安罗替尼联合化疗对二线化疗失败晚期非小细胞肺癌的疗效分析

摘要/Abstract

摘要：

目的观察安罗替尼联合化疗对二线化疗失败晚期非小细胞肺癌(NSCLC)患者的疗效及安全性。方法回顾性分析2017年1月至2019年10月安徽医科大学附属巢湖医院肿瘤科收治的80例二线化疗失败的晚期NSCLC患者,根据治疗方案不同,分为对照组(n=36)和观察组(n=44),对照组采用培美曲塞+顺铂治疗,观察组采用培美曲塞+顺铂+安罗替尼治疗。比较两组肿瘤客观缓解率(ORR)、疾病控制率(DCR)、中位无进展生存期(PFS)、总生存期(OS),患者治疗前、后血清血管内皮生长因子(VEGF)、癌胚抗原(CEA)、糖类抗原199(CA199)水平变化以及治疗相关不良反应。结果治疗2个周期后,对照组和观察组患者ORR分别为5.56%(2/36)、18.18%(8/44),差异无统计学意义(χ²=1.85,P=0.174);对照组、观察组DCR分别为58.33%(21/36)、81.82%(36/44),观察组DCR明显高于对照组,差异具有统计学意义(χ²=5.33,P=0.021)。对照组和观察组患者中位PFS分别为4.0个月、6.0个月,观察组明显长于对照组,差异有统计学意义(χ²=28.47,P<0.001);两组患者中位OS分别为13.0个月、14.8个月,差异无统计学意义(χ²=1.56,P=0.212)。治疗2个周期后两组患者血清VEGF[(21.72±5.42)ng/Lvs. (36.97±7.53)ng/L,t=14.13,P<0.001;(16.61±4.14)ng/Lvs. (38.85±8.61)ng/L,t=23.09,P<0.001]、CEA[(4.91±1.58)ng/mlvs. (6.62±2.84)ng/ml,t=4.64,P<0.001;(3.07±1.32)ng/mlvs. (7.08±3.31)ng/ml,t=11.50,P<0.001]、CA199[(16.83±5.23)U/mlvs. (20.95±7.94)U/ml;t=3.75,P<0.001;(13.37±5.85)U/mlvs. (21.66±8.72)U/ml,t=7.55,P<0.001]水平均较治疗前明显下降,且治疗后观察组血清VEGF、CEA、CA199水平均明显低于对照组(t=4.78,P<0.001;t=5.68,P<0.001;t=2.76,P=0.007)。观察组血压升高发生率明显高于对照组[25.00%(11/44)vs. 2.78%(1/36),χ²=7.67,P=0.006]。结论培美曲塞+顺铂+安罗替尼方案用于二线化疗失败的晚期NSCLC患者治疗,可提高DCR、延长患者PFS,改善血清肿瘤相关标志物水平,不良反应可控。

关键词:癌,非小细胞肺,预后,安罗替尼,疗效评估

Abstract:

Objective To observe the efficacy and safety of anlotinib combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) who failed second-line chemotherapy.MethodsA retrospective analysis was performed on 80 patients with advanced NSCLC who had failed second-line chemotherapy admitted in the Department of Oncology of Chaohu Hospital of Anhui Medical University from January 2017 to October 2019, and the patients were divided into control group (n=36) and observation group (n=44) according to the different treatment regimens. The control group was given pemetrexed + cisplatin, and the observation group adopted pemetrexed + cisplatin + anlotinib. The objective response rate (ORR), disease control rate (DCR), median progression-free survival (PFS), overall survival (OS), changes in levels of serum vascular endothelial growth factor (VEGF), carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199) and treatment-related adverse reactions were compared between the two groups.ResultsAfter 2 cycles of treatment, the ORR in the control group and observation group were 5.56% (2/36) and 18.18% (8/44), with no statistically significant difference (χ²=1.85,P=0.174). The DCR in the two groups were 58.33% (21/36) and 81.82% (36/44), and the DCR in the observation group was significantly higher than that in the control group, with a statistically significant difference (χ²=5.33,P=0.021). The median PFS in the two groups were 4.0 months and 6.0 months, and the median PFS in the observation group was longer than that in the control group, with a statistically significant difference (χ²=28.47, P<0.001). The median OS in the two groups were 13.0 months and 14.8 months, with no statistically significant difference (χ²=1.56,P=0.212). The levels of serum VEGF [(21.72±5.42) ng/Lvs.(36.97±7.53) ng/L,t=14.13,P<0.001; (16.61±4.14) ng/Lvs. (38.85±8.61) ng/L,t=23.09,P<0.001], CEA [(4.91±1.58) ng/mlvs. (6.62±2.84) ng/ml,t=4.64,P<0.001; (3.07±1.32) ng/mlvs. (7.08±3.31) ng/ml,t=11.50,P<0.001] and CA199 [(16.83±5.23) U/mlvs. (20.95±7.94) U/ml,t=3.75,P<0.001; (13.37±5.85) U/mlvs. (21.66±8.72) U/ml,t=7.55,P<0.001] in the control group and observation group after 2 cycles of treatment were significantly decreased compared with those before treatment, and the levels of serum VEGF, CEA and CA199 in the observation group were significantly lower than those in the control group (t=4.78,P<0.001;t=5.68,P<0.001;t=2.76,P=0.007). The incidence of elevated blood pressure in the observation group was significantly higher than that in the control group [25.00% (11/44)vs.2.78% (1/36),χ²=7.67,P=0.006].ConclusionPemetrexed + cisplatin + anlotinib regimen for patients with advanced NSCLC who failed second-line chemotherapy can improve DCR, prolong PFS and improve the levels of serum tumor-related markers, with controllable adverse reactions.

