Recent Advances in Locoregional Therapy of Hepatocellular Carcinoma

Simple Summary Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second most common oncological reason for death. Liver resection and transplantation are considered the only potential cure options for HCC. The majority of patients, however, are late in presentation and, therefore, are considered non-suitable for surgery at the time of diagnosis. Locoregional therapies are becoming integral to its management along with systemic therapies. This review discusses the role and the advances of locoregional therapies in HCC management. Abstract Hepatocellular carcinoma (HCC) is responsible for 90% of primary hepatic cancer cases, and its incidence with associated morbidity and mortality is growing worldwide. In recent decades, there has been a revolution in HCC treatment. There are three main types of locoregional therapy: radiofrequency ablation, transarterial chemoembolisation, and transarterial radioembolisation. This article summarises recent advances in locoregional methods.


Introduction
Hepatocellular carcinoma (HCC) is responsible for 90% of primary hepatic cancer cases. Its incidence is growing; currently, it is the fifth most common cancer worldwide, accounting for over 800,000 new cases in 2018 [1]. According to Cancer Today by WHO, it is the second most common oncological reason for death, with 50% of cases occurring in East Asia [1]. Its incidence tripled between 1980 and 2020 in the United States [2]. In Asia and Africa, HCC is usually associated with hepatitis B, whereas, in Europe, Japan, and the US, it is more often associated with hepatitis C, non-alcoholic fatty liver disease (NAFLD) and chronic alcohol abuse [1,3,4]. Other factors associated with HCC are genetic haemochromatosis, tyrosinosis, alpha-one antitrypsin deficiency, and primary biliary cirrhosis [3,5].
The diagnosis of HCC Is based on a combination of clinical, laboratory, radiographic, and histopathologic features [5]. The imaging diagnosis is based on the detection of the lesion's vascularity [6]. Advanced imaging techniques, such as contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI), have shown promising results in detecting and characterising HCC [6]. CEUS utilises microbubble-based contrast agents to provide real-time imaging of the tumour vasculature, allowing for improved lesion detection and differentiation from non-malignant liver lesions. On the other hand, MRI offers multiparametric imaging capabilities, including dynamic contrast-enhanced and diffusion-weighted imaging, enabling better tumour characterisation and assessment of treatment response [6,7] (Figure 1). Moreover, molecular imaging techniques, such as treatment response [6,7] (Figure 1.). Moreover, molecular imaging techniques, such as positron emission tomography (PET) using tracers like fluorodeoxyglucose (FDG), have shown potential in assessing HCC metabolic activity and predicting prognosis [6]. Recent advancements in imaging technology have also facilitated the integration of artificial intelligence (AI) algorithms to aid in diagnosing and staging HCC. These AI-based approaches leverage machine learning techniques and large datasets to improve the accuracy and efficiency of HCC diagnosis, allowing for earlier detection and intervention [8]. The tumour typically starts as a small nodule and grows during the asymptomatic phase [3]. It doubles in a median of 6 months [3]. The 1 year survival is 50-90% among untreated patients with Child-Pugh A and only 20% with Child-Pugh C [3]. The 5 year survival is low, at less than 20% worldwide [1]. Treatment is challenging as it depends on the tumour burden and the level of associated liver cirrhosis [1]. Unfortunately, despite the availability of targeted screening for HCC among high-risk groups and improvements in the prevention and treatment of risk factors, such as hepatitis B/C or NAFLD, mortality rates continue to rise [3,5,10,11]. Only 10-30% of HCC patients are candidates for surgical treatment-a curative option-because most cancers are recognised at an intermediate or advanced stage [12][13][14]. However, adding biochemical markers-such as alpha fetoprotein-significantly increases the early detection of HCC in clinical practice [15].
