da Motta Girardi Daniel, Correa Tatiana Strava, Crosara Teixeira Marcela, Dos Santos Fernandes Gustavo
Division of Medical Oncology, Hospital Sírio-Libanês, SGAS 613 conj E Bl B, Brasilia, DF, 70200730, Brazil.
J Gastrointest Cancer. 2018 Sep;49(3):227-236. doi: 10.1007/s12029-018-0121-4.
Hepatocellular carcinoma is the fifth most common cancer globally and the second leading cause of cancer-related mortality worldwide. Despite the established efficacy of screening programs for at-risk individuals, most patients are diagnosed at later stages of disease, wherein the tumor characteristics or liver disease progressions do not allow for curative interventions. Many cytotoxic chemotherapeutic agents have been tested in patients with advanced disease with disappointing outcomes and poor tolerance; therefore, no standard systemic therapy emerged until the approval of sorafenib in 2006.
Despite the toxicity and low response rate, sorafenib had shown a significant survival benefit in phase III clinical trials, thus encouraging clinical research aimed at advancing the field of molecular therapy. Disrupted signaling pathways related to hepatocellular carcinoma (HCC) include the Wnt/β-catenin, Ras/Raf/MAPK, phosphatidyl inositol 3-kinase/Akt/mechanistic target of rapamycin, hepatocyte growth factor/c-mesenchymal-epithelial transition, IGF, vascular endothelial growth factor, and platelet-derived growth factor pathways, and a variety of agents targeting these pathways are currently under investigation. Additionally, better comprehension of the complex mechanisms underlying the ability of tumor cells to escape immune surveillance has led to impressive results with immunotherapy in many types of cancer, and this treatment strategy is currently being developed for HCC patients. Previous and ongoing targeted therapy and immunotherapy trials for HCC are discussed in this review.
肝细胞癌是全球第五大常见癌症，也是全球癌症相关死亡的第二大主要原因。尽管针对高危个体的筛查项目已证实有效，但大多数患者在疾病晚期才被诊断出来，此时肿瘤特征或肝脏疾病进展已不允许进行根治性干预。许多细胞毒性化疗药物已在晚期疾病患者中进行了测试，结果令人失望，耐受性也很差；因此，在2006年索拉非尼获批之前，没有出现标准的全身治疗方法。
尽管索拉非尼存在毒性且缓解率较低，但在III期临床试验中已显示出显著的生存获益，从而鼓励了旨在推动分子治疗领域发展的临床研究。与肝细胞癌（HCC）相关的信号通路紊乱包括Wnt/β-连环蛋白、Ras/Raf/MAPK、磷脂酰肌醇3-激酶/Akt/雷帕霉素作用靶点、肝细胞生长因子/c-间充质-上皮转化、胰岛素样生长因子、血管内皮生长因子和血小板衍生生长因子通路，目前正在研究多种针对这些通路的药物。此外，对肿瘤细胞逃避免疫监视能力背后复杂机制的更好理解已在许多类型癌症的免疫治疗中取得了令人瞩目的成果，目前正在为HCC患者开发这种治疗策略。本综述讨论了既往和正在进行的针对HCC的靶向治疗和免疫治疗试验。
