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

recurrence rates, and higher overall efficacy [defined by the World Health Organization as (complete
[38]
remission + partial remission)/total number × 100%] than RFA-alone . These studies show that combined
sorafenib and RFA has the potential to increase the treatment area of the tumor in intermediate-stage HCC
with improved overall survival and decreased recurrence rates.

Lenvatinib is a relatively newer MTA that became available in 2018. Because of recent studies that have
shown potential success in RFA and lenvatinib in the treatment of intermediate HCC, Wang et al.
conducted a retrospective study that enrolled patients to be treated with lenvatinib with sequential RFA vs.
[39]
lenvatinib alone . Enrolled patients must have intermediate-stage HCC, Child-Pugh class A, heavy tumor
burden, and not have received any prior systemic treatment. Compared to lenvatinib alone, the
[39]
combination group had longer PFS and OS without a significant increase in adverse events . Therefore,
this combination treatment may be a viable option in patients with high tumor burden but good liver
function.

RFA and immunotherapy
Currently, there are few clinical trials involving combined RFA with other molecular targeting agents or
immunotherapy. A comparative study looked at combined RFA-CIT and RFA alone in patients with
primary HCC who received RFA with curative intent. Results showed a significant increase in PFS in the
[40]
RFA-CIT compared to RFA alone . There was a randomized trial that looked at one and two-year
recurrence rates and median time to overall tumor recurrence in BCLC 0-B HCC patients treated with
combined RFA-[(131)I] metuximab and RFA alone. Results demonstrated that the combined group had a
greater anti-recurrence benefit than RFA alone, with overall tumor recurrence at 17 months vs. 10 months,
[41]
respectively . A phase III randomized controlled trial conducted in Korea showed that patients who
underwent curative treatment for HCC (surgery, RFA, or percutaneous ethanol injection) had a longer
recurrence-free and overall survival with adjuvant immunotherapy with activated CIK cells (CD3 +/CD56 +
[42]
and CD3 +/CD56 - T cells and CD3-/CD56 + natural killer cells) than without . The same institution then
followed up with a retrospective study to look at the efficacy of this combination treatment in real-world
clinical practice. During a median follow-up of 28 months, adjuvant immunotherapy in patients who have
had curative treatment (surgery or RFA) had a significantly longer RFS . Both of these studies
[43]
demonstrated a good safety profile. This combination of immunotherapy after RFA was also seen in a
retrospective study looking at patients with established recurrent HCC. Patients were included in the study
if they were diagnosed with recurrent HCC that was previously treated with hepatic resection or RFA.
Recurrence had to be a solitary tumor or no more than three nodules, each < 3 cm in size. They were treated
with either RFA alone or RFA with anti-PD-1 therapy. The 1-year recurrence-free survival rate was
significantly higher in the anti-PD-1 plus RFA group than in RFA alone, 32.5% and 10.0%, respectively, after
propensity score matching . Overall, these studies imply that the safety and efficacy of immunotherapy
[44]
after RFA treatment may reduce the recurrence of HCC more than RFA therapy alone. However, most of
these studies are small and lacking in a large multicenter randomized controlled trial.

SIRT/TARE and systemic therapy
There are few studies examining combined SIRT and systemic therapy. The SORAMIC randomized
controlled trial compared the efficacy and safety of SIRT with sorafenib vs. sorafenib alone in patients with
advanced HCC. The combination of SIRT and sorafenib did not result in a significantly higher median OS
than sorafenib alone. However, a subgroup analysis showed that there was a survival benefit in certain
groups: non-cirrhotics, non-alcoholic cirrhotics, and patients less than 65 years of age . A prospective
[45]
phase II trial evaluated the safety and efficacy of Child-Pugh class A patients with advanced or metastatic
HCC treated with sorafenib followed by Y glass microspheres. Median PFS was 10.3 months and OS was
90
13.2 months. Safety analysis showed that the therapy was well tolerated . Further studies may look into this
[46]