不可切除的肝门部胆管癌的治疗进展

Advances in treatment of unresectable hilar cholangiocarcinoma

摘要:

肝门部胆管癌（hCCA）是位于二级肝管与胆囊管开口之间的胆管上皮起源的恶性肿瘤，又称为Klatskin瘤。手术是hCCA唯一潜在的治愈性方法。切缘性质是行切除手术的患者获得长期生存最关键的因素，而作为胆管癌最常见的亚型，hCCA的病理学类型多为低-中分化腺癌，侵袭能力强，恶性程度高，早期症状不明显且无有效的检出手段，所以多数患者在诊断时已处于疾病晚期，丧失手术指征。虽然新辅助放化疗联合原位肝移植已经被证实是部分局部晚期不可切除的hCCA的有效治疗方式，但纳入标准严格，肝源短缺，部分患者在等待肝源的期间肿瘤进展，失去移植条件，因此该治疗方式无法成为大多数患者的治疗方案。传统的放化疗虽然在一定程度上延长了不可切除hCCA患者的生存时间，但其治疗效果始终有限。有研究表明新辅助放化疗能够将部分不可切除的hCCA降期为可切除，提高R₀切除率，但相关数据较少且陈旧，缺乏可信度。随着科技的进步，包括立体定向放疗、三维适行放疗、放射粒子植入等在内的新型放疗技术和光动力疗法的出现，hCCA的局部治疗进入了更加精准的时代。近年来，随着基因检测的发展和对肿瘤微环境的深入研究，在分子生物学层面抑制肿瘤进展是各种实体肿瘤研究的热门方向，针对不同靶点的靶向药物、免疫检查点抑制剂（PD1/PD-L1抗体、CTLA4抗体）层出不穷，并取得了突飞猛进的进展，为不可切除的hCCA的治疗提供了新的方向。但就目前的研究来看，靶向治疗、免疫治疗虽然在肝内胆管癌的治疗中取得了相当不错的成绩，但是在hCCA治疗中的表现仍令人不满意。不可切除的hCCA的单一治疗效果较差，多种治疗方式联合治疗是当前研究的重点。本文主要综述不可切除的hCCA的治疗进展及新辅助治疗在实现R₀切除方面的可行性，旨在为此类患者的治疗提供一定的参考。

Abstract:

Hilar cholangiocarcinoma (hCCA), also known as Klatskin tumor, is a malignant tumor that originates from the biliary epithelium between the secondary hepatic duct and the opening of the cystic duct. Surgery is the only potentially curative treatment for hCCA. The nature of the surgical margins is the most critical factor in the long-term survival of patients undergoing resection. However, as the most common subtype of cholangiocarcinoma, the pathological type of hCCA is mostly low to moderately differentiated adenocarcinoma, which is highly invasive and malignant, with no obvious early symptoms and no effective means of detection, so most patients are already at an advanced stage of the disease at the time of diagnosis and have lost the indication for surgery. Although neoadjuvant chemoradiotherapy combined with in orthotopic liver transplantation has been demonstrated to be an effective treatment modality for some locally advanced unresectable hCCA, it cannot become a treatment option for most patients because of the strict inclusion criteria, shortage of liver sources, and loss of transplantation condition in some patients due to tumor progression while waiting for liver sources. Although conventional chemoradiotherapy prolongs the survival time of patients with unresectable hCCA to some extent, its efficacy remains limited. Some researches have indicated that neoadjuvant chemoradiotherapy can downgrade a previously unresectable hCCA into a resectable one and improve the R₀ resection rate, but it lacks credibility because of the limited amount and obsolescence of the relevant data. With the advancement of technology, photodynamic therapy and new radiotherapy techniques including stereotactic radiotherapy, three-dimensional conformal radiotherapy and radioactive particle implantation have emerged, local treatment of hCCA has entered a more precise era. In recent years, with the development of genetic testing and in-depth research on tumor microenvironment, inhibiting tumor progression at the molecular biology level is a popular direction for research on various solid tumors. Targeted drugs for different targets and immune checkpoint inhibitors (PD1/PD-L1 antibodies, CTLA4 antibodies) have emerged and made rapid progress, providing a new direction for the treatment of unresectable hCCA. However, as far as the current research is concerned, although targeted therapy and immunotherapy have achieved excellent results in the treatment of intrahepatic cholangiocarcinoma, their performance in the treatment of hCCA is still unsatisfactory. A single treatment of unresectable hCCA is less effective, the combination of multiple treatment modalities is the focus of current research. This article mainly addresses the progress in the treatment unresectable hCCA and the feasibility of neoadjuvant therapy in achieving R₀ resection, hoping to provide some reference for the treatment of such patients.