放疗联合PD-1抑制剂治疗驱动基因阴性非小细胞肺癌脑转移患者的疗效分析

张献文; 孙谦; 蔡丰; 赵梦蝶; 宋世龙; 陈如君; 江浩

doi:10.16766/j.cnki.issn.1674-4152.003787

放疗联合PD-1抑制剂治疗驱动基因阴性非小细胞肺癌脑转移患者的疗效分析

doi: 10.16766/j.cnki.issn.1674-4152.003787

蚌埠医科大学第一附属医院放疗科，安徽蚌埠 233004

基金项目:

国家自然科学基金项目 82403993

蚌埠医学院自然科学重点项目 2021byzd159

安徽省临床医学研究转化专项项目 202304295107020078

详细信息

通讯作者:
江浩，E-mail: jianghao1223@163.com

中图分类号: R734.2 R730.58
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出版历程
- 收稿日期: 2024-10-08

Prognostic analysis of radiotherapy combined with PD-1 inhibitors in patients with driver-gene negative non-small cell lung cancer and brain metastases

Department of Radiotherapy, the First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui 233004, China

摘要

摘要: 目的观察颅脑放疗(RT)与程序性死亡受体1(PD-1)抑制剂联合治疗在驱动基因阴性非小细胞肺癌(NSCLC)伴脑转移(BMs)患者中的疗效及不良反应, 探讨其临床应用价值。方法收集2021年1月—2023年7月蚌埠医科大学第一附属医院接受RT的90例NSCLC伴BMs患者，根据是否联合PD-1抑制剂治疗分为放疗组(40例)和联合组(50例)。采用Kaplan-Meier方法和Cox回归模型评估颅内近期疗效、颅内局部无进展生存(iLPFS)、颅内远处无进展生存(iDPFS)和总生存(OS)。结果随访至2024年7月，放疗组和联合组的颅内客观缓解率(iORR)分别为45.0%(18/40)和72.0%(36/50, P=0.009)；放疗组和联合组中位iLPFS、iDPFS、OS分别11个月(95% CI: 8.77~13.23)、14个月(95% CI: 7.69~20.31)、14个月(95% CI: 11.98~16.02)和22个月(95% CI: 18.23~25.77)、21个月(95% CI: 13.24~28.76)、21个月(95% CI: 17.63~24.37)，差异均有统计学意义(P < 0.05)。单因素与多因素分析显示，联合PD-1抑制剂治疗是影响iLPFS与iDPFS的独立预后因素。分层分析显示，放疗尽早介入，尤其是放疗与PD-1抑制剂同步治疗(≤2周)的患者具有更优的iLPFS(P=0.007)和iDPFS(P=0.027)，但OS差异无统计学意义(P=0.385)。2组患者不良反应均可耐受。结论 RT联合PD-1抑制剂治疗，尤其是RT与PD-1抑制剂同时应用(≤2周)可提高驱动基因阴性NSCLC伴BMs患者的iLPFS、iDPFS，有利于改善OS。
- 非小细胞肺癌 /
- 脑转移 /
- 放疗 /
- 程序性死亡受体1抑制剂
Abstract: Objective Observation of the efficacy and adverse reactions of combined treatment of cranial radiation therapy (RT) and programmed death-1 (PD-1) inhibitors in patients with driver gene negative non-small cell lung cancer (NSCLC) with brain metastases (BMs), and exploration of its clinical application value. Methods A total of 90 NSCLC BM patients who received RT at the First Affiliated Hospital of Bengbu Medical University from January 2021 to July 2023 were included. They were divided into the radiotherapy group (40 cases) and the combination group (50 cases), based on whether they were treated with PD-1 inhibitors. Kaplan-Meier method and Cox regression model were used to evaluate intracranial short-term efficacy, intracranial local progression free survival (iLPFS), intracranial distant progression free survival (iDPFS), and overall survival (OS). Results By July 2024, the intracranial objective response rate (iORR) was 45.0% and 72.0% in the radiotherapy group and the combination group, respectively (P=0.009). The median iLPFS, iDPFS, and OS for the radiotherapy group were 11 months (95% CI: 8.77-13.23), 14 months (95% CI: 7.69-20.31), and 14 months (95% CI: 11.98-16.02), respectively. In the combination group, the corresponding medians were 22 months (95% CI: 18.23-25.77), 21 months (95% CI: 13.24-28.76), and 21 months (95% CI: 17.63-24.37), respectively, with statistically significant differences (P < 0.05). Univariate and multivariate analysis showed that combined PD-1 inhibitor therapy is an independent prognostic factor for iLPFS and iDPFS. Stratified analysis showed that early intervention of RT, especially when synchronized with PD-1 inhibitors (≤ 2 weeks), resulted in significantly improved iLPFS (P=0.007) and iDPFS (P=0.027), though no statistically significant difference was observed in OS (P=0.385). Both groups of patients tolerated adverse reactions. Conclusion The combination therapy of RT and PD-1 inhibitors, especially when administered simultaneously (≤ 2 weeks), improves iLPFS and iDPFS in patients with driver gene-negative NSCLC BMs, contributing to improved OS.
- Non-small cell lung cancer /
- Brain metastases /
- Radiotherapy /
- Programmed death-1 inhibitors
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图 1 3组NSCLC BMs患者颅内局部无进展生存曲线