Key words:Carcinoma,non-small-cell lung,Prognosis,Anlotinib,Efficacy evaluation

盛晓安, 汪超, 肖鑫, 童斯浩. 安罗替尼联合化疗对二线化疗失败晚期非小细胞肺癌的疗效分析[J]. 国际肿瘤学杂志, 2022, 49(3): 134-139.

Sheng Xiao'an, Wang Chao, Xiao Xin, Tong Sihao. Efficacy analysis of anlotinib combined with chemotherapy for advanced non-small cell lung cancer after failure of second-line chemotherapy[J]. Journal of International Oncology, 2022, 49(3): 134-139.

图/表5

表1

两组二线化疗失败晚期NSCLC患者一般临床资料比较[ x -±s/例]"

一般临床特征	对照组(n=36)	观察组(n=44)	t/χ²值	P值
年龄(岁)	56.15±8.38	54.84±9.86	0.63	0.529
体重指数(kg/m²)	22.11±2.72	21.69±2.94	0.66	0.513
性别
男	24	29	0.01	0.943
女	12	15
病理类型
腺癌	28	31	0.55	0.459
鳞状细胞癌	8	13
临床分期
ⅢB	6	5	0.13	0.720
Ⅳ	30	39
EGFR突变
是	9	12	0.05	0.818
否	27	32
PS评分(分)
0~1分	26	30	0.15	0.695
2分	10	14
吸烟史
有	25	28	0.30	0.585
无	11	16
一线化疗
长春瑞滨+顺铂	11	15
紫杉醇+顺铂	15	17	0.12	0.940
双氟胞苷+顺铂	10	12
二线化疗
紫杉醇+顺铂	7	11
吉西他滨+顺铂	14	16	0.35	0.839
多西他赛+顺铂	15	17

表1

组别	CR	PR	SD	PD	客观缓解	疾病控制
对照组(n=36)	0(0)	2(5.56)	19(52.78)	15(41.67)	2(5.56)	21(58.33)
观察组(n=44)	0(0)	8(18.18)	28(63.64)	8(18.18)	8(18.18)	36(81.82)
Z/χ²值	2.57	1.85	5.33
P值	0.010	0.174	0.021

表2

图1

表3

两组二线化疗失败晚期NSCLC患者治疗前后血清VEGF、CEA、CA199水平比较( x -±s)"

组别	VEGF (ng/L)								CEA (ng/ml)						CA199(U/ml)
组别	治疗前	治疗后		t值		P值			治疗前	治疗后	t值	P值			治疗前	治疗后			t值		P值
对照组(n=36)	36.97±7.53		21.72±5.42		14.13		<0.001	6.62±2.84		4.91±1.58	4.64		<0.001	20.95±7.94			16.83±5.23	3.75		<0.001
观察组(n=44)	38.85±8.61		16.61±4.14		23.09		<0.001	7.08±3.31		3.07±1.32	11.50		<0.001	21.66±8.72			13.37±5.85	7.55		<0.001
t值	1.03		4.78					0.66		5.68				0.38			2.76
P值	0.309		<0.001					0.512		<0.001				0.707			0.007

