Maximizing therapeutic outcomes in hepatocellular carcinoma: Insights into combinatorial strategies

Abstract

In this editorial, we review the article by Ma and colleagues, published in the World Journal of Gastrointestinal Oncology. Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Although transarterial chemoembolization (TACE) has been used effectively for several years, particularly in patients with intermediate-stage HCC, the quest for the optimal combination therapy to enhance its efficacy and HCC treatment strategies persists. Combining TACE with tyrosine kinase inhibitors (TKIs) like sorafenib or lenvatinib has shown confusing results in improving both progression-free survival and overall survival. Similarly, combining TACE with immune checkpoint inhibitors (ICIs) has demonstrated potential efficacy by reshaping the tumor microenvironment and activating immune responses. Recent studies suggest combining TACE with TKIs and ICIs may offer synergistic effects. Additionally, combining TKIs and ICIs with other local treatments like microwave ablation or hepatic arterial infusion chemotherapy has shown promise in enhancing efficacy. However, more extensive prospective studies are needed to validate these findings. Overall, these combinations represent a promising direction in HCC management, emphasizing the need for further research to optimize treatment outcomes.

Key Words: Hepatocellular carcinoma; Transarterial chemoembolization; Transarterial radioembolization; Tyrosine kinase inhibitors; Immune checkpoint inhibitors

Core Tip: Combining transarterial chemoembolization (TACE) with tyrosine kinase inhibitors and immune checkpoint inhibitors shows promise in enhancing therapeutic outcomes for hepatocellular carcinoma (HCC) patients, offering viable alternatives when TACE alone is ineffective or unsuitable. Further exploration and validation of these combination therapies with TACE, as well as investigating other local treatment options for potential synergistic effects, are warranted to optimize HCC treatment strategies.

INTRODUCTION

Hepatocellular carcinomas (HCC), frequently attributed to alcohol consumption and viral hepatitis in terms of etiology, stand out among prevalent cancers and constitute a leading cause of cancer-related mortality[1]. Transarterial chemoembolization (TACE) has been a used and efficacious treatment option for patients with intermediate-stage HCC, notably those with well-preserved performance status, favorable portal blood flow, and well-characterized lesions [Barcelona Liver Cancer (BCLC) Stage B], as well as for those in earlier stages (BCLC-Stage A) where resection is not feasible[2,3]. In TACE, for HCC, the hepatic arteries, which are the major arteries supplying the tumor, are selectively blocked. This process leads to the targeted necrosis of tumor cells by inducing the accumulation of chemotherapeutic agents at high concentrations within the tumors[4]. While TACE remains an effective and essential therapeutic approach in HCC management, instances where it is deemed inappropriate or proves unsuccessful prompt the exploration of alternative strategies. In scenarios where TACE is unsuitable or yields less than favorable outcomes, the efficacy of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) is well-documented. These agents are utilized in treating HCC either as monotherapy or in various combinations, offering viable alternatives when TACE is not feasible or proves ineffective[3].

As the landscape of HCC treatment evolves, understanding the role of TACE as a standard therapeutic modality and exploring emerging strategies involving TKIs and ICIs becomes imperative. This editorial aims to elucidate the current status of TACE and delve into the evolving landscape of HCC therapeutics, providing insights into integrating novel approaches for optimizing patient outcomes.

TACE PLUS TKIS

There is evidence suggesting that TACE may upregulate angiogenesis following ischemia, potentially leading to a decrease in the effectiveness of TACE[5]. In context, various hypotheses have been proposed to enhance the efficacy of TACE, one of which involves the synergistic effect of combining TACE with angiogenesis inhibition. The addition of systemic therapeutic agents to TACE has not shown a positive contribution, particularly in patients with low intrahepatic tumor burden, and is not a routine practice. However, studies exploring this avenue have predominantly involved sorafenib, a multikinase inhibitor known to inhibit vascular endothelial growth factor (VEGF), with claims that combining it with TACE could enhance the effectiveness of the latter. Two randomized phase-3 trials investigating the addition of sorafenib to TACE did not demonstrate a significant positive impact on progression-free survival (PFS)[6,7]. In contrast, the tactics study, conducted by Kudo et al[8], reported a significantly longer median PFS in the TACE + sorafenib arm compared to TACE alone (25.2 months vs 13.5 months; respectively, P = 0.006). The distinction of the tactics study from other negative studies lies in its different interpretation of the term "progression". In this study, the appearance of a new lesion in the liver was not immediately considered as progression, and if appropriate, re-TACE was deemed suitable. Additionally, researchers were allowed to continue sorafenib treatment based on investigator preference and patient tolerability. Patients deemed unsuitable for TACE were considered as progressing. Therefore, the authors postulated that these positive results might be attributed to a longer median duration of sorafenib use compared to other studies (38.7 wk vs approximately 20 wk). Furthermore, a meta-analysis incorporating 17 studies suggested that adding sorafenib to TACE led to a moderate increase in PFS but did not contribute to overall survival (OS)[9].

