肌减少症对实体瘤患者免疫检查点抑制剂治疗影响的meta分析

doi:10.3969/j.issn.1004-583X.2022.10.002

摘要/Abstract

摘要：

目的探究肌减少症对免疫检查点抑制剂(immune checkpoint Inhibitor, ICIs)的短期疗效、远期预后和免疫相关不良反应的影响。方法对PubMed、EMBASE和Cochrane数据库中在2021年6月前发表的关于肌减少症对免疫治疗的实体瘤患者短期疗效、远期预后和免疫相关不良反应影响的文献进行检索。采用Review Manager 5.3软件和Stata14.0软件进行统计分析。结果共有27篇文献被纳入荟萃分析,Meta分析结果显示合并肌减少症可降低肿瘤患者免疫治疗的客观反应率(RR=0.11,95%CI:0.02~0.54)和疾病控制率(RR=0.55,95%CI:0.39~0.78)。同时,治疗前合并肌减少症是肿瘤患者预后不良的危险因素(OS: HR=1.60, 95%CI:1.30~1.97;PFS: HR=2.81,95%CI:1.88~4.22),甚至在治疗期间肌减少也是患者预后不良的危险因素。合并肌减少症会增加患者发生严重免疫相关不良事件的风险(RR=1.27;95%CI:0.74~2.19)。结论肌减少症是肿瘤患者免疫治疗效果和预后不佳的危险因素。

关键词: 肌减少症, 免疫检查点抑制剂, 癌症免疫治疗, 预后

Abstract:

Objective To explore the effect of sarcopenia on the short-term efficacy, long-term prognosis and immune-related adverse events (irAEs) of immune checkpoint Inhibitor (ICIs). Methods A systematic search were conducted in the PubMed, EMBASE, and Cochrane databases to include relevant studies published before June 2021. Results A total of 27 studies were included in the Meta-analysis, which showed that the patients with sarcopenia had worse the objective response rate (RR=0.11, 95%CI: 0.02-0.54) and disease control rate (RR=0.55, 95%CI:0.39-0.78) than those without the disease. In addition, pooled sarcopenia was found to be a unfavorable prognostic factor of prognosis in tumor patients (OS: HR=1.60, 95%CI: 1.30-1.97; PFS: HR=2.81, 95%CI: 1.88-4.22). Furthermore, sarcopenia tended toward irAEs (RR=1.27;95%CI:0.74-2.19). Conclusion Sarcopenia may be considered as a risk factor for poor therapeutic effect and prognosis in cancer patients.

Key words: sarcopenia, immune checkpoint inhibitors, cancer immunotherapy, prognosis

中图分类号:

R746.4

叶倩, 凌志, 殷旭东. 肌减少症对实体瘤患者免疫检查点抑制剂治疗影响的meta分析[J]. 临床荟萃, 2022, 37(10): 889-898.

Ye Qian, Ling Zhi, Yin Xudong. Sarcopenia on immune checkpoint inhibitors in solid tumor patients with sarcopenia: A meta-analysis[J]. Clinical Focus, 2022, 37(10): 889-898.

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链接本文: https://huicui.hebmu.edu.cn/CN/10.3969/j.issn.1004-583X.2022.10.002

