消化道肿瘤免疫相关不良事件的临床分析

目的探讨消化系统恶性肿瘤中免疫检查点抑制剂(immune checkpoint inhibitors, ICIs）导致免疫相关不良事件(immune-related adverse events, irAEs)的特征及危险因素。方法 回顾性分析2019年4月至2021年10月北京大学肿瘤医院诊治的95例接受ICIs治疗的消化系统恶性肿瘤患者的临床资料和irAEs发生情况。irAEs、内分泌irAEs危险因素分析采用二元Logistic回归分析。结果 95例患者共应用ICIs治疗458例次，中位应用3例次(范围：1~33例次）。irAEs的发生率为55.8%，3~4级irAEs发生率为9.5%。最常见的irAEs为皮肤irAEs(27.4%）和内分泌irAEs(22.1%）。内分泌irAEs中甲状腺功能减退最常见(16.8%），肾上腺皮质功能减退(2.1%）和垂体炎(1.1%）少见。多数irAEs发生于免疫治疗初期，78.2%发生于12周内。过敏反应、皮肤irAEs最早发生，中位发生时间分别为2周(范围：0.9～3.1周）和3.8周(范围：0.9～17.9周），内分泌irAEs中位发生时间为6.9周(范围：3.0～52.1周）。多因素分析显示，女性(OR=5.197, 95%CI：1.166～23.154, P=0.031)和微卫星高度不稳定(microsatellite instability-high，MSI-H） (OR=35.048, 95%CI：2.756～445.787, P=0.006)是内分泌irAEs发生风险增加的独立危险因素，免疫治疗联合化学药物治疗(OR=0.107, 95%CI：0.021～0.412, P=0.001）是内分泌irAEs的独立保护性因素。结论在消化系统恶性肿瘤中应用ICIs具有较好的安全性。女性和MSI-H患者出现内分泌irAEs风险增加，联合化学药物治疗可能降低内分泌irAEs发生风险。

Clinical analysis of immune-related adverse events in gastrointestinal cancer

Objective To identify the characteristics and risk factors associated with immune-related adverse events (irAEs) in gastrointestinal cancer patients treated with immune checkpoint inhibitors (ICIs). Methods We retrospectively investigated clinical data of 95 gastrointestinal cancer patients from April 2019 to October 2021 in Peking University Cancer Hospital. The clinical characteristics and irAEs data of these patients were analyzed. Binary Logistic regression analysis was used to identify irAEs and endocrine irAEs risk factors. Results In the 95 patients enrolled, the total number and median number of ICIs treatment cycles were 458 and 3(range:1-33). The incidence of irAEs and grade 3-4 irAEs were 55.8% and 9.5%, respectively. The most common irAEs were skin irAEs (27.4%) and endocrine irAEs (22.1%). Among endocrine irAEs, hypothyroidism occurred most frequently (16.8%), while adrenocortical dysfunction (2.1%) and hypophysitis (1.1%) were rare. Most irAEs occurred in the early stage of immunotherapy, and 78.2% occurred within 12 weeks. The earlier onset irAEs were allergy and skin irAEs, with a median occurrence time of 2 weeks (range:0.9－3.1 weeks) and 3.8 weeks (range:0.9－17.9 weeks), respectively. The median onset time of endocrine irAEs was 6.9 weeks (range:3.0－52.1 weeks). Multivariate analysis revealed that female(OR=5.197,95%CI：1.166－23.154,P=0.031） and microsatellite instability-high (MSI-H）(OR=35.048, 95%CI：2.756－445.787, P=0.006）were independent risk factors of endocrine irAEs. Immunotherapy combined with chemotherapy (OR=0.107, 95%CI：0.021－0.412, P=0.001） was an independent protective factors. Conclusion The application of ICIs in patients with gastrointestinal cancer was well tolerated. Female and MSI-H patients have an increased risk of endocrine irAEs. Immunotherapy combined with chemotherapy may reduce the risk of endocrine irAEs.