Two treatment methods for hepatocellular carcinoma: Lenvatinib or bevacizumab combined with sintilimab and interventional therapy

Abstract

In their study, Han et al compared the efficacy of bevacizumab plus sindilizumab plus interventional therapy with that of lenvatinib plus sindilizumab plus interventional therapy for patients with intermediate and advanced hepatocellular carcinoma. The triple therapy, which integrates interventional therapy, targeted therapy, and immunotherapy, has emerged as a promising research focus in the treatment of liver cancer. Consequently, it is of utmost significance to select an appropriate combination of interventional therapy, targeted therapy, and immunotherapy for patients suffering from intermediate and advanced liver cancer.

Key Words: Hepatocellular carcinoma; Bevacizumab; Lenvatinib; Sintilimab; Interventional treatment

Core Tip: Interventional therapy combined with immunotherapy and targeted therapy can significantly prolong the survival of intermediate and advanced hepatocellular carcinoma, but there are very few comparative studies studying the combination of different molecular targeted drugs, different immunotherapeutic drugs, and interventional therapy. Han et al studied the efficacy of lenvatinib or bevacizumab combined with sintilimab and interventional therapy, which can help clarify the efficacy of the combination of different drugs, providing a basis for clinicians to choose the correct treatment strategy for intermediate and advanced hepatocellular carcinoma.

TO THE EDITOR

We are delighted to see the high-quality article published in the World Journal of Gastroenterology by Han et al[1]. The research team retrospectively analyzed data from patients with intermediate and advanced hepatocellular carcinoma (HCC) who received either the bevacizumab plus sindilizumab plus interventional therapy (BeSiIT) or lenvatinib plus sindilizumab plus interventional therapy (LeSiIT) treatment regimen at the Tianjin Medical University Cancer Hospital. Propensity score matching was employed to mitigate the effect of confounding variables and compare the efficacy and safety profiles between the two groups. Notably, Han et al[1] made an innovative contribution by proposing α-fetoprotein and carcinoembryonic antigen score (AFCE) as potential prognostic indicators. AFCE can emerge as a novel and valuable predictor in the field of HCC in the foreseeable future, warranting further studies for validation.

Current status of triple therapy

HCC is the sixth most common malignant tumor and the fourth leading cause of cancer-related deaths worldwide. The majority of Chinese patients with HCC are diagnosed at an intermediate to advanced stage[2]. Interventional therapy in combination with antitumor agents is a hot topic in the treatment of intermediate to advanced HCC. In one study, combination therapy with lenvatinib, sindilizumab, and transarterial chemoembolization (TACE) has shown promising results among patients with advanced HCC[3]. Yuan et al[4] indicated that the combination of TACE with a tyrosine kinase inhibitor and a programmed death 1 (PD-1) inhibitor is safe and can provide a survival benefit compared to TACE alone. In a single-arm phase II trial, lenvatinib combined with PD-1 inhibitor and TACE showed promising antitumour activities with a manageable safety profile in patients with advanced stage HCC[5]. We have already summarized the relevant articles on the combination of different kinds of targeted drugs therapy plus sintilimab plus interventional therapy in recent years (Table 1)[3-10]. These studies have demonstrated that triple therapy can provide great benefits to patients with HCC. These studies strongly indicate that triple therapy can provide significant benefits to patients with liver cancer. The combination of BeSiIT, as well as the combination of LeSiIT, are two commonly adopted treatment regimens in the clinical treatment of intermediate and advanced HCC, both recommended as first-line treatments in China.

Table 1 Articles about targeted drugs plus sintilimab plus interventional therapy on hepatocellular carcinoma.

