β-榄香烯联合吉非替尼治疗一线应用吉非替尼后缓慢进展晚期肺腺癌患者的临床疗效

摘要/Abstract

摘要：

目的探讨β-榄香烯联合吉非替尼治疗一线应用吉非替尼后缓慢进展晚期肺腺癌患者的临床疗效及对生命质量和免疫功能的影响。方法采用前瞻性队列研究设计,纳入我院2017年6月至2018年12月收治的符合入组标准的晚期肺腺癌患者,采用随机数字表法分为试验组和对照组,试验组给予榄香烯联合吉非替尼治疗,对照组仅给予吉非替尼治疗。治疗2周期后比较两组患者的临床疗效、生命质量及免疫功能。并随访从疾病缓慢进展至疾病出现快速进展的时间(PFS2)。结果共纳入61例患者,试验组、对照组分别为30例和31例。试验组和对照组的疾病控制率分别为83.3%(25/30)和58.1%(18/31),差异有统计学意义(χ²=4.680,P=0.031),试验组近期疗效优于对照组,差异有统计学意义(Z=-2.623,P=0.009)。试验组中位PFS2为4.20个月(95%CI为3.94~4.46),对照组中位PFS2为4.00个月(95%CI为2.94~5.07),差异有统计学意义(χ²=4.948,P=0.026)。两组生命质量比较,在躯体功能、情绪功能、总体生命质量方面,试验组治疗前后评分差值较对照组高,差异均有统计学意义[6.67(-6.66,20.00)vs.0(-6.66,6.66),Z=-2.429,P=0.015;29.17(2.08,56.26)vs.12.49(-14.59,39.57),Z=-2.263,P=0.024;16.67(-33.33,56.67)vs.8.34(-18.74,35.42),Z=-2.249,P=0.025]。免疫功能方面,试验组治疗后CD4⁺T细胞水平较治疗前升高(44.27%±6.78%vs.41.17%±3.73%,t=-2.426,P=0.022),CD8⁺T细胞水平较治疗前降低(21.47%±3.18%vs.23.50%±2.37%,t=2.532,P=0.017)。治疗后试验组CD4⁺T细胞水平明显高于对照组(44.27%±6.78%vs.39.63%±5.80%,t=2.725,P=0.011)。结论β-榄香烯联合吉非替尼治疗一线吉非替尼治疗后缓慢进展晚期肺腺癌患者有一定的疗效,生命质量和免疫功能均有所改善,值得临床进一步研究。

关键词:癌,非小细胞肺,抗药性,肿瘤,榄香烯,吉非替尼

Abstract:

ObjectiveTo investigate the efficacy of β-elemene combined with gefitinib in the treatment of advanced lung adenocarcinoma patients with slow progression after first-line gefitinib treatment and its effects on quality of life and immune function.MethodsA prospective cohort study design was used to enroll patients with advanced lung adenocarcinoma who met the inclusion criteria from June 2017 to December 2018 in our hospital. They were divided into experimental group and control group by random number table method. The experimental group was given elemene combined with gefitinib, and the control group was only given gefitinib. The clinical efficacy, quality of life and immune function of the two groups were compared after 2 cycles of treatment. The PFS2 (time from slow progression of disease to rapid progression of disease) was followed up.ResultsA total of 61 patients were included. There were 30 cases in the experimental group and 31 cases in the control group. The disease control rates of the experimental group and the control group were 83.3% (25/30) and 58.1% (18/31) respectively, and the difference was statistically significant (χ²=4.680,P=0.031). The short-term efficacy of the experimental group was better than that of the control group, and the difference was statistically significant (Z=-2.623,P=0.009). The median PFS2 of the experimental group was 4.20 months (95%CI: 3.94-4.46), and the median PFS2 of the control group was 4.00 months (95%CI: 2.94-5.07), with a statistically significant difference (χ²=4.948,P=0.026). Quality of life was compared between the two groups: in terms of physical function, emotional function and overall quality of life, score differences before and after treatment of the experimental group were higher than those of the control group, with statistically significant differences [6.67(-6.66, 20.00)vs.0(-6.66, 6.66),Z=-2.429,P=0.015; 29.17(2.08, 56.26)vs.12.49(-14.59, 39.57),Z=-2.263,P=0.024; 16.67(-33.33, 56.67)vs.8.34(-18.74, 35.42),Z=-2.249,P=0.025]. In terms of immune function, CD4⁺T cells level in the experimental group increased after treatment compared with that before treatment (44.27%±6.78%vs.41.17%±3.73%,t=-2.426,P=0.022), and CD8⁺T cells level decreased compared with that before treatment (21.47%±3.18%vs.23.50%±2.37%,t=2.532,P=0.017). After treatment, the level of CD4⁺T cells in the experimental group was significantly higher than that in the control group (44.27%±6.78%vs.39.63%±5.80%,t=2.725,P=0.011).Conclusionβ-elemene combined with gefitinib has a certain effect in the treatment of advanced lung adenocarcinoma patients with slow progression after first-line gefitinib treatment, and the quality of life and immune function are improved. It is worthy of further clinical research.

