糖皮质激素对晚期肿瘤患者免疫疗效影响的Meta分析

doi:10.3969/j.issn.1004-583X.2022.07.002

摘要/Abstract

摘要：

目的探讨糖皮质激素(glucocorticoid, GC)的使用对接受免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)治疗的肿瘤患者的总生存期(overall survival, OS)和无进展生存期(progression-free survival, PFS)的影响。方法使用PubMed、Wiley、Web of Science和Cochrane Library数据库检索2020年10月以前发表的有关肿瘤患者在接受ICIs治疗期间,GC使用对患者预后影响的文献,采用Review Manager 5.3软件和Stata14.0软件进行统计分析。结果总共有23篇文献被纳入荟萃分析,Meta分析结果显示在晚期肿瘤患者接受ICIs治疗期间,GC的使用是死亡( $H R$ =1.54, 95% $C I$ =1.29~1.83)和疾病进展( $H R$ =1.82, 95% $C I$ =1.36~2.43)的危险因素。此外,亚组分析结果显示,GC用于缓解脑水肿、癌痛等肿瘤相关并发症时会增加患者死亡( $H R$ =2.14, 95% $C I$ =1.62~2.81)和疾病进展( $H R$ =2.26,95% $C I$ =1.72~2.96)的风险。然而,GC被用于处理免疫相关不良反应(immune-related adverse events,irAEs)等非肿瘤相关性并发症,GC的使用与未使用或者小剂量(<10 mg/d)使用相比差异无统计学意义( $P$ >0.05)。结论当GC用于处理肿瘤相关性并发症时,GC的使用对接受免疫治疗的肿瘤患者的预后会造成负面影响。

关键词: 糖皮质激素类, 肿瘤, 免疫检查点抑制剂, 预后

Abstract:

Objective To evaluate the application of glucocorticoid on the overall survival (OS) and progression-free survival (PFS) of the cancer patients receiving immune checkpoint inhibitors (ICIs). Methods PubMed, Wiley, Web of Science and Cochrane Library databases were applied to search the papers for effects of GC on cancer patients during the therapy period of receiving ICIs published prior to October 2020. Review Manager 5.3 software and Stata 14.0 software were used for statistical analysis. Results A total of 23 studies were included in the meta analysis, Meta-analysis showed that for patients with advanced cancer during the period of ICIs, the application of GC was a risk factor for death ( $H R$ =1.54, 95% $C I$ =1.29-1.83) and disease progression ( $H R$ =1.82, 95% $C I$ =1.36-2.43). Moreover, the subgroup analysis showed that GC applied to relief tumor-related complications including the cerebraledema and cancer pain increased the risk of death ( $H R$ =2.14, 95% $C I$ =1.62-2.81) and disease progression ( $H R$ =2.26, 95% $C I$ =1.72-2.96). While GC was used to treat non-tumor-related complications including immune-related adverse events (irAEs), and the difference between the use of GC and no-use or low dose of GC (<10 mg/d) wasn’t statistically significant ( $P$ >0.05). Conclusion The application of GC has negative effects on the prognosis of cancer patients receiving immunotherapy when it is used to treat tumor-related complications.

Key words: glucocorticoids, cancer, immune checkpoint inhibitors, prognosis

中图分类号:

R347
R739.9

叶倩, 凌志, 刘申香, 路国涛, 殷旭东. 糖皮质激素对晚期肿瘤患者免疫疗效影响的Meta分析[J]. 临床荟萃, 2022, 37(7): 591-598.

Ye Qian, Ling Zhai, Liu Shenxiang, Lu Guotao, Yin Xudong. Meta analysis on effects of glucocorticoid on the immunotherapy of advanced cancer[J]. Clinical Focus, 2022, 37(7): 591-598.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2022.07.002