https://huicui.hebmu.edu.cn/CN/Y2022/V37/I10/889

图/表 11

参考文献 43

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作者	发表年份	地区	样本量	肿瘤类型	ICIs种类	诊断指标	测量指标	分界值	结果	质量评价
Dercle^[7]	2016	法国	251	实体瘤	PD-1/PD-L1抑制剂	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	OS	高(8分)
Shiroyama^[8]	2019	日本	42	肺癌	Pembrolizumab Nivolumab	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m²	PFS, OS, DCR	高(8分)
Nishioka^[9]	2019	日本	38	肺癌	Pembrolizumab Nivolumab	PMA by CT	腰2-3层面骨骼肌	▲PMA≥ 10% mPMA	PFS, OS, DCR	高(8分)
Cortellini^[10]	2020	意大利	100	实体瘤	Pembrolizumab Nivolumab Atezolizumb others	SMI by CT	腰3层面骨骼肌	男性:48.4 cm²/m² for BMI<25, 50.2 cm²/m² for BMI≥25 女性:36.9 cm²/m² for BMI<25, 59.6 cm²/m² for BMI≥25	PFS, OS, ORR, irAEs	高(7分)
Crombé^[11]	2020	法国	117	实体瘤	PD-1/PD-L1抑制剂	PMI by CT	腰3层面腰大肌	▲PMI<三分位数最小值	PFS	高(7分)
Roch^[12]	2020	法国	142	肺癌	Pembrolizumab Nivolumab	SMI by CT	腰3层面骨骼肌	男性:52.4 cm²/m² 女性:38.5 cm²/m² ▲SMI≥5% mSMI	PFS, OS, DCR	高(8分)
Takada^[13]	2020	日本	103	肺癌	Pembrolizumab Nivolumab	SMI by CT	腰3层面骨骼肌	男性:25.63 cm²/m² 女性:21.73 cm²/m²	PFS, OS, DCR, ORR	高(7分)
Bilen^[14]	2020	美国	90	实体瘤	NR	SMI by CT	腰3层面骨骼肌	男性:55.97 cm²/m² 女性:37.39 cm²/m²	PFS, OS	高(7分)
Kim^[15]	2020	韩国	102	肝癌	Nivolumab	SMI by CT	腰3层面骨骼肌	男性:42 cm²/m² 女性:38 cm²/m²	PFS, OS, DCR, ORR	高(8分)
Kano^[16]	2020	日本	31	胃癌	Nivolumab	PMI by CT	腰3层面腰大肌	男性:3.6 cm²/m² 女性:2.9 cm²/m²	PFS,DCR,ORR, irAEs	高(7分)
Shimizu^[17]	2020	日本	27	尿路上皮癌	Pembrolizumab	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m² ▲PMI≥10% mPMI	PFS, OS, irAEs	高(8分)
Fukushima^[18]	2020	日本	28	尿路上皮癌	Pembrolizumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² 女性:25 cm²/m²	PFS,ORR,irAEs	高(7分)
Corellini^[19]	2020	意大利	23	肺癌	Nivolumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	PFS,OS,ORR, irAEs	高(7分)
Nishioka^[20]	2021	日本	156	肺癌	Pembrolizumab Nivolumab Atezolizumb	SMI和SMA by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	PFS, ORR	高(7分)
Daly^[21]	2017	爱尔兰	84	黑色素瘤	Ipilimumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI < 25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m² ▲SMI≥7.5% mSMI	OS,irAEs	中(6分)
Deike-Hofmann^[22]	2019	德国	147	黑色素瘤	Ipilimumab	PMD by CT	腰3层面腰大肌	45HU(四分位数最小值)	PFS	中(6分)
Chu^[23]	2020	加拿大	97	黑色素瘤	Ipilimumab	SMD by CT	腰3层面骨骼肌	42HU for BMI<25, 20HU for BMI≥25	PFS, OS, DCR, ORR	中(6分)
Hirsch^[24]	2020	法国	92	实体瘤	Nivolumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	irAEs	中(6分)
Hu^[25]	2020	美国	156	黑色素瘤	Pembrolizumab	PMI by CT	腰3层面腰大肌	男性:5.45 cm²/m² 女性:3.85 cm²/m²	ORR, irAEs	中(6分)
Young^[26]	2020	美国	287	黑色素瘤	Ipilimumab+Nivolumab Pembrolizumab Nivolumab Atezolizumb	SMI和SMD by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25 kg/m², 53 cm²/m² for BMI ≥ 25 kg/m² 女性: 41 cm²/m² 41HU for BMI<25 kg/m², 33HU for BMI≥25 kg/m²	PFS, OS	中(6分)
Akce^[27]	2020	美国	57	肝癌	PD-1抑制剂	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² 女性:39 cm²/m²	PFS, OS	中(6分)
Minami^[28]	2020	日本	74	肺癌	Pembrolizumab Nivolumab Atezolizumb	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m²	PFS, OS, DCR, ORR	中(6分)
Kim^[29]	2020	韩国	149	胃癌	Pembrolizumab Nivolumab	SMI by CT	腰3层面骨骼肌	男性:49 cm²/m² 女性:31 cm²/m²	PFS, OS, DCR, ORR	中(6分)
Tsukgaoshi^[30]	2020	日本	30	肺癌	Nivolumab	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m²	ORR	中(6分)
Youn^[31]	2021	加拿大	44	黑色素瘤	Ipilimumab+Nivolumab Nivolumab	SMD by CT	腰3层面骨骼肌	25.65HU	OS	中(6分)
Loosen^[32]	2021	德国	88	实体瘤	PD-1/PD-L1抑制剂	SMI by CT	腰3层面骨骼肌	▲SMI≥6.18 mm²/cm	OS	中(6分)
Magri^[33]	2019	意大利	46	肺癌	Nivolumab	SMI by CT	腰3层面骨骼肌	NR	OS	低(4分)