Key words:Carcinoma,non-small-cell lung,Drug resistance,neoplasm,Elemene,Gefitinib

宋春青, 张颖, 张志国, 郭宏伟, 陆汉红, 韩磊. β-榄香烯联合吉非替尼治疗一线应用吉非替尼后缓慢进展晚期肺腺癌患者的临床疗效[J]. 国际肿瘤学杂志, 2020, 47(5): 272-277.

Song Chunqing, Zhang Ying, Zhang Zhiguo, Guo Hongwei, Lu Hanhong, Han Lei. Efficacy of β-elemene combined with gefitinib in the treatment of advanced lung adenocarcinoma patients with slow progression after first-line gefitinib treatment[J]. Journal of International Oncology, 2020, 47(5): 272-277.

图/表5

表1

两组一线应用吉非替尼后缓慢进展晚期肺腺癌患者基本特征比较[例(%)/M(P25,P75)]"

基本特征	试验组(n=30)	对照组(n=31)	χ²/Z值	P值
性别
男	20(66.7)	20(64.5)	0.310	0.860
女	10(33.3)	11(35.5)
年龄(岁)	68.00(63.75,72.25)	69.00(62.00,76.00)	-1.392	0.164
性别ECOG评分
0	5(16.7)	4(12.9)
1	14(46.7)	20(64.5)	2.043	0.360
2	11(36.7)	7(22.6)
主要转移部位
骨	8(26.7)	7(22.6)
肝	11(36.7)	11(35.5)
肾上腺	2(6.7)	5(16.1)	1.536	0.820
淋巴结	6(20.0)	6(19.4)
其他	3(10.0)	2(6.5)
文化程度
小学及以下	13(43.3)	16(51.6)
初中	12(40.0)	10(32.3)	0.476	0.788
高中及以上	5(16.7)	5(16.1)
PFS1(月)	8.00(6.85,9.15)	8.00(6.80,9.20)	-0.022	0.983

表1

组别	CR	PR	SD	PD	疾病控制	有效
试验组(n=30)	0	4(13.3)	21(70.0)	5(16.7)	25(83.3)	4(13.3)
对照组(n=31)	0	0(0)	18(58.1)	13(41.9)	18(58.1)	0(0)
Z/χ²值	-2.623	4.680	2.515
P值	0.009	0.031	0.113

表2

图1

表3

两组一线应用吉非替尼后缓慢进展晚期肺腺癌患者二线治疗前后生命质量差值比较[M(P25,P75)]"

生命质量	试验组(n=30)	对照组(n=31)	Z值	P值
躯体功能	6.67(-6.66,20.00)	0(-6.66,6.66)	-2.429	0.015
角色功能	0(-33.31,33.31)	0(-33.31,33.31)	-0.646	0.519
社会功能	16.67(-16.66,50.00)	16.67(-16.66,50.00)	-0.161	0.872
认知功能	0(-33.34,33.34)	0(-20.84,20.84)	-0.431	0.667
情绪功能	29.17(2.08,56.26)	12.49(-14.59,39.57)	-2.263	0.024
疲倦	30.00(-11.11,11.11)	0(0,0)	-0.367	0.714
恶心呕吐	0(0,0)	0(0,0)	-0.303	0.762
疼痛	0(-16.66,16.66)	0(0,0)	-0.715	0.474
呼吸困难	0(0,0)	0(0,0)	-0.074	0.941
睡眠困难	0(-33.33,33.33)	0(-8.33,8.33)	-0.530	0.596
食欲减退	0(0,0)	0(0,0)	-0.404	0.686
便秘	0(0,0)	0(0,0)	-0.273	0.785
腹泻	0(0,0)	0(0,0)	-0.009	0.993
经济困难	0(-33.33,33.33)	0(0,0)	-0.889	0.374
总体生命质量	16.67(-33.33,56.67)	8.34(-18.74,35.42)	-2.249	0.025

表3

组别	试验组(n=30)		对照组(n=31)
CD3⁺	54.53±7.86	57.20±6.14	-1.504	0.144	55.40±7.02	56.13±6.99	-0.382	0.705
CD4⁺	41.17±3.73	44.27±6.78	-2.426	0.022	40.07±4.09	39.63±5.80^a	0.345	0.733
CD8⁺	23.50±2.37	21.47±3.18	2.532	0.017	22.17±2.68	21.60±4.10	0.716	0.480
NK细胞	27.77±5.44	28.47±6.24	-1.769	0.087	26.97±3.42	27.30±4.18	-0.744	0.463