表3

表4

两组二线化疗失败晚期NSCLC患者不良反应发生情况比较(例)"

不良反应	对照组(n=36)			观察组(n=44)			χ²值	P值
不良反应	1~2级	3~4级	合计	1~2级	3~4级	合计	χ²值	P值
恶心呕吐	5	1	6	8	2	10	0.46	0.500
肝功能异常	4	0	4	6	0	6	0.12	0.734
肾功能异常	3	0	3	4	0	4	-	>0.999
血小板降低	2	0	2	1	0	1	-	0.585
骨髓抑制	1	0	1	2	0	2	-	>0.999
口腔黏膜炎	0	0	0	4	0	4	-	0.123
血压升高	1	0	1	10	1	11	7.67	0.006
咯血	0	0	0	2	0	2	-	0.499
乏力	2	0	2	7	0	7	2.13	0.146
手足综合征	1	0	1	4	0	4	-	0.372

表4

参考文献13

[1]	中国医师协会肿瘤医师分会; 中国临床肿瘤学会血管靶向治疗专家委员会; 中国抗癌协会肿瘤靶向治疗专业委员会. 盐酸安罗替尼治疗晚期肺癌中国专家共识(2020版)[J]. 中华肿瘤杂志, 2020, 42(10):807-816. DOI: 10.3760/cma.j.cn112152-20200721-00669. doi:10.3760/cma.j.cn112152-20200721-00669
[2]	李凡敏, 魏茂刚, 范华, 等. 培美曲塞联合铂类方案三线治疗晚期非小细胞肺癌的临床疗效及疾病预后[J]. 实用癌症杂志, 2018, 33(9):1424-1426. DOI: 10.3969/j.issn.1001-5930.2018.09.010. doi:10.3969/j.issn.1001-5930.2018.09.010
[3]	刘楠, 吴秀伟, 李烦繁, 等. 安罗替尼三线及以上治疗晚期非小细胞肺癌近期疗效和生命质量分析[J]. 国际肿瘤学杂志, 2019, 46(3):147-152. DOI: 10.3760/cma.j.issn.1673-422X.2019.03.004. doi:10.3760/cma.j.issn.1673-422X.2019.03.004
[4]	邹宜覃, 宁方政, 张景熙, 等. 盐酸安罗替尼治疗晚期非小细胞肺癌临床疗效及影响因素分析[J]. 国际呼吸杂志, 2020, 40(7):493-498. DOI: 10.3760/cma.j.cn131368-20190621-00932. doi:10.3760/cma.j.cn131368-20190621-00932
[5]	岳东升, 王长利. 非小细胞肺癌辅助靶向治疗进展[J]. 中国肿瘤临床, 2018, 45(23):1225-1229. DOI: 10.3969/j.issn.1000-8179.2018.23.173. doi:10.3969/j.issn.1000-8179.2018.23.173
[6]	刘思远, 李志鹏, 郑心. 肺抑瘤合剂联合AP化疗方案治疗非小细胞肺癌临床疗效观察[J]. 中国实验方剂学杂志, 2018, 24(3):185-190. DOI: 10.13422/j.cnki.syfjx.2018030185. doi:10.13422/j.cnki.syfjx.2018030185
[7]	刘冬英, 吴海鹰, 曾涌波, 等. INP和AP方案三线治疗晚期非小细胞肺癌的近期疗效观察[J]. 中华肿瘤防治杂志, 2016, 23(21):1441-1445. DOI: 10.16073/j.cnki.cjcpt.2016.21.008. doi:10.16073/j.cnki.cjcpt.2016.21.008
[8]	Wu D, Nie J, Dai L, et al. Salvage treatment with anlotinib for advanced non-small cell lung cancer[J]. Thorac Cancer, 2019, 10(7):1590-1596. DOI: 10.1111/1759-7714.13120. doi:10.1111/1759-7714.13120
[9]	Han B, Li K, Zhao Y, et al. Anlotinib as a third-line therapy in patients with refractory advanced non-small-cell lung cancer: a multicentre, randomised phase Ⅱ trial (ALTER0302)[J]. Br J Cancer, 2018, 118(5):654-661. DOI: 10.1038/bjc.2017.478. doi:10.1038/bjc.2017.478
[10]	汪硕敏, 顾康生. 血清癌胚抗原、铁蛋白和糖基抗原199在非小细胞肺癌诊断中的临床价值[J]. 安徽医科大学学报, 2018, 53(9):1444-1447. DOI: 10.19405/j.cnki.issn1000-1492.2018.09.026. doi:10.19405/j.cnki.issn1000-1492.2018.09.026
[11]	黄丽珍, 车建华, 段相会, 等. 非小细胞肺癌患者血清CYFRA21-1、VEGF及CEA的表达及与临床病理特征的相关性研究[J]. 现代生物医学进展, 2018, 18(7):1344-1347. DOI: 10.13241/j.cnki.pmb.2018.07.031. doi:10.13241/j.cnki.pmb.2018.07.031
[12]	陈小燕, 任燕, 张海波, 等. 安罗替尼上市后不良反应高血压的监测[J]. 泰山医学院学报, 2020, 41(5):357-359. DOI: 10.3969/j.issn.1004-7115.2020.05.008. doi:10.3969/j.issn.1004-7115.2020.05.008
[13]	徐伟佳, 高勇, 吴雪. 临床药师对3例安罗替尼治疗晚期肺癌致不良反应的药学监护[J]. 中国药房, 2019, 30(19):2727-2731. DOI: 10.6039/j.issn.1001-0408.2019.19.26. doi:10.6039/j.issn.1001-0408.2019.19.26

