胆道恶性肿瘤免疫相关不良事件的预防与处理

doi:10.16139/j.1007-9610.2025.02.04

摘要/Abstract

摘要：

免疫检查点抑制剂（ICIs）联合化疗已成为晚期胆道恶性肿瘤（BTC）的一线标准治疗方案。然而，ICIs的应用伴随着独特的免疫相关不良事件（irAEs）风险。BTC病人由于常伴有基础肝功能异常、胆道梗阻等特殊情况，其irAEs的诊断和管理面临更大挑战，特别是免疫相关性肝炎的鉴别诊断。本文旨在系统综述BTC免疫治疗的现状、irAEs的发生谱系、临床特点、预防策略以及管理原则，重点探讨BTC病人irAEs管理的特殊性及应对措施，以优化BTC病人的免疫治疗管理，最大化治疗获益并保障病人安全，并展望未来的研究方向。

关键词: 胆道恶性肿瘤, 免疫治疗, 免疫检查点抑制剂, 免疫相关不良事件

Abstract:

Immune checkpoint inhibitors (ICIs) combined with chemotherapy has become the first-line standard treatment for advanced biliary tract cancers (BTC). However, the application of ICIs comes with its risks of immune-related adverse events (irAEs). BTC patients often face greater challenges in the diagnosis and management of irAEs, especially in the differential diagnosis of immune related hepatitis, due to the presence of special conditions such as underlying liver dysfunction and biliary obstruction. We aimed to systematically review the current status of BTC immunotherapy, the spectrum of irAEs, clinical characteristics, prevention strategies, and management principles. We focused to investigate the specificity and response measures of irAEs management in BTC patients, optimizing immunotherapy management for BTC patients, maximizing treatment benefits and ensuring patient safety, and exploring the future research directions.

Key words: Biliary tract cancer(BTC), Immunotherapy, Immune checkpoint inhibitor(ICI), Immune-related adverse event(irAE)

中图分类号:

R735.8

刘坤, 郭伟. 胆道恶性肿瘤免疫相关不良事件的预防与处理[J]. 外科理论与实践, 2025, 30(2): 112-119.

LIU Kun, GUO Wei. Prevention and management of immune-related adverse events for biliary tract cancers[J]. Journal of Surgery Concepts & Practice, 2025, 30(2): 112-119.

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试验名称	治疗线	治疗方案	对照组	主要终点	结果 (中位OS期)	TRAEs (≥G3) 发生率 (联合治疗组)
TOPAZ-1^[5]	一线	Durvalumab + GemCis	Placebo + GemCis	OS	12.8个月比 11.5 个月 (HR=0.80, P=0.021)	12.8%
KEYNOTE^[6]-966	一线	Pembrolizumab + GemCis	Placebo + GemCis	OS	12.7个月比 10.9 个月 (HR=0.83, P=0.0034)	15.1%
KEYNOTE-158^[8]	后线	Pembrolizumab (MSI-H/dMMR)	-	ORR	ORR 40.9% (BTC队列)	12.9% (总体人群)
KEYNOTE-028^[13]	后线	Pembrolizumab (PD-L1+)	-	ORR	ORR 17% (胆道癌队列)	17% (胆管癌队列)
CA209-538^[14]	后线	Nivolumab+ Ipilimumab	-	ORR	ORR 23% (Ⅱ期研究)	15%

irAEs 类型	G1级处理	G2级处理	G3~G4级处理	G5级处理
皮肤 (皮疹)	对症 (外用激素/抗组胺)	暂停ICI + 口服激素[泼尼松0.5~1 mg/(kg·d)] + 对症	永久停ICI + 高剂量激素[泼尼松1~2 mg/(kg·d)] ± 住院 ± 免疫抑制剂 (若激素无效)	死亡
胃肠 (腹泻/结肠炎)	对症 (止泻/补液)	暂停ICI + 口服激素[泼尼松0.5~1 mg/(kg·d)] + 对症	永久停ICI + 高剂量激素[(泼尼松1~2 mg/(kg·d)] + 住院 + 排除感染 + 英夫利昔单抗(若激素无效)	死亡
肝脏 (肝炎)	继续ICI + 加强监测	暂停ICI + 口服激素[泼尼松0.5~1 mg/(kg·d)] (若持续/恶化)	永久停ICI + 高剂量激素 [(泼尼松1~2 mg/(kg·d)] + 住院 + 吗替麦考酚酯(若激素无效)	死亡
内分泌 (甲状腺功能异常/垂体炎/肾上腺功能异常)	监测 + 对症(激素替代)	暂停/继续ICI + 激素替代治疗 ± 咨询内分泌科	永久/暂停ICI + 高剂量激素 (仅限垂体/肾上腺危象) + 激素替代 + 咨询内分泌科	死亡
肺 (肺炎)	监测(若无症状) / 对症治疗	暂停ICI + 口服/静脉激素[泼尼松1 mg/(kg·d)] ± 住院 ± 排除感染	永久停ICI + 高剂量激素[泼尼松1~2 mg/(kg·d)] + 住院 + 排除感染 + 广谱抗生素 ± 英夫利昔单抗/吗替麦考酚酯 (若激素无效)	死亡

肝损伤原因	关键鉴别点	辅助检查
IMH	通常无症状；ALT/AST升高为主；与ICI用药时间相关；排除性诊断	肝功能动态监测；病毒/自身抗体阴性；影像学无明确梗阻/进展；肝活检
肿瘤进展	肝内转移灶增大/新发；胆道梗阻加重；肿瘤标志物升高	CT/MRI/PET-CT；肿瘤标志物 (CA19-9, CEA)
胆道梗阻/感染	黄疸、腹痛、发热；胆红素、ALP、GGT升高明显；白细胞/CRP升高	腹部B超/CT/MRCP；血常规；感染指标；胆汁培养
化疗肝损伤 (GemCis)	ALT/AST升高，通常轻中度，与化疗周期相关；停药后可恢复	肝功能监测
病毒性肝炎	HBV DNA/HCV RNA阳性；相应抗原/抗体阳性	乙肝/丙肝标志物检测
其他药物/酒精	详细用药史/饮酒史	停用可疑药物/戒酒后观察
自身免疫性肝病	相关自身抗体阳性 (ANA、ASMA、抗LKM抗体等)；IgG升高	自身免疫性肝病抗体谱；免疫球蛋白定量