作者	发表年份	地区	样本量	肿瘤类型	ICIs种类	诊断指标	测量指标	分界值	结果	质量评价
Dercle^[7]	2016	法国	251	实体瘤	PD-1/PD-L1抑制剂	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	OS	高(8分)
Shiroyama^[8]	2019	日本	42	肺癌	Pembrolizumab Nivolumab	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m²	PFS, OS, DCR	高(8分)
Nishioka^[9]	2019	日本	38	肺癌	Pembrolizumab Nivolumab	PMA by CT	腰2-3层面骨骼肌	▲PMA≥ 10% mPMA	PFS, OS, DCR	高(8分)
Cortellini^[10]	2020	意大利	100	实体瘤	Pembrolizumab Nivolumab Atezolizumb others	SMI by CT	腰3层面骨骼肌	男性:48.4 cm²/m² for BMI<25, 50.2 cm²/m² for BMI≥25 女性:36.9 cm²/m² for BMI<25, 59.6 cm²/m² for BMI≥25	PFS, OS, ORR, irAEs	高(7分)
Crombé^[11]	2020	法国	117	实体瘤	PD-1/PD-L1抑制剂	PMI by CT	腰3层面腰大肌	▲PMI<三分位数最小值	PFS	高(7分)
Roch^[12]	2020	法国	142	肺癌	Pembrolizumab Nivolumab	SMI by CT	腰3层面骨骼肌	男性:52.4 cm²/m² 女性:38.5 cm²/m² ▲SMI≥5% mSMI	PFS, OS, DCR	高(8分)
Takada^[13]	2020	日本	103	肺癌	Pembrolizumab Nivolumab	SMI by CT	腰3层面骨骼肌	男性:25.63 cm²/m² 女性:21.73 cm²/m²	PFS, OS, DCR, ORR	高(7分)
Bilen^[14]	2020	美国	90	实体瘤	NR	SMI by CT	腰3层面骨骼肌	男性:55.97 cm²/m² 女性:37.39 cm²/m²	PFS, OS	高(7分)
Kim^[15]	2020	韩国	102	肝癌	Nivolumab	SMI by CT	腰3层面骨骼肌	男性:42 cm²/m² 女性:38 cm²/m²	PFS, OS, DCR, ORR	高(8分)
Kano^[16]	2020	日本	31	胃癌	Nivolumab	PMI by CT	腰3层面腰大肌	男性:3.6 cm²/m² 女性:2.9 cm²/m²	PFS,DCR,ORR, irAEs	高(7分)
Shimizu^[17]	2020	日本	27	尿路上皮癌	Pembrolizumab	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m² ▲PMI≥10% mPMI	PFS, OS, irAEs	高(8分)
Fukushima^[18]	2020	日本	28	尿路上皮癌	Pembrolizumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² 女性:25 cm²/m²	PFS,ORR,irAEs	高(7分)
Corellini^[19]	2020	意大利	23	肺癌	Nivolumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	PFS,OS,ORR, irAEs	高(7分)
Nishioka^[20]	2021	日本	156	肺癌	Pembrolizumab Nivolumab Atezolizumb	SMI和SMA by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	PFS, ORR	高(7分)
Daly^[21]	2017	爱尔兰	84	黑色素瘤	Ipilimumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI < 25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m² ▲SMI≥7.5% mSMI	OS,irAEs	中(6分)
Deike-Hofmann^[22]	2019	德国	147	黑色素瘤	Ipilimumab	PMD by CT	腰3层面腰大肌	45HU(四分位数最小值)	PFS	中(6分)
Chu^[23]	2020	加拿大	97	黑色素瘤	Ipilimumab	SMD by CT	腰3层面骨骼肌	42HU for BMI<25, 20HU for BMI≥25	PFS, OS, DCR, ORR	中(6分)
Hirsch^[24]	2020	法国	92	实体瘤	Nivolumab	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25, 53 cm²/m² for BMI≥25 女性: 41 cm²/m²	irAEs	中(6分)
Hu^[25]	2020	美国	156	黑色素瘤	Pembrolizumab	PMI by CT	腰3层面腰大肌	男性:5.45 cm²/m² 女性:3.85 cm²/m²	ORR, irAEs	中(6分)
Young^[26]	2020	美国	287	黑色素瘤	Ipilimumab+Nivolumab Pembrolizumab Nivolumab Atezolizumb	SMI和SMD by CT	腰3层面骨骼肌	男性:43 cm²/m² for BMI<25 kg/m², 53 cm²/m² for BMI ≥ 25 kg/m² 女性: 41 cm²/m² 41HU for BMI<25 kg/m², 33HU for BMI≥25 kg/m²	PFS, OS	中(6分)
Akce^[27]	2020	美国	57	肝癌	PD-1抑制剂	SMI by CT	腰3层面骨骼肌	男性:43 cm²/m² 女性:39 cm²/m²	PFS, OS	中(6分)
Minami^[28]	2020	日本	74	肺癌	Pembrolizumab Nivolumab Atezolizumb	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m²	PFS, OS, DCR, ORR	中(6分)
Kim^[29]	2020	韩国	149	胃癌	Pembrolizumab Nivolumab	SMI by CT	腰3层面骨骼肌	男性:49 cm²/m² 女性:31 cm²/m²	PFS, OS, DCR, ORR	中(6分)
Tsukgaoshi^[30]	2020	日本	30	肺癌	Nivolumab	PMI by CT	腰3层面腰大肌	男性:6.36 cm²/m² 女性:3.92 cm²/m²	ORR	中(6分)
Youn^[31]	2021	加拿大	44	黑色素瘤	Ipilimumab+Nivolumab Nivolumab	SMD by CT	腰3层面骨骼肌	25.65HU	OS	中(6分)
Loosen^[32]	2021	德国	88	实体瘤	PD-1/PD-L1抑制剂	SMI by CT	腰3层面骨骼肌	▲SMI≥6.18 mm²/cm	OS	中(6分)
Magri^[33]	2019	意大利	46	肺癌	Nivolumab	SMI by CT	腰3层面骨骼肌	NR	OS	低(4分)

