Role of Transarterial Chemoembolization in the Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. According to the Barcelona Clinic Liver Cancer (BCLC) staging system, transarterial chemoembolization (TACE) is the first-line recommendation for intermediate-stage HCC. In real-world clinical practice, TACE also plays an important role in early- and advanced-stage HCC. This review article by the experts from Chinese Liver Cancer Clinical Study Alliance (CHANCE) summarizes the available clinical evidence pertaining to the current application of TACE in patients with early-, intermediate-, and advanced-stage HCC. In addition, combination of TACE with other treatment modalities, especially immunotherapy, is reviewed.

Graphical abstract

Introduction

With increasing incidence and mortality, hepatocellular carcinoma (HCC) is one of the most common and fatal cancers worldwide.1,2 Approximately 72% of all new cases of HCC are diagnosed in Asia and Western countries are also experiencinmg an increasing trend of incidence.3 HCC mainly occurs against a background of chronic liver disease caused by hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcohol abuse. or metabolic disorders.2 The Barcelona Clinic Liver Cancer (BCLC) staging system is commonly applied as the staging and treatment recommendation system for HCC.4,5 Despite improved surveillance programs, approximately 80% of patients with HCC have intermediate- or advanced-stage disease at the time of diagnosis, which is the main cause of dismal long-term prognosis.2

According to the BCLC staging system, transarterial chemoembolization (TACE) is the first-line treatment option for intermediate-stage HCC. The BCLC staging system also introduces the concept of treatment stage migration, which means that TACE should be considered and recommended for patients with early-stage HCC in whom the recommended first-line treatment choices have failed or are not feasible.4 In addition, the BRIDGE study demonstrated that TACE is most widely applied not only for intermediate but also for advanced HCC in clinical practice.6 The application of TACE for intermediate and locally advanced HCC is also recommended by the China liver cancer (CNLC), Japan Society of Hepatology (JSH), Asia Pacific Association for the Study of the Liver (APASL), and Hong Kong Liver Cancer (HKLC) staging systems (Fig. 1).7–10 Reported by the experts from Chinese Liver Cancer Clinical Study Alliance (CHANCE), the goal of this review article is to summarize the most recent data and evidence from studies and guidelines regarding the application of TACE for the management of HCC especially in the era of immunotherapy.

Fig. 1. Summary and comparison of the recommendations of TACE for HCC in different guidelines.

BCLC, Barcelona Clinic Liver Cancer; CNLC, China liver cancer; cTACE, conventional transarterial chemoembolization; DEB-TACE, drug-eluting bead transarterial chemoembolization; ECOG, Eastern Cooperative Oncology Group; HCC, hepatocellular carcinoma; JSH, Japan Society of Hepatology; NCCN, National Comprehensive Cancer Network; PVTT, portal vein tumor thrombosis; TACE, transarterial chemoembolization.

TACE for intermediate HCC

Patient selection

The BCLC staging system defines intermediate HCC as presence of multifocal nodules (>3 nodules or a maximum nodule diameter of >3 cm), preserved liver function, no cancer-related symptoms, i.e. Eastern Cooperative Oncology Group (ECOG) 0, and no macrovascular invasion or extrahepatic spread.4 The recently updated BCLC staging system stratifies patients with intermediate-stage (BCLC-B) into three groups according to tumor burden and liver function.4 TACE is recommended as the first-line choice for the second subgroup, i.e. patients without the option for liver transplantation but who have preserved portal flow and in whom selective access to feeding tumor arteries is feasible.4 Notably, the updated BCLC staging system recommends that intermediate-stage HCCs with diffuse, infiltrative, extensive liver involvement do not benefit from TACE, and systemic therapy is the recommended first-line choice for these patients. The treatment recommendations of the European Association for the Study of the Liver (EASL), the American Association for the Study of Liver Diseases (AASLD), the APASL, and the JSH for intermediate-stage HCC are similar. All recommend TACE as first-line choice for all BCLC-B patients.8,9,11,12 The CNLC staging system recommends TACE as first-line choice for intermediate HCC with more than three lesions, which is different from the other recommendations mentioned above.7 Figure 2 shows a typical case of TACE treatment for patients with HCC.

