质子泵抑制剂对晚期实体肿瘤免疫检查点抑制剂治疗效果的影响

摘要/Abstract

摘要：

目的评估使用质子泵抑制剂(PPI)对免疫检查点抑制剂(ICI)治疗晚期实体肿瘤临床效果的影响。方法回顾性分析2016年11月至2020年12月于扬州大学附属医院接受ICI治疗的晚期实体肿瘤患者204例,根据在ICI治疗开始前后1个月内是否伴随使用PPI分为PPI组(n=73)与Non-PPI组(n=131)。探究PPI使用与患者临床病理特征的相关性,评价两组患者的临床疗效。Kaplan-Meier生存曲线分析PPI使用对患者总生存期(OS)及无进展生存期(PFS)的影响。Cox风险比例模型分析PPI使用是否为影响患者预后的独立指标。结果在晚期实体肿瘤ICI治疗过程中,PPI使用与患者性别、年龄、肿瘤类型、美国东部协作组评分、免疫治疗药物种类及治疗策略均无关(均P>0.05)。Non-PPI组客观缓解率优于PPI组(45.0%vs.24.7%,χ²=8.286,P=0.004);Non-PPI组疾病控制率优于PPI组(75.6%vs.52.0%,χ²=11.755,P=0.001)。晚期实体肿瘤患者中PPI组患者中位OS(3.4个月vs. 6.1个月)及中位PFS(2.8个月vs.4.0个月)均短于Non-PPI组(χ²=9.563,P=0.002;χ²=5.761,P=0.016)。单因素分析显示,在接受ICI治疗的晚期实体肿瘤患者中,PPI与OS显著相关(HR=1.85,95%CI为1.242.76,P=0.003);PPI(HR=1.65,95%CI为1.092.51,P=0.019)和年龄(HR=1.56,95%CI为1.052.32,P=0.029)均与PFS显著相关。多因素分析显示,PPI为影响患者OS(HR=1.90,95%CI为1.272.85,P=0.002)及PFS(HR=1.73,95%CI为1.122.65,P=0.013)的独立预后因素。亚组分析发现,在肺癌患者ICI治疗过程中PPI组(n=64)中位OS(3.2个月vs. 6.2个月)及中位PFS(2.2个月vs. 3.8个月)较Non-PPI组(n=34)短(χ²=16.187,P<0.001;χ²=5.106,P=0.020)。单因素分析显示,PPI与接受ICI治疗的肺癌患者OS(HR=2.97,95%CI为1.705.22,P<0.001)、PFS(HR=1.97,95%CI为1.093.55,P=0.025)均相关;多因素显示,PPI是影响接受ICI治疗的肺癌患者OS(HR=3.38,95%CI为1.876.11,P<0.001)及PFS(HR=2.31,95%CI为1.224.38,P=0.010)的独立预后因素。结论PPI的使用降低了ICI治疗晚期实体肿瘤的效果,尤其在肺癌中更显著。接受ICI治疗的晚期实体肿瘤患者应谨慎使用PPI。

关键词:质子泵抑制剂,肿瘤,预后,免疫检查点抑制剂

Abstract:

ObjectiveTo evaluate the effects of proton pump inhibitors (PPIs) on the clinical outcomes for advanced solid tumor patients treated with immune checkpoint inhibitors (ICIs).MethodsA total of 204 patients with advanced solid tumors who received ICIs in the Affiliated Hospital of Yangzhou University from November 2016 to December 2020 were retrospectively analyzed. The patients were divided into PPIs group (n=73) and Non-PPIs group (n=131) according to whether they received PPIs within 1 month before or after the initiation of ICIs treatment. The correlations between the uses of PPIs and the clinical characteristics of patients were explored, and the clinical efficacy of the two groups was evaluated. Kaplan-Meier survival curve was applied to analyze the effects of PPIs uses on overall survival (OS) and progression-free survival (PFS) of patients. The Cox proportional hazards model was used to clarify whether PPIs was an independent indicator of patients' prognosis.ResultsDuring ICIs treatment of advanced solid tumors, the use of PPIs was not correlated with the patients' gender, age, tumor type, the score of the United States Eastern Collaborative Group, types of immunotherapy drugs and treatment strategy (allP>0.05). The objective response rate of the Non-PPIs group was better than that of the PPIs group (45.0%vs.24.7%,χ²=8.286,P=0.004). The disease control rate of the Non-PPIs group was better than that of the PPIs group (75.6%vs.52.0%,χ²=11.755,P=0.001). In patients with advanced solid tumors, the median OS (3.4 monthsvs. 6.1 months) and median PFS (2.8 monthsvs. 4.0 months) in the PPIs group were shorter than those in the Non-PPIs group (χ²=9.563,P=0.002;χ²=5.761,P=0.016). Univariate analysis showed that among patients with advanced solid tumors treated with ICIs, PPIs uses was significantly correlated with OS (HR=1.85, 95%CI: 1.24-2.76,P=0.003); PPIs uses(HR=1.65, 95%CI: 1.09-2.51,P=0.019) and age (HR=1.56, 95%CI: 1.05-2.32,P=0.029) were significantly correlated with PFS. Multivariate analysis showed that PPIs uses was an independent prognostic factor affecting OS (HR=1.90, 95%CI: 1.27-2.85,P=0.002) and PFS (HR=1.73, 95%CI: 1.12-2.65,P=0.013). Meanwhile, subgroup analysis discovered that in the course of ICIs treatment of lung cancer patients, the median OS (3.2 monthsvs. 6.2 months) and median PFS (2.2 monthsvs. 3.8 months) in the PPIs group (n=64) were shorter than those in the Non-PPIs group (n=34) (χ²=16.187,P<0.001;χ²=5.106,P=0.020). Univariate analysis showed that PPIs uses was associated with OS (HR=2.97, 95%CI: 1.70-5.22,P<0.001) and PFS (HR=1.97, 95%CI: 1.09-3.55,P=0.025) in lung cancer patients treated with ICIs. Multivariate analysis showed that PPIs uses was an independent prognostic factor for OS (HR=3.38, 95%CI: 1.87-6.11, P<0.001) and PFS (HR=2.31, 95%CI: 1.22-4.38,P=0.010) in lung cancer patients treated with ICIs.ConclusionThe use of PPIs reduces the effect of ICIs in the treatment of advanced solid tumor, especially in lung cancer. PPIs should be used cautiously in patients with advanced solid tumors treated with ICIs.

