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Page 12 of 15 Li et al. Hepatoma Res. 2026;12:36

definitive comparative evidence. Prospective trials specifically designed to test the impact of different
sequencing approaches - while controlling for TACE technique, retreatment protocols, and continuity of
systemic therapies - are essential to determine whether sequencing significantly influences synergy and long-
term outcomes.

Second, the endpoints used in these trials need to be modernized to better capture clinically meaningful
benefits. In settings where active subsequent therapies and crossover are common, OS may be diluted,
making it statistically challenging to measure. Therefore, composite endpoints incorporating time to
untreatable progression, liver function preservation, conversion to curative therapy rates, and patient-
reported outcomes should be considered, as they more accurately reflect the true clinical benefit. When using
TACE-specific endpoints, simplicity and clinical interpretability should be prioritized to facilitate broad
adoption and reproducibility.

Third, TACE operational standardization should align more closely with real-world practice. A persistent
gap exists between the on-demand TACE approach used in clinical practice and the protocol-driven session
limits seen in trials. Future studies should incorporate adaptive, response-guided TACE algorithms,
considering imaging response, liver reserve, and performance status, rather than relying on fixed session caps
that may under-treat or over-treat certain patient subgroups.

CONCLUSION
Future progress hinges on large-scale, intelligently designed trials that simultaneously address these
intertwined questions, including timing, endpoint selection, and TACE standardization. The goal is to move
beyond demonstrating PFS superiority and to reliably deliver the OS benefit that defines meaningful
therapeutic advancement for patients with intermediate-to-advanced HCC.

DECLARATIONS
Authors’ contributions
Responsible for the review design, manuscript revisions, and funding acquisition: Zhu G, Guo J, Chen L, Li C
The main authors responsible for writing the manuscript: Li C, Chen L
Contributed to sections of the manuscript and the creation of tables: Bao H, Wang Y

Availability of data and materials
Not applicable.

AI and AI-assisted tools statement
During the preparation of this manuscript, the AI tool ChatGPT (version 5.1, released 2025-08-07) was used
solely for language editing and grammatical polishing. The tool did not influence the study design, data
collection, analysis, interpretation, or the scientific content of the work. All authors take full responsibility
for the accuracy, integrity, and final content of the manuscript.

Financial support and sponsorship
This work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major
Project (2024ZD0520400, 2024ZD0520403), National Natural Science Foundation of China
(82372066,82572339), Interventional Medicine Research Special Fund Project of Jiangsu Medical Association
[SYH-3201140-0045 (2022002)], Jiangsu Provincial Natural Science Foundation Youth Fund (BK20251691),
The Natural Science Foundation of Jiangsu Province (BG2024007). The funding sources had no role in the
writing of the report or the decision to submit the paper for publication.

Conflicts of interest
All authors declared that there are no conflicts of interest.