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Page 2 of 15 Wu et al. Hepatoma Res 2023;9:6 https://dx.doi.org/10.20517/2394-5079.2022.37

for early-stage HCC but require either a single nodule or small tumor sizes, respectively. However, for those
[3]
who are not surgical candidates, treatment with RFA has shown to be just as effective and less invasive .
Unfortunately, HCC often presents in advanced stages not amendable for transplantation or resection.
Current guidelines for the treatment of unresectable HCC recommend either locoregional therapy (LRT) or
systemic therapy. The recommendations do not specify one treatment over the other due to inadequate
[4,5]
evidence regarding the balance of benefits vs. harm . Trans-arterial chemoembolization (TACE), a form of
LRT, is the standard treatment for intermediate-stage HCC up to Child-Pugh class B without vascular
invasion or extrahepatic spread. TACE has been shown to significantly delay tumor progression and
improve median survival compared to best supportive care . However, multiple sessions of TACE increase
[6]
the risk of systemic toxicity .
[7]

Historically, there was no effective therapy for the treatment of advanced HCC in patients who have failed
local therapies until sorafenib, which was the first systemic agent to show an increase in survival when
compared to a placebo . Although sorafenib was the standard of care and first-line agent for advanced
[8,9]
HCC for over a decade [Figure 1], interest in other systemic agents such as immune checkpoint inhibitors
and immunotherapy has grown rapidly -either as a single or a combined agent- which have become
standard therapy in advanced HCC. Immunotherapy enhances the immune system response against tumor-
associated antigens (TAA) and has become the first-line agent in advanced unresectable HCC. For instance,
the combination of atezolizumab plus bevacizumab has demonstrated improved overall survival (OS) and
progression-free survival (PFS) compared to sorafenib . Tremelimumab and durvalumab combination has
[11]
also demonstrated superior outcomes compared to Soreafinib in the HIMALAYA trial .
[12]
In addition to monotherapy, there have also been efforts in clinical trials to evaluate the efficacy of
combined systemic therapy and LRT therapies to take advantage of their synergistic effects. Although LRT
is the standard therapy for early and intermediate-stage HCC, clinical trials have shown its use is associated
with a brief upregulation of vascular endothelial growth factor (VEGF), which is vital in HCC pathogenesis.
The upregulation of VEGF is likely from the ischemic injury to the surrounding arteries following LRT
treatment, and higher levels of VEGF have been shown to correlate with poorer outcomes after
treatment [13,14] . It could be for this reason that high rates of tumor recurrence occur after LRT treatment for
HCC. Therefore, antiangiogenic agents, such as sorafenib, were proposed as an adjuvant treatment to LRTs
to combat its angiogenic properties and inhibit tumor growth post-treatment. Furthermore, LRT has also
been used with immunotherapy to boost the body’s immune response against TAAs. Although the
mechanism is unclear, supposedly, the post-LRT necrotic area releases tumor antigens that induce dendritic
cells, inflammatory cytokines, and T-cells to infiltrate and stimulate the antitumor response. Therefore,
when done in conjunction with immunotherapy, the synergistic effects strengthen the immune response to
residual tumors .
[15]

Here, we review the available clinical trials assessing the combined therapeutic efficacy of LRTs and
systemic therapy.

LOCOREGIONAL THERAPIES
Locoregional therapies include two major types: local ablative techniques and intra-arterial therapies.

Local ablative techniques for HCC involved the percutaneous insertion of a needle into the tumor to deliver
chemical or thermal ablation. These methods of percutaneous ablation are often curative treatments for
early-stage HCC. The most commonly used ablative therapy is RFA, which is the first-line option for non-