[1]	钱晓涛, 石子宜, 胡格, 吴晓维.Ⅲ~ⅣA期食管鳞状细胞癌放化疗后行巩固化疗的疗效：一项真实世界临床研究[J]. 国际肿瘤学杂志, 2024, 51(6): 326-331.
[2]	杨蜜, 别俊, 张加勇, 邓佳秀, 唐组阁, 卢俊.局部晚期可切除食管癌新辅助治疗疗效及预后分析[J]. 国际肿瘤学杂志, 2024, 51(6): 332-337.
[3]	范志鹏, 余静, 胡静, 廖正凯, 徐禹, 欧阳雯, 谢丛华.炎症标志物的变化趋势对一线接受免疫联合化疗的晚期非小细胞肺癌患者预后的预测价值[J]. 国际肿瘤学杂志, 2024, 51(5): 257-266.
[4]	杨琳, 路宁, 温华, 张明鑫, 朱琳.炎症负荷指数与胃癌临床关系研究[J]. 国际肿瘤学杂志, 2024, 51(5): 274-279.
[5]	刘萍萍, 何学芳, 张翼, 杨旭, 张珊珊, 季一飞.原发性脑胶质瘤患者术后复发危险因素及预测模型构建[J]. 国际肿瘤学杂志, 2024, 51(4): 193-197.
[6]	万芳, 杨钢, 李睿, 万启晶.食管癌患者血清miR-497、miR-383水平及临床意义[J]. 国际肿瘤学杂志, 2024, 51(4): 204-209.
[7]	姚益新, 沈煜霖.血清SOCS3、TXNIP水平对肝细胞癌TACE治疗预后的预测价值[J]. 国际肿瘤学杂志, 2024, 51(4): 217-222.
[8]	姚昌菊, 朱治法, 张梅.晚期腹膜后去分化脂肪肉瘤1例并文献复习[J]. 国际肿瘤学杂志, 2024, 51(4): 254-256.
[9]	孙维蔚, 姚学敏, 王鹏健, 王静, 贾敬好.基于血液学指标探讨免疫治疗晚期非小细胞肺癌预后因素及列线图构建[J]. 国际肿瘤学杂志, 2024, 51(3): 143-150.
[10]	刘玉兰, 井海燕, 孙静, 宋伟, 沙丹.胃癌免疫治疗疗效预测及预后标志物的研究进展[J]. 国际肿瘤学杂志, 2024, 51(3): 175-180.
[11]	彭琴, 蔡玉婷, 王伟.KPNA2在肝癌中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(3): 181-185.
[12]	陈波光, 王苏贵, 张永杰.血清胆碱酯酶与炎症标志物在ⅠA~ⅢA期乳腺癌预后中的作用[J]. 国际肿瘤学杂志, 2024, 51(2): 73-82.
[13]	金旭东, 陈忠坚, 毛伟敏.MTAP基因在恶性间皮瘤中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(2): 99-104.
[14]	黄镇, 陈永顺.循环肿瘤DNA在肝细胞癌诊疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(1): 59-64.
[15]	王潇, 李盈, 罗玉杰, 晋舒.基于列线图模型探讨血清学指标对鼻咽癌预后的判断价值[J]. 国际肿瘤学杂志, 2023, 50(8): 463-469.