Globally, multiple staging systems are used to select the best treatment option for patients. The first one is the Okuda staging system, which is based on three factors: liver functional status (albumin, ascites, and bilirubin) and tumor stage (more or less than 50% of liver area involved). It is used in Japan and other countries. The second is the Barcelona Clinic Liver Cancer (BCLC) system, comprising tumour stage, liver function, and physical status. This system has been widely adopted in Europe for HCC staging and treatment [5]. Thirdly, the mUICC staging system, adopted by Korea, is based on the number of tumours, the diameter of the largest tumour, and vascular or bile duct invasion [5]. The tumour typically starts as a small nodule and grows during the asymptomatic phase [3]. It doubles in a median of 6 months [3]. The 1 year survival is 50-90% among untreated patients with Child-Pugh A and only 20% with Child-Pugh C [3]. The 5 year survival is low, at less than 20% worldwide [1]. Treatment is challenging as it depends on the tumour burden and the level of associated liver cirrhosis [1]. Unfortunately, despite the availability of targeted screening for HCC among high-risk groups and improvements in the prevention and treatment of risk factors, such as hepatitis B/C or NAFLD, mortality rates continue to rise [3,5,10,11]. Only 10-30% of HCC patients are candidates for surgical treatment-a curative option-because most cancers are recognised at an intermediate or advanced stage [12][13][14]. However, adding biochemical markers-such as alpha fetoprotein-significantly increases the early detection of HCC in clinical practice [15].
Globally, multiple staging systems are used to select the best treatment option for patients. The first one is the Okuda staging system, which is based on three factors: liver functional status (albumin, ascites, and bilirubin) and tumor stage (more or less than 50% of liver area involved). It is used in Japan and other countries. The second is the Barcelona Clinic Liver Cancer (BCLC) system, comprising tumour stage, liver function, and physical status. This system has been widely adopted in Europe for HCC staging and treatment [5]. Thirdly, the mUICC staging system, adopted by Korea, is based on the number of tumours, the diameter of the largest tumour, and vascular or bile duct invasion [5].
The stages of HCC vary worldwide in their presentation. In the UK, patients usually present with advanced disease, which is most often detected among people with already abnormal liver function. In contrast, 80% of HCC cases in Japan are detected when asymptomatic due to widespread screening of all people with liver cirrhosis [3]. At the time of diagnosis, 75% of HCC nodules are inoperable [16,17]. When tumours have not expanded outside the liver, locoregional treatments are applied to downstage and increase the number of liver transplant candidates or improve outcomes of patients undergoing liver resection [18][19][20][21]. The potential increase in early-stage detection based on imaging and biochemical markers may lead to increased utilisation of locoregional therapies, which currently play a leading role in 50-60% of HCC treatments [4]. The choice of liver transplantation, resection, percutaneous ablation, transarterial chemoembolisation (TACE), and/or radioembolisation treatment largely depends on tumour burden and location, as well as comorbidities [5,22]. Systemic therapy is used in moderate and advanced diseases. Classical oncological treatments, such as cytotoxic chemotherapy and hormonal therapy, have not proven successful in hepatic cancer [2]. In recent years, multiple immunotherapy options and drugs have become available [2]. The first systemic treatment for HCC was sorafenib-a multi-kinase inhibitor [2,4,22]. Around 50-60% of HCCs are managed primarily by locoregional therapies, defined as imaging-guided liver tumour-directed procedures [4]. They can be based on local ablation or intraarterial technique. The primary aim is to prolong survival by decreasing or, if feasible, eliminating the burden of hepatic tumours [4]. Patients with advanced diseases and those in the terminal stage should receive the best supportive, palliative care [5].
The treatment algorithm for HCC is constantly changing, mainly driven by the expansion of criteria for hepatic resection, advancement of locoregional and radiation therapies, and novel systemic therapies [5].
Optimal management of liver cancers depends on a multidisciplinary approach, with input and collaboration from diagnostic radiology, pathology, hepatology, transplant surgery, surgical oncology, medical oncology, radiation oncology, and interventional radiology to achieve individualised and evidence-driven patient care. Patient preferences should also be taken into consideration [7,10].
Current guidelines recommend 6 monthly surveillance of high-risk patients with ultrasound [23,24]. Further research is ongoing to optimise follow-up pathways, especially regarding MRI-based imaging [6,7]. mRECIST has become a standard tool for measuring radiological endpoints that are added to the standard cancer overall survival rates [25].
This review aims to present the up-to-date status of locoregional therapies for HCC.