Fig. 2. Images obtained in patients with HCC treated with TACE.

A 73-year-old man had a history of chronic hepatitis B ≥20 years. The baseline CT showed a huge intrahepatic lesion without peritumoral star lesions or vascular invasion (red dotted circle). There is no extrahepatic spread. The patient was treated with DEB-TACE combined with oral donafenib (0.2 g). The 1- and 5-month follow-up MRI after DEB-TACE showed that the patient achieved a continued complete response. The patient is still being followed-up. CT, computed tomography; DEB-TACE, drug-eluting bead transarterial chemoembolization; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; TACE, transarterial chemoembolization.

The major contraindications for TACE in patients with intermediate-stage HCC in the guidelines include decompensated cirrhosis (jaundice, refractory ascites, overt hepatic encephalopathy, and hepatorenal syndrome), extensive tumor involving both liver lobes, renal insufficiency (creatinine ≥2 mg/dL or creatinine clearance <30 mL/min), serious coagulation dysfunction that is not amenable to treatment, technical contraindications such as untreatable arteriovenous fistula, presence of cachexia or multiple organ failure, and distal extensive metastasis with an expected survival <3 months.

TACE techniques

Two major techniques for performing TACE are widely adopted worldwide, which are conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE). Conventional TACE, also known as lipiodol TACE, was developed in the early 1980s in Japan. It was subsequently established as the standard treatment based on the results of two randomized controlled trials (RCTs) that showed a significant survival benefit.13,14 During cTACE, emulsion mixtures of lipiodol and cytotoxic drugs such as doxorubicin, epirubicin, or cisplatin are delivered to the tumor-feeding arteries, followed by administration with gelatin sponge or particles. DEB-TACE, which entails the delivery of microspheres charged with cytotoxic drugs, can achieve sustained drug release into the surrounding tissues over time and embolization. To date, data from several clinical trials suggest that DEB-TACE shows comparable efficacy to cTACE and has relatively fewer cytotoxic drug-related adverse events.15,16 Use of multifunction embolization microspheres has also been explored in vivo, and in vitro experiments, and in clinical trials. They are designed to be biodegradable, are visible by imaging, and can load different therapeutic agents.17–19

Balloon-occluded TACE (B-TACE) was first introduced in 2009 and uses a balloon microcatheter inflated within the tumor-feeding arteries. The theoretical basis of B-TACE is the hemodynamic changes caused by the balloon inflation that further results in the accumulation of dense lipiodol emulsion in the HCC nodule. Transarterial embolization, also called bland embolization, refers to transarterial administration of an embolic agent without additional chemotherapy, and is aimed at occluding small feeding arteries and inducing tumor ischemia and necrosis. In addition, TACE combined with bicarbonate infusion was reported to enhance the anticancer activity by targeting intratumoral lactic acidosis.20

Response assessment and treatment outcomes

Conventional evaluation of outcomes with the Response Evaluation Criteria In Solid Tumors (RECIST) criteria, which are based on tumor diameter shrinkage, tends to underestimate tumor response. Currently, the most widely accepted and applied evaluation of tumor response are the modified RECIST (mRECIST) criteria which are rules based on using contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) to measure the reduction in viable tumor burden.21 The AASLD recommends progression-free survival (PFS) as a potential surrogate endpoint instead of overall survival (OS) for TACE-related trials.22 Several ongoing trials of TACE combined with systemic therapy also use PFS as the primary endpoint or co-primary endpoint with OS (Table 1). Novel response assessment and prediction approach such as radiomics, glycans, and glycosylation, has also been applied for patients treated with a combination of TACE with other treatments; however, its applicability in clinical practice needs further exploration and discussion.23–25

Table 1. Ongoing randomized controlled trials of TACE combined with immunotherapy.

