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Wu et al. Hepatoma Res 2023;9:6 https://dx.doi.org/10.20517/2394-5079.2022.37 Page 7 of 15

combined therapy in specific subgroups.

Given the synergistic immunomodulatory effects of SIRT and immunotherapy, there have been a couple of
recent clinical trials to test the efficacy and safety of this combined therapy. Two small retrospective trials
examined patients with advanced HCC but preserved liver function (Child-Pugh class A-B7) who had
received nivolumab and SIRT. Both of these studies documented that the most common adverse event was
hepatobiliary toxicity; otherwise, the therapy appears to be safe [47,48] . Zhan et al noted that PFS was 5.7
months and median OS after the first immunotherapy and first radioembolization was 17.2 and 16.5
[47]
months, respectively . Furthermore, a phase II single-arm trial evaluated the objective response rate (based
on the RECIST 1.1 criteria) of Child-Pugh class A cirrhotics with advanced HCC not amenable to resection,
90
who were treated with nivolumab and Y SIRT. The objective response rate was 30.6%. Five out of 40
patients had serious adverse events, including Steven-Johnson syndrome, hepatitis E infection, fever, liver
abscesses, and ascites . There are more ongoing clinical trials evaluating SIRT and immunotherapy,
[49]
including two-arm prospective trials.

TACE and sorafenib
The promise of adding sorafenib to prior TACE treatment was first suggested by a subgroup analysis of the
SHARP trial. In this subanalysis, sorafenib treatment in patients with prior TACE resulted in longer median
[50]
OS and TTP than placebo . However, many clinical trials since then have attempted to demonstrate the
efficacy of this combined treatment without success.

The phase III post-TACE trial took Japanese and Korean Child-Pugh class A cirrhotics with unresectable
HCC, who had > 25% tumor shrinkage with TACE 1-3 months prior, and randomized them to sorafenib or
placebo. The primary endpoint looked at median TTP in the sorafenib and placebo groups, which was 5.4
[51]
and 3.7 months, respectively, P = 0.252 . Therefore, the addition of sorafenib was not shown to prolong
TTP. Although it was thought that the results could be due to the delay in sorafenib administration after
TACE, a smaller single-center randomized controlled trial demonstrated a significantly longer TTP in
Child-Pugh class A intermediate-stage chronic hepatitis C virus (HCV) HCC, who received sorafenib 30
[52]
days after TACE compared to placebo . Both studies did not have any unexpected adverse events.

The phase II SPACE trial randomized patients with intermediate-stage multinodular HCC without
macrovascular invasion or extrahepatic spread to DEB-TACE plus sorafenib or placebo. Sorafenib was
administered continuously, starting about one week prior to the first TACE. The median TTP in DEB-
TACE plus sorafenib was 169 days vs. 166 days in the placebo group, and the median OS was not
[53]
significantly prolonged in the group with sorafenib . Another similar study, phase III TACE 2, also looked
at the efficacy of continuous sorafenib plus DEB-TACE and placebo plus DEB-TACE in Child-Pugh class A
unresectable, liver-confined HCC. The primary endpoint was PFS, which was not significantly different
between the sorafenib and placebo groups . Therefore, studies evaluating continuous administration of
[54]
sorafenib with TACE in intermediate-stage HCC amenable to TACE have not shown any increased efficacy
compared to TACE alone.

Furthermore, some studies also looked at interrupted administration of sorafenib in combination with
TACE. Interrupted schedule focused on briefly holding sorafenib around the time of TACE therapy to
minimize the combined toxicity of the two drugs. The phase II SOCRATES trial showed TPP of 16.4
months and median OS of 20.1 months in locally advanced unresectable HCC treated with sorafenib-TACE.
Overall, there did not seem to be any additional toxicity with the combined therapy compared to sorafenib
[55]
or TACE alone . Another phase II trial, START, evaluated interrupted dosing of sorafenib with TACE in