组别	HR(95%CI)	P值
肿瘤类型
肺癌	1.57(1.22~2.0)	0.000
黑色素瘤	1.41(0.84~2.38)	0.190
其他	1.73(1.29~2.32)	0.000
ICIs类型
Pembrolizumab	4.0(1.18~13.56)	0.030
nivolumab	1.49(0.88~2.52)	0.013
Ipilimumab	2.12(1.17~3.84)	0.010
其他	1.55(1.22~1.97)	0.000
诊断指标
SMI	1.62(1.33~1.97)	0.000
PMI	1.97(0.88~4.42)	0.100
SMD	1.47(0.79~2.75)	0.230
PMD	-	-
地区
亚洲	1.41(0.98~2.01)	0.060
欧美	1.71(1.31~2.22)	0.000

组别	HR(95%CI)	P值
肿瘤类型
肺癌	1.57(1.22~2.0)	0.000
黑色素瘤	1.41(0.84~2.38)	0.190
其他	1.73(1.29~2.32)	0.000
ICIs类型
Pembrolizumab	4.0(1.18~13.56)	0.030
nivolumab	1.49(0.88~2.52)	0.013
Ipilimumab	2.12(1.17~3.84)	0.010
其他	1.55(1.22~1.97)	0.000
诊断指标
SMI	1.62(1.33~1.97)	0.000
PMI	1.97(0.88~4.42)	0.100
SMD	1.47(0.79~2.75)	0.230
PMD	-	-
地区
亚洲	1.41(0.98~2.01)	0.060
欧美	1.71(1.31~2.22)	0.000

组别	HR(95%CI)	P值
肿瘤类型
肺癌	1.36(0.95~1.95)	0.090
黑色素瘤	1.24(0.97~1.59)	0.090
其他	1.6(1.26~2.02)	<0.01
ICIs类型
Pembrolizumab	2.98(1.53~5.80)	0.001
Nivolumab	1.64(1.06~2.55)	0.030
Ipilimumab	1.63(1.19~2.23)	0.002
其他	1.26(1.04~1.54)	0.020
诊断指标
SMI	1.47(1.22~1.77)	<0.01
PMI	1.87(0.94~3.59)	0.070
SMD	0.97(0.70~1.34)	0.860
PMD	1.67(1.14~2.45)	0.008
地区
亚洲	1.44(1.03~2.01)	0.030
欧美	1.38(1.15~1.66)	0.000