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mg/day; 21.0 weeks). TACE-2 used response-guided DEB-TACE, but sorafenib exposure remained limited
(660 mg/day; 120 days), with fewer TACE procedures delivered in the sorafenib arm. In contrast, TACTICS
adopted RECICL-based TACE-specific PFS and did not regard new intrahepatic lesions alone as treatment
failure, allowing on-demand TACE until unTACEable progression, TACE refractoriness, toxicity, or
withdrawal. Although OS remained nonsignificant, post-trial active treatment was more frequent in the
TACE-alone arm (76.3% vs. 58.8%). Thus, the available evidence suggests that effective TACE exposure and
adequate systemic treatment duration are crucial; future trials should optimize stopping rules by integrating
radiographic progression, technical TACE feasibility, liver reserve, drug tolerability, and post-progression
therapy.

Refining the population most likely to benefit
Across these trials, the target population has gradually shifted from broadly defined TACE-eligible patients
to clinically enriched subgroups with higher intrahepatic tumor burden but preserved Child-Pugh/ALBI
function . Earlier sorafenib-based trials, such as SPACE and TACE-2, mainly enrolled intermediate-stage or
[57]
liver-confined HCC without clear enrichment for patients at high risk of TACE failure, which may have
diluted potential benefit. Although the overall OS benefit of TACTICS was not statistically significant, post
hoc analysis showed that the PFS and OS advantages of TACE-sorafenib were more evident in patients
beyond the up-to-seven criteria, but only one-third of patients were beyond the up-to-seven criteria at
baseline. This suggested that combination therapy may be more relevant for patients whose tumor burden is
too high for durable control with repeated TACE alone, but who still have sufficient liver reserve to tolerate
both TACE and systemic therapy. Recent positive trials further support this selection trend. LAUNCH tested
TACE-lenvatinib in advanced HCC, a population including large intrahepatic tumor burden, portal vein
thrombosis, and extrahepatic spread, and demonstrated significant OS and PFS benefits over lenvatinib
alone. Therefore, future trials should not simply ask whether all TACE-eligible patients benefit from
combination therapy, but should prospectively define risk-enriched populations, particularly high tumor
burden, preserved Child-Pugh/ALBI function, technically feasible selective TACE, and limited systemic
spread.

Therefore, the lessons from TACE-targeted therapy are not merely historical. They define the key design
requirements for modern triple-therapy trials: early and sustained systemic exposure, clinically meaningful
TACE continuation rules, and enrichment of patients likely to fail TACE alone but still retain adequate
hepatic reserve.

TRIPLE THERAPY (TACE PLUS ICI AND ANTI-VEGF/TKI): PERSISTENT OS CHALLENGES
With immunotherapy plus anti-angiogenic therapy emerging as a dominant systemic backbone, triple
therapy integrating TACE with ICI and anti-VEGF/TKI has become a logical next step. Real-world evidence
and target-trial emulation studies have reported encouraging disease control [58,59] . Meanwhile, several
randomized trials have provided more rigorous signals of benefit, most consistently in PFS and ORR.
However, OS remains immature or difficult to improve definitively in intermediate-stage populations where
subsequent effective therapies and crossover can dilute survival differences. Below, we summarized and
reflected pivotal randomized trials using a standardized evidence-focused template.

THE EMERALD-1 TRIAL
EMERALD-1 was the first reported phase III trial evaluating TACE combined with immunotherapy and
[12]
anti-angiogenic therapy. This multiregional, randomized, double-blind, placebo-controlled study compared
TACE plus durvalumab and bevacizumab, TACE plus durvalumab, and TACE plus placebo in patients with
unresectable HCC eligible for embolization [Table 2]. The enrolled population was broad and clinically
heterogeneous, including patients with Barcelona Clinic Liver Cancer (BCLC) stage A-C disease;