Radiofrequency Ablation (RFA)
Radiofrequency ablation was introduced in the 1990s as a treatment for osteoid osteomas [26]. It is now considered the standard treatment option among local ablative techniques for very-early-stage hepatic tumours (<2 cm) and for early-stage tumours that were disqualified from the surgical approach [4]. RFA has often been deemed a curative treatment modality, with a 5 year overall survival rate of around 40-70% [2,12,27]. It is also considered the most promising locoregional treatment [28][29][30][31][32]. The electrodes are inserted into pathological tissue, and, by delivering high-frequency alternating currents, they induce coagulative necrosis and tissue desiccation [28][29][30][31][32]. The major advantages of RFA are the potential for repeatability and safety for people with significant medical comorbidities due to the lack of a need for general anaesthesia [28,33]. There is also moderate evidence for using microwaves for ablation, and low evidence for using cryoablation and irreversible electroporation [4].
Local tumour progression post RFA is the Achilles heel of this well-established treatment modality [12,34]. The 5 year tumour recurrence has been reported to be as high as 80%. RFA also suffers from the following limitations: ablation volume up to 5 cm, limitations related to tumour localisation (i.e., hilar or subphrenic), heat-sink effect, spreading by intratumoral pressure during RFA, and tumour seeding [28,[35][36][37][38].
Every medical procedure has inherent complication risks. RFA can be complicated by severe haemorrhage, RFA needle-track seeding, abscess formation, perforation of the gastrointestinal tract, liver failure, biloma, biliary stricture, portal vein thrombosis, and haemothorax or pneumothorax requiring drainage. It has been reported that complications affect 0.6-8.9% of procedures [28,39,40]. It is worth noting that the departments treating larger numbers of patients per month had a smaller number of complications and deaths [28,41].
There are conflicting reports in the literature comparing RFA to local surgical resection. Nevertheless, local surgical resection provides better long-term oncological outcomes [42,43].
Usually, RFA is performed under ultrasonographic guidance. Recently, six reported studies compared RFA using intraprocedural CT/MRI fusion imaging versus the standard of treatment. They suggested using fusion imaging to treat large tumours in difficult anatomical positions [44].
Advanced imaging with CT or MRI is typically used to assess treatment efficacy [28]. It is separated into the following categories: 1.
Grade A-absolutely curative with 5 mm ablative margin around the entire tumour.

2.
Grade B-relatively curative, mostly as grade A with some places with the lower margin.

3.
Grade C-an incomplete ablative margin around the tumour, although no residual tumour is apparent.
It was reported that liver ultrasound elastography with liver stiffness could be a reliable tool for predicting recurrence after RFA [46].
RFA is often compared with microwave frequency ablation, as they are primary types of percutaneous thermal ablation. Recent summaries of studies comparing those two techniques found little to no difference in their efficacy and safety [47][48][49][50][51][52][53].
Unanswered questions remain about combination techniques. A meta-analysis of 854 patients suggested that adding percutaneous ethanol injections improves overall survival; however, the evidence is heterogeneous [54]. A network meta-analysis of 3675 patients with advanced HCC revealed that the RAF with hepatic arterial infusion chemotherapy (HAIC) achieved the highest probability of 1 year overall survival and overall response rate [55]. TACE combined with RFA or MWA can provide significantly better overall survival (HR, 0.50, 95% confidence interval [CI]: 0.40-0.62), progression-free survival (HR, 0.47, 95% CI: 0.37-0.61), and local tumour control (OR, 0.36, 95% CI: 0.24-0.53) than TACE monotherapy for patients with intermediate-stage HCC, without increasing the risk of major complications (OR, 1.26, 95% CI: 0.74-2.16) [56]. Moreover, TACE + RFA offer comparable oncologic outcomes in patients with HCC compared to surgical resection and with the added benefit of lower morbidity [57].
There is continued effort to identify the best treatment technique for HCC. A study by Kwak et al. compared percutaneous and laparoscopic RAF for HCC in the subphrenic region. The laparoscopic approach resulted in fewer local tumour progressions and increased overall survival; therefore, it is proposed as a method of choice [58].
Within the last 3 years, we identified nine randomised controlled trials involving RFA for HCC. They are summarised in Table 1.