Trial (NCT number)	Enrollment	Population under study (BCLC stage)	Therapies under comparison	Primary endpoint(s)
EMERALD-1 (NCT03778957)	710	Candidates for first TACE (BCLC-B)	TACE plus durvalumab plus bevacizumab vs. TACE plus durvalumab vs. TACE plus placebo	PFS for placebo vs. combination
CHECKMATE-74W (NCT04340193)	765	Candidates for first TACE (BCLC-B)	TACE plus nivolumab plus ipilimumab vs. TACE plus nivolumab vs. TACE	OS and TTTP
LEAP-012 (NCT04246177)	950	Candidates for first TACE (BCLC-B)	TACE plus pembrolizumab plus lenvatinib vs. TACE plus oral placebo plus IV placebo	OS and PFS
TACE-3 (NCT04268888)	522	Candidates for first TACE (BCLC-B)	DEB-TACE plus nivolumab vs. DEB-TACE	OS (TTTP for the phase II portion)
RENOTACE (NCT04777851)	496	Candidates for first TACE (BCLC-B)	Regorafenib plus nivolumab vs. TACE	PFS
ABC-HCC (NCT04803994)	434	Candidates for first TACE (BCLC-B)	Atezolizumab plus bevacizumab vs. TACE	Time to failure of treatment

BCLC, Barcelona Clinic Liver Cancer; DEB-TACE, drug-eluting beads transarterial chemoembolization; OS, overall survival; PFS, progression-free survival; TACE, transarterial chemoembolization; TTTP, time to TACE progression.

Two milestone RCTs reported 1-year survival probabilities of 75% and 57%.14 A systematic review of 14 RCTs also found that TACE improved the survival of patients with unresectable HCC.26 Arterial embolization improved 2-year survival compared with controls. In addition, treatment induced objective responses in 35% of patients. Notably, all included RCTs in the systematic review were published between 1988 and 2002. Another systematic review of the treatment efficacy and safety of lipiodol TACE for HCC was published in 2016.27 It included 10,108 patients in 101 studies, and the results showed a median OS of 19.4 months, without any new unexpected safety concerns. Figure 3 shows the results of reported objective response rate (ORR) of TACE for intermediate-stage HCC. Table 2 shows reported outcomes of RCTs for TACE in the treatment of HCC.13–16,28–40

Fig. 3. Results of reported objective response rate of TACE for intermediate HCC.

BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; ORR, objective response rate; TACE, transarterial chemoembolizarion.

Table 2. Reported outcomes of randomized controlled trials for TACE in HCC.