Lenvatinib, a TKIs with multikinase inhibitory properties, including VEGF receptor 1-3 inhibition, has been proven as a first-line treatment agent non-inferior to sorafenib for untreated HCC[10]. In a phase-3 randomized trial (LAUNCH) predominantly comprising Hepatitis B virus (HBV)-related HCC, 338 patients with advanced-stage, previously untreated HCC were randomized to TACE + lenvatinib or lenvatinib alone arms[11]. With a median follow-up of 17 months, the combination arm demonstrated superior median PFS and OS compared to lenvatinib alone [for PFS; 10.6 vs 6.4 months, hazard ratio (HR): 0.43, P < 0.001; for OS; 17.8 vs 11.5 months, HR: 0.45, P < 0.001]. However, as expected, Grade 3-4 toxicity was higher in the combination arm. Despite the positive effects observed with the combination of TACE and lenvatinib in this study, the fact that the study was conducted only in the Chinese population, mostly including HBV-related cases, suggests caution in the routine global use of TACE + lenvatinib. However, the study provides valuable insights into the feasibility of combining local treatments with systemic therapies.

TACE PLUS ICIS

ICIs have proven efficacy in the treatment of unresectable/metastatic HCC, particularly for patients unsuitable for local therapies, either as monotherapy or in combination with other drugs[12]. As mentioned earlier, studies are underway to investigate the combination of ICIs with TACE to enhance TACE effectiveness. Physiopathologically, it is believed that the efficacy of TACE results not only from its direct ischemic and cytotoxic effects but also from its ability to reshape the tumor microenvironment[13,14]. Locally released cellular debris and cytokines after TACE may activate the immune system[15].

Recent analyses of specimens obtained from patients who underwent TACE before resection or transplantation have demonstrated positive peripheral immune cell responses compared to samples from untreated patients. This supports the potential effectiveness of combining ICIs with TACE[16]. In a recent retrospective study from China, patients treated with TACE plus a programmed death ligand-1 (PD-1) inhibitor (camrelizumab or sintilimab) as neoadjuvant therapy were evaluated. The combination treatment showed a 75% objective response rate (ORR) with a significant decrease in alpha-fetoprotein (AFP) levels and acceptable toxicity[17].

TACE PLUS ICIS PLUS TKI

In a prospective single-arm study exploring the efficacy and safety of the combination of TACE, lenvatinib, and camrelizumab in patients with HCC with portal vein thrombosis, promising results were reported. The study included 69 patients, and over a median follow-up of 17.3 months, an ORR of 26.1% and a disease control rate (DCR) of 78.3% were observed. The median PFS and OS were 9.3 months and 18.2 months, respectively. The grade 3 and above adverse events rate was 34.8%, mainly manageable toxicities[18]. This prospective study in a population with a relatively poor prognosis yielded hopeful outcomes for the combination usage.

In a study by Ma et al[19], which is the focus of this editorial, the effectiveness and independent predictive factors of using lenvatinib and anti-PD-1 agents (sintilimab, nivolumab, camrelizumab, pembrolizumab, toripalimab) in combination with TACE were evaluated. In this retrospective single-arm study involving 102 patients with a median follow-up of 12.63 months, median OS and median PFS were found to be 26.43 months and 10.07 months, respectively. Regarding treatment response rates, ORR and DCR were reported as 61.76% and 81.37%, respectively. Triplet therapy was shown to have more effective results in patients with BCLC Stage B, early decrease in neutrophil-to-lymphocyte ratio, and significant AFP response. The potential synergistic effect of triple combination regimens is likely. TACE induces hypoxia post-treatment, activating hypoxia-inducible factor 1a, responsible for regulating pro-angiogenic factors, particularly VEGF, and promoting angiogenesis, tumor cell regrowth, and metastatic potential[18,20].