https://huicui.hebmu.edu.cn/CN/Y2022/V37/I7/591

图/表 8

图1 文献筛选流程

表1 研究的一般特征

作者	发表年份 (年)	样本量 (例)	国家	中位随访时间(月)	疾病	分期	ICI类型	研究终点	$H R$ (PFS)	$H R$ (OS)	NOS 评分
Arbour^[8]	2018	640	美国	-	肺癌	进展	纳武利尤单抗或帕博利珠单抗或阿特珠单抗或德瓦单抗	OS/PFS	1.31	1.66	7
Parakh^[11]	2018	45	澳大利亚	8.7	黑色素瘤	Ⅳ	纳武利尤单抗+伊匹单抗或者纳武利尤单抗单药	PFS	7.69	-	7
Tamiya^[12]	2019	213	日本	11.0	肺癌	Ⅲ~Ⅳ	帕博利珠单抗单药	PFS	3.161	-	7
Riccciuti^[13]	2019	650	美国	-	肺癌	Ⅳ	抗-PD-L1或者抗-PD-1+抗-CTLA4	OS/PFS	1.4/0.62	1.6/0.9	8
Parakh^[14]	2017	66	澳大利亚	7.0	黑色素瘤	Ⅳ	纳武利尤单抗或帕博利珠单抗	OS/PFS	2.06	1.72	7
Shafqat^[15]	2018	157	美国	6.7	多种	Ⅳ	纳武利尤单抗或帕博利珠单抗或阿特珠单抗	PFS	0.383	-	6
Tozuka^[16]	2020	197	日本	14.3	肺癌	进展	纳武利尤单抗或帕博利珠单抗或阿特珠单抗	OS/PFS	2.96	4.06	7
Sukari^[17]	2019	168	美国	26.2	多种	Ⅳ	纳武利尤单抗+帕博利珠单抗	OS	-	0.81	8
Adachi^[18]	2020	296	日本	22.6	肺癌	Ⅳ	纳武利尤单抗	PFS	2.85	-	8
Acharya^[19]	2017	72	美国	8.9	黑色素瘤	Ⅳ	纳武利尤单抗或帕博利珠单抗或伊匹单抗	OS	-	2.32	8
Scott^[20]	2018	210	美国	-	肺癌	进展	纳武利尤单抗	OS	-	2.30	6
Fucà^[21]	2018	151	意大利	28.6	肺癌	Ⅳ	抗-PD-L1或抗-PD-1+抗-CTLA4	OS/PFS	1.88	2.38	8
Chasset^[22]	2015	45	法国	21.9	黑色素瘤	Ⅲ~Ⅳ	伊匹单抗	OS	-	5.82	7
Dumenil^[23]	2018	65	法国	-	肺癌	ⅢB~Ⅳ	纳武利尤单抗	OS/PFS	3.27	1.31	6
Hendriks^[24]	2019	1 052	法国/荷兰	15.8	肺癌	进展	抗-PD-L1或抗-PD-1	OS/PFS	2.78	2.37	7
Tanguchi^[25]	2015	201	日本	-	肺癌	Ⅳ	纳武利尤单抗	PFS	2.37	-	6
Zaragoza^[26]	2015	58	法国	31.0	黑色素瘤	Ⅲ~Ⅳ	伊匹单抗	OS	-	1.07	6
Yamaguchic^[27]	2020	131	日本	11.1	肺癌	Ⅲ~Ⅳ	纳武利尤单抗或帕博利珠单抗	OS/PFS	0.73	0.83	6
Faje^[28]	2018	98	美国	-	黑色素瘤	Ⅳ	伊匹单抗	OS/PFS	3.22	4.17	6
Giglio^[29]	2020	413	法国	24.4	肺癌	ⅢB~Ⅳ	抗-PD-L1	OS/PFS	2.64	4.53	8
Facchinetti^[30]	2020	153	法国	18.2	肺癌	ⅢB~Ⅳ	帕博利珠单抗	OS/PFS	0.8	0.6	7
Patil^[31]	2019	11 143	美国	-	肺癌	进展	-	OS	-	1.16	6
Drakaki^[32]	2019	2 213	美国	-	多种	进展	-	OS	-	1.34/1.24/1.44	6