Trial (year)	Arms	BCLC stage	End point(s)	Outcome(s)
Llovet et al. (2002)13	TAE (n=37)/cTACE (n=40) vs. symptomatic treatment (n=35)	N/A	OS	25.3/28.7 months vs. 17.9 months; p=0.009 (cTACE vs. symptomatic treatment)
Lo et al. (2002)14	cTACE (n=40) vs. symptomatic treatment (n=39)	N/A	survival	1-year, 2-year, and 3-year survival rates: 57%, 31%, and 26% vs. 32%, 11%, and 3%; p=0.005
Okusaka et al. (2009)28	TAI (n=82) vs. cTACE (n=79)	N/A	OS	22.3 months vs. 21.2 months; p=0.383
Lammer et al. (2010) (PRECISION V trial)15	DEB-TACE (n=93) vs. cTACE (n=108)	A/B	6-month ORR	51.6% vs. 43.5%; p=0.11
Kudo et al. (2011) (POST-TACE trial)29	cTACE (responders) plus sorafenib (n=229) vs. cTACE plus placebo (n=229)	N/A	TTP	5.4 months vs. 3.7 months; p=0.252
Yu et al. (2014)30	TEA (n=49) vs. cTACE (n=49)	A/B/C	OS	24.3 months vs. 20.1 months; p=0.513
Golfieri et al. (2014) (PRECISION ITALIA trial)16	DEB-TACE (n=89) vs. cTACE (n=88)	A/B/C	2-year survival rate	56.8% vs. 55.4%; p=0.949
Kudo et al. (2014) (BRISK-TA trial)31	cTACE or DEB-TACE plus brivanib (n=249) vs. cTACE plus placebo (n=253)	A/B/C/D	OS	26.4 months vs. 26.1 months; p=0.53
Lencioni et al. (2016) (SPACE trial)32	DEB-TACE plus sorafenib (n=154) vs DEB-TACE plus placebo (n=153)	B	TTP	5.6 months vs. 5.5 months; P=0.072
Meyer et al. (2017) (TACE 2 trial)33	DEB-TACE plus sorafenib (n=157) vs DEB-TACE plus placebo (n=156)	A/B	PFS	7.8 months vs. 7.7 months; p=0.85
Ikeda et al. (2018)34	cTACE with miriplatin (n=129) vs. cTACE with epirubicin (n=128)	N/A	OS	36.5 months vs. 37.1 months; p=0.946
Kudo et al. (2018) (ORIENTAL trial)35	cTACE plus orantinib (n=445) vs. cTACE plus placebo (n=444)	A/B/C	OS	31.1 months vs. 32.3 months; p=0.435
Park et al. (2019) (STAH trial)36	cTACE plus sorafenib (n=170) vs. sorafenib (n=169)	A/B/C	OS	12.8 months vs. 10.8 months; p=0.290
Ikeda et al. (2020) (JIVROSG-1302 PRESIDENT trial)37	DEB-TACE (n=99) vs. cTACE (n=101)	A/B/C	3-month CR rate	27.6% vs. 75.2%; p<0.0001
Kudo et al. (2021) (TACTICS trial)38	cTACE plus sorafenib (n=80) vs. cTACE (n=76)	A/B/C	PFS; OS	25.2 months vs. 13.5 months; p=0.006; 36.2 months vs. 30.8 months; p=0.40
Zhu et al. (2022)39	cTACE with dicycloplatin (n=22, A1) vs. cTACE with dicycloplatin plus epirubicin (n=25, A2) vs. cTACE with epirubicin (n=24, B)	A/B	ORR	50.0% vs. 44.0% vs. 29.17%; p=0.093 (A1 vs. B); P=0.338 (A2 vs. B)
Peng et al. (2022) (LAUNCH trial)40	lenvatinib plus cTACE/DEB-TACE (n=170) vs. lenvatinib (n=168)	C	OS	17.8 months vs. 11.5 months; p<0.001

BCLC, Barcelona Clinic Liver Cancer; cTACE, conventional transarterial chemoembolization; DEB-TACE, drug-eluting beads transarterial chemoembolization; HCC, hepatocellular carcinoma; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TACE, transarterial chemoembolization; TAE, transarterial embolization; TAI, transarterial infusion chemotherapy; TEA; transarterial ethanol ablation; TTP, time to tumor progression.

Repeat TACE and TACE failure/refractory

Considering its palliative nature, repeat TACE is often required to achieve better tumor control and long-term prognosis. Several previous studies have found that repeat TACE conferred a survival benefit.41 Nevertheless, repeat TACE was associated with increased side effects and impaired liver function. Therefore, the potential treatment benefits must be carefully weighed against the side effects of repeat TACE. Currently, on-demand mode and scheduledmode are the two major modes of repeat TACE in clinical practice. For on-demand mode, repeat TACE is considered only if a viable tumor or local and/or distant intrahepatic recurrence is observed during routine follow-up.11 Notably, the concept of viable tumor has not yet been accurately defined. For scheduled mode, repeat TACE is performed at fixed intervals regardless of the tumor response after previous TACE.

According to the EASL, TACE should not be repeated if substantial necrosis is not achieved after two rounds of treatment or when follow-up treatment fails to induce marked necrosis at sites that have progressed after an initial tumor response, or if there is occurrence of untreatable progression defined as tumor progression associated with a clinical profile that prevents re-treatment.11 Notably, the JSH indicates that new occurrence of intrahepatic lesion(s) is a natural process of liver disease, and that it should not be regarded as disease progression. Therefore, TACE should not be stopped if new intrahepatic lesion(s) occurs.8 Both the AASLD and CNLC provide no detailed recommendation for the optimal time to stop TACE.7,12 Several prognostic models or scores have been used to help stratify patients who are more likely to benefit from initial or repeat TACE. However, none of these models have been strongly recommended by the guidelines.42,43

