Hepatocellular carcinoma (HCC) is one of the leading malignancies worldwide. At diagnosis, up to 30% of patients have intermediate-stage HCC according to the Barcelona Clinic Liver Cancer system.1 Transarterial chemoembolisation (TACE) has emerged as the first-line treatment for intermediate-stage HCC, supported by two randomised controlled trials2 3 and a meta-analysis4 that demonstrated superior survival outcomes compared with best supportive care or suboptimal therapies.

Because patients with intermediate-stage HCC comprise a heterogeneous group characterised by a wide range of tumour burdens and liver function, the effectiveness of TACE as first-line treatment may not be universal, particularly in subgroups with high tumour burden or suboptimal liver function. To address this issue, sub-staging of intermediate-stage HCC based on tumour burden and liver function has been proposed in several criteria, including the Bolondi,5 Kinki,6 and MICAN (Modified Intermediate Stage of Liver Cancer) criteria.7 These criteria have demonstrated discriminative prognostic value in identifying subgroups of patients with intermediate-stage HCC.7 8 Given that survival outcomes of patients treated with TACE can vary across substages of intermediate-stage HCC, it is clinically essential to identify thresholds of tumour burden and liver function that preclude the use of TACE according to survival benefit.

Sorafenib has been established as the standard of care for advanced HCC since 2007, based on the demonstration of its significant survival superiority over placebo.9 10 11 Subgroup analyses of clinical trials have shown that sorafenib exerts positive therapeutic efficacy in intermediate-stage HCC, with reported overall survival (OS) ranging from 14.5 to 20.6 months,9 12 13 which is comparable to the OS achieved with TACE. Sorafenib treatment can serve as a benchmark for evaluating the survival benefit of TACE. If TACE does not provide a significant survival benefit compared with sorafenib, it may not be appropriate to subject patients to TACE rather than systemic therapy, given that TACE is invasive and potentially harmful to the liver. Patients may benefit from systemic therapy before liver function becomes suboptimal.

It has been hypothesised that specific baseline parameters of tumour burden and liver function, at which TACE fails to show superior survival benefit compared with sorafenib, could be defined as indicators of TACE unsuitability. This study aimed to define specific indicators of TACE unsuitability at baseline in patients with intermediate-stage HCC according to thresholds of tumour burden and liver function, as judged by the survival benefit of TACE over sorafenib.

Due to the limited number of eligible participants, all available cases with complete clinical data were included. All patients with unresectable HCC who received TACE or sorafenib therapy from January 2005 to December 2019 at Prince of Wales Hospital were enrolled in the study, provided they met all eligibility criteria. Unresectability of intermediate-stage HCC was determined by a multidisciplinary team comprising a surgeon, an interventional radiologist, and an oncologist. Inclusion criteria were treatment-naïve, Barcelona Clinic Liver Cancer-B stage HCC diagnosed by biopsy or a typical vascular pattern on cross-sectional imaging; intrahepatic disease without vascular invasion; and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Exclusion criteria included age under 18 years or Eastern Cooperative Oncology Group performance status score of 2 or above; prior treatment before initial TACE; receipt of hepatectomy, liver transplantation, or local therapy after initial TACE; and any imaging evidence from computed tomography (CT), magnetic resonance imaging, or positron emission tomography/CT showing vascular invasion by tumour (including portal vein tumour thrombus) or extrahepatic metastasis (Fig 1). To identify thresholds for TACE unsuitability, OS of patients treated with TACE was compared with that of patients treated with sorafenib within subgroups defined by baseline tumour burden and liver function. Overall survival was defined as the interval between the initiation of TACE or sorafenib and death from any cause. Patients who were alive or lost to follow-up were censored.

