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Review
. 2021 Apr 13:8:635243.
doi: 10.3389/fmolb.2021.635243. eCollection 2021.

Locoregional Combined With Systemic Therapies for Advanced Hepatocellular Carcinoma: An Inevitable Trend of Rapid Development

Xin Li  1 , Yaxi Wang  1   2 , Xin Ye  3 , Ping Liang  1
Affiliations
Review

Locoregional Combined With Systemic Therapies for Advanced Hepatocellular Carcinoma: An Inevitable Trend of Rapid Development

Xin Li et al. Front Mol Biosci. .

Abstract

Despite the application of antiviral drugs and improved surveillance tools, the number of patients diagnosed with hepatocellular carcinoma (HCC) at an advanced stage and with a dismal prognosis is still on the rise. Systemic treatment with multiple multitargeted tyrosine kinase inhibitors (TKIs), such as sorafenib, has been a widely utilized approach for a decade. In addition, the use of a combination of TKIs with other types of compounds, including immune checkpoint inhibitors (ICIs) and antiangiogenic inhibitors, has shown efficacy in treating advanced HCC. However, the presence of intolerable adverse events, low disease response and control rates, and relative short overall survival of such combinatory therapies makes novel or optimized therapies for advance HCC urgently needed. Locoregional therapy (transarterial chemoembolization, and thermal ablation) can destroy primary tumors and decrease tumor burden and is widely used for HCC management. This type of treatment modality can result in local hypoxia and increased vascular permeability, inducing immunogenic effects by releasing tumor antigens from dying cancer cells and producing damage-associated molecular patterns that facilitate antiangiogenic therapy and antitumor immunity. The combination of systemic and locoregional therapies may further produce synergistic effects without overlapping toxicity that can improve prognoses for advanced HCC. In preliminary studies, several combinations of therapeutic modes exhibited promising levels of safety, feasibility, and antitumor effects in a clinical setting and have, thus, garnered much attention. This review aims to provide a comprehensive, up-to-date overview of the underlying mechanisms of combined systemic and locoregional therapies in the treatment of advanced HCC, commenting on both their current status and future direction.

Keywords: hepatocellular carcinoma; immune checkpoint inhibitors; thermal ablation; transarterial chemoembolization; tyrosine kinase inhibitors.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Combination therapies for the treatment of advanced hepatocellular carcinoma. Multitreatment modalities were used for managing tumor progress, and the detailed procedures are also described as follows: First, for the purpose of tumor burden reduction, the cancerous blood supply was obstructed using transcatheter arterial chemoembolization (TACE). Then, microwave ablation will further promote the tumor destruction in a manner of inducing an irreversible heat injury. Third, due to the necrosis and apoptosis of cancer cells, tumor-associated antigens (TAAs) and some cytokines such as VEGF, HIF, and FGF will be released into circulation, following an acute antitumor immune reaction and proangiogenic effects, respectively. Finally, immune checkpoint inhibitors (anti-PD1 mAb and anti-CTLA4 mAb) were used in order to remove the inhibition of antitumor effects and enhance the tumor-killing ability of CTLs. Moreover, antiangiogenesis therapy restrains the formation of blood vessels and leads to vascular normalization, which, in turn, synergically increases the infiltrated frequency of CTLs in tumor lesions.
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