Current research status of transarterial therapies for hepatocellular carcinoma

Abstract

With continuous advancements in interventional radiology, considerable progress has been made in transarterial therapies for hepatocellular carcinoma (HCC) in recent years, and an increasing number of research papers on transarterial therapies for HCC have been published. In this editorial, we comment on the article by Ma et al published in the recent issue of the World Journal of Gastrointestinal Oncology: “Efficacy and predictive factors of transarterial chemoembolization combined with lenvatinib plus programmed cell death protein-1 inhibition for unresectable HCC”. We focus specifically on the current research status and future directions of transarterial therapies. In the future, more studies are needed to determine the optimal transarterial local treatment for HCC. With the emergence of checkpoint immunotherapy modalities, it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.

Key Words: Hepatocellular carcinoma; Transarterial therapies; Transarterial chemoembolization; Hepatic artery infusion chemotherapy; Transarterial embolization; Transarterial radioembolization

Core Tip: Articles on transarterial therapies for hepatocellular carcinoma (HCC) were systematically reviewed. The results of this study showed that transarterial therapies combined with systemic therapy strategies are research hotspots in this field, and researchers dedicated to transarterial therapies for HCC should pay attention to these topics in the future.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common malignant tumor of the liver and is the sixth most common cancer and the third leading cause of cancer deaths worldwide[1,2]. Hepatectomy and liver transplantation are radical treatments for early HCC[3]. However, most patients with HCC are already in the middle or advanced stages at the time of diagnosis and have lost the opportunity for surgical treatment. Studies have shown that transarterial therapies, including transarterial chemoembolization (TACE), transarterial embolization (TAE), hepatic artery infusion chemotherapy (HAIC) and transarterial radioembolization (TARE), yield survival benefits in patients with unresectable HCC[4-7]. Although these transarterial therapies all have the potential to control HCC, the evidence for selecting appropriate patients and specific treatments is still limited[8]. In recent years, scholars have conducted in-depth research on transarterial therapies for HCC, and many research papers on transarterial therapies for HCC have been published. In this study, we focus specifically on the current research status and future directions of transarterial therapies.

TACE

TACE is the standard treatment for Barcelona Clinic Liver Cancer (BCLC) B HCC patients[9]. However, due to the heterogeneity of HCC, improving the efficacy of TACE is a challenge that requires further investigation[10,11]. Studies have confirmed that TACE combined with radiofrequency ablation (RFA) is superior to RFA alone, especially for patients with large-sized HCCs[12,13]. The efficacy of TACE combined with radiation therapy is superior to that of TACE alone[14], especially for advanced HCC patients with vascular invasion[15]. In theory, TACE causes tumor tissue hypoxia, resulting in vascular endothelial growth factor (VEGF) upregulation, which may lead to tumor revascularization and local recurrence. TACE combined with antiangiogenic agents is expected to inhibit the revascularization effect due to the TACE-induced upregulation of VEGF and delay tumor progression or recurrence. However, the results of clinical randomized controlled trials comparing TACE combined with sorafenib and TACE alone are inconsistent, i.e., neither the SPACE nor TACE 2 trials showed any clinical benefit[16,17]; however, the TACTICS trial reported positive results. In the TACTICS trial, the progression-free survival (PFS) of patients in the TACE + sorafenib group (25.2 months) was significantly greater than that of patients in the TACE alone group (13.5 months) (P = 0.006)[18]. The inconsistency of the results of these trials may be related to differences in the study protocols, especially the definition of tumor progression, and differences in the timing of sorafenib administration. In recent years, immunotherapy has shown great potential in the treatment of HCC[19-24]. The combination of TACE and immunotherapy is promising. A number of studies have shown that for patients with unresectable HCC, TACE combined with a tyrosine kinase inhibitor (TKI) plus an immune checkpoint inhibitor (ICI) is more satisfactory than TKI plus an ICI alone or TACE + sorafenib, exhibiting better efficacy and safety[25-38].

TAE

TAE, also known as bland embolization, is the injection of an embolic substance into the feeding artery of a HCC via a catheter under X-ray fluoroscopy to achieve a therapeutic effect by inducing lesion ischemia[39]. Due to the lack of chemical toxicity and radiotoxicity, the tumor response is mainly due to the cell death mechanism during hypoxia; therefore, TAE is advantageous for some patients in whom healthy liver parenchyma needs to be retained. Compared with supportive care, TAE provides a survival benefit for patients with unresectable HCC[40].

Currently, the comparison of TAE and TACE is still the focus of studies, but the study results are not consistent. Many studies have shown that there is no significant difference in overall survival (OS) between TAE and conventional TACE (cTACE)[41,42]. There are also some data showing that cTACE is superior to TAE in terms of treatment response[43]. For example, Meyer et al[43] performed a randomized controlled trial to compare the efficacy of TAE and TACE, and the results showed that the end-of-treatment RECIST responses [complete response + partial response] were 13.2% and 32.6% (P = 0.04), respectively; the mRECIST responses were 47.3% and 67.4%, respectively; and the median OS and PFS were 17.3 and 16.3 months (P = 0.74) and 7.2 and 7.5 months (P = 0.59), respectively.

