Abstract: The last three years have seen remarkable progress in comprehending predisposing factors and upgrading our treatment arsenal concerning hepatocellular carcinoma (HCC). Until recently, there were no means to withstand the progression of viral hepatitis-associated liver cirrhosis to HCC. A deeper understanding of the molecular mechanism of the disease, the use of biomarkers, and the follow-up, allowed us to realize that conventional chemotherapy failing to increase survival in patients with advanced HCC tends to be exiled from clinical practice. Multi-kinase inhibitors (TKIs) such as sorafenib, lenvatinib targeting mainly the vascular endothelial growth factor receptors 1– 3 VEGFRs 1– 3 provided until recently the standard of care for these patients, as first- or second-line treatment. Since May 2020, the atezolizumab plus bevacizumab combination (immunotherapy plus anti-VEGF) has become the new reference standard in first-line HCC treatment. Additionally, anti-programmed cell death protein 1 (anti-PD-1) immunotherapy can be used as a second-line treatment following first-line treatment’s failure. Phase III clinical trials have recently suggested the efficacy of novel anti-angiogenic factors such as cabozantinib and ramucirumab as a second-line treatment option. With considerations about toxicity arising, clinical trials are investigating combinations of the aforementioned targeted therapies with immunotherapy as first-line treatment. This paper aims to perform a systematic review describing the evolving treatment options for HCC over the last decades, ranging from neoadjuvant treatment to systemic therapy of advanced-stage HCC. With the landscape of HCC treatment shifting towards novel agents the forming of a new therapeutic algorithm for HCC seems to be imperative.

Keywords: hepatocellular carcinoma, immunotherapy, targeted therapy, tyrosine kinase inhibitors, biomarkers

中文翻译：

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肝细胞癌：治疗选择的格局变化概述

摘要：在过去的三年中，在理解诱发因素和提升我们关于肝细胞癌（HCC）的治疗手段方面取得了显着进展。直到最近，还没有任何方法可以抵抗病毒性肝炎相关性肝硬化向肝癌的发展。对疾病的分子机制，生物标志物的使用以及后续措施的更深入了解，使我们认识到，常规化疗未能增加晚期HCC患者的生存率，往往会被临床实践所淘汰。多激酶抑制剂（TKI），例如索拉非尼，兰瓦替尼，主要靶向血管内皮生长因子受体1–3 VEGFR 1–3，直到最近才为这些患者提供一线或二线治疗的标准治疗。自2020年5月以来，Atezolizumab联合贝伐单抗联合（免疫疗法加抗VEGF）已成为一线HCC治疗的新参考标准。此外，在一线治疗失败后，抗程序性细胞死亡蛋白1（anti-PD-1）免疫疗法可以用作二线治疗。III期临床试验最近表明，新型抗血管生成因子（例如卡博替尼和雷莫昔单抗）可作为二线治疗选择。考虑到毒性的产生，临床试验正在研究上述靶向疗法与免疫疗法作为一线治疗的组合。本文旨在进行系统的回顾，描述过去几十年中从新辅助治疗到晚期肝癌全身治疗的不断发展的肝癌治疗选择。

关键词：肝细胞癌，免疫治疗，靶向治疗，酪氨酸激酶抑制剂，生物标志物