Effectiveness of transarterial chemoembolization in combination with lenvatinib and programmed cell death protein-1 inhibition for unresectable hepatocellular carcinoma

Abstract

This editorial comments on the study by Ma et al, which delves into the efficacy and predictive factors associated with the combination of transarterial chemoembolization, lenvatinib, and programmed cell death protein-1 inhibition for the management of unresectable hepatocellular carcinoma. Analysing data from a retrospective study involving 102 patients, the treatment showcased a median overall survival (OS) of 26.43 months and a median progression-free survival (PFS) of 10.07 months. Notably, the objective response rate and disease control rate reached 61.76% and 81.37%, respectively. Specific factors such as Barcelona Clinic Liver Cancer (BCLC) Classification B-stage, early neutrophil-to-lymphocyte ratio response, and early alpha-fetoprotein response (> 20% decrease) correlated with superior OS and PFS. The triple therapy exhibited promising efficacy, particularly in BCLC B-stage disease, with prognostic markers aiding in patient stratification. Acknowledging the retrospective nature of the study design, future research should address this limitation and incorporate longer follow-up periods for a comprehensive evaluation of long-term outcomes.

Key Words: Hepatocellular carcinoma, Transarterial chemoembolization, Lenvatinib, Programmed cell death protein-1 inhibitors, Unresectable hepatocellular carcinoma

Core Tip: Transarterial chemoembolization (TACE) combined with lenvatinib and programmed cell death protein-1 (PD-1) inhibitors presents an encouraging therapeutic approach for unresectable hepatocellular carcinoma (HCC). This triple therapy demonstrates well-tolerated outcomes with a median overall survival of 26.43 months and a median progression-free survival of 10.07 months. Notably, patients with Barcelona Clinic Liver Cancer B-stage, exhibiting early neutrophil-to-lymphocyte ratio and alpha-fetoprotein responses, show superior clinical outcomes. Understanding these predictive factors can guide treatment decisions and enhance the efficacy of TACE/lenvatinib/PD-1 therapy in unresectable HCC.

INTRODUCTION

Hepatocellular carcinoma (HCC) stands as a leading cause of cancer-related deaths globally, marked by an unfavourable prognosis. HCC poses a significant global health burden, and its management continues to evolve with the exploration of novel therapeutic strategies. The primary risk factor for HCC in Asia is chronic hepatitis B virus infection, whereas HCC in Western countries is predominantly associated with hepatitis C virus infection and alcohol intake[1]. These differing risk factors lead to variations in the genetic landscape, molecular subtypes, and clinical phenotypes of HCC cases between Asia and Western countries. Coffee, statins, metformin and aspirin are protective against the development of HCC in multiple observational studies[2].

In its early stages, HCC can be efficiently managed through approaches such as resection, liver transplantation, or ablation. Regrettably, individuals are frequently diagnosed with intermediate or advanced stages of the disease, primarily due to the lack of noticeable symptoms during the early phases. Upon diagnosis of HCC, healthcare providers commonly rely on the Barcelona Clinic Liver Cancer (BCLC) staging system to guide treatment decisions. This system integrates multiple factors to ascertain the most suitable course of action. A pivotal element of this system is the Child-Pugh score, which takes into account the Eastern Cooperative Oncology Group (commonly known as ECOG) performance status, tumour burden (including portal invasion status and hepatic spread), and an evaluation of underlying liver function. In cases of decompensated cirrhosis, additional evaluation using the Model for End-Stage Liver Disease (MELD) score is recommended, while in compensated liver disease, factors like alpha-fetoprotein (AFP) concentration and the albumin-bilirubin score are considered.

HCC patients are stratified into five stages: very early: BCLC 0; early: BCLC A; intermediate: BCLC B; unresectable: BCLC C; and end-stage: BCLC D. Approximately 40% of HCC patients are diagnosed early, rendering them suitable candidates for curative local interventions like radiofrequency ablation or surgical procedures like hepatic transplantation or even hepatic resection. An ominous prognostic factor in HCC is the presence of portal vein tumour thrombus, which is detected in about 10%–60% of HCC cases during the time of diagnosis itself. This condition signifies a median survival period of merely 2.7–4.0 months in the absence of intervention[3]. For most patients diagnosed with HCC, chemoembolization or radioembolization turns out to be effective. These treatment modalities aim to address the specific challenges posed by the intermediate stage of HCC, where curative options are limited and the disease is not amenable to surgical resection. Employing systemic therapies, chemoembolization, or radioembolization becomes crucial to manage HCC progression, providing a tailored approach based on the individual characteristics of the tumour and the patient's overall health.

In advanced stages of the disease, systemic therapies like sorafenib and lenvatinib are recommended as primary treatment modalities according to guidelines from the BCLC and the European Association for the Study of the Liver (commonly referred to as the EASL)[4,5]. Japanese and Chinese guidelines prefer hepatic arterial infusion chemotherapy as the primary treatment for HCC[4,6].