In total, 420 patients were enrolled in the study: 358 received TACE and 62 received sorafenib (Table 1). The TACE group included significantly more older and female patients. The median tumour size was significantly larger in the sorafenib group compared with the TACE group. No significant differences were observed between the two groups in terms of the modified albumin–bilirubin (mALBI) grade distribution or tumour multiplicity. Among patients initially treated with TACE, the median number of TACE sessions was two (range, 1-4); 124 patients received one session, 78 received two sessions, 53 received three sessions, and 103 received more than three sessions. After developing refractoriness to TACE, 60 patients subsequently received systemic agents; of these, 35 received sorafenib, eight received adriamycin, four received doxorubicin, six received lenvatinib, and seven received other agents.

Patients were classified into six subgroups according to baseline tumour burden and liver function. Tumour burden was subcategorised using the up-to-7, up-to-11, and N3-S5-S10 criteria. The up-to-7 and up-to-11 criteria were derived from the sum of the maximum tumour size (in cm) and the tumour number, with cut-off values of 7 or 11, respectively. Accordingly, patients were categorised as within or beyond the up-to-7 and up-to-11 criteria. In the N3-S5-S10 system, tumour burden was subcategorised according to the combination of tumour number and maximum tumour size; three tumour nodules and 5 cm or 10 cm in size served as the respective cut-off values. This categorisation resulted in the following six subgroups: (1) tumour number ≤3, tumour size ≤5 cm; (2) tumour number ≤3, tumour size >5 cm to ≤10 cm; (3) tumour number ≤3, tumour size >10 cm; (4) tumour number >3, tumour size ≤5 cm; (5) tumour number >3, tumour size >5 cm to ≤10 cm; and (6) tumour number >3, tumour size >10 cm (Fig 1).

Liver function subgroups were classified according to the mALBI grade.14 The mALBI grades were determined using the ALBI score, calculated as (log₁₀ [bilirubin level (μmol/L)] × 0.66) + (albumin level [g/L] × –0.085). Based on three cut-off ALBI scores, grades were defined as follows: grade 1 (≤–2.60), grade 2a (>–2.60 to ≤–2.27), grade 2b (>–2.27 to ≤–1.39), and grade 3 (>–1.39). Because the sample size of patients receiving sorafenib with mALBI grade 1 or 2a was relatively small, these two subgroups were combined for analysis. Additionally, given that no patient with mALBI grade 3 received sorafenib, this subgroup was excluded from the analysis (Fig 1).

The TACE procedures were performed using digital subtraction angiography equipment via a femoral approach under local anaesthesia.15 16 In brief, a microcatheter was used to catheterise tumour-feeding arteries at the lobar, segmental, or subsegmental level, depending on tumour size. An emulsion of cisplatin–ethiodised oil (Platosin; Pharmachemie BV, Haarlem, the Netherlands), consisting of up to 20 mg aqueous cisplatin (20 mL) and up to 20-mL ethiodised oil mixed in a 1:1 volume ratio, was administered until flow stasis occurred or a maximum dose of 40-mL emulsion was delivered. Digital subtraction angiography, with or without non-contrast multiplanar CT, was used to confirm treatment completeness. A gelatin sponge (5-10 mL) was used to embolise the feeding arteries.

Postprocedure monitoring included blood tests for liver function and tumour markers within 2 days, at 2 weeks, and then every 1 to 3 months, as well as CT imaging every 3 months. Systemic therapy was administered to patients with well-preserved liver function who developed TACE refractoriness, as indicated by continuous elevation of tumour markers and CT evidence of tumour progression.

According to the customary protocol at Prince of Wales Hospital, The Chinese University of Hong Kong during the study period, patients with unresectable intermediate-stage HCC and no contraindications to TACE were prioritised for TACE treatment. Patients who declined TACE were treated with sorafenib; as a result, some patients in the sorafenib group had smaller tumours or fewer tumour nodules. Sorafenib was administered orally at a prescribed dose of 400 mg twice daily. In the event of intolerable side-effects or serious adverse events, oncologists could adjust the treatment by reducing the dose or discontinuing the drug.