表4

参考文献16

[1]	Wu YL, Zhou C, Liam CK, et al. First-line erlotinib versus gemci-tabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase Ⅲ, randomized, open-label, ENSURE study[J]. Ann Oncol, 2015,26(9):1883-1889. DOI: 10.1093/annonc/mdv270. doi:10.1093/annonc/mdv270pmid:26105600
[2]	Park K, Tan EH, O'Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial[J]. Lancet Oncol, 2016,17(5):577-589. DOI: 10.1016/S1470-2045(16)30033-X. doi:10.1016/S1470-2045(16)30033-Xpmid:27083334
[3]	Choi YW, Jeon SY, Jeong GS, et al. EGFR exon 19 deletion is associated with favorable overall survival after first-line gefitinib therapy in advanced non-small cell lung cancer patients[J]. Am J Clin Oncol, 2018,41(4):385-390. DOI: 10.1097/COC.0000000000000282. doi:10.1097/COC.0000000000000282pmid:26967328
[4]	Chen Q, Quan Q, Ding L, et al. Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors[J]. Oncotarget, 2015,6(28):24904-24911. DOI: 10.18632/oncotarget.4570. doi:10.18632/oncotarget.4570pmid:26172562
[5]	Yang JJ, Chen HJ, Yan HH, et al. Clinical modes of EGFR tyrosine kinase inhibitor failure and subsequent management in advanced non-small cell lung cancer[J]. Lung Cancer, 2013,79(1):33-39. DOI: 10.1016/j.lungcan.2012.09.016. doi:10.1016/j.lungcan.2012.09.016pmid:23079155
[6]	Park K, Yu CJ, Kim SW, et al. First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION study[J]. JAMA Oncol, 2016,2(3):305-312. DOI: 10.1001/jamaoncol.2015.4921. doi:10.1001/jamaoncol.2015.4921pmid:26720423
[7]	张裘, 沈倩. EGFR突变阳性且经EGFR-TKI治疗后缓慢进展的晚期非小细胞肺癌患者联合化疗对疗效的影响[J]. 临床和实验医学杂志, 2017,16(11):1105-1107. DOI: 10.3969/j.issn.1671-4695.2017.11.021.
[8]	陈琦, 李雄英, 唐夏焘. 榄香烯通过 c-Met 信号通路逆转由肝细胞生长因子诱导的吉非替尼耐药作用[J]. 中国病理生理杂志, 2018,34(3):469-473. DOI: 10.3969/j.issn.1000-4718.2018.03.015.
[9]	郜飞宇, 张爱琴, 孙燕. 榄香烯对肺腺癌PC9/ZD细胞株吉非替尼耐药的逆转作用[J]. 中华中医药学刊, 2014,32(1):131-133, 230. DOI: 10.13193/j.issn.1673-7717.2014.01.044.
[10]	陈芝, 俞建东, 唐超园, 等. 榄香烯注射液对吉非替尼在PC-9/GR细胞内转运动力学影响[J]. 中成药, 2018,40(2):284-290. DOI: 10.3969/j.issn.1001-1528.2018.02.007.
[11]	Cheng H, Ge X, Zhuo S, et al. β-elemen synergizes with gefitinib to inhibit stem-like phenotypes and progression of lung cancer via downregulating EZH2[J]. Front Pharmacol, 2018,9:1413. DOI: 10.3389/fphar.2018.01413. doi:10.3389/fphar.2018.01413pmid:30555330
[12]	Lin L, Li L, Chen X, et al. Preliminary evaluation of the potential role of β-elemene in reversing erlotinib-resistant human NSCLC A549/ER cells[J]. Oncol Lett, 2018,16(3):3380-3388. DOI: 10.3892/ol.2018.8980. doi:10.3892/ol.2018.8980pmid:30127938
[13]	王一喆, 胡雪君. β-榄香烯治疗晚期非小细胞肺癌的临床应用现状及研究进展[J]. 现代肿瘤医学, 2018,26(10):1643-1646. DOI: 10.3969/j.issn.1672-4992.2018.10.042.
[14]	刘显红, 张爽, 王胜, 等. 吉非替尼治疗晚期肺腺癌缓慢进展后原药继续治疗的疗效及安全性[J]. 中国老年学杂志, 2013,33(24):6142-6144. DOI: 10.3969/j.issn.1005-9202.2013.24.035.
[15]	张清华. 吉非替尼联合榄香烯注射液对EGFR突变阳性的晚期肺腺癌患者的疗效观察[J]. 中国医学前沿杂志(电子版), 2016,8(10):113-116. DOI: 10.12037/YXQY.2016.10-28. doi:10.12037/YXQY.2016.10-28
[16]	麻杰, 陈娟, 赵冰洁, 等. 抗癌药物β-榄香烯及其衍生物的研究进展[J]. 中草药, 2018,49(5):1184-1191. DOI: 10.7501/j.issn.0253-2670.2018.05.030.