TACE
TACE involves the injection of chemotherapy into liver tumours with a microembolus effect using iodised oil-based emulsion (lipiodol oil) to achieve arterial branch closure supplying the tumour in addition to medicinal suppression of tumour growth [21,67,68]. In 1972, the first surgical ligation of the hepatic artery with the consecutive injection of 5-fluorouracil to the portal vein was used to treat a liver tumour, which showed that the approach of blood interruption and local chemotherapy was safe. The development of an endovascular approach promptly followed it [69]. Today, an interventional radiologist enters the vascular system via the femoral approach, and then inserts the instruments to branch the hepatic artery supplying the tumour by navigating through the abdominal aorta, celiac trunk, and common hepatic artery.
TACE is the standard of care for intermediate-stage lesions (a multinodular liver-only disease in asymptomatic patients with compensated liver function). It usually contributes to the 2-2.5 year survival rate [3,4]. TACE can produce tumour necrosis and affects survival in selected patients with good liver reserve [3]. With preserved liver function, the risk of liver failure after c-TACE for HCC with portal vein invasion is acceptably low [1]. There is no consensus on optimal chemotherapeutic agents and no standardisation worldwide [1,70]. When used with lipiodol, there is an improvement in symptoms of pain and bleeding from HCC [3]. Neoadjuvant TACE can be used for patients with longer expected waiting list times for liver resection (specifically >6 months) or postoperatively in patients with a high risk of HCC recurrence [71][72][73][74].
A higher incidence of systemic adverse effects is connected with TACE due to the use of oil-based substances [68,75]. To mitigate this problem, TACE with drug-eluting beads (DEB-TACE) has been developed. It provides more selective and controlled drug delivery with microspheres [68,[76][77][78]. Comparing those two treatment modalities for unresectable or recurrent HCC directly, there is no strong evidence of its increased efficacy, but it is associated with fewer side-effects [68].
There is ongoing research into clinical prognostication and patient selection for TACE. High pre-treatment albumin/bilirubin grade and aspartate aminotransferase-to-platelet index are associated with poorer outcomes [79,80]. Age, diabetes mellitus (DM), and the number of TACE sessions are risk factors for acute kidney injury-which increases mortality 4.74-fold-in patients with HCC after TACE [81]. Recently, an albumin-based algorithm was proposed [82].
There is a risk of incomplete treatment response after TACE, especially in large tumours, which are difficult to access. External beam radiotherapy provides favourable local control, but further systemic treatment could be required to improve overall survival [83]. Combining TACE with microwave ablation MWA improves 1, 2, and 3 year overall survival when compared to TACE alone for liver tumours greater than 5 cm [84,85].
There are no established imaging markers used for the prediction of TACE response. However, the delta of ADC values on MRI imaging higher than 20% facilitates early objective response to treatment [86,87]. To assess the presence of residual tumours, contrastenhanced ultrasound can also be used. Its sensitivity is 0.85, specificity is 0.94, and accuracy is 93.5% [88]. There are many developments in post-procedure prognostication, and the optimal cut-off points in predicting the complete response of target lesions were a 52% ALT increase and a 46% AST increase after cTACE compared to the pre-treatment values [89].
The best intraarterial approach for unresectable HCC remains elusive. A network meta-analysis of 55 RCTs compared results of 5763 diverse patients among bland transarterial embolisation (TAE), cTACE, DEB-TACE, or transarterial radioembolisation (TARE), either alone or combined with adjuvant chemotherapy, local liver ablation, or external radiotherapy. All embolisation strategies improved survival, with TACE + external radiation/liver ablation achieving the highest [90]. Another study suggested the superiority of DEB-TACE over other treatment strategies [91].
Within the last 3 years, we identified 19 randomised controlled trials involving TACE for HCC. They are summarised in Table 2.