Categorical variables were presented as numbers (percentages), while continuous variables were summarised as median (interquartile range), median (95% confidence interval [95% CI]), or depending on the results of normality testing. The Chi squared test was used to compare categorical data, and the Mann-Whitney U test was performed for continuous data. Kaplan-Meier curves and Cox proportional hazards models were used to compare OS values among subgroups. The log-rank test and hazard ratio (HR) were utilised to assess survival differences between subgroups. A sensitivity analysis of survival outcomes was conducted, excluding participants who received systemic therapy after TACE. A P value <0.05 was considered statistically significant. Statistical analyses were performed using SPSS (Windows version 25.0; IBM Corp, Armonk [NY], United States).

The median OS of all patients who received TACE was significantly longer than that of patients who received sorafenib (19.37 [16.89-21.85] months vs 5.12 [4.37-5.84] months, P<0.001; Fig 2a). When stratified by mALBI grade, patients with mALBI grade 1 or 2a had significantly longer median OS in the TACE group compared with the sorafenib group (23.83 [18.53-29.13] months vs 6.60 [3.61-9.59] months, P<0.001; Fig 2b). Similarly, patients with mALBI grade 2b had significantly longer median OS in the TACE group than in the sorafenib group (16.20 [11.91-20.49] months vs 4.39 [3.44-5.35] months, P<0.001; Fig 2c).

The median OS of patients treated with sorafenib, stratified by mALBI grade and tumour burden, is summarised in Table 2. As the sorafenib subgroups with tumour number ≤3 had a relatively small sample size (n=8) according to the N3-S5-S10 criteria, these patients were not further subdivided based on tumour size. Instead, they were combined into a single subgroup with tumour number ≤3 to increase the sample size for comparison with the TACE group. Consequently, OS in the combined sorafenib subgroup (tumour number ≤3, any tumour size) was used for comparison with OS in the three tumour-size TACE subgroups of tumour number ≤3 (Table 2).

The distribution of sample sizes was uneven across the sorafenib subgroups with tumour number >3 based on the N3-S5-S10 criteria, which may have introduced bias in the survival outcomes, such as a lower tumour burden being associated with worse OS. To avoid underestimation of OS in any tumour-size subgroup when comparing with the TACE subgroups, the longest OS among the subgroups with tumour number >3 was utilised as the OS value for all these subgroups in the analysis, irrespective of tumour size (Table 2). As no patients with mALBI grade 2 were present in the tumour burden subgroup defined as within up-to-7, the OS of patients with tumour burden beyond up-to-7 (Table 2) who were treated with sorafenib was used as the control.

Table 3 presents the median OS of patients treated with TACE or sorafenib, stratified by mALBI grade 1 or 2a and tumour burden. Across all subgroups defined by various tumour burden criteria, patients who received TACE achieved significantly longer OS than those who received sorafenib (all P<0.05), with HRs favouring TACE (ranging from 0.130 to 0.331). Sensitivity analysis showed that survival was not significantly different between TACE and sorafenib in the subgroup with tumour number >3 and tumour size >10 cm (HR=0.418 [95% CI=0.147-1.171]; P=0.097).

In subgroups with mALBI grade 2b, defined by either the up-to-7 or up-to-11 criteria, patients who received TACE exhibited significantly longer median OS than those who received sorafenib across all subgroups (all P<0.05; Table 4). However, when using the N3-S5-S10 criteria, TACE resulted in a significantly longer median OS than sorafenib only in the subgroups with tumour number ≤3 (any tumour size) and in the subgroup with tumour number >3 and tumour size ≤5 cm (both P<0.05; Table 4). In the subgroups with tumour number >3 and tumour size >5 cm to ≤10 cm, and those with tumour number >3 and tumour size >10 cm, although TACE subgroups demonstrated longer median OS than sorafenib subgroups (6.07 vs 3.74 months and 7.73 vs 3.74 months, respectively), the differences were not statistically significant (Table 4). Sensitivity analysis showed that survival was also not significantly different between TACE and sorafenib in the additional subgroup with tumour number ≤3 and tumour size >10 cm (HR=0.474 [95% CI=0.185-1.261]; P=0.120).

