Abstract: Liver cancer was the fourth leading cause of cancer death in 2015 with increasing incidence between 1990 and 2015. Orthotopic liver transplantation, surgical resection and ablation comprise the only curative therapy options. However, due to the late manifestation of clinical symptoms, many patients present with intermediate or advanced disease, resulting in no curative treatment option being available. Whereas intermediate-stage hepatocellular carcinoma (HCC) is usually still addressable by transarterial chemoembolization (TACE), advanced-stage HCC is amenable only to pharmacological treatments. Conventional cytotoxic agents failed demonstrating relevant effect on survival also because their use was severely limited by the mostly underlying insufficient liver function. For a decade, tyrosine kinase inhibitor (TKI) sorafenib was the only systemic therapy that proved to have a clinically relevant effect in the treatment of advanced HCC. In recent years, the number of substances for systemic treatment of advanced HCC has increased enormously. In addition to tyrosine kinase inhibitors, immune checkpoint inhibitors (ICI) and antiangiogenic drugs are increasingly being applied. The combination of anti-programmed death ligand 1 (PD-L1) antibody atezolizumab and anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has become the new standard of care for advanced HCC due to its remarkable response rates. This requires more and more complex clinical decisions regarding tumor therapy. This review aims at summarizing recent developments in systemic therapy, considering data on first- and second-line treatment, use in the neoadjuvant and adjuvant setting and combination with locoregional procedures.

Keywords: hepatocellular carcinoma, systemic therapy, checkpoint inhibitors, neoadjuvant treatment, adjuvant treatment


中文翻译：

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肝细胞癌的全身药物：最近的临床试验揭示了关于测序和临床决策的新复杂性的哪些内容？

摘要：肝癌是 2015 年癌症死亡的第四大原因，其发病率在 1990 年至 2015 年间不断增加。原位肝移植、手术切除和消融是唯一的治疗选择。然而，由于临床症状出现较晚，许多患者出现中度或晚期疾病，导致没有有效的治疗选择。中期肝细胞癌 (HCC) 通常仍可以通过经动脉化疗栓塞 (TACE) 来治疗，而晚期 HCC 只能采用药物治疗。传统的细胞毒性药物未能表现出对生存的相关影响，也是因为它们的使用受到大多数潜在的肝功能不足的严重限制。十年来，酪氨酸激酶抑制剂 (TKI) 索拉非尼是唯一被证明在治疗晚期 HCC 方面具有临床相关效果的全身疗法。近年来，用于全身治疗晚期 HCC 的药物数量大幅增加。除了酪氨酸激酶抑制剂外，免疫检查点抑制剂（ICI）和抗血管生成药物的应用也越来越多。抗程序性死亡配体 1 (PD-L1) 抗体阿特珠单抗 (atezolizumab) 和抗血管内皮生长因子 (VEGF) 抗体贝伐珠单抗 (bevacizumab) 的组合因其显着的缓解率而成为晚期 HCC 的新治疗标准。这需要关于肿瘤治疗的越来越复杂的临床决策。本综述旨在总结全身治疗的最新进展，考虑一线和二线治疗的数据、新辅助和辅助治疗的使用以及与局部手术的结合。

关键词:肝细胞癌, 全身治疗, 检查点抑制剂, 新辅助治疗, 辅助治疗