Among the options for advanced disease, the combination of transarterial chemoembolization (TACE), lenvatinib administration, and inhibition of programmed cell death protein-1 (PD-1) has emerged as a promising approach for unresectable HCC. The integration of targeted therapies and immunomodulation presents a multifaceted strategy to address the complexities of HCC treatment. TACE has long been established as a standard locoregional therapy for unresectable HCC, providing both cytotoxic and ischemic effects[7]. The multitargeted tyrosine kinase inhibitor lenvatinib demonstrates efficacy in inhibiting angiogenesis and tumour growth[8]. Additionally, the inclusion of PD-1 inhibitors enhances the antitumor immune response, potentially improving overall treatment outcomes[9]. In recent years, a new era in treating HCC complicated by portal vein tumour thrombus has emerged, marked by the utilization of immune checkpoint inhibitors, particularly in combination with tyrosine kinase inhibitors and local therapies.

In contrast to TACE-sorafenib, TACE-lenvatinib has demonstrated superior outcomes in terms of progression-free survival (PFS), disease control rate, and overall survival (OS) for individuals with unresectable HCC[10]. Notably, in specific subgroups, such as BCLC B-stage or patients refractory to TACE, TACE-lenvatinib combination has shown superiority.

The study under review investigates the efficacy and predictive factors associated with this tripartite therapeutic regimen in unresectable HCC[11]. As traditional treatments often face challenges in achieving sustained responses, the integration of TACE with systemic therapies offers a comprehensive approach to address intrahepatic and systemic disease components.

In this editorial review, we delve into the key findings of the study, exploring the clinical implications and advancing our understanding of personalized approaches to HCC management. The identification of predictive factors contributing to treatment success holds the potential to refine patient selection and optimize the outcomes of this innovative therapeutic combination.

EDITORIAL COMMENTARY

The study conducted by Ma et al[11] significantly contributes to our understanding of the application of TACE alongside lenvatinib and PD-1 inhibitors for managing unresectable HCC. Through a thorough retrospective analysis spanning from March 2019 to April 2022, the authors sought to assess both the efficacy of this triple therapeutic approach and the predictive factors associated with it.

The outcomes derived from the 102 enrolled patients present promising results. The median OS of 26.43 months and median PFS of 10.07 months underscore the potential effectiveness of TACE/lenvatinib/PD-1 treatment. Particularly noteworthy are the favourable objective response rate and disease control rate at 61.76% and 81.37%, respectively.

Critically, the study identifies particular patient cohorts showing enhanced OS and PFS, particularly those categorized as BCLC B-stage, individuals exhibiting early neutrophil-to-lymphocyte ratio (i.e., ‘NLR’) response, and those demonstrating an early AFP response (> 20% decrease). This nuanced identification of predictive factors offers valuable insights for tailoring treatment strategies to maximize efficacy.

Despite the retrospective nature of the study, the findings suggest that the TACE/lenvatinib/PD-1 regimen is well-tolerated and holds promising efficacy for patients with unresectable HCC. The recognized predictive factors provide a solid foundation for refining patient selection, ultimately enhancing clinical outcomes with this combination therapy. In essence, this study is a notable addition to the evolving landscape of HCC management, calling for further exploration in prospective trials.

CLINICAL IMPLICATIONS

The findings from this study hold significant clinical implications for the management of unresectable HCC. The observed efficacy and tolerability of TACE combined with lenvatinib and PD-1 inhibitors underscore the potential of this triple therapy as a viable treatment option. The identified predictive factors, including BCLC B-stage, early NLR response, and early AFP response, offer clinicians valuable insights for patient stratification. Tailoring the TACE/lenvatinib/PD-1 regimen based on these factors may contribute to improved OS and PFS. Ultimately, however, we anticipate that this study will prompt clinicians to consider a personalized approach, taking into account individual patient characteristics, to optimize outcomes in unresectable HCC cases. Further prospective investigations are warranted to validate these findings and refine treatment algorithms in the pursuit of enhanced clinical efficacy and patient outcomes.

CONCLUSION

In conclusion, this editorial review underscores the effectiveness and safety of integrating TACE with lenvatinib and PD-1 inhibition for unresectable HCC. The study provides valuable insights into factors influencing clinical outcomes, with BCLC B-stage, early NLR response, and early AFP response emerging as key predictors of superior OS and PFS. The encouraging efficacy and tolerability of the TACE/lenvatinib/PD-1 regimen suggest its potential as an effective therapeutic approach for unresectable HCC. Collectively, these findings underscore the importance of personalized treatment strategies, emphasizing the need for further research to validate and optimize this triple therapy, and ultimately enhancing clinical decision-making and patient care in the challenging landscape of unresectable HCC management.