国际肿瘤学杂志

国际肿瘤学杂志 ›› 2026, Vol. 53 ›› Issue (8): 452-463.doi: 10.3760/cma.j.cn371439-20250719-00074

• 论著 • 上一篇    下一篇

irTD预测模型与中晚期肿瘤免疫治疗生存获益真实队列研究

李雪芹1, 龚泉1, 张利娟1, 陈曦2, 李仕娟1, 周春艳1, 李俊1, 庄莉1()   

  1. 1 昆明医科大学第三附属医院 云南省肿瘤医院 北京大学肿瘤医院云南医院康复与姑息医学科， 昆明 650118
    2 昆明医科大学第三附属医院 云南省肿瘤医院 北京大学肿瘤医院云南医院急诊部门诊化疗中心， 昆明 650118
  • 收稿日期:2025-07-19 出版日期:2026-08-08 发布日期:2026-07-21
  • 通讯作者: 庄莉，Email： kekzhuangli@163.com
  • 作者简介:

    李雪芹：数据收集、整理，统计学分析及论文撰写；龚泉、张利娟：论文修改；陈曦、李仕娟、周春艳、李俊：数据整理、统计学分析、论文修改；庄莉：研究指导、论文修改

  • 基金资助:
    “兴滇英才支持计划”医疗卫生人才专项(CZ0096-901895);云南省教育厅科学研究项目(2025J0289)

irTD predictive model and a real cohort study on the survival benefits in advanced tumor immunotherapy

Li Xueqin1, Gong Quan1, Zhang Lijuan1, Chen Xi2, Li Shijuan1, Zhou Chunyan1, Li Jun1, Zhuang Li1()   

  1. 1 Department of Rehabilitation and Palliative Medicine， Third Affiliated Hospital of Kunming Medical University， Yunnan Cancer Hospital， Peking University Cancer Hospital Yunnan， Kunming 650118， China
    2 Department of Emergency Outpatient Chemotherapy Center， Third Affiliated Hospital of Kunming Medical University， Yunnan Cancer Hospital， Peking University Cancer Hospital Yunnan， Kunming 650118， China
  • Received:2025-07-19 Online:2026-08-08 Published:2026-07-21
  • Contact: Zhuang Li， Email： kekzhuangli@163.com
  • Supported by:
    Medical and Health Talents Special Project of "Xingdian Talent Support Program"(CZ0096-901895);Scientific Research Project of Yunnan Provincial Department of Education(2025J0289)