Figure 1. iLPFS curves among the three groups of BMs patients with NSCLC

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图 2 3组NSCLC BMs患者颅内远处无进展生存曲线

Figure 2. iDPFS curves among the three groups of BMs patients with NSCLC

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图 3 3组NSCLC BMs患者总生存曲线

Figure 3. OS curves among the three groups of BMs patients with NSCLC

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表 1 2组NSCLC BMs患者临床基线特征比较(例)

Table 1. Comparison of clinical baseline characteristics between the two groups of BMs patients with NSCLC (cases)

特征	放疗组(n=40)	联合组(n=50)	统计量	P值
性别			0.508^a	0.476
男性	26	36
女性	14	14
年龄			3.441^a	0.067
≤60岁	13	26
>60岁	27	24
吸烟			0.573^a	0.449
是	20	29
否	20	21
ECOG评分			-1.412^b	0.158
0分	9	21
1分	25	21
2分	6	8
病理类型
鳞癌	8	17	2.171^a	0.141
腺癌	32	33
脑转移数目			-0.156^b	0.876
1个	13	14
2~4个	15	22
≥5个	12	14
颅外转移			1.825^a	0.177
有	13	10
无	27	40
放疗模式			2.851^a	0.240
SRT	18	30
SRT+WBRT	9	11
WBRT	13	9
注：^a为χ²值，^b为Z值。ECOG评分为东部肿瘤协作组(Eastern Cooperative Oncology Group)评分。

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表 2 2组NSCLC BMs患者近期疗效分析[例(%)]

Table 2. Recent efficacy analysis between the two groups of BMs patients with NSCLC [cases (%)]

组别	例数	iCR	iPR	iSD	iPD	iORR	iDCR
放疗组	40	1(2.5)	17(42.5)	14(35.0)	8(20.0)	18(45.0)	32(80.0)
联合组	50	11(22.0)	25(50.0)	12(24.0)	2(4.0)	36(72.0)	48(96.0)
χ²值		7.312	0.502	1.309	4.254	6.750	4.254
P值		0.007	0.479	0.253	0.039	0.009	0.039

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表 3 NSCLC BMs患者iLPFS的单因素及多因素分析

Table 3. Univariate and multivariate analysis of iLPFS in BMs patients with NSCLC

变量	单因素分析		多因素分析
变量	HR(95% CI)	P值	HR(95% CI)	P值
性别(女性)	0.69(0.37~1.21)	0.185
年龄(>60岁)	1.31(0.76~2.25)	0.329
吸烟(否)	0.76(0.44~1.29)	0.308
ECOG评分
1分	1.85(0.99~3.48)	0.055	1.50(0.70~3.20)	0.295
2分	2.86(1.21~6.75)	0.017	3.63(1.35~9.80)	0.011
病理类型(腺癌)	0.93(0.69~1.26)	0.646
BMs数目
2~4个	1.30(0.66~2.55)	0.452	1.48(0.71~3.11)	0.295
≥5个	2.19(1.06~4.50)	0.033	2.62(1.09~6.31)	0.032
颅外转移(无)	0.75(0.41~1.37)	0.351
放疗模式
SRT+WBRT	1.48(0.75~2.92)	0.258	0.88(0.39~1.96)	0.748
WBRT	2.41(1.26~4.60)	0.008	1.56(0.74~3.28)	0.244
联合PD-1抑制剂(否)	3.70(2.04~6.72)	< 0.001	3.79(1.99~7.19)	< 0.001
注：以男性、年龄≤60岁、吸烟(是)、ECOG评分0分、病理类型鳞癌、BMs数目1个、颅外转移(有)、放疗模式SRT、联合PD-1抑制剂(是)为参照。变量赋值如下，性别，男性=0，女性=1；年龄≤60岁=0，>60岁=1；吸烟，是=0，否=1；ECOG评分，0分=0，1分=1，2分=2；病理类型，鳞癌=0，腺癌=1；脑转移数目，1个=(0, 0)，2~4个=(1, 0)，≥5个=(0, 1)；颅外转移，有=0，无=1；放疗模式，SRT=(0, 0)，SRT+WBRT=(1, 0)，WBRT=(0, 1)；联合PD-1抑制剂，是=0，否=1。

