免疫相关不良事件中糖皮质激素及免疫抑制剂管理策略对患者生存结局的影响：系统评价与Meta分析

doi:10.19401/j.cnki.1007-3639.2025.10.002

摘要/Abstract

摘要：

免疫检查点抑制剂（immune checkpoint inhibitor，ICI）已经彻底革新了肿瘤治疗，但其应用常伴随免疫相关不良事件（immune-related adverse event，irAE），需要使用糖皮质激素或二线免疫抑制剂予以处理。然而，这些治疗策略对irAE患者预后的影响及其机制尚不清楚。本系统评价与Meta分析旨在评估irAE患者中糖皮质激素及二线免疫抑制剂的使用对生存结局的影响。检索PubMed、Embase、Web of Science、Cochrane Library、SinoMed、CNKI、万方数据库，纳入近10年（至2025年5月）发表的关于ICI相关irAE患者中激素及免疫抑制剂使用对生存结局影响的观察性研究（回顾性/前瞻性队列、病例对照研究）及随机对照试验的事后分析。由两名研究者独立完成文献筛选、数据提取与文献质量评价，采用R语言进行Meta分析。本研究已在PROSPERO上注册（注册号：1144835）。共纳入11篇文献，涉及 7 255例患者。Meta分析结果显示irAE患者中，激素使用vs未使用在总生存期（overall survival，OS）（HR=0.73，95% CI：0.45~1.18）及无进展生存期（progression-free survival，PFS）（HR=0.68，95% CI：0.00~98.01）方面差异均无统计学意义。在post-irAE OS（HR=0.95，95% CI：0.92~0.98）及post-irAE PFS（HR=0.96，95% CI：0.94~0.99）分析中，累积糖皮质激素剂量增加呈轻度保护性趋势。二线免疫抑制剂联合使用相比激素单用，在post-irAE OS（HR=1.40，95% CI：1.11~1.76）及post-irAE PFS（HR=1.32，95% CI：1.08~1.62）中显著增加疾病进展或死亡风险。敏感性分析显示，主要显著结果具有良好稳健性。当前证据提示，ICI相关irAE患者中，激素管理策略对生存结局的影响存在差异。累积激素剂量增加未表现为危险因素，二线免疫抑制剂联合使用可能增加生存风险。未来需进一步优化irAE管理策略，平衡免疫抑制治疗风险与抗肿瘤疗效，并通过前瞻性研究进一步验证。

关键词: 免疫检查点抑制剂, 免疫相关不良事件, 糖皮质激素, 免疫抑制剂, 生存结局, Meta分析, 系统评价

Abstract:

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but their use is frequently complicated by immune-related adverse events (irAEs), which often require management with corticosteroids or additional immunosuppressive agents. The prognostic impact of these therapeutic strategies in the setting of irAEs has not been systematically elucidated. This systematic review and meta-analysis aimed to evaluate the impact of corticosteroid (CS) and second-line immunosuppressant (IM) use on survival outcomes among patients who developed irAEs during ICI therapy. Following a preregistered protocol (PROSPERO CRD1144835), we systematically searched PubMed, Embase, Web of Science, Cochrane Library, SinoMed, CNKI and Wanfang to identify studies published in the past 10 years (up to May 2025) reporting on the association between CS and IM use and survival outcomes in ICI-treated patients with irAEs. Two reviewers independently performed study selection, data extraction, and quality assessment. Meta-analyses were performed using R software. A total of 11 studies comprising 7 255 patients were included. Meta-analysis showed that CS use versus no use was not significantly associated with overall survival (OS) (HR=0.73, 95% CI: 0.45-1.18) or progression-free survival (PFS) (HR=0.68, 95% CI: 0.00-98.01). For post-irAE survival outcomes, higher cumulative CS dose (per 1 000 mg increment) was associated with a mild protective effect on post-irAE OS (HR=0.95, 95% CI: 0.92-0.98) and post-irAE PFS (HR=0.96, 95% CI: 0.94-0.99). In contrast to CS alone, IM use in combination with CS was associated with significantly increased risk of disease progression or death for post-irAE OS (HR=1.40, 95% CI: 1.11-1.76) and post-irAE PFS (HR=1.32, 95% CI: 1.08-1.62). Sensitivity analyses demonstrated good robustness of the main significant results. Current evidence suggests that CS and IM management strategies may differentially affect survival outcomes in patients with irAEs following ICI therapy. Increased cumulative CS dose is not associated with worse outcomes, whereas the addition of second-line IMs may increase the risk of adverse survival outcomes. Further prospective studies are warranted to optimize irAE management strategies and to balance the risks of immunosuppressive therapy with anticancer efficacy.