Due to the small sample size, it was difficult to demonstrate a clear survival benefit of TACE over sorafenib; thus, the risk of overestimating the survival benefit of TACE, due to potential bias from more advanced disease in the sorafenib group, was likely minimised. For example, given the limited number of patients in the subgroups with tumour number >3 and tumour size >5 cm to ≤10 cm and those with tumour number >3 and tumour size >10 cm, these two subgroups were combined into one subgroup (tumour number >3 and tumour size >5 cm). In this combined subgroup, TACE (n=38) still yielded no significant survival benefit over sorafenib (n=14), with OS values of 6.07 months (4.10-8.03) and 3.74 months (1.71-5.78), respectively (HR=0.586 [95% CI=0.325-1.054]; P=0.071).

Subgroup analysis in this study revealed that, within the limitations of the data, TACE probably did not confer a statistically significant survival benefit over sorafenib for patients with mALBI grade 2b and a high tumour burden (number >3 and size >5 cm, or number ≤3 and size >10 cm), or for patients with mALBI grade 1 or 2a and tumour burden of number >3 and size >10 cm. In contrast, TACE did provide a survival benefit when the beyond up-to-7 or beyond up-to-11 criteria were applied. These findings suggest that the use of more precise criteria to define tumour burden and liver function could help identify specific subgroups unsuitable for TACE. Such criteria highlight the threshold at which TACE no longer provides a survival advantage over sorafenib, thereby indicating TACE unsuitability. These indicators would be valuable in guiding the clinical management of intermediate-stage HCC. The small sample size in the sorafenib group may have limited the statistical power to detect a survival benefit of TACE in subgroups with tumour number >3 and size >5 cm. Given that the overall results showed a consistent trend favouring TACE, validation through further studies with larger sample sizes is warranted.

In recent years, systemic therapy for HCC has undergone rapid development, leading to the emergence of new drugs after sorafenib. The combination of certain agents has shown significant improvements in survival compared with sorafenib alone. The IMbrave150 study demonstrated that treatment with atezolizumab plus bevacizumab resulted in a significantly longer median OS than sorafenib alone (19.2 vs 13.4 months).17 Similarly, both sintilimab plus a bevacizumab biosimilar18 and tremelimumab plus durvalumab19 provided significant survival benefits over sorafenib in patients with unresectable HCC. Nevertheless, sorafenib remains the first-line standard treatment and the most effective single agent for advanced HCC. It serves as a benchmark for newer single-agent therapies such as lenvatinib, nivolumab, and durvalumab, which have shown statistical non-inferiority in survival compared with sorafenib.19 20 21 Therefore, the use of sorafenib as the control arm versus TACE in this study is reasonable. With the rapid advancement of systemic agents, novel treatment strategies—such as switching to systemic therapy22 or initiating systemic therapy upfront followed by curative conversion23—have been advocated for patients with intermediate-stage HCC who may not benefit from TACE or repeated TACE. In such cases, it is important to define specific indicators of TACE unsuitability among patients with intermediate-stage HCC, in whom systemic therapy may potentially improve survival.

The concept of TACE unsuitability has emerged in conjunction with the development and availability of systemic therapies.24 In patients with intermediate-stage HCC, TACE unsuitability has been defined as the presence of mALBI grade 2b and tumour burden beyond the up-to-7 criteria.25 26 This definition was based on worse survival in patients with mALBI grade 2b and the beyond up-to-7 criteria relative to patients displaying better liver function and lower tumour burden, without addressing the potential survival benefit of TACE over alternative treatment options in this subgroup. However, this definition has two key limitations. First, it lacks clinical evidence demonstrating greater survival benefit from other alternative treatments when TACE is withheld. Second, there remains controversy regarding the optimal criteria for defining high tumour burden. If the beyond up-to-7 criteria is used as the criterion for TACE unsuitability, the majority of patients with intermediate-stage HCC would be considered unsuitable, which is both unrealistic and unsupported. In the present study, 79% of patients had high tumour burden beyond up-to-7, comparable to the 70% reported by Hung et al.27

