Current impact in the treatment of advanced hepatocellular carcinoma: The challenge remains

Abstract

Hepatocellular carcinoma remains a significant cause of mortality worldwide, particularly among patients with liver cirrhosis. In most cases, surveillance in cirrhotic patients is neglected, leading to a diagnosis when the neoplasm is at an advanced stage. Within this context, Zhou et al carried out a network meta-analysis to demonstrate the effectiveness of hepatic arterial infusion chemotherapy, concluding that it is a superior approach compared to sorafenib and transarterial chemoembolization in the treatment of advanced hepatocellular carcinoma. Unfortunately, the meta-analysis in question lacks methodological rigor, preventing the authors from making more definitive assertions. Additionally, we understand that transarterial chemoembolization, when properly indicated, is a highly effective therapeutic option, and that sorafenib, given the results of new therapies based on immune checkpoint inhibitors, is no longer the recommended drug for the treatment of these patients. Therefore, we believe the use of hepatic arterial infusion chemotherapy is increasingly limited and lacks strong scientific support.

Key Words: Hepatocellular carcinoma; Meta-analysis; Treatment; Liver diseases; Liver neoplasms

Core Tip: Hepatocellular carcinoma remains a significant cause of mortality worldwide, particularly among patients with liver cirrhosis. In most cases, diagnosis is made at an advanced stage. Within this context, Zhou et al carried out a network meta-analysis to demonstrate the effectiveness of hepatic arterial infusion chemotherapy, concluding that it is a superior approach compared to sorafenib and transarterial chemoembolization in the treatment of advanced hepatocellular carcinoma. Unfortunately, the meta-analysis in question lacks methodological rigor, preventing the authors from making more definitive assertions. In conclusion, we believe the use of hepatic arterial infusion chemotherapy is increasingly limited and lacks strong scientific support.

TO THE EDITOR

This article is regarding the paper published by Zhou et al[1] in 2024. Hepatocellular carcinoma (HCC) remains the fourth leading cause of cancer-related mortality worldwide. Its incidence and mortality rates are closely aligned, indicating a high fatality rate. HCC is the leading cause of death among patients with cirrhosis, and its incidence is rising, particularly in countries with a high sociodemographic index[2,3]. This issue is compounded by the neglect of surveillance in cirrhotic patients, which hinders early diagnosis and curative treatment[4]. As a result, the use of palliative procedures becomes necessary. In this context, we read with great interest the study by Zhou et al[1], which employs a network meta-analysis (NMA) to demonstrate the effectiveness of hepatic arterial infusion chemotherapy (HAIC), concluding that it is superior to sorafenib and transarterial chemoembolization (TACE) for the treatment of advanced HCC.

NMA

NMA is a statistical method that allows the simultaneous comparison of multiple treatments by integrating direct and indirect evidence from randomized controlled trials (RCTs), thereby increasing statistical power. However, its application presents challenges. The validity of an NMA depends on the quality and homogeneity of the included studies, as variations in study design, populations, and outcome measures can introduce heterogeneity and bias. Combining interventional studies (e.g., RCTs) with observational studies (e.g., cross-sectional and cohort studies) can lead to misinterpretation of the results. Additionally, including RCTs with poor methodological quality can introduce bias. In this article, as evidenced by the risk of bias assessment, none of the included studies had adequate blinding, which significantly affected their quality[5]. A more comprehensive search of major databases could have minimized this bias, which was not conducted in this study. Therefore, we believe the authors could not definitively conclude the effectiveness of HAIC.

NEED FOR TAILORED TREATMENT

Despite this, it is worth noting that the 2014 Japanese guidelines, which strongly recommended HAIC for patients with portal invasion at the main portal branch[6], were significantly revised in 2021[7], restricting HAIC’s use. The authors of the updated consensus explicitly state that the advent of current systemic therapies has relegated HAIC to a less prominent role, particularly due to the lack of studies comparing HAIC with systemic therapies, especially immunotherapy. The document concludes that for Child-Pugh class A patients with HCC who are ineligible for resection or locoregional therapy due to vascular invasion, systemic therapy is recommended. However, HAIC may be considered for cases with significant vascular invasion. If patients develop vascular invasion after multiple TACE sessions and no longer respond to TACE, systemic therapy is preferred, as HAIC is unlikely to provide benefit in such cases.

TACE

Including patients with unresectable HCC, particularly those classified as Barcelona Clinic Liver Cancer stage B (BCLC-B), in the study may not be appropriate, as BCLC-B patients derive significant benefit from TACE. Although the authors express skepticism regarding TACE, it remains an effective treatment when well-indicated, with good survival rates and minimal adverse effects. Generally, median survival for TACE should not fall below 30 months[8]. In our experience, median survival reached 33.2 months, with 1-, 2-, and 5-year survival rates of 75%, 54%, and 27%, respectively, and adverse effects observed in less than 15% of cases[9]. More recently, we evaluated conventional TACE and drug-eluting beads-TACE in 268 HCC patients receiving palliative care, and the outcomes were comparable[10]. TACE’s role is gaining prominence, particularly when combined with systemic therapy (e.g., anti-programmed death-ligand 1 immunotherapy and anti-vascular endothelial growth factor), which has shown improved progression-free survival[11].

CHALLENGES IN TREATMENT

Sorafenib, once the standard of care for over a decade[12], has lost its status. The conclusion of the present study is thus less relevant and unfavorable, as sorafenib is no longer a first-line therapy in most centers and is not recommended by leading hepatology societies. Its use is now primarily restricted to patients who cannot receive immunological therapies[13]. In agreement with the authors, we emphasize that HAIC is not recommended in the Western world, as per guidelines from the American Association for the Study of Liver Diseases[14], American Gastroenterological Association[15], American Society of Clinical Oncology[16], BCLC[17], European Association for the Study of the Liver[18,19], and European Society for Medical Oncology[20,21]. Interestingly, HAIC is also not widely endorsed in the Eastern literature. The Asian Pacific Association for the Study of the Liver excludes HAIC from its latest guideline[22]. Furthermore, the procedure is absent from the multicenter insight study, which investigates the real-world epidemiology of HCC and clinical practices in the Asia-Pacific region[23]. Notably, the latest Japanese consensus[7], now recommends atezolizumab and bevacizumab as first-line treatments for advanced HCC in patients with good performance status and liver function, as these therapies have shown efficacy in this population[24].

CONCLUSION

Emerging first-line treatments for advanced HCC, such as tremelimumab combined with durvalumab[25,26], and drugs in phase 3 trials, including nivolumab and ipilimumab, have shown promising results in interim analyses[27]. With these advancements, it is increasingly critical to identify biomarkers for response prediction to new systemic therapies (immune checkpoint inhibitors) and explore novel therapeutic targets[28]. Thus, proposing an invasive method requiring specialized expertise, as HAIC does, appears less practical, particularly as it is only available in a limited number of centers worldwide. Finally, we emphasize that the best treatment for HCC should be determined by a hepatologist. However, their role must be contextualized within a multidisciplinary team to ensure the optimal approach for each patient population.