The concept of TACE failure/refractory was introduced in order to avoid ineffective repeat TACE.44–46 The definition of the JSH-Liver Cancer Study Group of Japan (LCSGJ) and updated in 2014 is most widely used in clinical practice and clinical trials.44 Nevertheless, the objectivity and rationality of such definition is debated. Without high-level evidence support, the concept suggests switching to systemic agent monotherapy if TACE failure/refractoriness occurs. In contrast, a recently published article reviewing the current evidence on subsequent treatment after TACE failure/refractoriness concluded that not only sorafenib, but also other therapies such as TACE with drug-eluting beads, hepatic arterial infusion chemotherapy, ablation, and TACE combined with systemic therapies are potentially useful as subsequent treatment after TACE failure/refractoriness.47 In addition, a nationwide online survey by the Chinese College of Interventionalists (CCI) in 2020 found an obvious difference in the recognition of TACE failure/refractoriness among Chinese clinicians based on existing definitions.48 Recently, an expert consensus on TACE refractoriness and subsequent therapies in HCC was published by the CCI.49 The CCI definition of TACE refractoriness is progression of the treated tumor(s) (progression disease according to mRECIST criteria seen on contrast-enhanced CT/MRI at 1–3 months after the latest TACE) compared with baseline after three or more consecutive standardized and precision TACE sessions.

TACE for HCC beyond intermediate-stage

Early and very early HCC

Early-stage HCC (BCLC A) is defined as solitary HCC irrespective of tumor size or as a multifocal HCC with up to three nodules (none >3 cm), preserved liver function, no cancer-related symptoms (ECOG 0), and no macrovascular invasion or extrahepatic spread. Very early HCC (BCLC 0) is a solitary HCC ≤2 cm.4 For that stage, curative approaches include liver transplantation (LT), surgical resection, or local ablation, and are generally recommended based on individual profiles. However, some patients refuse surgery or are unsuitable for surgery because of factors such as old age, hepatic dysfunction, and severe comorbidities. Moreover, the shortage of liver donors poses a challenge to transplantation, and ablation is not feasible for tumors with subcapsular, dome, or other high-risk locations.50,51

According to the treatment stage migration strategy, TACE treatment should be considered for these patients who are not candidates for any of the mentioned approaches.4 Several studies have reported that TACE was an effective alternative treatment that achieved long-term survival benefits in BCLC 0/A HCC patients for whom curative treatment was not feasible.52–55 TACE is recommended as the first-line downstaging treatment for LT to reduce tumor burden and allow patients to meet acceptable transplantation criteria.11,50 TACE is often chosen as a bridge therapy before LT and is associated with a decrease in the dropout rate for patients awaiting LT, especially when the anticipated waiting time exceeds six months.50,56,57

Advanced HCC

Advanced-stage stage HCC includes patients with vascular invasion or extrahepatic spread, preserved liver function, and ECOG performance score 1–2. Systemic therapy is recommended for those patients.4 Recently, immunotherapy-based combination protocols, such as atezolizumab plus bevacizumab, have become the first-line therapeutics for advanced-stage HCC after several trials demonstrated favorable results over sorafenib.58,59 Sorafenib or lenvatinib can still be considered for patients in whom immune checkpoint inhibitors are contraindicated.

The majority of guidelines do not recommend the use of TACE in advanced HCC patients; the only exception is the CNLC which recommends TACE as the first-line choice for patients with macrovascular invasion.7,11,12 However, the HCC BRIDGE study, a global large-scale, longitudinal cohort study that retrospectively included 18,031 patients in 14 countries and treated between January 2005 and September 2012, documented the real-life clinical management of HCC patients and found that TACE was the first-line treatment in nearly 50% patients with BCLC-C stage HCC.6 Previous studies demonstrated that TACE confered survival benefits over the best supportive care in patients with portal vein tumor thrombus.60,61 With the advent of the era of immunotherapy-based combination treatments, TACE may provide a potential synergistic anti-tumor effect when administered in combination with molecular and immune therapies.62

