ABSTRACT
Intermediate-stage hepatocellular carcinoma (HCC) encompasses a diverse patient population that requires individualized treatment strategies and a multidisciplinary approach. Recent advancements in systemic therapy have expanded the therapeutic options for intermediate-stage HCC, allowing for combination strategies such as systemic therapy with transarterial chemoembolization (TACE) and upfront systemic therapy for individuals deemed unsuitable for TACE. Additionally, the ongoing development of treatment modalities for intermediate-stage HCC has improved the potential for curative conversion and tumor downstaging. Nevertheless, consensus on the optimal management of intermediate-stage HCC remains limited. Thus, the primary aim of this study was to develop a set of consensus guidelines for the management of intermediate-stage HCC. To address this gap, the Taiwan Liver Cancer Association (TLCA) established a working group to develop a multidisciplinary strategy for managing intermediate-stage HCC. Here, we present eight consensus statements formulated by this expert panel, which outline criteria for TACE unsuitability, treatment recommendations based on TACE eligibility, and considerations for various modalities, including conventional TACE, drug-eluting bead TACE, and transarterial radioembolization, as well as the appropriate timing for initiating systemic therapy to enable curative conversion and downstaging. These statements provide specific, evidence-based recommendations for clinicians, addressing treatment pathways based on TACE eligibility and other key considerations for intermediate-stage HCC management. The development of this consensus guideline is intended to aid clinicians in selecting the most appropriate treatment pathway for intermediate-stage HCC, support personalized treatment planning, and ultimately enhance the feasibility of achieving curative conversion.
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Keywords: Hepatocellular carcinoma; Intermediate stage; Transarterial chemoembolization; Systemic therapy; Immunotherapy
INTRODUCTION
Intermediate-stage hepatocellular carcinoma (HCC) encompasses a heterogeneous patient population, necessitating tailored treatment strategies and a multidisciplinary approach [
1]. Recent advances in systemic therapy have contributed to improved outcomes through combination approaches, such as systemic therapy with transarterial chemoembolization (TACE) or upfront systemic therapy in individuals deemed unsuitable for TACE [
2]. Additionally, evolving therapeutic options have increased the potential for curative outcomes and tumor downstaging in intermediate-stage HCC [
3,
4].
In recent years, several consensus guidelines for HCC management have been proposed [
1,
5-
7]. However, with the continued emergence of clinical trial and real-world data, a unified consensus on optimal treatment strategies for intermediate-stage HCC remains an unmet need. For example, recent evidence from the 2024 EMERALD-1 and LEAP-012 trials supports combining immunotherapy with TACE to improve progression-free survival (PFS) following locoregional treatment [
8,
9].
In response to these developments, the Taiwan Liver Cancer Association (TLCA) convened a multidisciplinary working group to establish updated treatment guidelines for intermediate-stage HCC. Here, we present eight consensus statements from this expert panel, addressing criteria for TACE unsuitability, treatment recommendations based on TACE eligibility, and considerations among various treatment modalities, including conventional TACE, drug-eluting bead TACE (DEB-TACE), and transarterial radioembolization (TARE), as well as guidance on when to initiate systemic therapy to enable potential curative conversion and tumor downstaging.
METHODS
Expert panel
The intermediate-stage HCC working group panel consisted of 24 experts, including 14 hepatologists, four hepatobiliary surgeons, three medical oncologists, and three interventional radiologists, nominated from among the experts and committee members of the TLCA. Four members were assigned to conduct detailed literature reviews prior to discussion. The expert panel convened on three occasions since July 2024.
Definition of intermediate-stage HCC
The definition of intermediate-stage HCC varies between the APPLE consensus and the Barcelona Clinic Liver Cancer (BCLC) staging system. Following a formal vote, the TLCA panel adopted the BCLC stage B classification to define intermediate-stage HCC for this consensus guideline [
6].
The methodological framework for this guideline was based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, an internationally endorsed method for rating the quality of evidence in systematic reviews [
10]. Incorporating GRADE allowed for comprehensive appraisal of the supporting evidence, ensuring methodological rigor in the development of each recommendation. The quality of evidence underlying each statement was systematically evaluated using GRADE criteria (
Table 1). All statements were independently reviewed for appropriateness and clarity by members of the drafting committee. Final consensus recommendations were formulated based on a thorough synthesis of evidence from systematic reviews.
Statement 1: Intermediate-stage (BCLC B) HCC is a heterogeneous group, and treatment should be tailored based on tumor burden and liver reserve (agreement 100%)
Intermediate-stage HCC represents a highly heterogeneous disease, encompassing a broad range of tumor burdens and liver function statuses [
11]. Survival outcomes in previous randomized controlled trials evaluating TACE have varied substantially, ranging from 14 to 37 months, likely due to significant differences in patient characteristics across studies [
2]. Liver functional reserve and tumor burden are critical determinants incorporated into various subclassification systems and prognostic models designed to predict outcomes following TACE [
12]. These models typically include baseline liver function assessments, such as the Child–Pugh score or ALBI grade, tumor burden criteria like tumor size, number, up-to-7 and up-to-11 criteria, and tumor markers including AFP [
13-
17].
Although TACE has historically been the standard treatment for intermediate-stage HCC, it is not universally beneficial. Alternative strategies, such as upfront systemic therapies, have been proposed for individuals either unsuitable for or unlikely to respond to TACE [
1,
18,
19]. Conversely, curative-intent options, including surgical resection, local ablation, or liver transplantation (LT) under extended criteria, may be feasible for select individuals with intermediate-stage HCC and limited tumor burden [
20,
21]. Accordingly, effective management of intermediate-stage HCC demands tailored therapeutic strategies and a multidisciplinary approach, with treatment selection individualized based on tumor burden and liver reserve to optimize outcomes and improve survival.
Statement 2: TACE is widely used for treating unresectable intermediate-stage HCC. However, not all patients are suitable for TACE, particularly those with a tumor burden exceeding the up-to-11 criteria or with unfavorable radiological patterns (agreement 100%, evidence B)
Achieving radiologic responses while preserving liver function following TACE is critical for prolonging overall survival (OS) in individuals with HCC. Therefore, identifying those unlikely to respond to TACE or at high risk of hepatic function deterioration is essential to avoid unnecessary TACE in individuals who are poor responders.
Definitions of high tumor burden differ across various subclassification systems and prognostic models [
12,
22,
23]. The up-to-7 criteria are frequently applied to define high tumor burden in intermediate-stage HCC, as demonstrated in models such as Bolondi’s subclassifications [
24], the Kinki criteria [
25], and the STATE score [
16]. However, up-to-7 was originally developed for early-stage HCC candidates under evaluation for LT [
22,
26]. and may not accurately stratify tumor burden in intermediate-stage HCC. Recent studies indicate that the up-to-11 criteria outperform up-to-7 in predicting survival outcomes after TACE [
14]. In Taiwan, the 7–11 criteria have been introduced to classify intermediate-stage HCC into low, intermediate, and high tumor burden groups [
14,
15]. The 7–11 criteria effectively predict radiologic response and OS in intermediate-stage HCC [
27], with cure conversion rates after immunotherapy decreasing as tumor burden increases [
3]. Moreover, individuals exceeding the up-to-11 threshold experience a significantly elevated risk of hepatic function deterioration following TACE [
27,
28]. Therefore, a tumor burden exceeding the up-to-11 criteria is strongly discouraged for TACE due to the low likelihood of radiologic response and the high risk of hepatic function deterioration, whereas an intermediate tumor burden (between upto- 7 and up-to-11) is regarded as relatively unsuitable for TACE.
Radiologic pattern is also an important criterion for assessing TACE unsuitability [
1]. Radiologic features of HCC can be classified into encapsulated nodular type, simple nodular type with extranodular growth, confluent multinodular type, and infiltrative type [
29]. A study from Taiwan reported that encapsulated nodular HCC had the highest objective response rate (ORR) after TACE (58%), followed by the extranodular type (45.8%), confluent multinodular type (29%), and infiltrative type (19.5%) [
30]. Both tumor burden and radiologic morphology were significantly associated with ORR and OS. These findings suggest that confluent multinodular and infiltrative HCC demonstrate markedly poorer ORR and OS following TACE and should be considered key factors in identifying TACE-unsuitable individuals. A combined approach, integrating tumor burden thresholds, radiologic features, and prognostic models such as the ALBI-TAE score developed in a Taiwanese cohort [
14], can enhance the identification of patients who are less likely to benefit from TACE.