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表 4 NSCLC BMs患者iDPFS的单因素及多因素分析

Table 4. Univariate and multivariate analysis of iDPFS in BMs patients with NSCLC

变量	单因素分析		多因素分析
变量	HR(95% CI)	P值	HR(95% CI)	P值
性别(女性)	0.79(0.45~1.41)	0.431
年龄(>60岁)	1.40(0.82~2.41)	0.222
吸烟(否)	0.71(0.41~1.22)	0.210
ECOG评分
1分	1.26(0.69~2.29)	0.453
2分	2.05(0.85~4.91)	0.108
病理类型(腺癌)	1.09(0.60~2.01)	0.771
BMs数目
2-4个	0.86(0.44~1.66)	0.642	0.88(0.46~1.71)	0.709
≥5个	1.70(0.87~3.39)	0.093	1.58(0.79~3.16)	0.194
颅外转移(无)	0.71(0.38~1.28)	0.257
放疗模式
SRT+WBRT	1.17(0.59~2.29)	0.658
WBRT	1.71(0.88~3.30)	0.113
联合PD-1抑制剂(否)	1.95(1.13~3.38)	0.017	1.81(1.04~3.15)	0.035
注：以男性、年龄≤60岁、吸烟(是)、ECOG评分0分、病理类型鳞癌、BMs数目1个、颅外转移(有)、放疗模式SRT、联合PD-1抑制剂(是)为参照。

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表 5 NSCLC BMs患者OS的单因素及多因素分析

Table 5. Univariate and multivariate analysis of OS in BMs patients with NSCLC

变量	单因素分析		多因素分析
变量	HR(95% CI)	P值	HR(95% CI)	P值
性别(女性)	0.66(0.39~1.14)	0.134
年龄(>60岁)	1.89(1.14~3.15)	0.014	1.99(1.17~3.78)	0.011
吸烟(否)	0.68(0.41~1.11)	0.124
ECOG评分
1分	1.99(1.10~3.58)	0.023	1.97(0.99~3.95)	0.055
2分	5.28(2.43~11.49)	< 0.001	8.85(3.48~22.49)	< 0.001
病理类型(腺癌)	1.08(0.62~1.91)	0.780
BMs数目
2-4个	0.75(0.41~1.39)	0.362
≥5个	1.40(0.74~2.63)	0.304
颅外转移(无)	0.60(0.36~1.01)	0.055	0.36(0.18~0.72)	0.004
放疗模式
SRT+WBRT	1.57(0.86~2.85)	0.141	0.90(0.45~1.79)	0.761
WBRT	2.21(1.13~3.66)	0.019	2.19(1.09~4.39)	0.027
联合PD-1抑制剂(否)	1.04(1.00~2.67)	0.049	1.11(0.64~1.90)	0.717
注：以男性、年龄≤60岁、吸烟(是)、ECOG评分0分、病理类型鳞癌、BMs数目1个、颅外转移(有)、放疗模式SRT、联合PD-1抑制剂(是)为参照。

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表 6 2组NSCLC BMs患者不良反应比较(例)

Table 6. Comparison of adverse reactions between the two groups of BMs patients with NSCLC (cases)

不良反应	任意级别		χ²值	P值	3-4级		P值
不良反应	放疗组	联合组	χ²值	P值	放疗组	联合组	P值
乏力	4	9	1.151	0.371	0	0
皮疹/瘙痒	0	6		0.032^a	0	0
食欲下降	10	11	0.112	0.805	0	0
恶心/呕吐	8	12	0.206	0.800	0	0	-
骨髓抑制	4	4		0.999^a	0	1	0.999^a
肝功能异常	1	2		0.999^a	0	0
甲状腺功能异常	0	5		0.063^a	0	0
ICIs相关肺炎	0	3		0.251^a	0	0
放射性脑损伤	9	11	0.003	0.999	1	0	0.999^a
注：^a为采用Fisher精确检验。

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