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Page 8 of 15 Wu et al. Hepatoma Res 2023;9:6 https://dx.doi.org/10.20517/2394-5079.2022.37

intermediate unresectable HCC. Median PFS was 384 days and TTP was 415 days. The estimated 3-year OS
was 86.1%. Only 8.1% of patients discontinued the trial due to adverse events (AEs), and although 52 of 192
[56]
patients experienced serious AEs, only four were considered to be related to sorafenib . Similar
conclusions were also reached by the single-arm phase II study showing promising efficacy and tolerable
safety profile with treatment with sorafenib-TACE . Although these results suggest the interrupted
[57]
administration of sorafenib plus TACE is efficacious with a relatively tolerable safety profile, randomized
comparative studies were lacking until the recent TACTICS trial.

So far, the larger randomized controlled trials mentioned previously (post-TACE, SPACE, TACE-2) have all
been negative trials, showing no benefit of the addition of sorafenib to TACE. The multicenter randomized
controlled TACTICS trial examined the efficacy and safety of TACE plus sorafenib compared with TACE
alone in unresectable HCC and is the first positive trial, demonstrating the efficacy of the combined
treatment. Sorafenib was given 2-3 weeks prior to the first TACE session in an interrupted administration.
The primary endpoint was met with PFS significantly higher in sorafenib-TACE (25.6 months) than in
TACE alone (13.5 months) with a hazard ratio (HR) of 0.59. In addition, time to cancer progression and
spread was also significantly higher in the combined therapy group than in TACE alone. The reasons why
the TACTICS trial was able to demonstrate improved clinical outcomes stem largely from two concepts.
First, it was shown in exploratory analyses of the post-TACE and SPACE trial that a longer duration of
sorafenib treatment was associated with significantly favorable TTP than shorter durations. The shorter
duration of treatment was due to utilizing the RECIST1.1 or modified RECIST (mRECIST) criteria for
tumor progression, which resulted in earlier termination of therapy even though it is thought that patients
meeting these criteria still have disease amendable to further treatment of TACE. Therefore, the TACTICS
trial used the Response Evaluation Criteria in Cancer of the Liver (RECICL), which resulted in a longer
duration of treatment (38.7 weeks) compared to previous trials (17-21 weeks). Second, although there is no
good data currently out on the preferred timing of sorafenib administration prior to and after TACE, the
TACTICS trial started sorafenib considerably earlier than previous trials, 2-3 weeks and 3-7 days,
respectively. The earlier pe-treatment with sorafenib likely allowed for reduced vascular ischemic injury and
[58]
reduced upregulation of VEGF .
So far, the studies of TACE plus sorafenib have largely included intermediate-stage HCC that qualify for
locoregional therapy. Although, the phase III STAH trial, a large Korean multicenter study, included
patients with advanced HCC indicated for palliative systemic therapy (including those refractory to TACE,
with vascular invasion, or with extrahepatic spread). Patients were randomized to receive sorafenib alone or
in combination with TACE. Results showed no significant improvement in OS in sorafenib-TACE vs.
sorafenib alone, 12.8 vs. 10.8 months, respectively (HR 0.91; P = 0.290). However, sorafenib-TACE did
significantly improve TTP, PFS, and tumor response rates compared to sorafenib alone .
[59]

TACE with bevacizumab
Bevacizumab is a human monoclonal anti-VEGF alpha antibody that is FDA-approved for use in multiple
[60]
metastatic tumors such as renal cancer, lung cancer, and colon cancer . Bevacizumab was associated with
strong angiogenesis inhibition in pre-clinical HCC models. [61]

There have been several data on the use of Bevacizumab alone in unresectable HCC. A systematic review of
phase II clinical trials involving bevacizumab for the treatment of advanced HCC showed promising results.
8 trials (n = 300 patients) were included in this review which showed overall median progression-free
survival and overall survival (5.3-9.0) months and (5.9-13.7) months, respectively .Bevacizumab plus
[62]
TACE combination was examined in a pilot study of IV bevacizumab (intravenous) plus TACE, and there