[Analysis on the incidence and perioperative outcomes of immune-related adverse events in preoperative immunotherapy for colorectal cancer based on multicenter real-world data].

Objective: To investigate the incidence of immune-related adverse events (irAEs) and corresponding perioperative outcomes among patients with colorectal cancer who received neoadjuvant immunotherapy and underwent curative radical resection. Methods: This was a retrospective, multicenter, real-world cohort study. A total of 452 patients with pathologically confirmed colorectal adenocarcinoma who completed neoadjuvant immunotherapy and curative radical surgery were enrolled from five tertiary hospitals between January 1, 2020 and December 31, 2024. The participating institutions included Beijing Friendship Hospital, Capital Medical University; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; The Sixth Affiliated Hospital, Sun Yat-sen University; The First Affiliated Hospital of Nanchang University; and The Second Affiliated Hospital, Zhejiang University. The median age of the overall cohort was 58.5 years.

In terms of clinical TNM staging, 86 patients (19.0%) were at stage Ⅱ and 366 (81.0%) were at stage Ⅲ. Based on MMR/MSI status, 116 patients (25.7%) were identified as deficient mismatch repair/high microsatellite instability (dMMR/MSI-H), and the remaining 336 (74.3%) as proficient mismatch repair/microsatellite stable (pMMR/MSS). Regarding treatment modalities, 92 patients (20.4%) received single-agent immune checkpoint inhibitor (ICI) therapy, 22 (4.9%) dual ICI combination therapy, 30 (6.6%) immunotherapy combined with chemotherapy, and 308 (68.1%) immunotherapy combined with chemoradiotherapy. All irAEs were graded in accordance with the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0), and grade ≥3 irAEs were defined as severe irAEs.

The primary outcomes were the overall incidence and organ-specific distribution of irAEs. Secondary outcomes covered irAE risks stratified by treatment regimens and MMR/MSI status, overall pathological complete response (pCR) rate, as well as perioperative clinical outcomes.

Temporal trend analysis was conducted after logical validation of the initial onset time of irAEs. Results: The overall incidence of all-grade irAEs reached 24.6% (111/452), including 73 cases (16.2%) of grade 1, 24 (5.3%) of grade 2, 7 (1.5%) of grade 3, 5(1.1%) of grade 4 and 2 (0.4%) of grade 5. Severe irAEs (grade ≥3) occurred in 14 patients, accounting for 3.1% of the total cohort. A total of 157 irAE episodes were documented, among which single-organ involvement was observed in 65 patients (58.6%) and multi-organ involvement in 46 patients (41.4%). The most frequently affected organ systems were skin and mucous membranes (40 episodes, 25.5%), endocrine and thyroid system (36 episodes, 22.9%), hematopoietic system (34 episodes, 21.7%), hepatobiliary system (21 episodes, 13.4%), and gastrointestinal tract (9 episodes, 5.7%).

Other involved systems comprised musculoskeletal system (6 episodes, 3.8%), urinary and renal system (6 episodes, 3.8%), cardiovascular system (4 episodes, 2.5%), and general systemic reactions (1 episode, 0.6%). One fatal grade 5 event consisting of fulminant myocarditis complicated with malignant arrhythmia and liver failure was recorded. Stratified by treatment strategy, the incidence of all-grade irAEs was 23.9% (22/92) for single-agent ICI, 27.3% (6/22) for dual ICI combination, 23.3% (7/30) for immunochemotherapy and 24.7% (76/308) for immunochemoradiotherapy; the corresponding incidence of severe irAEs was 3.3%, 4.5%, 3.3%, and 2.9%, respectively. Univariate and multivariate regression analyses confirmed that MMR/MSI status was the only independent risk factor for irAE occurrence (OR=2.626,95%CI:1.566-4.402,P0.999).