表1 研究的一般特征

作者	发表年份 (年)	样本量 (例)	国家	中位随访时间(月)	疾病	分期	ICI类型	研究终点	$H R$ (PFS)	$H R$ (OS)	NOS 评分
Arbour^[8]	2018	640	美国	-	肺癌	进展	纳武利尤单抗或帕博利珠单抗或阿特珠单抗或德瓦单抗	OS/PFS	1.31	1.66	7
Parakh^[11]	2018	45	澳大利亚	8.7	黑色素瘤	Ⅳ	纳武利尤单抗+伊匹单抗或者纳武利尤单抗单药	PFS	7.69	-	7
Tamiya^[12]	2019	213	日本	11.0	肺癌	Ⅲ~Ⅳ	帕博利珠单抗单药	PFS	3.161	-	7
Riccciuti^[13]	2019	650	美国	-	肺癌	Ⅳ	抗-PD-L1或者抗-PD-1+抗-CTLA4	OS/PFS	1.4/0.62	1.6/0.9	8
Parakh^[14]	2017	66	澳大利亚	7.0	黑色素瘤	Ⅳ	纳武利尤单抗或帕博利珠单抗	OS/PFS	2.06	1.72	7
Shafqat^[15]	2018	157	美国	6.7	多种	Ⅳ	纳武利尤单抗或帕博利珠单抗或阿特珠单抗	PFS	0.383	-	6
Tozuka^[16]	2020	197	日本	14.3	肺癌	进展	纳武利尤单抗或帕博利珠单抗或阿特珠单抗	OS/PFS	2.96	4.06	7
Sukari^[17]	2019	168	美国	26.2	多种	Ⅳ	纳武利尤单抗+帕博利珠单抗	OS	-	0.81	8
Adachi^[18]	2020	296	日本	22.6	肺癌	Ⅳ	纳武利尤单抗	PFS	2.85	-	8
Acharya^[19]	2017	72	美国	8.9	黑色素瘤	Ⅳ	纳武利尤单抗或帕博利珠单抗或伊匹单抗	OS	-	2.32	8
Scott^[20]	2018	210	美国	-	肺癌	进展	纳武利尤单抗	OS	-	2.30	6
Fucà^[21]	2018	151	意大利	28.6	肺癌	Ⅳ	抗-PD-L1或抗-PD-1+抗-CTLA4	OS/PFS	1.88	2.38	8
Chasset^[22]	2015	45	法国	21.9	黑色素瘤	Ⅲ~Ⅳ	伊匹单抗	OS	-	5.82	7
Dumenil^[23]	2018	65	法国	-	肺癌	ⅢB~Ⅳ	纳武利尤单抗	OS/PFS	3.27	1.31	6
Hendriks^[24]	2019	1 052	法国/荷兰	15.8	肺癌	进展	抗-PD-L1或抗-PD-1	OS/PFS	2.78	2.37	7
Tanguchi^[25]	2015	201	日本	-	肺癌	Ⅳ	纳武利尤单抗	PFS	2.37	-	6
Zaragoza^[26]	2015	58	法国	31.0	黑色素瘤	Ⅲ~Ⅳ	伊匹单抗	OS	-	1.07	6
Yamaguchic^[27]	2020	131	日本	11.1	肺癌	Ⅲ~Ⅳ	纳武利尤单抗或帕博利珠单抗	OS/PFS	0.73	0.83	6
Faje^[28]	2018	98	美国	-	黑色素瘤	Ⅳ	伊匹单抗	OS/PFS	3.22	4.17	6
Giglio^[29]	2020	413	法国	24.4	肺癌	ⅢB~Ⅳ	抗-PD-L1	OS/PFS	2.64	4.53	8
Facchinetti^[30]	2020	153	法国	18.2	肺癌	ⅢB~Ⅳ	帕博利珠单抗	OS/PFS	0.8	0.6	7
Patil^[31]	2019	11 143	美国	-	肺癌	进展	-	OS	-	1.16	6
Drakaki^[32]	2019	2 213	美国	-	多种	进展	-	OS	-	1.34/1.24/1.44	6