Key words: Immune checkpoint inhibitors, Immune-related adverse events, corticosteroids, Immunosuppressants, Survival outcomes, Meta-analysis, Systematic review

中图分类号:

R730.51

兰欣悦, 周奕成, 陈东芹. 免疫相关不良事件中糖皮质激素及免疫抑制剂管理策略对患者生存结局的影响：系统评价与Meta分析[J]. 中国癌症杂志, 2025, 35(10): 906-919.

LAN Xinyue, ZHOU Yicheng, CHEN Dongqin. Survival impact of corticosteroid and immunosuppressant management strategies for immune-related adverse events in immune checkpoint inhibitor-treated patients: a systematic review and meta-analysis[J]. China Oncology, 2025, 35(10): 906-919.

图/表 13

图1

表1

表2

纳入研究中的糖皮质激素和免疫抑制剂使用特征"

Study	Sample details	CS type	Timing of initiation	Peak dose	Cumulative dose	Treatment duration	IM co-administration
Bai, et al^[10]	irAE n=509 CS group (peak dose >30 mg prednisone equivalent per day): n=164	Prednisone-equivalent only	Stratified: ≤8 weeks vs >8 weeks; ≤26 weeks vs >26 weeks	Stratified: High dose (≥60 mg/d) vs low dose (<60 mg/d)	Not reported	Median tapering duration: 6 days	Not reported
Bruyère, et al^[15]	irAE n=78 (grade ≥3) CS group: n=45; CS+IM group: n=8	Prednisone-equivalent only	Not reported	High-dose corticosteroids ≥1 mg/kg	Not reported	Median CTLA-4: 42 d; PD-1: 47 d	Incomplete reporting
Shimomura, et al^[16]	irAE n=144; CS group: n=66	Prednisone-equivalent only	Time from ICI initiation to corticosteroid use. Median: High dose: 84 d; Low dose: 91 d; Stratified: ≤60 d vs >60 d	Stratified: High dose (≥0.5 mg/kg) vs no corticosteroids Low dose (<0.5 mg/kg) vs no corticosteroids	Not reported	Median: High dose: 14 d; Low dose: 90 d	Not reported
Matsukane, et al^[17]	irAE n=400; CS group: n=170	Prednisone-equivalent only	Not reported	No-corticosteroid administration: Low dose (< 0.5 mg/ kg), moderate to high dose (0.5-2.0 mg/ kg), intravenous methylprednisolone pulse therapy (500-1 000 mg, 3 days). Stratified: Intravenous methylprednisolone pulse therapy vs no pulse therapy	Not reported	Not reported	Not reported
Cariou, et al^[18]	irAE n=184; CS group: 107; CS+IM group: n=20	Prednisone-equivalent only	Time from ICI initiation to corticosteroid use. Median (95% CI): CS group: 4.5 (1.6-9.1) months CS+IM group: 3.4 (2.0-9.3) months	Incomplete reporting	Not reported	Median (95% CI): CS group: 3.1 (2.7-4.4) months; CS+IM group: 7.1 (4.3-29.0) months	20 patients received anti-TNF alpha agents, cyclophosphamide, methotrexate, azathioprine
Robesti, et al^[19]	irAE n=195 CS group: n=99	Prednisone-equivalent only	Not reported	Incomplete reporting Stratified: CS alone use vs no use	Not reported	Not reported	Not reported