Statement 3: For intermediate-stage HCC that is unsuitable for TACE, systemic therapy should be initiated as the first-line treatment (agreement 95%, evidence C)
Based on multiple treatment guidelines, systemic therapy is recommended for individuals who are unsuitable or ineligible for effective TACE [
1,
6,
7,
29,
31]. Repeated TACE in individuals who have become refractory to treatment often leads to hepatic function deterioration and consequently poor prognosis [
32]. Subgroup analyses from four previous phase III clinical trials indicate that systemic therapy can be effective in individuals with BCLC stage B disease. In the REFLECT trial [
33], lenvatinib demonstrated similar OS (hazard ratio [HR]: 0.91, 95% confidence interval [CI]: 0.65–1.28; 18.5 vs. 17.3 months) but superior PFS compared to sorafenib (HR: 0.70, 95% CI: 0.50–0.99; 9.1 vs. 5.5 months). Japanese subset analyses [
34] revealed a higher ORR with lenvatinib than with sorafenib (OR: 10.2, 95% CI: 2.99–35.0; 61.3% vs. 11.8%). In the IMbrave150 trial [
35], patients treated with atezolizumab plus bevacizumab demonstrated a trend of better OS (HR: 0.64, 95% CI: 0.31–1.31; 25.8 vs. 18.1 months), PFS (HR: 0.66, 95% CI: 0.38–1.15; 12.6 vs. 8.6 months), and ORR (OR: 2.33, 95% CI: 0.79–6.91; 44% vs. 25%) than those with sorafenib. In the HIMALAYA trial, patients receiving the combination of tremelimumab and durvalumab exhibited a trend towards improved OS (HR, 0.87; 95% CI: 0.57–1.33) [
36], with 4-year update data indicating a hazard ratio of 0.81 (95% CI: 0.55–1.19) compared to those treated with sorafenib [
37]. Similarly, the CheckMate 9DW trial [
38] reported trends of enhanced OS with the administration of nivolumab plus ipilimumab. In summary, individuals with intermediate-stage HCC derived substantial benefits from systemic therapy across these trials, with superior tumor responses and survival outcomes compared to historical outcomes with TACE alone.
Lenvatinib administered prior to TACE may offer greater survival benefits for TACE-unsuitable individuals, such as those with bilobar multifocal nodules, compared to TACE alone [
39]. A proof-of-concept study reported that pretreatment with lenvatinib followed by TACE in individuals beyond the up-to-7 criteria with Child–Pugh A liver function resulted in favorable outcomes [
18]. Lenvatinib was associated with significantly longer PFS than that with TACE alone (16.0 vs. 3.0 months; HR: 0.19; 95% CI: 0.10–0.35;
P<0.001). Improved OS was also observed (37.9 vs. 21.3 months; HR: 0.48; 95% CI: 0.16–0.79;
P<0.01), demonstrating a clear advantage. Two real-world Japanese studies further indicated that lenvatinib followed by selective TACE improved TACE efficacy and prolonged outcomes. One study of 208 intermediate-stage HCC individuals receiving early lenvatinib or TACE alone [
40] showed, via Cox modeling adjusted by Inverse Probability Weighting (IPW), that lenvatinib significantly improved OS in those beyond up-to-7 (HR: 0.230; 95% CI: 0.059–0.904;
P=0.035). Another prospective study in 31 individuals with BCLC-B2 suggested lenvatinib offered OS of 17.0 months (95% CI: 15.3–19.2) and PFS of 10.4 months (95% CI: 6.6–13.8), with a comparable safety profile [
41]. Additionally, atezolizumab plus bevacizumab showed promising efficacy in uHCC beyond up-to-7 [
42], with 6-month PFS of 63.2% and mPFS of 8.0 months, and favorable ORR/disease control rate (DCR) per response evaluation criteria in solid tumors (RECIST) and modified RECIST (mRECIST) (17.7%/84.7% and 42.5%/86.2%, respectively). A recent real-world study comparing 21 patients receiving atezolizumab plus bevacizumab and 28 patients receiving lenvatinib for BCLC stage B HCC exceeding the up-to-7 criteria showed no significant differences in OS (19.8 vs. 22.2 months,
P=0.763), PFS (10.2 vs. 7.2 months,
P=0.343), ORR, or DCR between the atezolizumab–bevacizumab and lenvatinib groups [
43]. Another study comparing 177 TACE-unsuitable patients treated with atezolizumab plus bevacizumab and 181 patients treated with lenvatinib as first-line systemic therapy for BCLC stage B HCC demonstrated a significantly longer PFS in the atezolizumab–bevacizumab group after propensity score matching (10.2 vs. 6.9 months,
P=0.020) [
44]. Among the subgroup of patients with tumors exceeding the up-to-7 criteria, the median PFS was also significantly longer in the atezolizumab–bevacizumab group compared to the lenvatinib group (10.5 vs. 6.3 months,
P=0.044). These findings suggest that both therapeutic options are feasible, but atezolizumab-bevacizumab might be more suitable for this patient population; however, further large-scale prospective studies are needed to validate these results. In one retrospective real-world study [
45], TACE combined with lenvatinib and tislelizumab significantly improved PFS (8.5 vs. 4.4 months) and OS (31.5 vs. 18.5 months; all
P<0.001) compared to TACE alone in individuals beyond the up-to-11 criteria, with acceptable safety. Therefore, systemic therapy may be appropriate for managing intermediate-stage HCC beyond the up-to-11 criteria.
Statement 4: To improve outcomes (PFS) in intermediate- stage HCC, systemic therapy combined with TACE can be used in TACE-eligible cases (agreement 100%, evidence B)
In the context of intermediate-stage HCC with high tumor burden, emerging evidence supports the use of systemic therapies, including tyrosine kinase inhibitors (TKIs) or immunotherapies, in combination with TACE as a promising approach over TACE alone.
Sorafenib has demonstrated efficacy in intermediate-stage HCC across multiple large-scale real-world studies. For example, the GIDEON trial reported significantly longer median OS in individuals with BCLC-B disease treated with sorafenib compared to those with BCLC-C, suggesting benefit in earlier-stage disease [
46]. Additionally, combining sorafenib with TACE has been shown to improve outcomes in individuals with high tumor burden, where TACE alone may be insufficient (SOFIA trial: OS 20.6 vs. 8.4 months; INSIGHT trial: OS 19.6 vs. 13.6 months) [
47,
48]. The TACTICS trial, a randomized multicenter study, compared TACE plus sorafenib to TACE alone in unresectable HCC. Among 156 participants, 80 received combination therapy, and 76 underwent TACE alone. Median OS was 36.2 months in the combination group vs. 30.8 months in the TACE-alone group, though the difference was not statistically significant (HR: 0.861;
P=0.40). However, TACE-specific PFS significantly improved with combination therapy, particularly among individuals with tumor burdens beyond the up-to-7 criteria [
49,
50].
The TACTICS-L trial demonstrated the significant efficacy of combining lenvatinib with TACE in treating individuals with unresectable intermediate-stage HCC. The trial reported a high ORR of 79.0% at 4 weeks following the first TACE session. The best response ORR reached 88.7%, with a complete response (CR) rate of 67.7%. Median PFS was 28.0 months, indicating favorable long-term disease control. However, median OS was not reached during follow-up, suggesting a potential for extended survival benefit [
51]. An additional analysis compared lenvatinib-TACE (LEN-TACE) with TACE alone, using inverse probability weighting to adjust for baseline characteristics. Results indicated that LEN-TACE was more effective, particularly for individuals classified as “up-to-7 OUT.” This group demonstrated improved PFS (HR: 0.49) and OS (HR: 0.41) compared to the “up-to-7 IN” group, which also showed benefit with LEN-TACE but to a lesser degree (PFS HR: 0.70; OS HR: 0.89). The study concluded that “up-to-7 OUT” individuals are unsuitable for TACE monotherapy and that LEN-TACE offers a significantly superior treatment strategy for both groups [
52].
In one retrospective cohort study, Zhou et al. [
53] demonstrated that combining TACE with lenvatinib (TACE-Lenv) significantly improved outcomes in individuals with intermediate-stage HCC. Median OS was 28 months in the TACE-Lenv group vs. 12 months for TACE alone (
P=0.017). PFS was 8.2 months with TACE-Lenv compared to 3.7 months with TACE alone using mRECIST (
P=0.018), and 8.9 vs. 3.7 months using RECIST v1.1 (
P=0.003). Notably, subgroups with larger tumors (114 to 162 mm) experienced significant survival benefits (
P<0.05) [
53].
One retrospective study demonstrates that combining TACE with atezolizumab and bevacizumab (TACE+Atez/Bev) significantly improves outcomes in intermediate-stage HCC. After applying the PSM, the median OS was not reached for TACE+Atez/Bev vs. 21.4 months for TACE alone (
P=0.008), and median PFS was 21.7 vs. 9.7 months (
P=0.009). The combination also showed superior ORR (66.7% vs. 38.1%,
P=0.009) and DCR (92.9% vs. 57.1%,
P<0.001). The survival benefit (both PFS and OS) of combining TACE with atezolizumab and bevacizumab was significantly higher than that of TACE alone, especially when the tumor burden exceeds the up-to-7 criteria [
54].
Recently, two phase 3 studies investigating intermediate-stage HCC reported positive outcomes. The EMERALD-1 Phase 3 study met its primary endpoint, demonstrating a statistically significant improvement in PFS among individuals with unresectable HCC eligible for embolization. Median PFS was 15.0 months in the group receiving durvalumab, bevacizumab, and TACE, compared to 8.2 months in the placebo plus TACE group (HR: 0.77,
P=0.032). Most participants had intermediate-stage HCC, with some presenting with portal vein invasion (Vp1 or Vp2). The PFS benefit was consistent across subgroups, including baseline tumor burden within or beyond the up-to-7 criteria, and the safety profile was manageable. This regimen may represent a new standard of care regardless of tumor burden [
8].