表2 接受ICIs治疗患者的GC使用特点

作者	样本量 (例)	GC种类	使用时间窗	剂量	治疗目的
Arbour^[8]	90	强的松	ICI治疗前30天到开始治疗后	>10 mg vs <10 mg	肿瘤相关症状
Parakh^[11]	13	强的松或地塞米松	-	≥10 mg/d或2~8 mg	NS
Tamiya^[12]	14	-	ICI开始治疗后	-	NS
Riccciuti^[13]	93	强的松	ICI开始治疗后	>10 mg vs <10 mg	肿瘤相关症状/非肿瘤相关症状
Parakh^[14]	15	地塞米松	ICI开始治疗后	0.5~12 mg	肿瘤相关症状(BMS)
Shafqat^[15]	21	强的松	平均8.5周	-	非肿瘤相关症状(irAEs)
Tozuka^[16]	4	强的松	ICI开始治疗后	10 mg	肿瘤相关症状
Sukari^[17]	77	-	-	-	非肿瘤相关症状(irAEs)
Adachi^[18]	30	-	ICI开始治疗后	-	肿瘤相关症状(60%)/非肿瘤相关症状(30%)
Acharya^[19]	21	地塞米松	ICI开始治疗后	4 mg/d或4 mg/6~12 h	肿瘤相关症状(90%)
Scott^[20]	66	强的松	ICI开始治疗后	≥10 mg/d	肿瘤相关症状/非肿瘤相关症状
Fuca^[21]	35	强的松	ICI开始治疗后28天内	中位数280 mg(20~875 mg)	肿瘤相关症状/非肿瘤相关症状
Chasset^[22]	12	强的松	ICI开始治疗后30天内	平均数0.6 mg/kg(0.2~1.2 mg/kg)	肿瘤相关症状(BMS)
Dumenil^[23]	10	-	ICI开始治疗前1周	中位数25 mg(12.5~37.5 mg)	肿瘤相关症状(BMS)
Hendriks^[24]	141	-	ICI开始治疗后	-	肿瘤相关症状(BMS)
Tanguchi^[25]	12	-	-	中位数6.25 mg(1.56~12.5 mg)	肿瘤相关症状/非肿瘤相关症状
Zaragoza^[26]	15	-	ICI开始治疗前	-	-
Yamaguchic^[27]	NR	-	-	-	非肿瘤相关症状(irAEs)
Faje^[28]	64	强的松	ICI开始治疗后	22.4 mg vs 5 mg	非肿瘤相关症状(irAEs)
Giglio^[29]	114	强的松	ICI开始治疗后8周	≥10 mg	肿瘤相关症状/非肿瘤相关症状
Facchinetti^[30]	47	强的松	ICI开始治疗后	≥10 mg/d	NS
Patil^[31]	1581	强的松	ICI开始治疗后30内	≥10 mg	NS
Drakaki^[32]	556	-	ICI治疗前14天到开始治疗后30天内	-	肿瘤相关症状

表2 接受ICIs治疗患者的GC使用特点

作者	样本量 (例)	GC种类	使用时间窗	剂量	治疗目的
Arbour^[8]	90	强的松	ICI治疗前30天到开始治疗后	>10 mg vs <10 mg	肿瘤相关症状
Parakh^[11]	13	强的松或地塞米松	-	≥10 mg/d或2~8 mg	NS
Tamiya^[12]	14	-	ICI开始治疗后	-	NS
Riccciuti^[13]	93	强的松	ICI开始治疗后	>10 mg vs <10 mg	肿瘤相关症状/非肿瘤相关症状
Parakh^[14]	15	地塞米松	ICI开始治疗后	0.5~12 mg	肿瘤相关症状(BMS)
Shafqat^[15]	21	强的松	平均8.5周	-	非肿瘤相关症状(irAEs)
Tozuka^[16]	4	强的松	ICI开始治疗后	10 mg	肿瘤相关症状
Sukari^[17]	77	-	-	-	非肿瘤相关症状(irAEs)
Adachi^[18]	30	-	ICI开始治疗后	-	肿瘤相关症状(60%)/非肿瘤相关症状(30%)
Acharya^[19]	21	地塞米松	ICI开始治疗后	4 mg/d或4 mg/6~12 h	肿瘤相关症状(90%)
Scott^[20]	66	强的松	ICI开始治疗后	≥10 mg/d	肿瘤相关症状/非肿瘤相关症状
Fuca^[21]	35	强的松	ICI开始治疗后28天内	中位数280 mg(20~875 mg)	肿瘤相关症状/非肿瘤相关症状
Chasset^[22]	12	强的松	ICI开始治疗后30天内	平均数0.6 mg/kg(0.2~1.2 mg/kg)	肿瘤相关症状(BMS)
Dumenil^[23]	10	-	ICI开始治疗前1周	中位数25 mg(12.5~37.5 mg)	肿瘤相关症状(BMS)
Hendriks^[24]	141	-	ICI开始治疗后	-	肿瘤相关症状(BMS)
Tanguchi^[25]	12	-	-	中位数6.25 mg(1.56~12.5 mg)	肿瘤相关症状/非肿瘤相关症状
Zaragoza^[26]	15	-	ICI开始治疗前	-	-
Yamaguchic^[27]	NR	-	-	-	非肿瘤相关症状(irAEs)
Faje^[28]	64	强的松	ICI开始治疗后	22.4 mg vs 5 mg	非肿瘤相关症状(irAEs)
Giglio^[29]	114	强的松	ICI开始治疗后8周	≥10 mg	肿瘤相关症状/非肿瘤相关症状
Facchinetti^[30]	47	强的松	ICI开始治疗后	≥10 mg/d	NS
Patil^[31]	1581	强的松	ICI开始治疗后30内	≥10 mg	NS
Drakaki^[32]	556	-	ICI治疗前14天到开始治疗后30天内	-	肿瘤相关症状

