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Mathias-Machado et al. Hepatoma Res 2021;7:67 https://dx.doi.org/10.20517/2394-5079.2021.84 Page 5 of 12

In addition to sorafenib, other agents are approved for the treatment of advanced stage disease. Lenvatinib
[16]
was shown to be non-inferior to sorafenib in a phase III trial . Cabozantinib, regorafenib, and
ramucirumab demonstrated improved overall survival over placebo in sorafenib-experienced patients with
[17]
advanced HCC . The successes with drugs in advanced-stage disease often prime studies focused on the
translation into early stages of the disease in the neoadjuvant and adjuvant settings. However, after the
negative results of the STORM trial, none of these drugs have been evaluated in patients after resection or
ablation.

Chemotherapy and radiotherapy
The use of cytotoxic chemotherapy such as capecitabine or tegafur/uracil has been studied in the adjuvant
[18]
setting for HCC patients, but no robust results have been reported yet . Accordingly, the use of external
radiation therapy has not shown significant benefit in the post-resection setting. Controversial data indicate
a potential benefit from the use of intra-arterial injection of iodine-131, but more data are need in such
modalities .
[19]
Adjuvant immunotherapy
The biological background for the use of immunotherapy in HCC is based on the fact that the liver is an
organ with a remarkable immunotolerance due to the high antigenic load derived from the enteral-portal
circulation. Additionally, HCC develops in a microenvironment of chronic inflammation and underlying
liver disease. Low infiltration of CD8+ T lymphocytes, responsible for the antitumor immune response, and
a marked presence of exhausted lymphocytes and regulatory T lymphocytes are described in HCC,
contributing to an immunosuppressive and procarcinogenic microenvironment .
[8]

The HCC microenvironment is thought to play a key role in determining the risk of recurrence. A high
composite score incorporating density of CD8+, CD3+ T cells was associated with a reduced risk of
[20]
recurrence . In addition, trafficking of activated lymphocytes into the tumor is regulated by VEGF . Gene
[21]
sequencing can also be a tool to predict response to systemic treatment, such as immunotherapy and
VEGFR-directed TKIs. Translational studies with a limited number of patients suggested that CTNNB1
mutations seem to be associated with resistance to immunotherapy, while mutations in PI3K/mTOR
pathway seems to indicate resistance to TKIs .
[22]
In animal breast cancer models, local treatments such as surgery can modify tumor microenvironment
towards immunosuppression, which can subsequently promote tumor proliferation and metastasis.
Similarly, ablation can induce tumor antigen release and stimulate inflammatory and cytokine production
within the treated site. Therefore, the rationale of adding immunotherapy post local treatments is warranted
[23]
in HCC .

Immunotherapy consists of different modalities that comprehend the use of tumor peptide-based vaccines,
cell therapies (CART and TCR), cytokines-induced killer cells, and immune checkpoint inhibitors (anti-
PD1, anti-PDL1, and anti-CTLA4).

Regarding adjuvant treatment post-resection or ablation, there are few published studies and a growing
number of ongoing studies.

Cytokine-induced killer cells consist of patient-harvested immune cells that are expanded ex vivo using
cytokines cultures (interleukin-2) and anti-CD3 antibodies, resulting in a cell population with strong
antitumor immune activity.