Syed, et al^[20]	irAE n=167 CS group: n=132 CS+IM group: n=35	Prednisone-equivalent only	Time from ICI initiation to corticosteroid use. Median (IQR): CS group: 2.99 (1.56, 7.84) months; CS+IM group: 2.77 (1.23, 8.13) months	Not reported	Not reported	Median (IQR): CS group: 2.17 (1.50, 4.00) months; CS+IM group: 3.00 (2.00, 5.08) months	Mycophenolate mofetil 15 (42.9%) patients, infliximab 12 (34.3%) patients, rituximab 3 (8.6%) patients, tocilizumab 2 (5.7%) patients, methotrexate 2 patients (5.7%), tacrolimus 2 (5.7%) patients; Stratified: CS+IM use vs CS alone use
Verheijden, et al^[21]	irAE n=606 CS group: 425 CS+IM group: 181	Prednisone-equivalent only	Time time from irAE onset to immunosuppression use. Median: 2 days	Median (IQR): CS group: 80 (60-107) mg; CS+IM group: 110 (80-160) mg; Stratified: 160 mg vs 40 mg	Median (IQR): 1 503-3 743 mg; CS+IM group: 3 900 (2 483-5 684) mg	Not reported	TNF inhibition 102 (56%) patients, mycophenolate mofetyl 59 (33%) patients, tacrolimus 22 (12%) patients, intravenous immunoglobulins (IVIg) 20 (11%) patients; vedolizumab 9 (5%) patients, methotrexate 5 (3%) patients, others 11 (6%) patients; Stratified: CS+IM use vs CS alone use
Curkovic, et al^[22]	irAE n=183 CS group: n=136 CS+IM group: NS	Prednisone-equivalent only	Time from ICI initiation to corticosteroid. Median (IQR): 49 (28-70.2) days Stratified: Per-day delay in CS initiation	Median (IQR): 80 (60-150) days; Stratified: Per 1 mg increase in peak dose	Incomplete reporting Stratified: Per 1 mg increase in cumulative dose	Not reported	Incomplete reporting; Stratified: CS+IM use vs CS alone use
Pichler, et al^[23]	irAE n=122 CS group: n=62	Prednisone-equivalent only	Not reported	Incomplete reporting; Stratified: CS alone use vs no use	Not reported	Not reported	Not reported
Verheijden, et al^[24]	irAE n=834 CS group: n=753 CS+IM group: n=79	Prednisone-equivalent only	50% within 1 day of irAE onset and 82% started within 1 week	Median (IQR): 75 (40-125) mg, which corresponded to 1.0 mg/kg (IQR, 0.54-1.51 mg/kg); Stratified: 0.5 vs 1.0 vs 2.0 mg/kg	Median (IQR): 1 850 (680-3 712) mg Stratified: Per 1 000 mg increase in cumulative dose	Median (IQR): 54 (20-102) days	Tumor necrosis factor (TNF) inhibition 44 (5%) patients; mycophenolate mofetil 22 (3%) patients; intravenous immunoglobulins (IVIg) 14 (2%) patients; others 9 (1%) patients; Stratified: CS+IM use vs CS alone use

表2

图2

图3

图4

表3

图5

图6

表4

图7

图8

附录Ⅰ

所有治疗组合的森林图综合数据"