The overall pCR rate of all enrolled patients was 49.8% (225/452). Conclusions: IrAEs, which are mostly mild-to-moderate and manifest as multi-organ involvement, are not rare during neoadjuvant immunotherapy for colorectal cancer. Skin, endocrine and hematopoietic systems are the predominantly affected sites, and the majority of irAEs are clinically manageable. Although severe irAEs remain uncommon, they are featured with delayed onset and life-threatening potential; in particular, cardiovascular toxicities such as fulminant myocarditis warrant close clinical vigilance. The onset of irAEs is not confined to the conventional neoadjuvant treatment period, hence sustained safety monitoring is required throughout the perioperative phase and even after treatment completion. 目的： 探讨接受新辅助免疫治疗并完成根治性手术的结直肠癌患者免疫相关不良事件（irAEs）的发生情况及围手术期结局。 方法： 本研究为回顾性、多中心、真实世界队列研究。收集5家医院（首都医科大学附属北京友谊医院、华中科技大学同济医学院附属协和医院、中山大学附属第六医院、南昌大学第一附属医院以及浙江大学附属第二医院）于2020年1月1日至2024年12月31日期间，接受新辅助免疫治疗并完成根治性手术切除、且经病理确诊为结直肠腺癌的共452例患者临床病理资料。全组患者中位年龄58.5岁，临床TNM分期Ⅱ期86例（19.0%）、Ⅲ期366例（81.0%）；根据错配修复/微卫星不稳定（MMR/MSI）状态，错配修复缺陷/高度微卫星不稳定型（dMMR/MSI-H组）116例（25.7%），错配修复功能完整/微卫星稳定型（pMMR/MSS组）为336例（74.3%）。治疗方式为免疫检查点抑制剂（ICI）单药治疗92例（20.4%），双重ICI联合治疗22例（4.9%），免疫联合化疗30例（6.6%），免疫联合放化疗308例（68.1%）。以不良事件通用术语标准（CTCAE）v5.0对患者的irAEs进行分级，并将CTCAE≥3级定义为严重irAEs。主要结局指标为irAEs总体发生率及器官系统分布情况；次要结局包括不同治疗方案和MMR/MSI状态分层下的irAEs风险、总体病理完全缓解（pCR）率及围手术期结局。对首发时间变量经逻辑校验后开展时序分析。 结果： 全组出现任意级别irAEs的发生率为24.6%（111/452）；其中CTCAE 1级73例（16.2%）、2级24例（5.3%）、3级7例（1.5%）、4级5例（1.1%）、5级2例（0.4%），≥3级irAEs共14例（3.1%）。按器官系统受累统计，共记录157例次irAEs，其中65例（58.6%）表现为单器官受累，46例（41.4%）存在多器官受累；受累系统依次为皮肤及黏膜40例次（25.5%），内分泌及甲状腺36例次（22.9%），血液及骨髓34例次（21.7%），肝胆系统21例次（13.4%）和胃肠道系统9例次（5.7%）；其余依次为骨关节或肌肉系统6例次（3.8%）、泌尿及肾系统6例次（3.8%）、心血管系统4例次（2.5%）及全身反应1例次（0.6%），包含1例暴发性心肌炎合并恶性心律失常和肝衰竭的5级事件。在不同治疗方案中，任意级别irAEs发生率分别为：ICI单药治疗为23.9%（22/92），双重ICI联合治疗为27.3%（6/22），免疫化疗为23.3%（7/30），免疫放化疗为24.7%（76/308）；≥3级irAEs发生率依次为3.3%（3/92）、4.5%（1/22）、3.3%（1/30）和2.9%（9/308）。单因素及多因素分析结果显示，仅MMR/MSI状态为irAEs发生的独立影响因素（OR=2.626，95%CI：1.566~4.402，P0.999）。全组总体pCR率为49.8%（225/452）。 结论： 结直肠癌新辅助免疫治疗中，irAEs并不少见，以轻中度、多系统分布为特征，皮肤、内分泌及血液系统为主要受累靶器官，多数可控；少数重症事件虽发生率低，却具有迟发性和潜在致命性，尤其暴发性心肌炎等心血管毒性需高度警惕。irAEs发生时间并不完全局限于常规新辅助治疗周期，围手术期及治疗结束后仍应持续监测。.