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Wu et al. Hepatoma Res 2023;9:6 https://dx.doi.org/10.20517/2394-5079.2022.37 Page 5 of 15

median OS in patients with HCC with progression despite treatment with sorafenib and AFP ≥ 400
[29]
compared to the best supportive care in the REACH-2 trial . This trial was significant for being the first
trial to select a patient population based on biomarkers. Most recently, the combination of atezolizumab-
bevacizumab was approved and recommended as first-line treatment for patients with advanced HCC,
performance status of 0-1, Child- Pugh A, and lack of active esophageal varices . This was based on a
[30]
global phase III trial looking at treatment with atezolizumab plus bevacizumab or sorafenib for unresectable
HCC without prior treatment. Treatment with atezolizumab-bevacizumab resulted in a significant
improvement in OS at 12 months with 67.2% vs. sorafenib with 54.6%. Median PFS was also improved in
the atezolizumab-bevacizumab group. The percentage of grade 3 or 4 adverse events was similar in both
[11]
groups .

Lastly, immunotherapy in HCC aims to strengthen the antitumor immune response through different
tumor microenvironments (TME) which can be divided into four subclasses (C1-C4). The C1 subclass lacks
+
priming T cells, and C2 is characterized by macrophages, CD4 , and CD8 T cells, and B cell infiltration. C3
+
is associated with worse outcomes and displays M2 macrophages and C4 promotes epithelial-mesenchymal
transition (EMT) . Currently, immune checkpoint inhibitors (ICI), which serve to boost the existing
[31]
immune response, are the most commonly used. Agents include PD-L1 antibodies (durvalumab,
atezolizumab, and avelumab), anti-PD-1 antibodies (nivolumab, pembrolizumab, and camrelizumab), and
anti-CTLA-4 antibodies (ipilimumab and tremelimumab). Nivolumab, a PD-1 inhibitor, is currently
approved as a second-line systemic treatment in advanced HCC patients who are ineligible for tyrosine
kinase inhibitors. The landmark CheckMate 459 trial showed a better safety profile of Nivolumab
monotherapy compared to Sorafenib but no significant OS (16.4 months with nivolumab vs. 14.7 months
[32]
with sorafenib) (HR, 0.85; 95%CI: 0.72-1.02; P = 0.075) ; as a result, the FDA Oncologic Drugs Advisory
Committee (ODAC) opposed the accelerated approval of Nivolumab monotherapy for patients with
advanced HCC. As mentioned previously, the combination of atezolizumab plus bevacizumab has led to
better overall and progression-free survival outcomes than sorafenib, leading the dual MTA and
immunotherapy to be a standard first-line therapy in advanced HCC. Finding biomarker predictors for ICI
response in HCC is one of the main unanswered questions. To date, several biomarkers have been studied,
[33]
including PD-L1, Tumor mutational burden (TMB), and Microsatellite instability (MSI) status . Further
research in this area is critical to allow for treatment response and disease monitoring.

COMBINATION OF LOCOREGIONAL AND SYSTEMIC THERAPIES
RFA and molecular targeting agents
Combined RFA and sorafenib was initially demonstrated in animal models to increase volumes of
coagulation with a significant decrease in tumor size after treatment . Since then, few studies have been
[15]
performed that have demonstrated some efficacy of RFA and sorafenib compared to RFA alone. Small
retrospective studies have shown that sorafenib-RFA treatment had a significantly larger ablated area, lower
incidence of recurrence, and better OS after treatment than RFA alone in early to intermediate stage HCC,
barcelona clinic liver cancer (BCLC) 0-B [34,35] . Furthermore, a randomized controlled trial looked at the TTP
and recurrence rate in medium-sized single HCC (3.1-5.0 cm) in hepatitis B virus (HBV) infected patients
treated with sorafenib-RFA and RFA alone. Results showed that the combined group with sorafenib
significantly decreased recurrence rates (56.7% vs. 87.5%) and increased TTP (17 months vs. 6.1 months)
compared to RFA alone. In addition, the combination therapy was relatively safe, and the addition of RFA
[36]
did not increase the risk of adverse effects compared to using sorafenib alone . However, the phase III
STORM trial demonstrated that there was no difference in the median recurrence-free survival between
[37]
adjuvant sorafenib and placebo after response with local ablation . A recent 2021 meta-analysis looking
into physical thermal ablation, including RFA and microwave ablation (MWA), combined with sorafenib
showed that the RFA + sorafenib group showed longer OS at one, two, and three years, lower two-year