TACE combined with other treatments

Combination with ablation

Percutaneous ablation through radiofrequency ablation (RFA) or microwave ablation (MWA) is recommended as the first treatment option for BCLC 0/A stage HCC patients who are not potential candidates for liver transplantation and surgical resection.4,11,12 RFA was shown to provide the same survival benefit in cases of HCC ≤2–3 cm compared with surgical resection, while MWA was shown to achieve more extensive tumor necrosis than RFA and was an effective method for treating HCC lesions ≤5 cm. Other ablative techniques, such as cryoablation, and irreversible electroporation are currently under investigation.

Several studies have explored the synergistic cytotoxic effects of the combination of TACE and ablation in selected populations of early- or intermediate-stage HCC. An RCT by Peng et al.63 compared the efficacy of TACE combined with RFA versus RFA alone in patients with solitary HCC ≤7 cm, or multinodular HCC within the Milan criteria. Patients treated with TACE plus RFA treatment had significantly better OS and recurrence-free survival than patients treated with RFA alone [hazard ratio (HR), 0.525; p=0.002 and HR, 0.575; p=0.009], respectively. The long-term survival outcomes were updated after approximately 6 years of follow-up, suggesting that TACE with RFA may be a better first-line treatment than RFA alone for patients with early-stage HCC.64 However, subgroup analysis demonstrated that HCC patients with tumor size ≤3 cm may not benefit as much from combination treatment when compared with those who had tumor size >3 cm. The results are in line with two previous meta-analyses that demonstrated greater effectiveness of TACE-RFA in patients with higher tumor burden.65,66 Another meta-analysis of data from eight retrospective studies and one RCT compared the survival outcomes and safety profile between TACE combined with RFA and surgical resection in patients with early-stage HCC.67 There were no significant differences between 1-, 3-, and 5-year OS and 1-year disease-free survival in the two groups regardless of matched data or unadjusted pooled data. Differences in 3- and 5-year disease-free survival in the propensity-matched cohort were not significant. Sequential TACE-RFA combination therapy also showed good efficacy in patients with recurrent early-stage HCC, and can be recommended for patients with tumors measuring 3–5 cm or in those who develop tumor recurrence 1 year or less after the initial treatment.68 The combination of TACE with other ablative techniques was also shown to achieve better outcomes than monotherapy in selected populations.69,70

Combination with molecular targeted agents

By embolizing tumor-feeding arteries, TACE leads to acute hypoxia, resulting in an increase in vascular endothelial growth factor (VEGF).71 Thus, the combination of tyrosine kinase inhibitors (TKIs) targeting on VEGF with TACE to decrease TACE-induced angiogenesis may potentially improve treatment efficacy of TACE due to the synergistic action (Fig. 4).62 Several phase II/III RCTs have investigated the treatment efficacy and safety of TACE combined with TKIs versus TACE monotherapy for intermediate-stage HCC.31–33,35 The SPACE and TACE-2 trials compared TACE plus sorafenib to TACE monotherapy.32,33 Two other RCTs compared TACE plus brivanib (BRISK-TA study) or orantinib (ORIENTAL study) to TACE monotherapy.31,35 Unfortunately, none of the four trials found any significant treatment benefit from TACE combined with TKIs.

Fig. 4. Possible mechanisms by which TACE and combination therapies provide benefit in HCC treatment.

HCC, hepatocellular carcinoma; HIF1α, hypoxia inducible factor-1 α; MDSC, myeloid-derived suppressor cell; PD1, programmed death 1; TACE, transarterial chemoembolization; VEGF, vascular endothelial growth factor.

