Combining local regional therapy and systemic therapy: Expected changes in the treatment landscape of recurrent hepatocellular carcinoma

Abstract

Improvements in early screening, new diagnostic techniques, and surgical treatment have led to continuous downward trends in hepatocellular carcinoma (HCC) morbidity and mortality rates. However, high recurrence and refractory cancer after hepatectomy remain important factors affecting the long-term prognosis of HCC. The clinical characteristics and prognosis of recurrent HCC are heterogeneous, and guidelines on treatment strategies for recurrent HCC are lacking. Therapies such as surgical resection, radiofrequency ablation, and transhepatic arterial chemoembolization are effective for tumors confined to the liver, and targeted therapy is a very important treatment for unresectable recurrent HCC with systemic metastasis. With the deepening of the understanding of the immune microenvironment of HCC, blocking immune checkpoints to enhance the antitumor immune response has become a new direction for the treatment of HCC. In addition, improvements in the tumor immune microenvironment caused by local treatment may provide an opportunity to improve the therapeutic effect of HCC treatment. Ongoing and future clinical trial data of combined therapy may develop the new treatment scheme for recurrent HCC. This paper reviews the pattern of recurrent HCC and the characteristics of the immune microenvironment, demonstrates the basis for combining local treatment and systemic treatment, and reports current evidence to better understand current progress and future approaches in the treatment of recurrent HCC.

Keywords: Immune checkpoint inhibitors; Local regional therapy; Recurrence type; Recurrent hepatocellular carcinoma; Systemic therapy; Tumor microenvironment.

Figure 1

Complementary effects of local therapy combined with systemic therapy in recurrent hepatocellular carcinoma. Local therapies, including surgery, transhepatic arterial chemoembolization (TACE), ablation, hepatic artery infusion chemotherapy (HAIC), stereotactic body radiotherapy (SBRT), are targeted-hepatocellular carcinoma (HCC) to reduce tumor load. Systematic therapy represented by tyrosine kinase inhibitor, vascular endothelial growth factor (VEGF) inhibitor, anti-cytotoxic T lymphocyte-associated protein 4 inhibitor; programmed cell death protein-1/programmed cell death ligand-1 inhibitor is mainly aimed at improving tumor microenvironment. VEGF inhibitor can reduce hypoxia induced angiogenesis after TACE. Local ablation, HAIC and SBRT can promote or regulate the release of tumor antigens and enhance the response of immunotherapy. The combination of local therapy and systematic therapy is expected to improve the outcome of recurrent HCC. rHCC: Recurrent hepatocellular carcinoma; TACE: Transhepatic arterial chemoembolization; SBRT: Stereotactic body radiotherapy; HAIC: Hepatic artery infusion chemotherapy; TKI: Tyrosine kinase inhibitor; VEGF: Vascular endothelial growth factor; CTLA4: Anti-cytotoxic T lymphocyte-associated protein 4; PD-1: Programmed cell death protein-1; PDL-1: Programmed cell death ligand-1; TME: Tumor microenvironment.