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as a core component of standardized TACE practice in China. Future prospective studies are warranted to
further quantify the impact of precision TACE on the optimal number of treatment sessions and long-term
survival.

TACE COMBINED WITH SYSTEMIC THERAPY
Optimization strategy of TACE treatment times in combination regimens
TACE combined with targeted therapy plus immunotherapy has been supported by increasing evidence.
Some key clinical studies on TACE combined with systemic therapy are summarized [Table 2]. The study
showed that the mPFS/mOS of the combined treatment group was significantly longer than that of the single
TACE group, and that the combined treatment could significantly improve patient prognosis. The
optimization of the number of TACE procedures in the combination therapy group can be verified from the
following perspectives:

1. Number stratification based on staging:
Intermediate HCC (BCLC stage B): A triple scheme study by Wang et al. showed that the median number of
TACE was 2 times, and sequential immunotherapy could increase the mOS to exceed 33 months . More
[33]
than three TACE sessions did not significantly improve the curative effect but increased the risk of liver
injury.

Advanced HCC (BCLC stage C): 1,244 patients were included in the CHANCE2201 study . The mOS of 2-3
[16]
times of TACE combined with targeted therapy plus immunotherapy was 22.6 months, which was
significantly better than that of the simple targeted therapy plus immunotherapy group (15.9 months);
however, the overall survival (OS) of more than four times of treatment was not significantly improved (23.1
months vs. 22.6 months, P = 0.38).

2. Dynamic adjustment based on efficacy response:
Patients with complete response/partial response (CR/PR): after TACE combined with targeted therapy plus
immunotherapy reaches CR/PR of mRECIST criteria, TACE can be suspended, and only targeted therapy
plus immunotherapy can be performed. In the LAUNCH study , the median number of TACE was 2, and
[34]
the 1-year recurrence-free survival rate was 68.7%.

Patients with stable disease/progressive disease (SD/PD): If they are evaluated as having SD after the first
TACE combination therapy, it is recommended to add one additional TACE within 2 months. In the case of
PD, the tumor blood supply needs to be re-evaluated. If the arterial blood supply is still present, the third
TACE can be attempted; otherwise, it will be converted to systemic treatment. Subgroup analysis of the
CHANCE001 study showed that such adjustment strategies improved the DCR of patients with PD from
[15]
32% to 57%.

3. Differences in the number of different joint modes:
Quadruple scheme (TACE + HAIC + targeted therapy + immunotherapy): Li et al. found no significant
difference in OS between the quadruple and triple schemes (23.9 months vs. 21.7 months, P = 0.43) .
[35]
However, the average number of TACE sessions decreased by one (1.8 vs. 2.7) because HAIC can enhance
the drug concentration through local perfusion and reduce dependence on multiple embolizations.

Mechanism of efficacy decline after multiple TACE
The reasons for the decrease in response rate caused by the increase in the number of TACE may include the
following: (1) vascular endothelial cell damage and neovascularization caused by multiple treatments lead to
a decline in the embolization effect, hence the microenvironment of the tumor changes, adaptive remodeling