Occurrence and Treatment of Endocrinologic Adverse Reactions Associated with Immune Checkpoint Inhibitors: a Single-center Real-world Study

doi:10.12114/j.issn.1007-9572.2022.0855

Abstract

Abstract:

Background

Immunotherapy-related endocrine adverse reactions are relatively common, which often lead to serious outcomes if not treated in time. However, the incidence of immunotherapy-related endocrine adverse reactions varies widely in previous literature reports without standard processing.

Objective

To investigate the occurrence and treatment process of endocrinologic adverse reactions caused by immune checkpoint inhibitors (ICIs) in the real world.

Methods

The clinical data of 204 patients with solid tumors treated with ICIs at the Third People's Hospital of Zhengzhou from January 2019 to March 2022 was retrospectively analyzed, the endocrinologic adverse reactions occured their treatment were observed and standardized management was conducted according to the adverse reactions grading.

Results

A total of 204 patients with solid tumors were included, involving 139 male patients and 65 female patients, with a median age of 65.4 (8.0, 88.4) years. The types of solid tumor were predominantly non-small cell lung cancer (43.1%) , the treatment drugs were mainly sindilizumab (47.1%) , and the treatment patterns were predominantly immunotherapy combined with targeted agents (57.4%) . 12 patients developed ICIs-related endocrinologic adverse reactions, including 9 cases (4.4%) of hypothyroidism (1 case of gradeⅠ, 7 cases of grade Ⅱ, 1 case of grade Ⅲ) with the median onset time of 7 (6, 10) weeks after the treatment of immunological drugs, 1 case (0.5%) of hyperthyroidism (gradeⅠ) occurred 9 weeks after the immunotherapy, 1 case (0.5%) of type 1 diabetes (gradeⅣ) occurred 6 weeks after auto-immunotherapy, 1 case (0.5%) of adrenal dysfunction (gradeⅢ) occurred 7 weeks after immunotherapy. All the 12 patients with endocrinologic adverse reactions were treated in time according to the hierarchical management process, and all their symptoms were improved or returned to normal, and continued to be treated with ICIs.

Conclusion

The risk of endocrinologic adverse reactions in the endocrine system is relatively high during the use of ICIs, especially abnormal thyroid function, which requires regular detection of endocrine indicators during treatment, timely intervention will not affect the subsequent treatment of ICIs.

Key words: Immune checkpoint inhibitors, Drug-related side effects and adverse reactions, Hypothyroidism, Hyperthyroidism, Diabetes mellitus, type 1, Adrenal insufficiency, Programmed death receptor 1, Programmed death ligand-1, Immune-related adverse events

摘要：

背景

免疫治疗相关性内分泌不良反应较为常见，若不及时处理常导致严重后果，但既往文献报道的该不良反应发生率差异较大，且无标准处理流程。

目的

探讨免疫检查点抑制剂（ICIs）导致的内分泌不良反应在真实世界中的发生情况及处理流程。

方法

回顾性分析2019年1月至2022年3月在郑州市第三人民医院使用ICIs治疗的204例实体瘤患者的临床资料，观察ICIs治疗期间发生的内分泌系统不良反应，并根据不良反应分级标准进行规范管理。

结果

204例实体瘤患者中男139例、女65例，中位年龄65.4（8.0，88.4）岁。实体瘤种类以非小细胞肺癌为主（43.1%），治疗药物以信迪利单抗为主（47.1%），治疗模式以免疫联合靶向药物为主（57.4%）。12例患者出现ICIs相关内分泌不良反应，其中9例（4.4%）为甲状腺功能减退（1例Ⅰ级，7例Ⅱ级，1例Ⅲ级），中位发生时间为自第1次免疫药物治疗后7（6，10）周；1例（0.5%）甲状腺功能亢进（Ⅰ级），自免疫治疗后9周发生；1例（0.5%）1型糖尿病（Ⅳ级），自免疫治疗后6周发生；1例（0.5%）肾上腺皮质功能减退（Ⅲ级），自免疫治疗后7周发生。12例ICIs相关内分泌不良反应患者按分级管理流程及时给予处理，症状均好转或恢复正常，后续均继续给予ICIs治疗。