Recently, Gao et al[44] studied the antitumor effect of TAE combined with the kringle 1 domain of human hepatocyte growth factor alpha (HGFK1, an angiogenesis inhibitor) in an in situ rabbit HCC model. The results showed that the expression levels of cluster of differentiation 31 (CD31), CD90, and Ki67 significantly decreased after treatment with TAE and HGFK1 and that both TAE and HGFK1 prolonged the survival of rabbits (P < 0.05)[44].

HAIC

HAIC involves the direct injection of chemotherapeutic drugs into the feeding artery of HCC through a catheter to increase the local drug concentration in the tumor, thereby increasing the response rate and reducing the systemic toxic side effects of chemotherapeutic drugs. HAIC is a promising method for the treatment of advanced HCC and has become increasingly popular in recent years[45,46].

Studies have shown that HAIC could improve OS and PFS in patients with advanced HCC[47,48]. After surgical resection, adjuvant HAIC-FOLFOX improved disease-free survival (DFS) in HCC patients with microvascular invasion (MVI). In a randomized multicenter trial[49], 315 patients with histologically confirmed MVI-positive HCC were randomly assigned to receive FOLFOX-HAIC adjuvant therapy (the treatment group with 157 patients) or conventional follow-up (the control group with 158 patients), and the results showed that the median DFS in the treatment group was 20.3 months and that in the control group was 10.0 months (P = 0.001); the 1-, 2-, and 3-year OS rates in the treatment group were 93.8%, 86.4%, and 80.4%, respectively, and those in the control group were 92.0%, 86.0%, and 74.9%, respectively.

Currently, the platinum-based HAIC regimen is recommended as the first-line treatment for advanced HCC in Asia (China and Japan). Gourd et al[50] reported that for patients with HCC at a stage suitable for TACE, the efficacy of HAIC in the treatment of advanced HCC may be greater than that of TACE[50,51].

Sorafenib and lenvatinib are internationally recognized first-line treatment drugs for advanced HCC[52-54]. Studies have shown that the outcomes of HAIC combined with targeted therapy are superior to those of TACE[55]. Chen et al[56] performed a network meta-analysis to analyze the difference in efficacy between HAIC combined with sorafenib and TACE combined with sorafenib for the treatment of unresectable HCC, and the results showed that the overall response rate of patients who received sorafenib + FOLFOX-HAIC treatment was significantly greater than that of patients who received other regimens [odds ratio (OR) = 22.18, 95%CI: 10.69-52.56]. There were significant differences between patients who received the sorafenib plus HAIC-oxaliplatin regimen and patients who received other treatment strategies in terms of OS [hazard ratio (HR) = 0.33, 95%CI: 0.25-0.44]. Sorafenib combined with HAIC and oxaliplatin improved OS; rank probability plots showed that there was a 99.9% likelihood of sorafenib plus FOLFOX-HAIC being the most effective treatment, followed by sorafenib plus TACE at a likelihood of 86.6% and sorafenib combined with cisplatin-HAIC at a likelihood of 75.6%; and the incidence of liver injury increased in the sorafenib plus TACE treatment group (OR = 5.93, 95%CI: 2.70-15.41), with no difference in the incidence of other serious adverse events between treatment groups. In addition, published studies have also shown the efficacy and safety of HAIC combined with ICIs and TKIs in the treatment of advanced HCC[57-61].

In summary, HAIC can be used as a standard treatment for advanced HCC, and HAIC combined with targeted therapy and immunotherapy may further improve the survival of patients with advanced HCC.

TARE

In TARE, Y90 and holmium-166 (166Ho) are delivered via resin or glass microspheres to the arterialized tumor vasculature to deliver an inhibitory dose to the tumor. The results of an early trial of TARE were not satisfactory. In recent years, with advancements in ablation techniques and personalized dosimetry, substantial progress has been made in TARE, which has played a prominent role in the locoregional treatment of HCC and has been incorporated into the 2022 BCLC algorithm[62].

TARE combined with targeted therapy and immunotherapy has also yielded good results[62-65]. Kaseb et al[63] first conducted a prospective study of Y-90 combined with sorafenib in the treatment of advanced HCC, with 38 patients with advanced/metastatic HCC and 34 patients who first received sorafenib treatment and then Y-90 GM treatment 4 weeks later. The results showed that the combination therapy was well tolerated, the median PFS and OS were 10.4 months (95%CI: 5.8-14.4) and 13.2 months (95%CI: 7.9-18.9), respectively, partial remission was achieved in 12 patients (35.3%), and the condition of 16 patients (47.0%) was stable. Recently, Yeo et al[64] studied the efficacy and safety of TARE combined with immunotherapy in patients with advanced HCC, with 1664 eligible advanced HCC patients. Among them, 142 patients received TARE + immunotherapy treatment, and 1522 patients received immunotherapy alone. The results showed that the median OS of the combination therapy group was significantly higher than that of the immunotherapy alone group (19.8 months vs 9.5 months); in the multivariate analysis, combination therapy was independently associated with reduced mortality. The favorable results for TARE + immunotherapy support the application prospects of TARE.