Key words:Proton pump inhibitors,Neoplasms,Prognosis,Immune checkpoint inhibitors

刘超星, 严雪冰, 杨梦雪, 童建东, 毛海燕. 质子泵抑制剂对晚期实体肿瘤免疫检查点抑制剂治疗效果的影响[J]. 国际肿瘤学杂志, 2022, 49(1): 26-32.

Liu Chaoxing, Yan Xuebing, Yang Mengxue, Tong Jiandong, Mao Haiyan. Effects of proton pump inhibitors on outcomes for advanced solid tumor patients treated with immune checkpoint inhibitors[J]. Journal of International Oncology, 2022, 49(1): 26-32.

图/表8

表1

接受ICI治疗的204例晚期实体肿瘤患者PPI使用情况与临床病理特征的关系(例)"

临床病理特征	例数	PPI组 (n=73)	Non-PPI组 (n=131)	χ²值	P值
性别
男	131	45	86	0.327	0.567
女	73	28	45
年龄(岁)
≤65	142	49	93	0.332	0.565
>65	62	24	38
肿瘤类型
肺癌	98	34	64
食管癌	48	12	36	5.406	0.067
其他	58	27	31
ECOG评分(分)
01	142	54	88	1.024	0.312
23	62	19	43
免疫治疗药物种类
信迪利单抗	63	19	44
卡瑞利珠单抗	42	15	27
替雷利珠单抗	39	15	24	2.572	0.766
特瑞普利单抗	27	9	18
帕博利珠单抗	21	9	12
纳武利尤单抗	12	6	6
治疗策略
ICI单药	79	28	51	0.007	0.936
联合治疗	125	45	80

表1

组别	CR	PR	SD	PD	客观缓解	疾病控制
PPI组(n=73)	0(0)	18(24.7)	20(27.4)	35(47.9)	18(24.7)	38(52.0)
Non-PPI组(n=131)	0(0)	59(45.0)	40(30.5)	32(24.4)	59(45.0)	99(75.6)
χ²值					8.286	11.755
P值					0.004	0.001

表2

图1

变量	OS		PFS
性别(男/女)	0.93	0.611.43	0.749	1.12	0.751.67	0.569
年龄(≤65岁/>65岁)	0.80	0.531.21	0.296	1.56	1.052.32	0.029
ECOG评分(01分/23分)	1.12	0.761.69	0.569	1.09	0.731.62	0.679
ICI治疗策略(ICI 单药/联合)	1.15	0.791.68	0.470	1.31	0.901.91	0.163
PPI(使用/未使用)	1.85	1.242.76	0.003	1.65	1.092.51	0.019

表3

变量	OS		PFS
性别(男/女)	0.84	0.521.26	0.468	0.95	0.601.50	0.839
年龄(≤65岁/>65岁)	1.44	0.882.33	0.145	1.61	1.002.58	0.050
ECOG评分(01分/23分)	1.22	0.801.84	0.352	1.25	0.821.92	0.300
ICI治疗策略(ICI 单药/联合)	1.18	0.791.75	0.424	1.31	0.881.96	0.185
PPI(使用/未使用)	1.90	1.272.85	0.002	1.73	1.122.65	0.013

表4

图2

变量	OS		PFS
性别(男/女)	0.63	0.271.47	0.284	0.98	0.482.01	0.957
年龄(≤65岁/>65岁)	1.46	0.842.53	0.178	1.54	0.882.71	0.131
ECOG评分(01分/23分)	1.24	0.742.07	0.420	1.37	0.812.30	0.242
ICI治疗策略(ICI 单药/联合)	1.18	0.711.94	0.524	1.21	0.722.03	0.469
PPI(使用/未使用)	2.97	1.705.22	<0.001	1.97	1.093.55	0.025

表5

变量	OS		PFS
性别(男/女)	2.17	0.865.46	0.101	0.75	0.331.70	0.487
年龄(≤65岁/>65岁)	1.88	1.023.45	0.042	1.72	0.913.25	0.093
ECOG评分(01分/23分)	1.59	0.902.83	0.115	1.75	0.993.09	0.056
ICI治疗策略(ICI 单药/联合)	1.66	0.932.99	0.089	1.64	0.903.02	0.109
PPI(使用/未使用)	3.38	1.876.11	<0.001	2.31	1.224.38	0.010

表6

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