Kawamura Etsushi, Matsubara Tsutomu, Kawada Norifumi
Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan.
Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka 545-8585, Japan.
Cancers (Basel). 2023 Aug 6;15(15):3993. doi: 10.3390/cancers15153993.
Intrahepatic cholangiocarcinoma (CC) accounts for approximately 20% of all biliary tract cancer (BTC) cases and 10-15% of all primary liver cancer cases. Many patients are diagnosed with unresectable BTC, and, even among patients with resectable BTC, the 5-year survival rate is approximately 20%. The BTC incidence rate is high in Southeast and East Asia and has increased worldwide in recent years. Since 2010, cytotoxic chemotherapy, particularly combination gemcitabine + cisplatin (ABC-02 trial), has been the first-line therapy for patients with BTC. In 2022, a multicenter, double-blind, randomized phase 3 trial (TOPAZ-1 trial) examined the addition of programmed death-ligand 1 immunotherapy (durvalumab) to combination gemcitabine + cisplatin for BTC treatment, resulting in significantly improved survival without notable additional toxicity. As a result of this trial, this three-drug combination has become the new standard first-line therapy, leading to notable advances in BTC management for the first time since 2010. The molecular profiling of BTC has continued to drive the development of new targeted therapies for use when first-line therapies fail. Typically, second-line therapy decisions are based on identified genomic alterations in tumor tissue. Mutations in fibroblast growth factor receptor 1/2/3, isocitrate dehydrogenase 1/2, and neurotrophic tyrosine receptor kinase A/B/C are relatively frequent in intrahepatic CC, and precision medicines are available that can target associated pathways. In this review, we suggest strategies for systemic pharmacotherapy with a focus on intrahepatic CC, in addition to presenting the results and safety outcomes of clinical trials evaluating immune checkpoint inhibitor therapies in BTC.
肝内胆管癌（CC）约占所有胆道癌（BTC）病例的20%，占所有原发性肝癌病例的10 - 15%。许多患者被诊断为不可切除的BTC，即使在可切除的BTC患者中，5年生存率也约为20%。BTC的发病率在东南亚和东亚地区较高，近年来在全球范围内呈上升趋势。自2010年以来，细胞毒性化疗，特别是吉西他滨 + 顺铂联合化疗（ABC - 02试验），一直是BTC患者的一线治疗方法。2022年，一项多中心、双盲、随机3期试验（TOPAZ - 1试验）研究了在吉西他滨 + 顺铂联合化疗中加入程序性死亡配体1免疫疗法（度伐利尤单抗）用于BTC治疗，结果显示生存率显著提高且无明显额外毒性。由于这项试验，这种三药联合疗法已成为新的标准一线治疗方法，自2010年以来首次在BTC治疗方面取得了显著进展。BTC的分子特征分析持续推动着一线治疗失败时使用的新靶向疗法的发展。通常，二线治疗决策基于肿瘤组织中已确定的基因组改变。成纤维细胞生长因子受体1/2/3、异柠檬酸脱氢酶1/2和神经营养酪氨酸受体激酶A/B/C的突变在肝内胆管癌中相对常见，并且有可靶向相关通路的精准药物。在本综述中，我们除了介绍评估BTC免疫检查点抑制剂疗法的临床试验结果和安全性结果外，还建议了以肝内胆管癌为重点的全身药物治疗策略。