The LEAP-012 Phase 3 trial demonstrated that lenvatinib, pembrolizumab, and TACE significantly improved outcomes in intermediate-stage HCC. Median PFS was 14.6 months vs. 10.0 months in the placebo group (HR: 0.66;
P=0.0002), and ORR was higher (46.8% vs. 33.3%;
P=0.0005). While OS data remain immature, early results suggest a favorable trend. Subgroup analysis showed consistent PFS benefit, with notable OS improvement in individuals with tumor burden scores between 6 and 12 [
9]. Furthermore, several Phase III clinical trials are currently underway to evaluate the efficacy of on-demand TACE combined with immune checkpoint inhibitors (with or without anti-vascular endothelial growth factor [VEGF] agents) compared to on-demand TACE alone in individuals with intermediate-stage HCC. These include TACE-3 (NCT04268888), CheckMate 74W (NCT04340193), TALENTACE (NCT047126430) [
55], and EMERALD-3 (NCT05301842). TACE is hypothesized to release neoantigens and act as an immune modulator, thereby enhancing the efficacy of systemic therapies through synergistic mechanisms. When combined with immune checkpoint inhibitors and anti-VEGF or TKIs agents, ondemand TACE or partial embolization may improve tumor response rates, especially in individuals with high tumor burden [
56].
Systemic therapies, including TKIs and immunotherapies (e.g., sorafenib, lenvatinib, durvalumab–bevacizumab, lenvatinib–pembrolizumab), when combined with TACE, have significantly improved survival in individuals with intermediate-stage HCC, particularly those with higher tumor burdens. These regimens are now favored over TACE alone. Growing evidence supports the integration of systemic therapy with TACE, which has been shown to enhance PFS in appropriate candidates. As a result, combination therapy is increasingly regarded as a promising treatment approach for intermediate-stage HCC. A comparison of systemic therapy studies involving individuals with intermediate-stage HCC eligible for TACE is provided in
Table 2.
It should be noted that none of the current trials to date have demonstrated a statistically significant improvement in OS compared to TACE alone. For example, although the TACTICS trial showed prolonged TACE-specific PFS, it failed to demonstrate a survival benefit. Similarly, the LEAP-012 and EMERALD-1 trials have thus far reported immature or neutral OS results. Nevertheless, in the setting of curative conversion, achieving a higher ORR may increase the likelihood of successful downstaging or conversion to curative therapies, which could potentially translate into improved OS outcomes in selected patients. Based on this, our committee reached a consensus to support the use of combination strategies primarily aimed at improving PFS and ORR. Otherwise, this approach should currently be considered investigational or selectively applied, pending confirmation from ongoing or future trials with mature OS data.
Statement 5: For TACE-refractory intermediate-stage HCC (failed by at least two TACE sessions), immunotherapy is recommended as the first-line treatment, with lenvatinib or sorafenib as alternatives (agreement 100%, evidence B)
TACE is frequently overused in individuals with intermediate-stage HCC, which can lead to deterioration in liver function [
28,
57,
58]. TACE failure or refractoriness in liver cancer management is defined by a poor tumor response or continued disease progression despite multiple TACE sessions. Insufficient tumor response refers to cases where over 50% of the lesion remains viable in two or more sessions, indicating limited therapeutic effect. Disease progression is characterized by two or more instances of tumor growth, evidenced by an increased number of tumors relative to pre-treatment imaging. Both scenarios indicate the need to transition from TACE to systemic therapy to ensure more effective management strategies are pursued for individuals with liver cancer [
1,
6,
7,
29,
59,
60].
A study by Ogasawara et al. [
32] demonstrated that switching to sorafenib in TACE-refractory intermediate-stage HCC significantly improved survival outcomes. Median OS was 25.4 months for the sorafenib group, compared to 11.5 months for individuals continuing TACE (
P=0.003). Additionally, the median time to disease progression (TTDP) was 22.3 months with sorafenib vs. 7.7 months with continued TACE (
P=0.001) [
32]. Similarly, Arizumi et al. [
61] evaluated 497 individuals with HCC treated with TACE and identified 56 as refractory. The sorafenib-treated group demonstrated a significantly longer OS (24.7 months) compared to the TACE group (13.6 months,
P=0.002). A recent real-world study compared 163 patients who continued with TACE and 108 patients who shifted to sorafenib treatment after confirmation of refractoriness to TACE therapy. In the sorafenib group, the median TTDP was 23.4 months, and the median OS was 25.3 months. In contrast, the TACE group had a median TTDP of 11.6 months and a median OS of 14.2 months (
P=0.0001) [
62]. These findings underscore the importance of early assessment of TACE efficacy and prompt transition to sorafenib when warranted. Sorafenib remains a viable systemic option for improving survival in intermediate-stage HCC following TACE failure [
61]. A multicenter cohort study further showed that lenvatinib significantly prolonged PFS compared to both sorafenib and TACE, with median PFS of 5.8, 3.2, and 2.4 months, respectively (
P<0.001), indicating superior efficacy [
63].
The encouraging outcomes of recent first-line systemic therapies, including IMbrave150 [
35,
64], HIMALAYA [
37], and CheckMate 9DW [
38], in most individuals with advanced-stage HCC also suggest potential benefit in intermediate-stages, such as BCLC stage B, where some may be refractory to TACE. Recent immunotherapies have improved OS and recurrence-free survival (RFS) compared to TKIs. The IMbrave150 exploratory analysis shows that atezolizumab combined with bevacizumab enhances OS and PFS compared to sorafenib in unresectable BCLC stage B HCC. Notably, 43% of patients in the atezolizumab–bevacizumab arm had received prior TACE treatment. The combination yielded HRs of 0.63 (OS) and 0.64 (PFS), with ORRs of 43–50%, outperforming sorafenib’s 26–30%. These findings support its use as a preferred therapy for systemic treatment-naive individuals ineligible for or progressing after locoregional therapies [
65]. A comparison table of systemic therapy trials in intermediate-stage HCC refractory to TACE is presented in
Table 3.
Phase 3 trials for intermediate-stage HCC often include individuals unresponsive to multiple TACE sessions. However, the current evidence base for immunotherapy in TACE-refractory BCLC stage B patients remains limited. Most of the available data on immunotherapy in this setting are derived from exploratory analyses of major phase III trials, which may be underpowered to draw definitive conclusions for the post-TACE-refractory population. Administering systemic therapy prior to TACE has shown promise by promoting vascular normalization, suppressing hypoxia-inducible factor-1, and upregulating VEGF, PDGF, and angiopoietin-2. These mechanisms enhance the delivery of lipiodol mixed with anticancer drugs, improving tumor targeting [
66,
67]. Although current evidence supporting the use of immunotherapy in TACE-refractory HCC remains limited, it is widely accepted that systemic therapy should be initiated in such cases, with immunotherapy currently preferred over TKIs as the first-line systemic treatment. Based on this rationale, our committee reached a unified agreement to recommend systemic therapy as the first-line treatment for TACE-refractory intermediate-stage HCC, supported by subgroup analyses of phase 3 trials and expert consensus. Nonetheless, dedicated prospective studies are warranted to confirm the survival benefit of immunotherapy in this specific patient population.
Statement 6: Y90 TARE may serve as an alternative therapy to TACE (agreement 100%, evidence B)
Yttrium-90 (
90Y) selective internal radiation therapy is a treatment method whereby radiation is delivered to liver tumors through the hepatic artery [
68]. Yttrium-90 microspheres are typically infused into the hepatic artery to localize radiation delivery to liver tumors, thereby maintaining radiation exposure to healthy liver tissue within a safe threshold to minimize damage. Unlike conventional transarterial chemoembolization (cTACE), the primary therapeutic effect arises from the radiotherapeutic action rather than ischemic or chemotherapeutic mechanisms due to embolization.
A prior phase II randomized controlled trial enrolled 72 patients with unresectable HCC, of whom 61 (84.7%) were classified as stage B according to the BCLC system [
69]. Interim analysis showed that among the 38 patients treated with TARE, the median TTP was 17.1 months, whereas for the 34 patients treated with DEB-TACE, the median TTP was 9.5 months (intention-to-treat [ITT] group HR, 0.36; 95% CI: 0.18–0.70;
P=0.002). Median OS for the TARE and DEB-TACE groups was 30.2 months and 15.6 months, respectively (ITT group HR, 0.48; 95% CI: 0.28–0.82;
P=0.006). These statistically significant differences led to early termination of the clinical trial.
The meta-analysis compared TACE and TARE, with OS as the primary endpoint and TTP as the secondary endpoint [
70]. Seventeen studies encompassing 2,465 patients were included, with the majority diagnosed with BCLC stage B disease, accounting for 42.8% of the total cohort. The results indicated no significant differences in OS between the two treatment modalities. Among the three studies that analyzed TTP, a significantly longer TTP was observed in the TARE group than in the TACE group (mean TTP of 17.5 months vs. 9.8 months; mean TTP difference of 4.8 months, 95% CI: 1.3–8.3 months).
Two TARE studies were conducted in Taiwan, both employing single-arm designs. One involved the RESIN registry, in which 83 of 107 participants had HCC, and 51 (61.5%) had BCLC stage B disease [
71]. The ORR among participants with HCC was 55.41%, with an OS of 24.07 months; eight individuals were successfully downstaged (DS) or downsized and proceeded to other therapies. The second study, conducted by Kaohsiung Chang Gung Memorial Hospital, enrolled 32 individuals with unresectable HCC [
72]. Only three experienced portal vein invasion, and the median follow-up was 18 months. OS rates at 3, 6, and 12 months were 94%, 87%, and 59%, respectively. The PFS rates were 78%, 64%, and 60%, respectively. In terms of tumor response, seven individuals (21.9%) achieved CR, 14 (43.7%) partial response (PR), four (12.5%) stable disease (SD), and seven (21.9%) progressive disease (PD); 11 individuals (34.4%) were successfully DS.