Recently, the phase II TACTICS trial comparing TACE plus sorafenib versus TACE monotherapy for intermediate HCC, demonstrated significant improvement in PFS based on a new definition of untreatable progression.72 Median PFS was 25.2 months in the combination group and 13.5 months in the TACE monotherapy group (p=0.006). Different from previous trials, in the TACTICS trial, sorafenib administration was initiated 3 weeks before the first TACE. Notably, the updated data showed that another co-primary endpoint, OS, was comparable, without a significant difference between the two groups.38

More recently, the primary analysis of TACTICS-L trial, which was a single-arm trial investigating the efficacy and safety of TACE plus lenvatinib for intermediate HCC, reported a promising outcome. A total of 62 patients were included, and lenvatinib was initiated 14–21 days prior to first TACE. The median PFS following the per Response Evaluation Criteria in Cancer of the Liver (RECICL) criteria was 24.4 months. The ORR evaluated using the RECICL was 79.0%, including a 53.2% complete response (CR).

Combination with immunotherapy

The successful prospective trials of anti-programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) agents for advanced HCC heralded the era of immunotherapy for HCC.73 Despite negative results of two phase III RCTs focusing on anti-PD-1 agent monotherapy for advanced HCC, several subsequent RCTs have demonstrated the advantage of a new strategy of combination of anti-PD-(L)1 and anti-VEGF or TKI agents over sorafenib for advanced HCC.58,59 It is now recommended as the preferred first-line choice for advanced HCC.4 TACE serves the function of transforming the immunosuppressive cold tumor to a hot tumor for HCC (Fig. 4). In detail, TACE results in necrosis of the tumor tissue as well as induces a hypoxic microenvironment, which increases the expression of PD-L1 on the surface of immune cells and tumor cells, reduces the release of immunosuppressive factors, and attenuates the inhibition to immune function. Therefore, the combination of TACE with anti-PD-(L)1 and molecular targeted therapies provides a potential synergistic anti-tumor effect. To date, only a few retrospective studies with small sample size have been reported on that topic.74,75 Several RCTs investigating the efficacy and safety of TACE combined with anti-PD-(L)1 and anti-VEGF or TKI agents for unresectable HCC are currently underway (Table 1).

To promote comprehensive treatment of liver cancer by multidisciplinary team, Chinese Liver Cancer Clinical Study Alliance (CHANCE) national registry platform sponsored by CCI was launched in April 20, 2021 in Nanjing, China. In addition, a nationwide, multicenter, retrospective study, the CHANCE 001 study, was then carried out. The study (NCT 04975932) included more than 800 HCC patients treated at 59 academic hospitals in China with either TACE plus anti-PD-(L)1 and molecular targeted therapies or TACE monotherapy. Details on this study will be reported soon.

Combination with other local treatments

Several studies focusing on the combination of TACE plus radiotherapy have reported promising results in intermediate-stage HCC patients, as well as advanced-stage HCC with portal vein tumor thrombosis (PVTT). A meta-analysis of 25 trials (11 RCTs and 14 non-RCTs) including 2,577 patients evaluated the efficacy and safety of TACE plus radiotherapy versus TACE alone for unresectable HCC.76 Patients receiving TACE plus radiotherapy had significantly better 1-, 2-, 3-, 4-, and 5-year survival and overall response. However, combination treatment was associated with a greater incidence of gastrointestinal and hepatobiliary complications that were easily managed and treated. Interestingly, a subgroup analysis found that TACE plus radiotherapy showed a tendency for increased survival in patients with PVTT compared with those without PVTT, although the trend was not significant. Yoon et al. conducted an RCT in HCC patients with macrovascular invasion to explore whether first-line combined TACE plus radiotherapy treatment can improve survival compared with sorafenib. TACE combined with radiotherapy was associated with significantly improved PFS, ORR, time to progression, and OS; therefore, it represents a viable, well-tolerated alternative to systemic therapies.