Transarterial Radioembolisation (TARE), Also Known as Selective Internal Radiation Therapy (SIRT)
Liver tissue is very sensitive to radiation. The main problem with external beam radiotherapy was that it had to pass through the healthy tissue, causing its destruction. Intraarterial therapy became a solution to this problem [10]. TARE involves an injection of β-emitting yttrium-90 (Y90), holmium-166 (166Ho) integrated inside the glass matrix or on the surface of the resin microspheres, or metuximab-131 [21,[111][112][113][114][115][116]. TARE can be performed with whole-liver treatment, as well as lobar or segmental approaches (the more distal catheter placement, the more localised the technique) [117].
TARE works by inducing necrosis and delaying tumour progression [118][119][120][121][122][123]. It is widely known that patients with HCC and portal vein thrombosis (PVT) are not amenable to TACE due to the high risk of ischemia and liver failure [5,24,124]. In particular, in this subset of patients, TARE provided competitive, if not more favourable, results compared to sorafenib [124][125][126]. Only limited HCC patients are responsive to immune checkpoint inhibitors, and a combination of these with RT may enhance the immune response; this phenomenon is named the systemic therapy augmented by radiotherapy (STAR) effect [12,127].
TARE appears to be a safe alternative treatment to TACE with a comparable complication profile and survival rates [21]. However, despite these undoubted advantages, a non-negligible proportion of advanced HCC patients still do not benefit from TARE, thus calling for more effective therapeutic regimens [124]. As combining systemic agents with locoregional treatments might represent a therapeutic tool in the armamentarium of hepato-oncology, there is no evidence that the addition of sorafenib prolongs survival or delay disease progression among HCC patients undergoing TARE [124].
TARE is well known to potentially lead to serious adverse events and suffers from a narrow safety profile, which limits its worldwide use despite favourable efficacy outcomes and cost-effective benefits [120,124]. It can lead to postradioembolisation syndrome (fatigue, nausea, vomiting, abdominal pain, and cachexia), radioembolisation-induced liver disease (jaundice, ascites, hyperbilirubinemia, and hypoalbuminemia 2-4 weeks post treatment), portal hypertension, and biliary complications (biliary strictures or cholecystitis), as well as radiation pneumonitis, gastrointestinal ulcers, and vascular injury [128][129][130]. However, in a meta-analysis of 1652 patients based on 11 studies, Y90-TARE not only improved 2 year overall survival and objective response among observational studies [130], but was also associated with fewer adverse events compared to TACE [90,130,131].
The current evidence suggests that there is a dose-response relationship for HCC tumours, with the best current evidence for the target mean dose of 100-250 Gy [132]. There is a need for the development of reporting standards and dose-dependent guidelines [132].
The reported economics of TARE as an interventional modality of HCC is largely variable. Overall, it appears cost-effective as a short-and long-term treatment of intermediateadvanced HCC [133].
Within the last 3 years, we identified four randomised controlled trials involving TARE for HCC. They are summarised in Table 3.  Table 1, ** also presented in Table 2.

Conclusions
Locoregional therapies have established their place in the HCC management algorithm. RFA has the potential for repeatability and safety for patients with significant medical comorbidities. The primary concerns with this procedure remain local tumour progression post RFA, needle-track seeding, and abscess formation.
TACE is the standard of care for intermediate-stage lesions. It can produce tumour necrosis and improve survival in patients with good liver reserve. Neoadjuvant TACE can be used for patients with longer expected waiting list times for liver surgery (resection or transplant). TACE with drug-eluting beads (DEB-TACE) provides more selective and controlled drug delivery with microspheres than cTACE. Although DEB-TACE is associated with fewer side-effects, it has no strong evidence of increased efficacy compared to cTACE.
TARE provides a safe alternative treatment to TACE with a comparable complication profile and survival rates. TARE is well known to potentially lead to serious adverse events and suffers from a narrow safety profile, which limits its worldwide use despite favourable efficacy outcomes and cost-effective benefits. A dose-response relationship exists for HCC tumours with the best current evidence for the target mean dose of 100-250 Gy. However, there is a need to develop reporting standards and dose-dependent guidelines.
More research is needed to identify the optimal locoregional HCC treatment, better identify the early predictive factors, and develop an individualised treatment regimen. With the availability of the checkpoint immunotherapy modalities, the interest in combining locoregional and systemic therapies has resurfaced, and results of the ongoing trials of these combinations are eagerly awaited.
Funding: This research received no external funding.

Conflicts of Interest:
The authors declare no conflict of interest.