mitigate this issue by targeting different pathways involved in tumor growth and survival. For example, combining HAIC with ICIs not only attacks the tumor directly but also modulates the immune environment, making it more hostile to cancer cells. This multifaceted attack can prevent the emergence of resistant tumor clones.

CONCLUSION

HAIC represents a promising locoregional treatment for advanced HCC, offering targeted drug delivery directly to liver tumors and minimizing systemic side effects. Despite not being widely endorsed by major liver disease guidelines due to limited evidence, HAIC has demonstrated notable efficacy in Asian countries. Although HAIC impact is sometimes overshadowed by other treatments like sorafenib or TACE, emerging evidence, including Zhou et al’s meta-analysis[27], suggests HAIC efficacy, particularly when used in combination therapies. Addressing the existing variability and geographical biases through comprehensive global databases and further randomized trials could enhance HAIC global adoption and optimize treatment outcomes for advanced HCC.