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World J Gastroenterol. Jul 28, 2022; 28(28): 3573-3585
Published online Jul 28, 2022. doi: 10.3748/wjg.v28.i28.3573
Combination approaches in hepatocellular carcinoma: How systemic treatment can benefit candidates to locoregional modalities
Leonardo Gomes da Fonseca, Raphael L C Araujo
Leonardo Gomes da Fonseca, Department of Medical Oncology, Instituto do Cancer do Estado de Sao Paulo, University of Sao Paulo, São Paulo 01246-000, São Paulo, Brazil
Leonardo Gomes da Fonseca, Raphael L C Araujo, Hospital e Maternidade Brasil - Rede D'Or São Luiz, Santo André 09030-590, São Paulo, Brazil
Raphael L C Araujo, Department of Digestive Surgery, Escola Paulista de Medicina - UNIFESP, São Paulo 04023-062, São Paulo, Brazil
Author contributions: Both authors performed the writing and prepared the figures and tables; Both authors designed the outline and coordinated the writing of the paper.
Conflict-of-interest statement: All authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Noncommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Raphael L C Araujo, MD, PhD, Adjunct Professor, Surgical Oncologist, Department of Digestive Surgery, Escola Paulista de Medicina - UNIFESP, Rua Botucatu, 740, Vila Clementino, São Paulo 04023-062, São Paulo, Brazil.
Received: January 17, 2022
Peer-review started: January 17, 2022
First decision: April 11, 2022
Revised: April 19, 2022
Accepted: June 26, 2022
Article in press: June 26, 2022
Published online: July 28, 2022

The management of hepatocellular carcinoma (HCC) is challenging because most patients have underlying cirrhosis, and the treatment provides, historically, a limited impact on the natural history of patients with advanced-stage disease. Additionally, recurrence rates are high for those patients who receive local and locoregional modalities, such as surgical (resection and transplantation) or image-guided (ablation and intra-arterial) therapies. Translational research has led to new concepts that are reshaping the current clinical practice. Substantial advancements were achieved in the understanding of the hallmarks that drive hepatocarcinogenesis. This has primed a successful incorporation of novel agents with different targets, such as anti-angiogenic drugs, targeted-therapies, and immune-checkpoint inhibitors. Although clinical trials have proven efficacy of systemic agents in advanced stage disease, there is no conclusive evidence to support their use in combination with loco-regional therapy. While novel local modalities are being incorporated (e.g., radioembolization, microwave ablation, and irreversible electroporation), emerging data indicate that locoregional treatments may induce tumor microenvironment changes, such as hyperexpression of growth factors, release of tumor antigens, infiltration of cytotoxic lymphocytes, and modulation of adaptative and innate immune response. Past trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial improvement. Current efforts are directed to investigate the role of immunotherapy-based regimens in this context. The present review aims to describe the current landscape of systemic and locoregional treatments for HCC, present evidence to support combination approaches, and address future perspectives.

Keywords: Liver cancer, Hepatocellular carcinoma, Immunotherapy, Systemic therapy, Ablation, Embolization

Core Tip: Management of hepatocellular carcinoma (HCC) is based on stages defined by tumor burden, liver function, and performance status. With the advent of more effective systemic treatments, such as immunotherapy and immunotherapy-based combinations, patients with advanced stage disease have better outcomes. The migration of systemic treatment to earlier stages, in combination with locoregional therapies, are expected to improve the outcomes and cure rates. Currently, the research field is moving towards an increasing interest in combining locoregional and systemic treatments for HCC.