Therefore, comprehensive evaluation is required when selecting between TACE and TARE [
73]. Relevant factors include the individual’s socioeconomic status, behavioral patterns, comorbidities, hepatic function, liver volume targeted, tumor stage, presence of vascular invasion, and extent of lung shunting. Additional considerations involve the treating physician’s expertise and whether the procedure is covered by the individual’s health insurance. Ultimately, the decision should be shared between the physician and the individual and tailored to the individual’s clinical context.
The combination of TARE and immunotherapy represents a novel therapeutic strategy currently under investigation. A recent phase I/IIa trial evaluating Yttrium-90 radioembolization in combination with durvalumab for patients with locally advanced, unresectable HCC reported an 18-month OS rate of 58.3%, a median PFS of 6.9 months, a CR rate of 29.2%, and an ORR of 83.3%. Grade 3 treatment-related adverse events occurred in 8.7% of patients [
74]. These findings suggest that the combination of TARE and immune checkpoint inhibitors demonstrates a favorable safety profile and promising antitumor activity, warranting further evaluation in large-scale, controlled trials.
Statement 7: The efficacy of DEB-TACE is comparable to that of cTACE, but the adverse reactions associated with cTACE can be alleviated (agreement 100%, evidence B)
HCC TACE is recommended as a primary treatment option for intermediate-stage HCC in current clinical guidelines [
5,
75,
76]. In cTACE, lipiodol and chemotherapeutic agents such as cisplatin or doxorubicin are administered via the hepatic artery, followed by gelatin sponge particles to embolize the tumor’s blood supply. DEB-TACE uses microspheres as both drug carriers and embolic agents to enable continuous release of cytotoxic agents, resulting in permanent vascular occlusion [
77]. Currently, three types of DEBs are available: (1) 100–300 μm DC Bead, (2) 30–60 μm HepaSphere, and (3) 200 μm LifePearl [
78]. Although smaller DEBs (<100 μm) may theoretically achieve more complete embolization, no head-to-head studies have directly compared DEB size. Therefore, safety concerns, such as pulmonary embolization, tumor rupture, and biliary injury, must be considered when using smaller particles.
A Turkish single-center study on DEB-TACE enrolled 133 individuals with unresectable HCC, 58 (48%) of whom were at intermediate-stage B [
79]. The treatment responses were as follows: CR in 20 individuals (17%), PR in 36 (32%), SD in 24 (21%), and PD in 35 (30%). The median follow-up period was 14 months (range, 1–77 months), and the median PFS and OS were 4 and 11 months, respectively. These findings suggest that DEB-TACE is an effective treatment strategy for unresectable HCC, including individuals with intermediate-stage B disease.
In a Chinese prospective study of 120 individuals with HCC [
80], 68 underwent cTACE (of whom 24, or 35.3%, had BCLC stage B), and 52 underwent DEB-TACE (24, or 56.2%, had BCLC stage B). The DEB-TACE group achieved a higher CR rate (30.8%) compared with that of the cTACE group (7.4%). In terms of survival, the DEB-TACE group had a longer median PFS of 15 months (95% CI: 12–18 months) compared with 11 months (95% CI: 10–12 months) in the cTACE group. Median OS was also longer in the DEB-TACE group, at 25 months (95% CI: 22–28 months) compared with 21 months (95% CI: 18–24 months) in the cTACE group. Multivariate analysis confirmed DEB-TACE as an independent predictor of CR.
However, a meta-analysis compared OS, adverse events, and response rates between individuals who received cTACE and DEB-TACE, incorporating a total of six randomized controlled trials [
81]. The meta-analysis identified no significant differences in treatment outcomes or major complications between the two groups.
A systematic review evaluated the safety and efficacy of cTACE and DEB-TACE using a comprehensive database search and a rigorous screening process [
82]. A total of 10 studies were included, comprising two randomized controlled trials, one meta-analysis, and seven observational studies. In total, 5,288 treatment-naive individuals with unresectable HCC were analyzed. The findings indicated comparable safety between the two modalities, but suggested superior efficacy for DEB-TACE when patients were carefully selected. However, the study did not specify the proportion of individuals with BCLC stage B disease.
Statement 8: For curative conversion of intermediate-stage HCC, liver-directed therapy, systemic therapy, or combined therapy followed by curative therapy should be considered to achieve a cancer-free and drug-free state (agreement 100%, evidence B)
TACE represents the standard therapy for most individuals with treatment-naïve intermediate-stage HCC, and whenever feasible, curative treatments should be prioritized over palliative treatments as they provide the best outcomes [
83]. As intermediate-stage HCC is potentially curable except in cases with an extremely high tumor burden, such as bilobar multifocal disease >10 or disease exceeding the up-to-11 criteria [
27], the therapeutic goal is to achieve clinical or pathological CR and a drug-free status.
LT enables the removal of both visible and microscopic tumor lesions, along with the diseased liver. For individuals beyond the Milan criteria, growing evidence over the last two decades supports expanding transplant criteria [
84-
88], while another strategy uses locoregional or systemic therapies to downstage the disease into Milan eligibility. The potential of TARE to induce tumor downstaging, thereby enabling previously ineligible patients to meet transplantation criteria, garnered substantial interest within the medical community. A recent prospective multiregional study based on the UNOS-DS criteria [
89] reported a high probability of initial downstaging with a low risk of subsequent progression (post-LT HCC recurrence rate, 7.9%) and comparable efficacy between TACE and yttrium-90 radioembolization (89% vs. 86%) as initial downstaging modalities. A retrospective study showed that approximately 39% of patients were successfully DS at 6 months, and 23% of these patients ultimately underwent curative treatment, primarily LT or resection, after Y-90 radioembolization [
90]. Patients who achieved DS had a significantly longer OS (51 vs. 10 months,
P<0.001) and PFS (47 vs. 11 months,
P<0.001) than those without DS. Surgery after DS further improved the survival, with a median OS of 71 months. In a large 11-year study of 413 patients [
91], with more than half of the patients (51.8%) beyond the up-to-7 criteria treated by yttrium-90 radioembolization, notably, 70 (17%) patients were DS to curative therapy (either resection or LT), and these individuals achieved dramatically prolonged survival (79.7 months), underscoring the potential of adequate radiation dosing and tumor control to improve long-term outcomes. Another study [
92] enrolled 214 patients treated with yttrium-90 radioembolization; 30% were successfully DS and listed for LT and 23% ultimately underwent transplantation. Patients receiving LT had a 5-year OS rate of 61%, with better outcomes observed in those with a lower tumor burden.
For more advanced HCC, combining TACE with local percutaneous thermal ablation may improve survival and limit disease progression. In individuals DS with TACE, local ablation may improve long-term outcomes. One retrospective study found that OS and DFS were similar between individuals undergoing radiofrequency ablation (RFA) for TACE-DS HCC and those who initially met the Milan criteria (
P=0.74 and
P=0.39, respectively) after propensity score matching [
93]. No significant differences were found in the OS and RFS rates (
P=0.981 and
P=0.586) between the groups following microwave ablation [
94]. Embolization may contribute to downstaging by shrinking tumors or eliminating satellite lesions, thus enabling transplantation with a curative intent.
External beam radiation therapy (EBRT) has also emerged as an option in select cases. In a meta-analysis, stereotactic body radiotherapy (SBRT) demonstrated comparable OS (HR: 0.83,
P=0.44) and significantly superior local control (HR: 0.25,
P=0.006) compared to TACE, without significant toxicity in patients with HCC [
95]. In patients on the LT waitlist, SBRT has been shown to be safe, achieving significantly higher tumor control rates and reducing the risk of waitlist dropout [
96]. SBRT is also an effective treatment option for patients with inoperable HCC who experience an incomplete response following TACE [
97]. In one study, individuals received SBRT as bridging therapy before LT, with 64% initially outside the Milan criteria; the 5-year posttransplant survival rate was 75% [
98]. The phase 2 TRENDY trial, which compared SBRT with TACE in patients with initially unresectable HCC eligible for definitive or downstaging therapy, found no significant difference in median time to progression between the two groups [
99]. However, SBRT showed a trend toward improved local control compared to TACE. These findings suggest that EBRT may offer advantages in local tumor control and PFS for patients with unresectable HCC, supporting its potential use as an alternative to conventional bridging or downstaging therapies. Collectively, numerous studies have demonstrated that locoregional therapy (LRT) can downstage intermediate-stage HCC initially beyond the Milan criteria but is limited to liveronly disease without vascular invasion, achieving eligibility for transplant in >80% of cases and yielding post-LT oncologic outcomes comparable to those within the criteria at baseline.