图2 接受ICIs治疗的患者中使用GC者与未使用GC者OS森林图注:steroids:糖皮质激素;no steroids:无糖皮质激素

图3 接受ICIs治疗的患者中使用GC者与未使用GC者PFS森林图注:steroids:糖皮质激素;no steroids:无糖皮质激素

表3 接受ICIs治疗的患者中使用GC者与未使用GC者OS亚组分析

项目	例数	OS $H R$ (95% $C I$ )	$P$	$I 2$	PFS $H R$ (95% $C I$ )	$P$	$I 2$
癌种
非小细胞肺癌	15	1.49(1.2~1.86)	0.0003	79%	1.75(1.31~2.34)	0.0001	76%
黑色素瘤	7	2.12(1.28~3.5)	0.004	73%	3.47(1.68~7.16)	0.0008	57%
尿路上皮癌	1	1.44(1.12~1.89)	-	-	-	-	-
ICI类型
抗PD-1/PD-L1	14	1.54(1.06~2.26)	0.03	81%	1.72(1.21~2.45)	0.003	81%
抗CTLA-4	3	3.02(1.12~8.18)	0.03	71%	3.22(1.42~7.3)	0.005	81%
其他	6	1.32(1.15~1.52)	<0.01	51%	1.95(1.04~3.65)	0.04	77%
适应证
肿瘤相关症状	8	2.14(1.62~2.81)	<0.01	26%	2.26(1.72~2.96)	<0.01	18%
非肿瘤相关症状	5	1.13(0.65~1.96)	0.68	70%	0.94(0.46~1.93)	0.87	78%
国家
亚洲	2	1.74(0.37~8.24)	0.48	89%	2.04(1.07~3.9)	0.03	83%
欧洲	7	1.95(1.03~3.67)	0.04	86%	1.80(0.96~3.36)	0.07	83%
美洲	9	1.39(1.2~1.63)	<0.01	63%	1.24(0.37~8.24)	0.34	72%
澳洲	2	1.72(0.93~3.17)	0.05	-	3.79(1.05~13.75)	0.04	79%
研究类型
单中心	10	1.91(1.25~2.93)	0.003	77%	1.59(1.01~2.50)	0.04	71%
多中心	13	1.28(1.09~1.50)	0.003	67%	2.01(1.35~2.99)	0.006	83%

表3 接受ICIs治疗的患者中使用GC者与未使用GC者OS亚组分析

项目	例数	OS $H R$ (95% $C I$ )	$P$	$I 2$	PFS $H R$ (95% $C I$ )	$P$	$I 2$
癌种
非小细胞肺癌	15	1.49(1.2~1.86)	0.0003	79%	1.75(1.31~2.34)	0.0001	76%
黑色素瘤	7	2.12(1.28~3.5)	0.004	73%	3.47(1.68~7.16)	0.0008	57%
尿路上皮癌	1	1.44(1.12~1.89)	-	-	-	-	-
ICI类型
抗PD-1/PD-L1	14	1.54(1.06~2.26)	0.03	81%	1.72(1.21~2.45)	0.003	81%
抗CTLA-4	3	3.02(1.12~8.18)	0.03	71%	3.22(1.42~7.3)	0.005	81%
其他	6	1.32(1.15~1.52)	<0.01	51%	1.95(1.04~3.65)	0.04	77%
适应证
肿瘤相关症状	8	2.14(1.62~2.81)	<0.01	26%	2.26(1.72~2.96)	<0.01	18%
非肿瘤相关症状	5	1.13(0.65~1.96)	0.68	70%	0.94(0.46~1.93)	0.87	78%
国家
亚洲	2	1.74(0.37~8.24)	0.48	89%	2.04(1.07~3.9)	0.03	83%
欧洲	7	1.95(1.03~3.67)	0.04	86%	1.80(0.96~3.36)	0.07	83%
美洲	9	1.39(1.2~1.63)	<0.01	63%	1.24(0.37~8.24)	0.34	72%
澳洲	2	1.72(0.93~3.17)	0.05	-	3.79(1.05~13.75)	0.04	79%
研究类型
单中心	10	1.91(1.25~2.93)	0.003	77%	1.59(1.01~2.50)	0.04	71%
多中心	13	1.28(1.09~1.50)	0.003	67%	2.01(1.35~2.99)	0.006	83%

图4 关于GC使用与免疫疗效的漏斗分析图 a.PFS;b. OS

图5 分别移除每篇文献后的敏感性分析

a.PFS;b.OS

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