Hepatic artery infusion chemotherapy: A resurgence

Abstract

In this manuscript, we comment on the article by Zhou et al, who assessed the efficacy of hepatic arterial infusion chemotherapy (HAIC) and its combination strategies for advanced hepatocellular carcinoma (HCC) using network meta-analysis methodology. We focus specifically on the potential advantages and role of HAIC in the treatment algorithm for advanced HCC. However, there remains numerous knowledge gaps before the role of HAIC can be established. There is significant heterogeneity of HAIC regimes with difficult interpretation of the clinical outcomes. Additionally, there is a lack of direct comparative data between HAIC, systemic chemotherapy, novel immunotherapies and targeted therapies. The underlying biochemical mechanisms that might explain the efficacy of HAIC and its effect on the HCC microenvironment requires further research. In the developing era of nanotechnology and targeted drug delivery systems, there is potential for integration of HAIC with novel technologies to effectively treat advanced HCC whilst minimising systemic complications.

Key Words: Hepatocellular carcinoma; Hepatic artery infusion chemotherapy; Immunotherapy; Targeted therapy; Transarterial chemoembolisation

Core Tip: In the current landscape of accumulating knowledge of hepatocellular carcinoma (HCC), tumour biology and developments in systemic therapies, the management of advanced HCC has become increasingly complicated. For hepatic arterial infusion chemotherapy (HAIC) to be first-line treatment for advanced HCC, the morbidity of hepatic artery port insertion must be at a low level, the HAIC regimens must be standardised, the optimal combination treatment strategy with HAIC and the role of HAIC in Western populations must be evaluated. The combined roles of HAIC with immunotherapy and delivery of chemotherapeutic drug nanoparticles to HCC tumour cells represents an exciting research and therapeutic strategy for advanced HCC.

TO THE EDITOR

In this manuscript, we appraise the meta-analysis by Zhou et al[1] which addressed the important clinical question of advanced hepatocellular carcinoma (HCC) management. We summarise the available evidence-based treatment options for advanced HCC, and highlight the potential advantages of hepatic arterial infusion chemotherapy (HAIC) and how HAIC might interact with the tumour microenvironment that may explain the observed efficacy of HAIC. We also postulate the future integration of HAIC with novel technologies such as nanotechnology and targeted drug delivery systems.

We believe this manuscript will stimulate the journal's readers to the original research manuscript and its contents will be relevant to surgeons and oncologists who manage patients with advanced HCC.

In the paper by Zhou et al[1], they investigated the role of HAIC and its combination treatments in the first-line management of patients with advanced HCC using network meta-analysis methodology. A literature search identified 9 randomised controlled trials and 35 cohort studies with a total of 5789 patients for the meta-analysis. The treatment comparators were HAIC alone vs HAIC with combination therapies [including local tumour ablation, trans-arterial chemoembolization (TACE), chemotherapy (S-1), targeted therapies (lenvatinib), immunotherapy (programmed death receptor 1) and radiotherapy] vs sorafenib and TACE. Zhou et al[1] concluded that HAIC had a better efficacy and safety profile compared to sorafenib and TACE, and HAIC combination therapy showed improved patient outcomes compared to HAIC alone. The study’s conclusion holds scientific merit and represents a novel perspective in advanced HCC therapies.

EDITORIAL COMMENTARY

This meta-analysis addressed the important clinical question of advanced HCC management. HCC is the fourth commonest cause of global cancer mortality and often presents at a late and advanced stage, which precludes curative surgical treatments due to tumour factors (size, multifocality, location) or underlying poor liver function. The prognosis of advanced HCC remains poor, with five-year survival rates of 5%-36%[2].

In the Barcelona Clinic Liver Cancer (BCLC) 2022 staging system, advanced HCC was defined as HCC with portal vein invasion, with or without extrahepatic spread, preserved liver function and performance status 1 or 2[3]. Furthermore, BCLC guides the treatment strategy for this group of patients.

The treatment of advanced HCC was previously limited to sorafenib, a tyrosine kinase inhibitor (TKI) and clinical trials showed a median survival gain of 10.2 months for sorafenib compared to best supportive care[4]. In fact, sorafenib was the only available agent for almost ten years before lenvatinib, another TKI, showed similar clinical outcomes to sorafenib[5]. In view of the limited treatment options for advanced HCC, alternative strategies were explored, which included HAIC.

HAIC is a treatment for HCC that involves infusion of high concentration cytotoxic chemotherapy into the hepatic artery via an implanted catheter port[6,7]. There is clinical evidence to support favourable outcomes for HAIC[8-11], and HAIC is recommended as the first-line treatment for advanced HCC in Korean[12] and Japanese[13] guidelines.