Upfront systemic therapy, followed by LRT, has emerged as a novel treatment strategy for intermediate-stage HCC. Use of VEGF inhibitors reduces microvascular density, tumor interstitial pressure, and vascular permeability while normalizing tumor vasculature, thereby enhancing drug delivery and improving the therapeutic effect of subsequent selective TACE [
67]. With advancements in systemic therapy, the conversion resection rate has increased to 15.9–30.6% [
100-
102]. LEN-TACE sequential therapy was developed through proof-of-concept studies demonstrating significant OS prolongation in patients with intermediate-stage HCC beyond the up-to-7 criteria [
18,
103]. Moreover, five of 30 individuals (17%) receiving LEN-TACE sequential therapy achieved cancer-free and drug-free status, suggesting the potential for cure in selected patients. Another strategy is atezolizumab/bevacizumab curative (ABC) conversion [
3], in which curative modalities such as resection, RFA, or curative TACE are employed after significant tumor regression (ORR per RECIST v1.1: 44%), achieving a cancer-free, drug-free status in 20–30% of 110 individuals. For patients with small confluent multinodular or PET-positive HCC, ABC-LEN-TACE sandwich therapy, consisting of atezolizumab/bevacizumab induction, LEN-TACE, and subsequent atezolizumab/bevacizumab, may offer a promising approach to achieve cancer-free and drug-free status and a potential cure for this subgroup [
104].
Other real-world data have also demonstrated that combining local and systemic therapies is a promising approach for improving tumor response and increasing surgical conversion rates through complementary mechanisms of action. One retrospective study showed that an upfront lenvatinib strategy followed by RFA to achieve deep response was associated with better OS (21.3 vs. 17.1 months) and PFS (12.5 vs. 5.5 months) than those with lenvatinib monotherapy in individuals with intermediate-stage HCC beyond the up-to-7 criteria [
105]. Another study enrolled 70 individuals, including 22 with intermediate-stage disease, and evaluated salvage surgery outcomes after conversion therapy using triple therapy (TACE plus lenvatinib and anti-programmed death-1 antibodies) in individuals initially diagnosed with uHCC [
106]. Pathological CR and major pathological response were observed in 29 (41.4%) and 59 (84.3%) individuals, respectively. The 2-year OS and RFS rates following surgery were 94.4% and 54.4%, respectively. The phase 2 START-FIT trial investigated the efficacy of sequential TACE and SBRT followed by avelumab in patients with locally advanced, unresectable HCC [
107]. Among the 33 patients enrolled, 18 (55%) were considered amenable to curative treatment, 4 (12%) underwent curative therapy, while 14 (42%) achieved a radiological CR and were managed with close surveillance. The finding highlights the potential of sequential TACE–SBRT combined with immunotherapy as a curative conversion strategy in selected patients with advanced HCC.
CONCLUSION
In summary, we present the TLCA guidelines for the management of intermediate-stage HCC, outlining criteria for TACE unsuitability, treatment recommendations for both eligible and ineligible individuals, and comparisons among treatment modalities including cTACE, DEB-TACE, and TARE. A summary of the consensus statements is shown in
Table 4. Additionally, the guidelines incorporate key considerations related to curative conversion and downstaging. The comprehensive treatment algorithm for intermediate- stage HCC is depicted in
Figure 1, while an updated TLCA treatment algorithm covering all disease stages is shown in
Figure 2. By refining these consensus recommendations, we aim to optimize treatment decision-making and support personalized therapeutic strategies, ultimately advancing the adoption of curative conversion therapy in intermediate-stage HCC.
FOOTNOTES
-
Authors’ contribution
I-Cheng Lee, Wei Teng, Hung-Wei Wang, and Tsung- Jung Lin drafted the manuscript. Yi-Hsiang Huang was responsible for study concept, design, supervision, and manuscript revision. Other authors contributed to the literature review, discussion, and consensus voting.
-
Acknowledgements
This consensus update was conducted by the expert committee. All consensus statements were developed by the TLCA intermediate-stage HCC working group. The TLCA expresses gratitude to all members of the expert committee for their contributions.
This consensus update was supported by the TLCA.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.Overall treatment recommendation algorithm for intermediate-stage HCC. BCLC, Barcelona Clinic Liver Cancer; DEB-TACE, drug-eluting bead TACE; HCC, hepatocellular carcinoma; LRT, locoregional therapy; TACE, transarterial chemoembolization; TARE, transarterial radioembolization.
Figure 2.Updated TLCA HCC treatment algorithm encompassing all disease stages. C-P, Child-Pugh; DDLT, deceased donor liver transplantation; EHM, extrahepatic metastasis; HAIC, hepatic arterial infusion chemotherapy; LA, local ablation; LDLT, living donor liver transplantation; MVI, macrovascular invasion; MWA, microwave ablation; RFA, radiofrequency ablation; RT, radiotherapy; TACE, transarterial chemoembolization; UCSF, University of California, San Francisco; WBC, white blood cells; SIRT, selective internal radiation therapy.
Table 1.Representations of quality of evidence and strength of recommendations
Table 1.
|
Category |
Grade |
Description |
|
Quality of evidence |
|
|
|
High quality |
A |
We are confident that the true effect approximates the effect estimates |
|
Moderate quality |
B |
Moderate confidence in the effect estimates. The true effect is approximately close to the effect estimate, but it may be substantially different |
|
Low quality |
C |
Confidence in the estimated effect is limited. The true effect may be substantially different from the effect estimate |
|
Very low quality |
D |
Effect estimates are largely unreliable. The true effect is likely to be substantially different from the effect estimate |
|
Strength of recommendation |
|
|
|
Strong recommendation for using intervention |
1 |
- |
|
Weak recommendation for using intervention |
2 |
- |
Table 2.Studies of systemic therapy in patients with intermediate-stage HCC who were eligible for TACE
Table 2.
|
Study |
Design |
Intervention and patient number |
Treatment response (%) |
mPFS (mo) |
mOS (mo) |
Tumor burden (beyond up-to-7): subgroup analysis |
|
TACTICS [50] |
Phase 3 |
TACE plus sorafenib (n=80) vs. TACE (n=76) |
ORR: 71.3 vs. 61.8 |
22.8 vs. 13.5 (HR: 0.661, P=0.02) |
36.2 vs. 30.8 (HR: 0.861, P=0.40) |
Not significant for PFS & OS |
|
TACTICS-L [51] |
Phase 2 |
TACE plus lenvatinib (n=62) |
ORR: 88.7 |
28 |
Not reached |
Not significant for PFS & OS |
|
CR: 67.7 |
|
Zhou et al. [53] |
Retrospective |
TACE plus lenvatinib (n=32) vs. TACE (n=32) (PSM) |
ORR: 94 vs. 47 |
8.2 vs. 3.7 (P=0.018) |
28.0 vs. 12.0 (P=0.017) |
Significant for PFS & OS |
|
DCR: 97 vs. 62 |
|
LEN-TACE [18] |
Retrospective |
LEN-TACE (n=30) vs. TACE (n=60) (PSM) |
ORR: 73.3 vs. 33.3 |
16 vs. 3 (HR: 0.19, P<0.001) |
37.9 vs. 21.3 (HR: 0.48, P<0.01) |
Significant for PFS & OS |
|
Zheng et al. [54] |
Retrospective |
TACE plus atezolizumab/ bevacizumab (n=42) vs. TACE (n=42) (PSM) |
ORR: 66.7 vs. 38.1 |
21.7 vs. 9.7 (P=0.009) |
Not reached vs. 21.4 (P=0.008) |
Significant for PFS & OS |
|
EMERALD-1 [8] |
Phase 3 |
1:1:1 randomization (n=616) to |
ORR: 43.6 vs. 41.0 vs. 29.6 |
15 vs. 10 vs. 8.2 (1 vs. 3, HR: 0.77, P=0.032; 1 vs. 3, HR: 0.94, P=0.638) |
NR |
Not significant for PFS & OS |
|
1. TACE, then durvalumab+bevacizumab |
|
2. TACE, then durvalumab |
|
3. TACE, then placebo |
|
LEAP-012 [9] |
Phase 3 |
1:1 randomization (n=480) to |
RECIST |
14.6 vs. 10.0 (HR: 0.66, P=0.0002) |
Both not reached (HR: 0.80, P=0.0867) |
Significant for PFS & OS |
|
1. Lenvatinib plus pembrolizumab plus TACE |
ORR: 46.8 vs. 33.3 |
|
mRECIST |
|
2. Placebo plus TACE |
ORR: 71.3 vs. 49.8 |
Table 3.Studies of systemic therapy in patients with intermediate-stage HCC who were refractory to TACE
Table 3.
|
Study |
Design |
Intervention and patient number |
Treatment response (%) |
mPFS (mo) |
mOS (mo) |
|
Ogasawara et al. [32] |
Retrospective |
Sorafenib-group, n=20 |
RECIST: DCR: 80 vs. 25 |
mTTDP: 22.3 vs. 7.7 (P=0.001) |
25.4 vs. 11.5 (P=0.003) |
|
TACE-group, n=36 |
mRECIST: DCR: 80 vs. 25 |
|
Ashour et al. [62] |
Retrospective |
Sorafenib-group, n=108 |
NR |
mTTDP: 23.4 vs. 11.6 (P=0.0001) |
25.3 vs. 14.2 (P=0.0001) |
|
TACE-group, n=163 |
|
Arizumi et al. [61] |
Retrospective |
Sorafenib-group, n=32 |
NR |
NR |
24.7 vs. 13.6 (P=0.002) |
|
TACE-group, n=24 |
|
Shimose et al. [63] |
Retrospective |
Lenvatinib-group, n=45 |
ORR: 42.2 vs. 1.9 vs. 6.8 |
mPFS: 5.8 vs. 3.2 vs. 2.8 (P<0.001) |
NR |
|
Sorafenib-group, n=53 |
DCR: 88.9 vs. 56.6 vs. 19 |
|
TACE-group, n=73 |
|
IMbrave 150 [64] |
Phase 3 (exploratory analysis) |
Atezolizumab+bevacizumab, n=49 |
RECIST: ORR: 43 vs. 26 |
IRF RECIST 1.1 |
25.8 vs. 21.9 |
|
Sorafenib, n=24 |
mRECIST: ORR: 50 vs. 30 |
mPFS: 12.6 vs. 8.6 |
|
Investigator-assessed RECIST 1.1 |
|
mPFS: 10.0 vs. 4.2 |
Table 4.Summary of the consensus statements
Table 4.