Rank	Journal	Publication time	Title
1	World Journal of Clinical Cases	2024 January	Lenvatinib combined with sintilimab plus transarterial chemoembolization as first-line treatment for advanced hepatocellular carcinoma[3]
2	International Journal of Surgery	2023 May	TACE-HAIC combined with targeted therapy and immunotherapy versus TACE alone for hepatocellular carcinoma with portal vein tumour thrombus: a propensity score matching study[4]
3	Liver International	2024 April	Lenvatinib, sintilimab plus transarterial chemoembolization for advanced stage hepatocellular carcinoma: A phase II study[5]
4	Journal of Cancer Research and Clinical Oncology	2024 September	Transarterial chemoembolization combined with sintilimab and lenvatinib for the treatment of unresectable hepatocellular carcinoma: A retrospective study[6]
5	Journal of Hepatology	2024 August	The efficacy and safety of radiofrequency ablation combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: A real-world study[7]
6	Journal of Hepatocellular Carcinoma	2023 April	A retrospective analysis of conversion therapy with lenvatinib, sintilimab, and arterially-directed therapy in patients with initially unresectable hepatocellular carcinoma[8]
7	Cancer Immunology, Immunotherapy	2024 November	Efficacy, safety, and biomarker analysis of TACE combined with lenvatinib plus sintilimab in unresectable hepatocellular carcinoma: A real-world study[9]
8	Hepatology	2024 October	Sintilimab plus bevacizumab combined with radiotherapy as first-line treatment for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter, single-arm, phase 2 study[10]

TACE-HAIC: Transarterial chemoembolization-hepatic arterial infusion chemotherapy.

Comparison of treatment in the BeSiIT and LeSiIT groups

Han et al[1] reported no significant differences in progression-free survival and overall survival between the BeSiIT and LeSiIT groups. Likewise, no remarkable alterations were detected in the objective remission rate and disease control rate. However, the conversion rate in the BeSiIT group surpassed that of the LeSiIT group, accompanied by a relatively lower incidence of adverse events. Consequently, from a general perspective, the combination of bevacizumab immunotherapy and interventional therapy may present as a more favorable treatment alternative for patients with advanced HCC. Nevertheless, patients with chronic liver disease inherently suffer from an elevated risk of bleeding and thromboembolic episodes. Bevacizumab, in particular, is associated with an increased propensity for inducing variceal bleeding, with a reported variceal bleeding rate of 10% in phase II trials[11]. Hence, among patients with advanced HCC complicated by severe esophagogastric fundal varices secondary to cirrhosis, the administration of lenvatinib in conjunction with immunotherapy and interventional therapy was potentially a more suitable treatment approach. Nonetheless, certain studies have shown that bleeding and thromboembolic events associated with bevacizumab may not be decisive factors when making a choice between bevacizumab and lenvatinib[12]. Future extensive clinical studies are warranted to address this issue. In scenarios where the safety and efficacy profiles of the two drugs exhibit minimal disparities, patients should consider various practical aspects, including financial considerations, to determine the most appropriate treatment option for their specific circumstances.

AFCE may become a new predictor

The AFCE was formulated based on specific hematological indices. It is calculated as the cumulative sum of the alpha-fetoprotein score and the carcinoembryonic antigen score for each patient. A comprehensive multivariate analysis indicated that AFCE exhibited a statistically significant correlation with the prognostic outcomes of patients with intermediate to advanced HCC who received the BeSiIT regimen. Notably, a lower pretreatment AFCE value was found to indicate a more favorable prognosis. AFCE represents an invaluable asset for patients with intermediate and advanced HCC, and given its simplicity and high speed in determination, it can emerge as a novel and promising predictor of prognosis in the management of HCC.

Limitations and future research directions

This paper has some limitations; as a retrospective single-center study, it was difficult to completely avoid selection bias despite adopting propensity score matching, which may affect the generalizability and extrapolation of the results. Future multi-center prospective randomized controlled trials are needed to validate the findings and improve the level of evidence and the reliability of findings. There exists a paucity of studies dedicated to comparative analyses among combination regimens involving molecularly targeted agents, immunotherapeutic agents, and interventional therapies. Han et al[1] explored the efficacy of distinct targeted agents in combination with sindolizumab and interventional therapies. More recently, Huang et al[13] compared programmed death ligand 1 inhibitors and PD-1 inhibitors in conjunction with bevacizumab and transvascular intervention for the treatment of unresectable HCC. These studies signify promising avenues for future research endeavors. Looking ahead, it is essential to conduct more prospective studies on comparative evaluations between different targeted agents or diverse immunotherapeutic agents when combined with interventional therapy to expand our knowledge and optimize treatment strategies in this field.

Conclusion

In intermediate and advanced HCC, the BeSiIT and LeSiIT groups showed acceptable toxicity and comparable progression-free survival, overall survival, and objective remission rate, and patients need to choose the appropriate regimen based on their actual situation.

ACKNOWLEDGEMENTS

We are grateful to the editors for their work and also to the reviewers for their comments, which made our article more rigorous.