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摘要：

目的 探讨免疫相关甲状腺功能障碍（irTD）的影响因素及其对中晚期恶性肿瘤患者生存预后的影响，并分析代谢因素的调节作用。方法 选取昆明医科大学第三附属医院2018年1月1日至2024年1月31日收治的70例接受免疫治疗的中晚期肿瘤患者作为研究对象，根据免疫检查点抑制剂（ICI）治疗后是否出现甲状腺功能障碍，将患者分为irTD组（n=53）和非irTD组（n=17），对irTD组患者免疫治疗前后相关指标进行比较。绘制受试者操作特征（ROC）曲线评估各指标对中晚期肿瘤患者ICI治疗后发生irTD的预测效能；采用多因素logistic回归分析肿瘤患者ICI治疗后发生irTD的危险因素；绘制Kaplan-Meier生存曲线进行生存分析并行log-rank检验；采用分层Cox风险比例回归模型评估中晚期肿瘤患者预后的影响因素。结果 irTD组肿瘤患者免疫治疗前、后促甲状腺激素（TSH）水平分别为3.24（2.16，4.01）、12.20（0.03，73.55）μIU/ml，甲状腺球蛋白抗体（TGAb）水平分别为19.87（12.82，216.00）、29.47（15.92，436.80）IU/ml、甲状腺过氧化物酶抗体（TPOAb）水平分别为4.04（2.00，130.43）、42.28（2.00，400.00）IU/ml，甲状腺球蛋白（TG）水平分别为5.67（1.48，17.81）、22.80（2.55，52.15）ng/ml，差异均有统计学意义（Z=4.36，P<0.001；Z=4.81，P<0.001；Z=4.64，P<0.001；Z=4.30，P<0.001）。ROC曲线分析显示，基线TSH、TGAb、TPOAb、抑制性T（Ts）细胞水平预测肿瘤患者免疫治疗后发生irTD的曲线下面积（AUC）分别为0.663、0.704、0.737、0.691，预测效能差异均无统计学意义（均P>0.05）。多因素分析显示，TSH≥1.87 μIU/ml（OR=4.12，95%CI为1.10~15.46，P=0.036），基线抗体阳性（OR=10.68，95%CI为1.21~94.43，P=0.033）均为肿瘤患者免疫治疗后发生irTD的独立危险因素。生存分析显示，irTD组和非irTD组患者的中位总生存期（mOS）分别为29、22个月，1年总生存（OS）率分别为88.5%和76.0%，差异有统计学意义（χ2=4.85，P=0.028）；亚组分析显示，在≥65岁、接受一线治疗、合并高脂血症、未合并高尿酸血症、未合并糖尿病、未联合手术、联合靶向治疗、C反应蛋白-白蛋白-淋巴细胞指数≤3、体质量指数（BMI）<18.5 kg/m2或18.5 kg/m2≤BMI<24 kg/m2患者中，irTD组的mOS均长于非irTD组（均P<0.05）；在肺腺癌、肺鳞状细胞癌、小细胞肺癌、其他癌种患者中，irTD组的mOS分别为43、29、18、15个月，差异有统计学意义（χ2=8.67，P=0.034），两两比较显示，在经Bonferroni法校正后，差异均无统计学意义（校正后均P>0.008 3）。多因素分析显示，在全体接受ICI治疗的肿瘤患者中，性别（HR=0.39，95%CI为0.18~0.84，P=0.016）、治疗线数（HR=0.33，95%CI为0.13~0.85，P=0.021）、发生irTD（HR=0.43，95%CI为0.19~0.95，P=0.037）、手术（HR=4.38，95%CI为1.26~10.55，P=0.017）均为OS的独立影响因素。在发生irTD的患者中，进一步按TSH水平进行亚组分层分析显示，美国东部肿瘤协作组体能状态评分（HR=0.19，95%CI为0.05~0.83，P=0.027）、BMI等级（HR=0.54，95%CI为0.29~0.98，P=0.043）及TSH>100 μIU/ml（HR=0.04，95%CI为0.00~0.60，P=0.021）均为该人群OS的独立影响因素。结论 基线TSH≥1.87 μIU/ml与甲状腺自身抗体升高均是中晚期肿瘤患者irTD发生的独立预测因素。发生irTD与患者更长的mOS相关，且该获益在合并高脂血症、未合并高尿酸血症及未合并糖尿病患者中持续存在，提示代谢状态可能影响irTD的预后价值。在irTD患者中，TSH>100 μIU/ml是OS的独立保护因素。

关键词: 免疫检查点抑制剂, 甲状腺毒症, 甲状腺功能减退症, 生物标记, 肿瘤, 生存分析, 代谢疾病, 真实世界研究

Abstract:

Objective To investigate the influencing factors of immune-related thyroid dysfunction （irTD） and its impact on survival prognosis in patients with advanced malignant tumors， and to analyze the regulatory role of metabolic factors. Methods A total of 70 patients with advanced tumors who received immunotherapy at the Third Affiliated Hospital of Kunming Medical University from January 1， 2018 to January 31， 2024 were selected as the study subjects. Based on the occurrence of thyroid dysfunction after immune checkpoint inhibitors （ICIs） treatment， patients were divided into the irTD group （n=53） and the non-irTD group （n=17）. The relevant indicators of the patients in the irTD group before and after immunotherapy were compared. Receiver operator characteristic （ROC） curves were plotted to evaluate the predictive efficacy of each indicator for irTD in advanced tumor patients after ICIs treatment. Multivariate logistic regression was used to identify the risk factors for irTD in tumor patients after ICIs treatment. Kaplan-Meier survival curves were plotted for survival analysis， and the log-rank test was performed. A stratified Cox proportional hazards regression model was used to evaluate the influencing factors of prognosis in patients with advanced tumors. Results In tumor patients with irTD， serum levels before and after immunotherapy were as follows： thyroid-stimulating hormone （TSH） was 3.24 （2.16， 4.01） and 12.20 （0.03， 73.55） μIU/ml； thyroglobulin antibody （TGAb） was 19.87 （12.82， 216.00） and 29.47 （15.92， 436.80） IU/ml； thyroid peroxidase antibody （TPOAb） was 4.04 （2.00， 130.43） and 42.28 （2.00， 400.00） IU/ml； and thyroglobulin （TG） was 5.67 （1.48， 17.81） and 22.80 （2.55， 52.15） ng/ml， with statistically significant differences （Z=4.36， P<0.001； Z=4.81， P<0.001； Z=4.64， P<0.001； Z=4.30， P<0.001）. ROC curve analysis showed that baseline TSH， TGAb， TPOAb， and suppressor T （Ts） cell levels had areas under the curve （AUCs） for predicting irTD after immunotherapy of 0.663， 0.704， 0.737， and 0.691， respectively， but pairwise comparisons revealed no significant differences in predictive efficacy （all P>0.05）. Multivariate analysis identified TSH≥1.87 μIU/ml （OR=4.12， 95%CI： 1.10-15.46， P=0.036） and baseline antibody positivity （OR=10.68， 95%CI： 1.21-94.43， P=0.033） as independent risk factors for irTD after immunotherapy in tumor patients. Survival analysis showed that the median overall survival （mOS） was 29 months in the irTD group and 22 months in the non-irTD group， with 1-year overall survival （OS） rates of 88.5% and 76.0%， respectively， with a statistically significant difference （χ2=4.85， P=0.028）. The subgroup analysis showed that in patients aged ≥65 years， receiving first-line therapy， with comorbid hyperlipidemia， without hyperuricemia， without diabetes， without combined surgery， with combined targeted therapy， with C-reactive protein-albumin-lymphocyte score ≤3， body mass index （BMI）<18.5 kg/m2 or 18.5 kg/m2≤BMI<24 kg/m2， the mOS in the irTD group was significantly longer than that in the non-irTD group （all P<0.05）. The mOS for patients with lung adenocarcinoma， lung squamous cell carcinoma， small cell lung cancer， and other histological subtypes in the irTD group was 43， 29， 18， and 15 months， respectively， with a statistically significant difference （χ2=8.67， P=0.034）. However， pairwise comparisons showed that there were no statistically significant differences after Bonferroni correction （all adjusted P>0.008 3）. Multivariate analysis revealed that among all patients receiving ICI treatment， sex （HR=0.39， 95%CI： 0.18-0.84， P=0.016）， treatment line （HR=0.33， 95%CI： 0.13-0.85， P=0.021）， occurrence of irTD （HR=0.43， 95%CI： 0.19-0.95， P=0.037）， and surgery （HR=4.38， 95%CI： 1.26-10.55， P=0.017） were all independent influencing factors for OS. Among patients who developed irTD， further subgroup analysis stratified by TSH level showed that all Eastern Cooperative Oncology Group performance status score （HR=0.19， 95%CI： 0.05-0.83， P=0.027）， BMI grade （HR=0.54， 95%CI： 0.29-0.98， P=0.043）， and TSH>100 μIU/ml （HR=0.04， 95%CI： 0.00-0.60， P=0.021） were independent influencing factors for OS in this population. Conclusions Baseline TSH≥1.87 μIU/ml and elevated thyroid autoantibodies are independent predictors of irTD in patients with advanced tumors. The occurrence of irTD is associated with prolonged mOS， and this survival benefit persists in patients with comorbid hyperlipidemia， as well as in those without hyperuricemia or diabetes， suggesting that metabolic status may influence the prognostic value of irTD. Among patients with irTD， TSH>100 μIU/ml is an independent protective factor for OS.

Key words: Immune checkpoint inhibitors, Thyrotoxicosis, Hypothyroidism, Biomarkers, tumor, Survival analysis, Metabolic diseases, Real-world study