结论

ICIs使用过程中，内分泌系统不良反应发生风险相对较高，尤其是甲状腺功能异常，需要治疗期间定期检测内分泌指标，及时处理并不会影响后续ICIs治疗。

关键词: 免疫检查点抑制剂, 药物相关性副作用和不良反应, 甲状腺功能减退症, 甲状腺功能亢进症, 糖尿病，1型, 肾上腺功能减退, 程序性死亡受体1, 程序性死亡配体1, 免疫相关不良反应

CHANG Junpei,CHEN Lu,WU Tong, et al. Occurrence and Treatment of Endocrinologic Adverse Reactions Associated with Immune Checkpoint Inhibitors: a Single-center Real-world Study[J]. Chinese General Practice, 2023, 26(17): 2095-2101. DOI: 10.12114/j.issn.1007-9572.2022.0855.
常俊佩,陈露,吴通等. 免疫检查点抑制剂相关内分泌不良反应的发生及处理：一项单中心真实世界研究[J]. 中国全科医学, 2023, 26(17): 2095-2101. DOI: 10.12114/j.issn.1007-9572.2022.0855.

Figures/Tables 4

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不良事件	Ⅰ级（G1）	Ⅱ级（G2）	Ⅲ级（G3）	Ⅳ级（G4）
甲状腺功能亢进	N	M+甲状腺抑制治疗	S	D
甲状腺功能减退	N	M+甲状腺素替代治疗	S	D
垂体炎	N	M+轻微、局灶性或非侵入性治疗	S	D
原发性肾上腺皮质功能减退	N	M	S	D
甲状旁腺功能减退	N	M	S	D
甲状旁腺功能亢进	N	M	—	—
1型糖尿病	空腹血糖<8.9 mmol/L	空腹血糖8.9~13.9 mmol/L	空腹血糖14.0~27.8 mmol/L，需住院治疗	空腹血糖>27.8 mmol/L，危及生命

不良事件	Ⅰ级（G1）	Ⅱ级（G2）	Ⅲ级（G3）	Ⅳ级（G4）
甲状腺功能亢进	N	M+甲状腺抑制治疗	S	D
甲状腺功能减退	N	M+甲状腺素替代治疗	S	D
垂体炎	N	M+轻微、局灶性或非侵入性治疗	S	D
原发性肾上腺皮质功能减退	N	M	S	D
甲状旁腺功能减退	N	M	S	D
甲状旁腺功能亢进	N	M	—	—
1型糖尿病	空腹血糖<8.9 mmol/L	空腹血糖8.9~13.9 mmol/L	空腹血糖14.0~27.8 mmol/L，需住院治疗	空腹血糖>27.8 mmol/L，危及生命

临床特征	构成比	临床特征	构成比
性别		PD-L1水平
男	139（68.1）	≥1%	38（18.6）
女	65（31.9）	<1%	55（27.0）
PS评分		未测	111（54.4）
0分	59（28.9）	治疗药物
1分	94（46.1）	信迪利单抗	96（47.1）
2分	51（25.0）	卡瑞利珠单抗	87（42.6）
实体瘤种类		替雷利珠单抗	12（5.9）
非小细胞肺癌	88（43.1）	派安普利单抗	5（2.4）
肝癌	19（9.3）	帕博利珠单抗	2（1.0）
小细胞肺癌	14（6.9）	度伐利优单抗	2（1.0）
食管癌	16（7.9）	治疗模式
肾癌	9（4.4）	单药	20（9.8）
尿路上皮癌	8（3.9）	免疫联合化疗	67（32.8）
大肠癌	18（8.8）	免疫联合靶向药物	117（57.4）
其他	32（15.7）

临床特征	构成比	临床特征	构成比
性别		PD-L1水平
男	139（68.1）	≥1%	38（18.6）
女	65（31.9）	<1%	55（27.0）
PS评分		未测	111（54.4）
0分	59（28.9）	治疗药物
1分	94（46.1）	信迪利单抗	96（47.1）
2分	51（25.0）	卡瑞利珠单抗	87（42.6）
实体瘤种类		替雷利珠单抗	12（5.9）
非小细胞肺癌	88（43.1）	派安普利单抗	5（2.4）
肝癌	19（9.3）	帕博利珠单抗	2（1.0）
小细胞肺癌	14（6.9）	度伐利优单抗	2（1.0）
食管癌	16（7.9）	治疗模式
肾癌	9（4.4）	单药	20（9.8）
尿路上皮癌	8（3.9）	免疫联合化疗	67（32.8）
大肠癌	18（8.8）	免疫联合靶向药物	117（57.4）
其他	32（15.7）