Combination	Study	HR	95% CI	Weight/%	Model
Corticosteroid use vs non-use (OS)	Robesti, et al	0.86	0.48-1.54	67.62
	Pichler, et al	0.52	0.22-1.21	32.38
	Pooled effect	0.73	0.45-1.18		Fixed-effect
Corticosteroid use vs non-use (PFS)	Robesti, et al	0.92	0.63-1.35	62.5
	Pichler, et al	0.41	0.17-0.99	37.5
	Pooled effect	0.68	0.00-98.01		Random-effect
Corticosteroid plus IM vs corticosteroids alone (post-irAE OS)	Verheijden, et al	1.34	0.99-1.82	57.38
	Verheijden, et al/CheckMate 067	0.93	0.50-1.72	14.07
	Verheijden, et al/CheckMate 142	6.10	0.27-137.42	0.55
	Verheijden, et al/CheckMate 214	1.41	0.68-2.92	10.02
	Verheijden, et al/CheckMate 648	1.49	0.44-5.08	3.53
	Verheijden, et al/CheckMate 743	1.46	0.71-3.01	10.15
	Verheijden, et al/CheckMate 9LA	6.80	2.24-20.65	4.31
	Pooled effect	1.40	1.11-1.76		Fixed-effect
Corticosteroid plus IM vs corticosteroids alone (post-irAE PFS)	Verheijden, et al	1.32	1.02-1.71	60.39
	Verheijden, et al/CheckMate 067	1.31	0.70-2.45	10.51
	Verheijden, et al/CheckMate 142	1.17	0.15-9.11	0.98
	Verheijden, et al/CheckMate 214	1.04	0.59-1.82	13.12
	Verheijden, et al/CheckMate 648	0.73	0.22-2.44	2.84
	Verheijden, et al/CheckMate 743	1.60	0.80-3.20	8.54
	Verheijden, et al/CheckMate 9LA	3.70	1.27-10.76	3.62
	Pooled effect	1.32	1.08-1.62		Fixed-effect
Corticosteroid plus IM vs corticosteroids alone (OS)	Curkovic, et al	1.94	1.12-3.36	16.29
	Syed, et al	0.82	0.46-1.47	15.97
	Verheijden, et al/CheckMate 067	0.94	0.51-1.74	15.65
	Verheijden, et al/CheckMate 142	6.63	0.31-142.69	2.75
	Verheijden, et al/CheckMate 214	1.47	0.71-3.04	14.5
	Verheijden, et al/CheckMate 648	1.28	0.38-4.35	9.91
	Verheijden, et al/CheckMate 743	1.36	0.66-2.81	14.51
	Verheijden, et al/CheckMate 9LA	12.19	3.82-38.88	10.42
	Pooled effect	1.66	0.82-3.34		Random-effect
Corticosteroid plus IM vs corticosteroids alone (PFS)	Syed, et al	0.75	0.46-1.23	18.08
	Curkovic, et al	1.63	0.99-2.66	18.05
	Verheijden, et al/CheckMate 067	1.44	0.82-2.53	16.12
	Verheijden, et al/CheckMate 142	1.04	0.15-7.32	2.68
	Verheijden, et al/CheckMate 214	1.05	0.62-1.78	17.09
	Verheijden, et al/CheckMate 648	0.59	0.18-1.95	6.23
	Verheijden, et al/CheckMate 743	1.18	0.61-2.29	13.7
	Verheijden, et al/CheckMate 9LA	4.46	1.63-12.22	8.05
	Pooled effect	1.24	0.80-1.91		Random-effect
Cumulative corticosteroid dose (post-irAE OS)	Verheijden, et al	0.93	0.88-0.98	36.13
	Verheijden, et al/CheckMate 067	0.97	0.91-1.04	23.47
	Verheijden, et al/CheckMate 142	8.96	0.45-179.27	0.01
	Verheijden, et al/CheckMate 214	0.98	0.91-1.06	17.98
	Verheijden, et al/CheckMate 648	0.98	0.85-1.13	5.16
	Verheijden, et al/CheckMate 743	0.90	0.82-0.98	13.47
	Verheijden, et al/CheckMate 9LA	0.89	0.75-1.05	3.78
	Pooled effect	0.95	0.92-0.98		Fixed-effect
Cumulative corticosteroid dose (post-irAE PFS)	Verheijden, et al	0.94	0.90-0.98	36.03
	Verheijden, et al/CheckMate 067	0.96	0.90-1.03	14.35
	Verheijden, et al/CheckMate 142	1.37	1.06-1.78	0.97
	Verheijden, et al/CheckMate 214	0.99	0.94-1.05	21.33
	Verheijden, et al/CheckMate 648	0.98	0.87-1.10	4.75
	Verheijden, et al/CheckMate 743	0.94	0.87-1.02	10.33
	Verheijden, et al/CheckMate 9LA	0.96	0.89-1.03	12.24
	Pooled effect	0.96	0.94-0.99		Fixed-effect