|
No. |
Consensus statement |
Agreement |
Evidence |
|
1 |
Intermediate-stage (BCLC B) hepatocellular carcinoma (HCC) is a heterogeneous group and treatment should be tailored based on tumor burden and liver reserve. |
100% |
|
|
2 |
Transarterial chemoembolization (TACE) is widely used for treating unresectable intermediate-stage HCC. However, not all patients are suitable for TACE, particularly those with a tumor burden exceeding the up-to-11 criteria or with unfavorable radiological patterns. |
100% |
B |
|
3 |
For intermediate-stage HCC that is unsuitable for TACE, systemic therapy should be initiated as the first-line treatment. |
95% |
C |
|
4 |
To improve outcomes (progression-free survival) in intermediate-stage HCC, systemic therapy combined with TACE can be used in TACE-eligible cases. |
100% |
B |
|
5 |
For TACE-refractory intermediate-stage HCC (failed by at least two TACE sessions), immunotherapy is recommended as the first-line treatment, with lenvatinib or sorafenib as alternatives. |
100% |
B |
|
6 |
Y90 radioembolization (TARE) may serve as an alternative therapy to TACE. |
100% |
B |
|
7 |
The efficacy of drug-eluting bead TACE is comparable to that of conventional TACE, but the adverse reactions associated with TACE can be alleviated. |
100% |
B |
|
8 |
For curative conversion of intermediate-stage HCC, liver-directed therapy, systemic therapy, or combined therapy followed by curative therapy should be considered to achieve a cancer-free and drug-free state. |
100% |
B |
Abbreviations
Barcelona Clinic Liver Cancer
conventional transarterial chemoembolization
independent review facility
progression-free survival
propensity score matching
response evaluation criteria in solid tumors
transarterial chemoembolization
transarterial radioembolization
Taiwan Liver Cancer Association
time to disease progression
REFERENCES
- 1. Kudo M, Han KH, Ye SL, Zhou J, Huang YH, Lin SM, et al. A changing paradigm for the treatment of intermediate-stage hepatocellular carcinoma: Asia-Pacific primary liver cancer expert consensus statements. Liver Cancer 2020;9:245-260.
- 2. Llovet JM, De Baere T, Kulik L, Haber PK, Greten TF, Meyer T, et al. Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021;18:293-313.
- 3. Kudo M, Aoki T, Ueshima K, Tsuchiya K, Morita M, Chishina H, et al. Achievement of complete response and drug-free status by atezolizumab plus bevacizumab combined with or without curative conversion in patients with transarterial chemoembolization-unsuitable, intermediate-stage hepatocellular carcinoma: a multicenter proof-of-concept study. Liver Cancer 2023;12:321-338.
- 4. Li M, Bhoori S, Mehta N, Mazzaferro V. Immunotherapy for hepatocellular carcinoma: the next evolution in expanding access to liver transplantation. J Hepatol 2024;81:743-755.
- 5. Singal AG, Llovet JM, Yarchoan M, Mehta N, Heimbach JK, Dawson LA, et al. AASLD Practice Guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology 2023;78:1922-1965.
- 6. Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol 2022;76:681-693.
- 7. Teng W, Wang HW, Lin SM. Management Consensus guidelines for hepatocellular carcinoma: 2023 update on surveillance, diagnosis, systemic treatment, and posttreatment monitoring by the Taiwan liver cancer association and the gastroenterological society of Taiwan. Liver Cancer 2024;13:468-486.
- 8. Sangro B, Kudo M, Erinjeri JP, Qin S, Ren Z, Chan SL, et al. Durvalumab with or without bevacizumab with transarterial chemoembolisation in hepatocellular carcinoma (EMERALD-1): a multiregional, randomised, double-blind, placebo-controlled, phase 3 study. Lancet 2025;405:216-232.
- 9. Kudo M, Ren Z, Guo Y, Han G, Lin H, Zheng J, et al. Transarterial chemoembolisation combined with lenvatinib plus pembrolizumab vs. dual placebo for unresectable, non-metastatic hepatocellular carcinoma (LEAP-012): a multicentre, randomised, double-blind, phase 3 study. Lancet 2025;405:203-215.
- 10. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al. Going from evidence to recommendations. Bmj 2008;336:1049-1051.
- 11. Piscaglia F, Ogasawara S. Patient selection for transarterial chemoembolization in hepatocellular carcinoma: importance of benefit/risk assessment. Liver Cancer 2018;7:104-119.
- 12. Koroki K, Ogasawara S, Ooka Y, Kanzaki H, Kanayama K, Maruta S, et al. Analyses of intermediate-stage hepatocellular carcinoma patients receiving transarterial chemoembolization prior to designing clinical trials. Liver Cancer 2020;9:596-612.
- 13. Kadalayil L, Benini R, Pallan L, O’Beirne J, Marelli L, Yu D, et al. A simple prognostic scoring system for patients receiving transarterial embolisation for hepatocellular cancer. Ann Oncol 2013;24:2565-2570.
- 14. Lee IC, Hung YW, Liu CA, Lee RC, Su CW, Huo TI, et al. A new ALBI-based model to predict survival after transarterial chemoembolization for BCLC stage B hepatocellular carcinoma. Liver Int 2019;39:1704-1712.
- 15. Kim JH, Shim JH, Lee HC, Sung KB, Ko HK, Ko GY, et al. New intermediate-stage subclassification for patients with hepatocellular carcinoma treated with transarterial chemoembolization. Liver Int 2017;37:1861-1868.
- 16. Hucke F, Pinter M, Graziadei I, Bota S, Vogel W, Müller C, et al. How to STATE suitability and START transarterial chemoembolization in patients with intermediate stage hepatocellular carcinoma. J Hepatol 2014;61:1287-1296.
- 17. Han G, Berhane S, Toyoda H, Bettinger D, Elshaarawy O, Chan AWH, et al. Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach. Hepatology 2020;72:198-212.
- 18. Kudo M, Ueshima K, Chan S, Minami T, Chishina H, Aoki T, et al. Lenvatinib as an initial treatment in patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh A liver function: a proof-of-concept study. Cancers (Basel) 2019;11.
- 19. Galle PR, Tovoli F, Foerster F, Wörns MA, Cucchetti A, Bolondi L. The treatment of intermediate stage tumours beyond TACE: From surgery to systemic therapy. J Hepatol 2017;67:173-183.
- 20. Kariyama K, Nouso K, Wakuta A, Oonishi A, Toyoda H, Tada T, et al. Treatment of intermediate-stage hepatocellular carcinoma in Japan: position of curative therapies. Liver Cancer 2020;9:41-49.
- 21. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on liver transplantation. J Hepatol 2024;81:1040-1086.
- 22. Biolato M, Galasso T, Marrone G, Miele L, Grieco A. Upper limits of downstaging for hepatocellular carcinoma in liver transplantation. Cancers (Basel) 2021;13.
- 23. Wang Q, Xia D, Bai W, Wang E, Sun J, Huang M, et al. Development of a prognostic score for recommended TACE candidates with hepatocellular carcinoma: a multicentre observational study. J Hepatol 2019;70:893-903.
- 24. Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F, et al. Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis 2012;32:348-359.
- 25. Kudo M, Arizumi T, Ueshima K, Sakurai T, Kitano M, Nishida N. Subclassification of BCLC B stage hepatocellular carcinoma and treatment strategies: proposal of modified Bolondi’s subclassification (Kinki criteria). Dig Dis 2015;33:751-758.
- 26. Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10:35-43.
- 27. Hung YW, Lee IC, Chi CT, Lee RC, Liu CA, Chiu NC, et al. Redefining tumor burden in patients with intermediate-stage hepatocellular carcinoma: the seven-eleven criteria. Liver Cancer 2021;10:629-640.
- 28. Chi CT, Lee IC, Lee RC, Hung YW, Su CW, Hou MC, et al. Effect of transarterial chemoembolization on ALBI grade in intermediate-stage hepatocellular carcinoma: criteria for unsuitable cases selection. Cancers (Basel) 2021;13.
- 29. Kudo M, Kawamura Y, Hasegawa K, Tateishi R, Kariyama K, Shiina S, et al. Management of hepatocellular carcinoma in Japan: JSH consensus statements and recommendations 2021 update. Liver Cancer 2021;10:181-223.
- 30. Hung YW, Lee IC, Chi CT, Lee RC, Liu CA, Chiu NC, et al. Radiologic patterns determine the outcomes of initial and subsequent transarterial chemoembolization in intermediate-stage hepatocellular carcinoma. Liver Cancer 2024;13:29-40.