Additionally, as mentioned earlier, TACE can be an immunomodulator by influencing the tumor microenvironment, potentially synergizing with ICIs. In addition to the study by Ma et al[19], several retrospective studies demonstrate the efficacy and safety of TACE + ICIs + TKIs combinations[21-24]. When collectively assessed, the triplet combination across all these studies has the potential to enhance the success of TACE and improve survival in HCC, showing a significant potential for synergistic effects. However, attention should be paid to possible toxicity risks during treatment, and further prospective randomized studies are needed to confirm these findings. In this context, the LEAP-012 Phase 3 prospective randomized trial is underway, evaluating the clinical benefits of adding lenvatinib plus pembrolizumab to TACE in patients with intermediate-stage HCC ineligible for curative treatment[2].

Other combinations

In unresectable HCC, the two combinations recommended by international guidelines with strong evidence levels are atezolizumab + bevacizumab and durvalumab + tremelimumab. Although patients with a history of TACE were allowed to participate in both studies, randomization did not permit the inclusion of individuals who had undergone local treatments up to 28 d before. In other words, simultaneous use of TACE was not allowed in these randomized trials. Therefore, making advanced interpretations regarding the effectiveness and safety of TACE in these randomized studies is not feasible[25,26].

CAN THE ADDITION OF ICIS AND TKIS TO OTHER LOCAL TREATMENTS INCREASE EFFICACY?

In addition to the detailed discussion of TACE treatment above, there are other local treatment methods known for cases ineligible for resection or transplantation or those where these treatments can be used as bridge therapy before such procedures. Local-regional treatments for HCC offer opportunities to control intrahepatic disease progression and improve survival. Among these treatments are percutaneous ablations (such as radiofrequency ablation and cryoablation) and treatments directed towards the transarterial catheter (transarterial radioembolization (TARE), intrahepatic chemo-infusion)[27]. To the best of our knowledge, there is currently no randomized prospective study investigating the combination of TKI + ICIs with local treatments outside of TACE; however, there are some retrospective studies. In a retrospective study evaluating the addition of a PD-1 inhibitor to microwave ablation-TACE treatment in 87 patients, the median PFS with triplet therapy was 10.0 months, whereas it was 4.7 months with microwave ablation-TACE alone (P < 0.001). Median OS was 17.0 months vs 8.5 months, respectively (P < 0.001)[28]. In another similar study, the combination of a PD-1 antibody and lenvatinib with hepatic arterial infusion chemotherapy was shown to be effective in treating advanced-stage HCC, with generally manageable side effects[29]. In a study conducted in TACE-refractory intermediate-advanced HCC patients, adding hepatic arterial infusion chemotherapy to patients already receiving lenvatinib + ICI was retrospectively evaluated. In this study involving 121 patients, both ORR (48.3% vs 23.8, P < 0.005) and DCR (87.9% vs 69.8%, P < 0.02) were significantly superior with the addition of local treatment. This efficacy was demonstrated in both median PFS (13.0 vs 7.2, P < 0.001) and median OS (24.0 vs 13.0, P = 0.001). Adding hepatic arterial infusion chemotherapy to TKI + ICIs in TACE-refractory HCC appears to be an effective option[30].

There is no large-scale study on the combined use of ICIs and TKIs with TARE. It has only been reported to be used effectively and safely in small series of patients and case reports[31,32]. Similarly, with radioembolization, such as chemoembolization and other local ablative treatments, we believe that both ICIs and VEGF inhibitors can be effective, improving response rates and survival. Further studies are essential in this regard. Additionally, in cases of HCC where treatment options are relatively rare, and the prognosis is poor, it may be a suitable approach to reapply local treatments in appropriate patients, as in the tactics study mentioned above, with positive results. Thus, in eligible patients, combining different local treatments with TKI + ICIs and maximizing the synergistic effect may be considered for prolonged efficacy and survival.

CONCLUSION

The evolving landscape of HCC management incorporates promising combinations of TACE with TKIs and ICIs. These novel approaches, whether in the context of TACE or alternative local treatments, demonstrate potential benefits in enhancing therapeutic outcomes for HCC patients, warranting further exploration and validation in more extensive studies.