The challenge in the establishment of HAIC and its combination therapy as a first-line treatment for advanced HCC remains the lack of robust clinical outcome and direct comparative data. Zhou at el[1] described the significant heterogeneity in HAIC chemotherapy regimens and HAIC was often combined with other loco-regional and systemic treatments. Whilst this study by Zhou et al[1] showed that HAIC had a better efficacy and safety profile compared to sorafenib and TACE, and HAIC combination therapy showed improved patient outcomes compared to HAIC alone, the clinical studies used for this network meta-analysis predated the clinical trial data from immunotherapies and targeted therapies. Taking into consideration the volume of randomised clinical trial data, clinical efficacy and improvement in overall and disease-free survival with the use of novel systemic therapies, one must evaluate the role of HAIC and its combination therapies in the management algorithm of advanced HCC.

Proponents of HAIC argue that it is a cheaper treatment option compared to sorafenib, lenvatinib and other systemic therapies. HAIC might also offer greater local control of vascular invasion for treatment naïve HCC with major vascular invasion[14]. Opponents of HAIC argue that insertion of the hepatic artery port to enable administration of the chemotherapy is an invasive surgical procedure. This will require laparotomy under general anaesthesia in patients who already have underlying impaired liver function. Laparoscopic[15] and percutaneous[16] hepatic artery port placement have been reported with satisfactory clinical success.

The 2022 BCLC guidelines recommended systemic therapies for advanced HCC[3]. First-line atezolizumab and bevacizumab or durvalumab and tremelimumab is advocated for patients who were unsuitable for sorafenib or lenvatinib. Patients that progressed on sorafenib or were intolerant to sorafenib would be offered second-line systemic treatment with either regorafenib, cabozantinib, ramucirumab or enrolled into clinical trials. Cabozantinib is indicated as third-line treatment. The efficacy of these systemic therapies has been shown in IMbrave150[17], Himalaya[18], Resorce[19], Celestia[20] and Reach-2[21] clinical trials. However, there remains no direct comparison study of HAIC vs systemic chemotherapy[6].

HCC is a complicated tumour at the genetic and molecular level[22]. The HCC tumour environment is predisposed to mutations leading to its resistance to systemic chemotherapy drugs. Drug resistance behaviour in HCC has been reported for sorafenib and cisplatin[23,24]. The proposed mechanisms for this drug resistance are multifactorial. At the molecular level, there are alterations in transmembrane transporters, signal transduction pathways and DNA damage and repair mechanisms[24]. In HCC tumour cells, there is expression of p-glycoprotein transmembrane transporter, which pumps chemotherapeutic drugs out of cells and reduces its drug concentration[25,26]. In addition, the HCC tumour environment is relatively hypoxic with impaired perfusion, thus intravenously administered systemic chemotherapy might only reach the tumour at subtherapeutic drug concentrations. Increasing the dose of systemic chemotherapy must be balanced against dose-related complications. With HAIC, the direct infusion of high concentration chemotherapy drugs into the HCC tumour environment might overcome both the p-glycoprotein and low tumour perfusion effect and augment the treatment response.

The observed efficacy of HAIC in advanced HCC might also be explained by effective local control of viable HCC tumour cells and arrest of the tumour mutagenesis process. The underlying biochemical mechanisms might involve reversal of abnormal expression of RNAs[27], cytokine-induced resistance[28], induction of tumour stem cells[29], chromosomal and DNA damage[30], expression of heat shock proteins, activation of autophagy[31] and alterations in apoptosis pathways[32].

The use of novel technologies such as nanotechnology combined with targeted drug delivery systems could further enhance the applications of HAIC in advanced HCC. Chemotherapeutic agents can be encapsulated within nanoparticles then delivered to HCC tumours, improving drug effectiveness and reducing systemic side effects[33]. Nano-based drug delivery systems might also overcome the challenge of transporter-induced efflux of chemotherapy drugs[34,35]. The combination of HAIC with targeted drug delivery systems might enable super-selective administration of HCC-specific chemotherapy agents to tumour cells only, but the clinical data remains lacking at present[36].

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

In the current landscape of accumulating knowledge of HCC tumour biology and developments in systemic therapies, the management of advanced HCC has become increasingly complicated[37]. For HAIC to be first-line treatment for advanced HCC, the morbidity of hepatic artery port insertion must be at a low and acceptable level, the chemotherapy regimens must be standardised, the optimal combination treatment strategy with HAIC needs to be established and the role of HAIC in Western populations must also be evaluated. The role of HAIC with immunotherapy might represent a promising treatment strategy that activates the patient’s immune system against HCC. The novel combination of HAIC with delivery of chemotherapeutic drug nanoparticles to HCC tumour cells is also an exciting area for research and a potential therapeutic strategy in advanced HCC[38].

CONCLUSION

HAIC and its combination therapies can improve clinical outcomes compared to sorafenib in selected cases of advanced HCC. In the treatment algorithm of advanced HCC, there remains knowledge gaps regarding the optimal role of HAIC and future research should address these gaps and focus on the potential complementary role of HAIC to systemic therapies and novel nanotechnologies.