- 31. Vogel A, Martinelli E. Updated treatment recommendations for hepatocellular carcinoma (HCC) from the ESMO Clinical Practice Guidelines. Ann Oncol 2021;32:801-805.
- 32. Ogasawara S, Chiba T, Ooka Y, Kanogawa N, Motoyama T, Suzuki E, et al. Efficacy of sorafenib in intermediate-stage hepatocellular carcinoma patients refractory to transarterial chemoembolization. Oncology 2014;87:330-341.
- 33. Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, et al. Lenvatinib vs. sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163-1173.
- 34. Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M, et al. REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol 2020;55:113-122.
- 35. Cheng AL, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Updated efficacy and safety data from IMbrave150: Atezolizumab plus bevacizumab vs. sorafenib for unresectable hepatocellular carcinoma. J Hepatol 2022;76:862-873.
- 36. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid 2022;1:EVIDoa2100070.
- 37. Sangro B, Chan SL, Kelley RK, Lau G, Kudo M, Sukeepaisarnjaroen W, et al. Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Ann Oncol 2024;35:448-457.
- 38. Yau T, Galle PR, Decaens T, Sangro B, Qin S, da Fonseca LG, et al. Nivolumab plus ipilimumab vs. lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet 2025;405:1851-1864.
- 39. Kudo M. Extremely high objective response rate of lenvatinib: its clinical relevance and changing the treatment paradigm in hepatocellular carcinoma. Liver Cancer 2018;7:215-224.
- 40. Tada T, Kumada T, Hiraoka A, Michitaka K, Atsukawa M, Hirooka M, et al. Impact of Early Lenvatinib Administration on Survival in Patients with Intermediate-Stage Hepatocellular Carcinoma: A Multicenter, Inverse Probability Weighting Analysis. Oncology 2021;99:518-527.
- 41. Kobayashi S, Fukushima T, Ueno M, Moriya S, Chuma M, Numata K, et al. A prospective observational cohort study of lenvatinib as initial treatment in patients with BCLC-defined stage B hepatocellular carcinoma. BMC Cancer 2022;22:517.
- 42. Hiraoka A, Kumada T, Tada T, Hirooka M, Kariyama K, Tani J, et al. Early experience of atezolizumab plus bevacizumab treatment for unresectable hepatocellular carcinoma BCLC-B stage patients classified as beyond up to seven criteria - multicenter analysis. Hepatol Res 2022;52:308-316.
- 43. Kimura M, Nishikawa K, Imamura J, Kimura K. Frontline evaluation: atezolizumab-bevacizumab vs. lenvatinib for BCLC stage B hepatocellular carcinoma exceeding the up-to-seven criteria. Cancer Med 2024;13:e70217.
- 44. Tada T, Kumada T, Hiraoka A, Hirooka M, Kariyama K, Tani J, et al. Comparison of prognostic impact of atezolizumab plus bevacizumab vs. lenvatinib in patients with intermediate-stage hepatocellular carcinoma. Liver Int 2024;44:113-124.
- 45. Chen S, Shuangyan T, Shi F, Cai H, Wu Z, Wang L, et al. TACE plus lenvatinib and tislelizumab for intermediate-stage hepatocellular carcinoma beyond up-to-11 criteria: a multicenter cohort study. Front Immunol 2024;15:1430571.
- 46. Marrero JA, Kudo M, Venook AP, Ye SL, Bronowicki JP, Chen XP, et al. Observational registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON study. J Hepatol 2016;65:1140-1147.
- 47. Iavarone M, Cabibbo G, Piscaglia F, Zavaglia C, Grieco A, Villa E, et al. Field-practice study of sorafenib therapy for hepatocellular carcinoma: a prospective multicenter study in Italy. Hepatology 2011;54:2055-2063.
- 48. Ganten TM, Stauber RE, Schott E, Malfertheiner P, Buder R, Galle PR, et al. Sorafenib in patients with hepatocellular carcinoma-results of the observational INSIGHT study. Clin Cancer Res 2017;23:5720-5728.
- 49. Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, et al. Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial. Gut 2020;69:1492-1501.
- 50. Kudo M, Ueshima K, Ikeda M, Torimura T, Tanabe N, Aikata H, et al. Final results of TACTICS: a randomized, prospective trial comparing transarterial chemoembolization plus sorafenib to transarterial chemoembolization alone in patients with unresectable hepatocellular carcinoma. Liver Cancer 2022;11:354-367.
- 51. Kudo M, Ueshima K, Saeki I, Ishikawa T, Inaba Y, Morimoto N, et al. A phase 2, prospective, multicenter, single-arm trial of transarterial chemoembolization therapy in combination strategy with lenvatinib in patients with unresectable intermediate-stage hepatocellular carcinoma: TACTICS-L trial. Liver Cancer 2024;13:99-112.
- 52. Kudo M. All stages of hepatocellular carcinoma patients benefit from systemic therapy combined with locoregional therapy. Liver Cancer 2023;12:395-404.
- 53. Zhou C, Chang B, Xiang Z, Li Z, Wu C, Bai M, et al. Transarterial chemoembolization (TACE) combined with lenvatinib vs. TACE alone in intermediate-stage hepatocellular carcinoma patients beyond up-to-seven criteria: a retrospective, propensity score-matched analysis. Acad Radiol 2024;31:4456-4465.
- 54. Zheng Y, Xiang Y, Shi H, Lin Z, Cheng S, Zhu J. Transarterial chemoembolization combined with atezolizumab plus bevacizumab vs. transarterial chemoembolization alone in intermediate-stage hepatocellular carcinoma: a multicenter retrospective study. J Hepatocell Carcinoma 2024;11:1079-1093.
- 55. Dong J, Han G, Ogasawara S, Liu R, Gu S, Liu F, et al. LBA2 TALENTACE: a phase III, open-label, randomized study of on-demand transarterial chemoembolization (TACE) combined with atezolizumab + bevacizumab (Atezo+Bev) or ondemand TACE alone in patients with systemically untreated, intermediate-to-high burden unresectable hepatocellular carcinoma (uHCC). Annals of Oncology 2025;36:S62.
- 56. Kudo M. A changing role of transarterial chemoembolization in the era of immune checkpoint inhibitor plus Anti-VEGF/TKI plus transarterial chemoembolization: from total embolization to partial embolization (immune boost transarterial chemoembolization). Liver Cancer 2024;13:335-343.
- 57. Maesaka K, Sakamori R, Yamada R, Tahata Y, Imai Y, Oshita M, et al. Initial treatment response to transarterial chemoembolization as a predictive factor for Child-Pugh class deterioration prior to refractoriness in hepatocellular carcinoma. Hepatol Res 2020;50:1275-1283.
- 58. Xia D, Wang Q, Bai W, Wang E, Wang Z, Mu W, et al. Optimal time point of response assessment for predicting survival is associated with tumor burden in hepatocellular carcinoma receiving repeated transarterial chemoembolization. Eur Radiol 2022;32:5799-5810.
- 59. Kudo M, Matsui O, Izumi N, Kadoya M, Okusaka T, Miyayama S, et al. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology 2014;87 Suppl 1:22-31.
- 60. Chang PY, Lee RC, Liang PC, Liu YS, Chuang VP, Wu DK, et al. Multidisciplinary Taiwan consensus for the use of conventional TACE in hepatocellular carcinoma treatment. Front Oncol 2023;13:1186674.
- 61. Arizumi T, Ueshima K, Minami T, Kono M, Chishina H, Takita M, et al. Effectiveness of sorafenib in patients with transcatheter arterial chemoembolization (TACE) refractory and intermediate-stage hepatocellular carcinoma. Liver Cancer 2015;4:253-262.
- 62. Ashour R, Rewisha E, Rady MA, Elkhadry SW, Abdelhalim H, Atef M. Effectiveness of sorafenib in treating intermediate-stage hepatocellular carcinoma patients refractory to transarterial chemoembolization. BMC Cancer 2024;24:1466.
- 63. Shimose S, Kawaguchi T, Tanaka M, Iwamoto H, Miyazaki K, Moriyama E, et al. Lenvatinib prolongs the progression-free survival time of patients with intermediate-stage hepatocellular carcinoma refractory to transarterial chemoembolization: a multicenter cohort study using data mining analysis. Oncol Lett 2020;20:2257-2265.
- 64. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894-1905.
- 65. Kudo M, Finn RS, Galle PR, Zhu AX, Ducreux M, Cheng AL, et al. IMbrave150: efficacy and safety of atezolizumab plus bevacizumab vs. sorafenib in patients with barcelona clinic liver cancer stage B unresectable hepatocellular carcinoma: an exploratory analysis of the phase III study. Liver Cancer 2023;12:238-250.
- 66. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249-257.
- 67. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58-62.
- 68. Jiang Z, Yang F, Wang W. Applications of yttrium-90 ((90)Y) in hepatocellular carcinoma. Onco Targets Ther 2024;17:149-157.
- 69. Dhondt E, Lambert B, Hermie L, Huyck L, Vanlangenhove P, Geerts A, et al. (90)Y radioembolization vs. drug-eluting bead chemoembolization for unresectable hepatocellular carcinoma: results from the TRACE phase II randomized controlled trial. Radiology 2022;303:699-710.