DRUG DELIVERY

Systemic chemotherapy is administered through peripheral veins and delivered throughout the body, but the main problems are insufficient drug uptake by targeted tumor tissues and systemic toxicity. The local application of anticancer drugs can produce substantially higher drug concentrations in tumor tissues with less systemic toxicity; various locoregional treatments, including intra-arterial treatments, have become HCC treatment strategies. However, local treatments via the hepatic artery also face various challenges, and the survival benefit is still limited. Therefore, it is necessary to develop drug transporters that can reach targets more effectively or to develop more effective drug delivery methods to improve therapeutic effects[66].

cTACE uses lipiodol-based emulsions combined with an embolizing agent for chemotherapy and embolization via transcatheter delivery to achieve powerful cytotoxic and ischemic effects. The chemotherapeutic drugs emulsified in iodized oil used in cTACE are poorly stable and may lead to systemic adverse effects[67,68]. Zhao et al[67] reported a composite hydrogel, Epi/Etpoil@MC/XG, that can stably distribute Etpoil and Epi and has been successfully applied for the embolization of feeding arteries in a VX2 tumor model. To alleviate the high incidence of systemic adverse reactions associated with cTACE, TACE with drug-eluting beads (DEB-TACE) was developed. DEB-TACE provides more selective and controllable drug delivery through microspheres, which slowly release chemotherapeutic drugs, maintain the action time of chemotherapeutic drugs, and increase the intensity of ischemia[69-71].

The balloon-occluded TACE (B-TACE) technique, which was first reported by Irie et al[72], refers to the use of a microballoon catheter to occlude the tumor feeding artery and then to perfuse the chemotherapeutic drug emulsion and gelatin sponge particles to cause the dense accumulation of chemical emulsions containing iodized oil in target nodules[72]. A preliminary study showed that the treatment effect of B-TACE was superior to that of cTACE[73,74]. In the future, randomized controlled trials with large sample sizes are needed to compare B-TACE with cTACE or DEB-TACE.

In contrast to TACE, which relies on the combination of chemotherapeutic agents and embolization-induced local ischemia to produce antitumor effects, TARE uses microspheres containing radioisotopes that are small in volume (20-60 μm), and these delivery techniques do not cause notable arterial occlusion[62,75,76]. With further in-depth research on radioisotope delivery, it is expected that TARE will play a more important role in the treatment of HCC. Both TACE and TARE are promising methods for the treatment of patients with unresectable HCC; the combined use of TACE and TARE in one treatment course may produce a synergistic cytotoxic effect, thus improving the treatment effect. Recently, some scholars have focused on the combined application of chemotherapy and radioembolization agents in the same delivery system[77]. Alregib et al[77] recently developed a novel biodegradable microsphere formulation loaded with a chemotherapeutic drug (Dox) and radioactive agent (Sm-153) for potential radio-chemoembolization in advanced HCC. The study results showed that this formulation met all the needed physicochemical properties of the radio-chemoembolization agent and achieved better in vitro cytotoxicity against HepG2 cells. The biological safety, radiation dosimetry and synergistic anticancer properties of this agent need to be further evaluated in subsequent studies.

CONCLUSION

With continuous advancements in interventional radiology, important progress has been made in transarterial therapies for HCC in recent years. The recent 2022 update of the BCLC treatment algorithm features the prominent role of locoregional treatment in HCC, and transarterial therapies have established their place in the BCLC treatment algorithm. Currently, studies on the combination of local transarterial therapies with other treatments, including local ablation, radiation therapy, and systemic therapy, are actively being conducted; in particular, the combination of transarterial therapies with targeted therapy and immunotherapy is a new research hotspot. The rationale of this combination treatment strategy is that transarterial therapies may enhance the anticancer immune response and that TKIs have a synergistic effect with ICIs due to the antitumoral immunological effects of some targeted drugs such as sorafenib[78]. In addition, the optimal selection of patients is an extremely important issue to improve the efficacy of transarterial treatments. Granito et al[79] recently demonstrated that transient hypertransaminasemia after superselective cTACE was a simple and accurate marker for predicting the treatment response. However, more attention should be given to the prognostic score with consideration of liver function, as any treatment that severely compromises liver function will shorten life expectancy rather than prolong it[80]. New prognostic models, including the neutrophil-lymphocyte ratio, radiomics and deep learning, have been the focus of relevant researchers in recent years[81-87]. In the future, more studies are needed to determine the optimal transarterial local and combination treatment strategies for HCC[60,61,65,88,89]. With the emergence of checkpoint immunotherapy modalities, it is expected that the results of trials of transarterial local therapy combined with systemic therapy will bring new hope to HCC patients.