The sub-staging system using the up-to-11 criteria has shown better discriminatory power than the up-to-7 criteria for predicting survival after TACE.28 29 Nonetheless, in this study, neither the up-to-7 nor the up-to-11 criteria were able to identify TACE unsuitability. The findings indicated that both the patient subgroup with mALBI grade 2b and tumour burden beyond the up-to-7 criteria, as well as the subgroup with mALBI grade 2b and tumour burden beyond the up-to-11 criteria, still derived survival benefits from TACE compared with sorafenib, indicating that these subgroups should not be considered TACE unsuitable. The lack of discriminatory power may be attributed to the persistently high heterogeneity among patients classified as having high tumour burden under to these two criteria. Worse survival after TACE in these subgroups, compared with patients displaying better liver function and lower tumour burden, does not justify entirely abandoning TACE in these patients.

We propose using the N3-S5-S10 criteria to define tumour burden, as these criteria allow for more specific subgrouping and enable the identification of TACE unsuitability with greater precision, thereby reducing the likelihood of denying patients a potentially beneficial treatment (TACE). Our findings demonstrate that the proposed criteria can identify TACE unsuitability precisely in specific subgroups where the up-to-7 or up-to-11 criteria fail to distinguish survival differences. Based on these findings, we recommend that physicians assess intermediate-stage HCC using both the mALBI grade and the N3-S5-S10 criteria—a more rigorous framework—to determine TACE unsuitability. To our knowledge, this is the first study to demonstrate the survival benefit of TACE over sorafenib in patients with intermediate-stage HCC stratified by both liver function and tumour burden, as well as to identify TACE unsuitability within these subgroups.

This study provided a larger sample size than previous studies comparing survival benefits between TACE and sorafenib. However, several limitations should be noted. First, the retrospective design of this study inevitably introduced patient selection bias between the TACE and sorafenib groups. Although there were significant differences in age, sex, and tumour size between the groups, such disparities in overall patient demographics might not have critically affected the validity of the survival comparisons, given that these were based on subgroup analyses. Second, the sample size was exceedingly small in some sorafenib subgroups with low tumour burden. The substantial disparity in patient numbers may have contributed to non-significant differences in OS between subgroups. We attempted to mitigate this limitation by combining subgroups with very small sample sizes. Third, some patients in the TACE group received systemic therapy after disease progression. Consequently, survival in the TACE group may have been overestimated as it reflected outcomes of TACE with or without systemic therapy, rather than TACE alone. Nonetheless, ‘TACE followed by systemic therapy’ represents standard clinical practice aimed at achieving the greatest patient benefit, and isolating a TACE-alone group for analysis would not be realistic. Notably, ‘TACE followed by systemic therapy’ accurately reflects real-world treatment practice and does not conflict with the study’s primary objective, which was to define specific indicators of TACE unsuitability at baseline rather than at the point when TACE becomes unsuitable. Finally, no power calculation was performed in the statistical analysis.

More precise criteria for TACE unsuitability are required. The combination of mALBI grade and N3-S5-S10 criteria may serve as a better indicator of TACE unsuitability than the beyond up-to-7 or beyond up-to-11 criteria for patients with intermediate-stage HCC. TACE likely offers no survival benefit compared with sorafenib beyond these thresholds. However, validation in a larger cohort is warranted.

Concept or design: SCH Yu.
Acquisition of data: LM Chen, L Li, EP Hui, W Yeo, SL Chan.
Analysis or interpretation of data: LM Chen, SCH Yu.
Drafting of the manuscript: LM Chen, SCH Yu.
Critical revision of the manuscript for important intellectual content: All authors.

All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

All authors have disclosed no conflicts of interest.

This research was funded by the Vascular and Interventional Radiology Foundation, Hong Kong. The funding body was not involved in the design of the study, collection of data, analysis/interpretation of data, or writing of the manuscript.

This research was approved by The Chinese University of Hong Kong–New Territories East Cluster Ethics Committee, Hong Kong (Ref No.: 2020.672). It was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation–Good Clinical Practice guidelines. The requirement for written informed patient consent was waived by the Committee due to the retrospective nature of the research.

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