- 70. Brown AM, Kassab I, Massani M, Townsend W, Singal AG, Soydal C, et al. TACE vs. TARE for patients with hepatocellular carcinoma: overall and individual patient level meta analysis. Cancer Med 2023;12:2590-2599.
- 71. Lee RC, Liang PC, Liang HL, Chen YF, Yu CY, Cheng PN, et al. Multicenter evaluation of the safety and efficacy of selective internal radiation therapy with yttrium-90 resin microspheres in Taiwan: data from the RESIN registry. J Gastroenterol Hepatol 2024;39:1318-1327.
- 72. Yu CY, Huang PH, Tsang LL, Hsu HW, Lim WX, Weng CC, et al. Yttrium-90 radioembolization as the major treatment of hepatocellular carcinoma. J Hepatocell Carcinoma 2023;10:17-26.
- 73. Behzadi AH, Haghani L, D’Souza DL, Flanagan S, Jones C. Practical considerations when choosing chemoembolization vs. radioembolization for hepatocellular carcinoma. Semin Intervent Radiol 2024;41:48-55.
- 74. Lee YB, Nam JY, Cho EJ, Lee JH, Yu SJ, Kim HC, et al. A phase I/IIa trial of yttrium-90 radioembolization in combination with durvalumab for locally advanced unresectable hepatocellular carcinoma. Clin Cancer Res 2023;29:3650-3658.
- 75. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11:317-370.
- 76. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J Hepatol 2025;82:315-374.
- 77. Chang Y, Jeong SW, Young Jang J, Jae Kim Y. Recent updates of transarterial chemoembolilzation in hepatocellular carcinoma. Int J Mol Sci 2020;21.
- 78. Chang WC, Hsu HH, Chiu SH, Huang WY, Lo CH, Lin HH, et al. Transcatheter arterial chemoembolization with drug-eluting beads for the treatment of hepatocellular carcinoma: recommended selection for small-caliber (<100 μm) beads. J Hepatocell Carcinoma 2021;8:937-949.
- 79. Alan AM, Alan O, Asadov R, Demirtas CO, Kani HT, Yumuk PF, et al. Evaluation of the effectiveness of drug-eluting transarterial chemoebolization in hepatocellular carcinoma. Hepatol Forum 2023;4:53-60.
- 80. Wen P, Chen SD, Wang JR, Zeng YH. Comparison of treatment response and survival profiles between drug-eluting bead transarterial chemoembolization and conventional transarterial chemoembolization in chinese hepatocellular carcinoma patients: a prospective cohort study. Oncol Res 2019;27:583-592.
- 81. Wang H, Cao C, Wei X, Shen K, Shu Y, Wan X, et al. A comparison between drug-eluting bead-transarterial chemoembolization and conventional transarterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis of six randomized controlled trials. J Cancer Res Ther 2020;16:243-249.
- 82. Ayyub J, Dabhi KN, Gohil NV, Tanveer N, Hussein S, Pingili S, et al. Evaluation of the safety and efficacy of conventional transarterial chemoembolization (cTACE) and drug-eluting bead (DEB)-TACE in the management of unresectable hepatocellular carcinoma: a systematic review. Cureus 2023;15:e41943.
- 83. Pecorelli A, Lenzi B, Gramenzi A, Garuti F, Farinati F, Giannini EG, et al. Curative therapies are superior to standard of care (transarterial chemoembolization) for intermediate stage hepatocellular carcinoma. Liver Int 2017;37:423-433.
- 84. Kaido T, Ogawa K, Mori A, Fujimoto Y, Ito T, Tomiyama K, et al. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery 2013;154:1053-1060.
- 85. Toso C, Meeberg G, Hernandez-Alejandro R, Dufour JF, Marotta P, Majno P, et al. Total tumor volume and alpha-fetoprotein for selection of transplant candidates with hepatocellular carcinoma: A prospective validation. Hepatology 2015;62:158-165.
- 86. Sapisochin G, Goldaracena N, Laurence JM, Dib M, Barbas A, Ghanekar A, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study. Hepatology 2016;64:2077-2088.
- 87. Yao FY, Mehta N, Flemming J, Dodge J, Hameed B, Fix O, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology 2015;61:1968-1977.
- 88. Yao FY, Xiao L, Bass NM, Kerlan R, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant 2007;7:2587-2596.
- 89. Mehta N, Frenette C, Tabrizian P, Hoteit M, Guy J, Parikh N, et al. Downstaging outcomes for hepatocellular carcinoma: results from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium. Gastroenterology 2021;161:1502-1512.
- 90. Regnault H, Chalaye J, Galetto-Pregliasco A, Perrin C, Derbel H, Amaddeo G, et al. Selective internal radiation therapy for unresectable HCC: The SIRT downstaging study. Hepatol Commun 2024;8.
- 91. Chen K, Tong AKT, Moe FNN, Ng DCE, Lo RHG, Gogna A, et al. The impact of radiation dose and tumour burden on outcomes in hepatocellular carcinoma: 11-year experience in a 413-patient cohort treated with yttrium-90 resin microsphere radioembolisation. Liver Cancer 2025;14:158-179.
- 92. Berardi G, Guglielmo N, Cucchetti A, Usai S, Colasanti M, Meniconi RL, et al. Transarterial radioembolization can downstage intermediate and advanced hepatocellular carcinoma to liver transplantation. Transplantation 2025;109:e54-e63.
- 93. Shi F, Wu M, Lian SS, Mo ZQ, Gou Q, Xu RD, et al. Radiofrequency ablation following downstaging of hepatocellular carcinoma by using transarterial chemoembolization: long-term outcomes. Radiology 2019;293:707-715.
- 94. Shi F, Lian S, Mai Q, Mo Z, Zhuang W, Cui W, et al. Microwave ablation after downstaging of hepatocellular carcinoma: outcome was similar to tumor within Milan criteria. Eur Radiol 2020;30:2454-2462.
- 95. Komiyama S, Takeda A, Tateishi Y, Tsurugai Y, Eriguchi T, Horita N. Comparison of stereotactic body radiotherapy and transcatheter arterial chemoembolization for hepatocellular carcinoma: Systematic review and meta-analysis. Radiother Oncol 2025;202:110614.
- 96. Wong TC, Lee VH, Law AL, Pang HH, Lam KO, Lau V, et al. Prospective study of stereotactic body radiation therapy for hepatocellular carcinoma on waitlist for liver transplant. Hepatology 2021;74:2580-2594.
- 97. Comito T, Loi M, Franzese C, Clerici E, Franceschini D, Badalamenti M, et al. Stereotactic Radiotherapy after Incomplete Transarterial (Chemo-) Embolization (TAE\TACE) vs. exclusive TAE or TACE for treatment of inoperable HCC: a phase III trial (NCT02323360). Curr Oncol 2022;29:8802-8813.
- 98. Sapisochin G, Barry A, Doherty M, Fischer S, Goldaracena N, Rosales R, et al. Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis. J Hepatol 2017;67:92-99.
- 99. Méndez Romero A, van der Holt B, Willemssen F, de Man RA, Heijmen BJM, Habraken S, et al. Transarterial chemoembolization with drug-eluting beads vs. stereotactic body radiation therapy for hepatocellular carcinoma: outcomes from a multicenter, randomized, phase 2 trial (the TRENDY trial). Int J Radiat Oncol Biol Phys 2023;117:45-52.
- 100. Sun HC, Zhou J, Wang Z, Liu X, Xie Q, Jia W, et al. Chinese expert consensus on conversion therapy for hepatocellular carcinoma (2021 edition). Hepatobiliary Surg Nutr 2022;11:227-252.
- 101. Tang H, Cao Y, Jian Y, Li X, Li J, Zhang W, et al. Conversion therapy with an immune checkpoint inhibitor and an antiangiogenic drug for advanced hepatocellular carcinoma: A review. Biosci Trends 2022;16:130-141.
- 102. Zhu XD, Huang C, Shen YH, Ji Y, Ge NL, Qu XD, et al. Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations. Liver Cancer 2021;10:320-329.
- 103. Kudo M. A new treatment option for intermediate-stage hepatocellular carcinoma with high tumor burden: initial lenvatinib therapy with subsequent selective TACE. Liver Cancer 2019;8:299-311.
- 104. Kudo M. Atezolizumab plus bevacizumab followed by curative conversion (ABC conversion) in patients with unresectable, TACE-unsuitable intermediate-stage hepatocellular carcinoma. Liver Cancer 2022;11:399-406.
- 105. Wang F, Numata K, Komiyama S, Miwa H, Sugimori K, Ogushi K, et al. Combination therapy with lenvatinib and radiofrequency ablation for patients with intermediate-stage hepatocellular carcinoma beyond up-to-seven criteria and Child-Pugh class A liver function: a pilot study. Front Oncol 2022;12:843680.
- 106. Wu JY, Zhang ZB, Zhou JY, Ke JP, Bai YN, Chen YF, et al. Outcomes of salvage surgery for initially unresectable hepatocellular carcinoma converted by transcatheter arterial chemoembolization combined with lenvatinib plus anti-PD-1 antibodies: a multicenter retrospective study. Liver Cancer 2023;12:229-237.
- 107. Chiang CL, Chiu KWH, Chan KSK, Lee FAS, Li JCB, Wan CWS, et al. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. Lancet Gastroenterol Hepatol 2023;8:169-178.
, TLCA Intermediate Stage HCC Working Group