附录Ⅰ

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Study	Country	Study design	Sample size	Cancer	Immunotherapy	Outcome	NOS
Bai, et al ^[10]	America, Australia	Multi-center retrospective cohort study	947	Melanoma	Nivolumab, pembrolizumab	PFS, post-irAE OS, post-irAE PFS	8
Bruyère, et al ^[15]	France	Single-center retrospective cohort study	828	Various	Anti-PD-(L)1 (90%) Anti-CTLA-4 (10%)	OS, PFS	7
Shimomura, et al ^[16]	Japan	Single-center retrospective cohort study	172	NSCLC	nivolumab pembrolizumab	OS, TTF	7
Matsukane, et al ^[17]	Japan	Single-center retrospective cohort study	935	Various	Nivolumab, pembrolizumab, durvalumab, atezolizumab, avelumab	OS	6
Cariou, et al ^[18]	France	Single-center prospective cohort study	184	Various	Nivolumab, pembrolizumab, nivolumab + ipilimumab	OS, PFS	8
Robesti, et al ^[19]	Multiple countries	Post hoc analysis of RCT	896	UC	Atezolizumab	OS, PFS, CSS	9
Syed, et al ^[20]	America	Single-center retrospective case-control study	167	NSCLC Melanoma	Anti-PD-(L)1, Anti-CTLA-4	OS, PFS	8
Verheijden, et al ^[21]	Multiple countries	Multi-center retrospective cohort study	606	Melanoma	Anti-PD-1 (33%), Anti-PD-1⁺ anti-CTLA-4 (67%)	Post-irAE OS, post-irAE PFS	9
Curkovic, et al ^[22]	America	Multi-center retrospective cohort study	226	Melanoma	Nivolumab + ipilimumab	OS, PFS	9
Pichler, et al ^[23]	Multiple countries	Multi-center retrospective cohort study	335	UC	Pembrolizumab, nivolumab, atezolizumab, avelumab	OS, PFS	8
Verheijden, et al ^[24]	Multiple countries	Post hoc analysis of RCT	1 959	Various	Nivolumab+ipilimumab	OS, PFS, post-irAE OS, post-irAE PFS	9

Risk factor	n	Egger's regression P value	Begg's rank correlation P value
Corticosteroid use vs non-use (OS)	2	-	-
Corticosteroid use vs non-use (PFS)	2	-	-
Corticosteroid plus IM vs corticosteroids alone (OS)	8	0.081	0.399
Corticosteroid plus IM vs corticosteroids alone (PFS)	8	0.805	0.905
Corticosteroid plus IM vs corticosteroids alone (post-irAE OS)	7	0.102	0.136
Corticosteroid plus IM vs corticosteroids alone (post-irAE PFS)	7	0.771	1.000
Cumulative corticosteroid dose (post-irAE OS)	7	0.325	0.562
Cumulative corticosteroid dose (post-irAE PFS)	7	0.022	0.239

Risk factor	Fixed effect model	Random effect model
Corticosteroid use vs non-use (OS)	0.73 (0.45-1.18)	0.73 (0.04-14.55)
Corticosteroid use vs non-use (PFS)	0.81 (0.57-1.15)	0.68 (0.00-98.01)
Corticosteroid plus IM vs corticosteroids alone (OS)	1.42 (1.09-1.85)	1.66 (0.82-3.34)
Corticosteroid plus IM vs corticosteroids alone (PFS)	1.21 (0.96-1.52)	1.24 (0.80-1.91)
Corticosteroid plus IM vs corticosteroids alone (post-irAE OS)	1.40 (1.11-1.76)	1.50 (0.90-2.49)
Corticosteroid plus IM vs corticosteroids alone (post-irAE PFS)	1.32 (1.08-1.62)	1.32 (1.04-1.69)
Cumulative corticosteroid dose (post-irAE OS)	0.95 (0.92-0.98)	0.95 (0.91-0.98)
Cumulative corticosteroid dose (post-irAE PFS)	0.96 (0.94-0.99)	0.96 (0.92-1.00)