Iodine-125 implantation, as a type of local brachytherapy, provides a long-term cytocidal effect at a low dose and minimal damage to normal tissue. Two retrospective matched-cohort studies revealed that TACE plus iodine-125 implantation improved survival in patients with early- and intermediate-stage HCC.77,78 For patients with malignant portal vein tumor thrombosis, iodine-125 seed implantation, integrated iodine-125 seed implantation, endovascular iodine-125 seed strands with/without portal vein stent placement, or self-expandable iodine-125 seed loaded irradiation stent combined with TACE may represent a safe and effective treatment modalities.79–82

Adverse events (AEs) of TACE

AEs or side effects of TACE for HCC are mainly intraoperative and postoperative. The former mainly includes allergic reactions, intraoperative bleeding, and biliary cardiac reflex. The latter mainly includes postembolization syndrome (PES) liver abscess, upper gastrointestinal bleeding, liver and renal failure, myelosuppression, and ectopic embolism.83 A systematic review including 217 selected studies showed that a total of 21,461 AEs were reported in 15,351 patients who underwent at least 27,497 treatment sessions of lipiodol TACE.27 The most frequent AE was PES (47.7%) including fever, vomiting, liver enzyme abnormalities, abdominal pain, and nausea.27

Comparison with transarterial radioembolization (TARE)

TARE is a modality for selective internal radiation therapy. It is performed by injecting radioactive microspheres loaded with yttrium-90 (Y90, a β-emitting isotope) into the arteries feeding the lesion(s). TARE has recently been recommended as a choice for early-stage HCC by the BCLC, whereas it has also been largely explored in intermediate and advanced HCC.4,84,85 TARE has been shown to confer similar survival duration compared with TACE.86 However, TARE was associated with significantly increased time to progression compared with TACE (>26 months versus 6.8 months).86 To date, no phase III RCTs have reported the comparative efficacy and safety of TARE versus TACE.

Precision TACE

Despite its widely application, standardization of TACE in clinical practice is hard to achieve. Lencioni et al.27 reported a systematic review including 10 108 patients with HCC treated with conventional TACE between 1980 and 2013 worldwide. The results showed considerable variability in the treatment efficacy of TACE between countries and time periods. The concept of precision TACE was introduced to maximize the standardization of TACE. Briefly, precision TACE requires physicians to perform TACE based on patient-specific condition, careful pretreatment preparation, accurate implementation, close follow-up, and whole-process management.

Perspective

TACE has an important role in the treatment of all stages of HCC. The indications for TACE have expanded, ranging from a curative approach for patients with early-stage HCC to palliative treatment for patients with advanced-stage HCC. Owing to limited evidence, TACE is recommended as the first-line choice mainly for intermediate-stage HCC by several guidelines. Further work is warranted to provide more evidence to support the indications and recommendations for TACE in patients with HCC. Besides, in the era of immunotherapy, TACE administrated in combination with immunotherapy-based systemic therapy offers a new paradigm for the treatment of unresectable HCC.

Abbreviations

AASLD

Association for the Study of Liver Diseases

AEs

adverse events

APASL

Asia Pacific Association for the Study of the Liver

BCLC

Barcelona Clinic Liver Cancer

B-TACE

balloon-occluded transarterial chemoembolization

CCI

Chinese College of Interventionalists

CHANCE

Chinese Liver Cancer Clinical Study Alliance

CNLC

China liver cancer

CR

complete response

CT

computed tomography

DEB-TACE

drug-eluting beads transarterial chemoembolization

EASL

European Association for the Study of the Liver

ECOG

Eastern Cooperative Oncology Group

HBV

hepatitis B virus

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HKLC

Hong Kong Liver Cancer

HR

hazard ratio

JSH

Japan Society of Hepatology

LCSGJ

Liver Cancer Study Group of Japan

LT

liver transplantation

mRECIST

modified Response Evaluation Criteria In Solid Tumor

MRI

magnetic resonance imaging

MWA

microwave ablation

OS

overall survival

ORR

objective response rate

PD-1

programmed death 1

PD-L1

programmed death ligand 1

PES

postembolization syndrome

PFS

progression-free survival

PVTT

portal vein tumor thrombosis

RCTs

randomized controlled trials

RECICL

Response Evaluation Criteria in Cancer of the Liver

RECIST

Response Evaluation Criteria In Solid Tumor

RFA

radiofrequency ablation

TACE

transarterial chemoembolization

TARE

transarterial radioembolization

TKIs

tyrosine kinase inhibitors

VEGF

vascular endothelial growth factor