奥拉帕尼联合贝伐珠单抗治疗复发性铂类敏感卵巢癌患者的疗效及对血清HE4、CA125、CTC水平的影响

doi:10.3760/cma.j.cn371439-20191116-00086

摘要/Abstract

摘要：

目的观察奥拉帕尼联合贝伐珠单抗在复发性铂类敏感卵巢癌患者中的疗效、安全性以及对血清人附睾蛋白4(HE4)、糖类抗原125(CA125)和循环肿瘤细胞(CTC)水平的影响。方法选取湖北医药学院附属东风医院2018年6月至2019年6月收治的96例复发性铂类敏感卵巢癌患者,按照随机数字表法分为对照组(n=48)和研究组(n=48)。对照组给予多柔比星脂质体联合卡铂化疗6个周期;研究组给予奥拉帕尼联合贝伐珠单抗治疗,奥拉帕尼持续给药,贝伐珠单抗治疗6个周期。评价两组患者中位无进展生存期(PFS)、客观有效率(ORR)、疾病控制率(DCR),比较两组患者治疗后血清HE4、CA125和CTC水平变化情况,观察患者治疗期间药物不良反应。结果研究组患者中位PFS为8.3个月,长于对照组的5.5个月,差异具有统计学意义(χ ²=5.134,P=0.025)。研究组患者ORR、DCR分别为52.08%(25/48)、81.25%(39/48),显著高于对照组的31.25%(15/48)、62.50%(30/48),差异均具有统计学意义(χ²=4.286,P=0.038;χ²=4.174,P=0.041)。治疗6个周期后研究组患者血清HE4[(123.60±31.52)pmol/L vs. (178.01±46.22) pmol/L]、CA125[(33.52±10.61)U/L vs. (50.32±11.09) U/L]和CTC[(2.19±0.24)个/5 ml vs. (3.25±0.31) 个/5 ml]水平均较对照组明显下降,差异均具有统计学意义(t=8.489,P=0.025;t=7.562,P=0.032;t=9.341,P=0.017)。研究组患者的胃肠反应发生率[35.42%(17/48) vs. 64.58%(31/48)]、骨髓抑制发生率[18.75%(9/48) vs. 41.67%(20/48)]、肝肾功能损伤发生率[2.08%(1/48) vs. 14.58%(7/48)]、心脏毒性发生率[4.17%(2/48) vs.18.75%(9/48)]、过敏反应发生率[0(0) vs. 8.33%(4/48)]、神经系统毒性发生率[2.08%(1/48) vs.16.67%(8/48)]等不良反应显著低于对照组,差异均具有统计学意义(χ²=8.167,P=0.004;χ²=7.584,P=0.006;χ²=4.909,P=0.027;χ²=5.031,P=0.025;χ²=4.174,P=0.041;χ²=6.008,P=0.014)。结论对于复发性铂类敏感卵巢癌患者,奥拉帕尼联合贝伐珠单抗疗效优于多柔比星脂质体联合卡铂化疗,并可延长患者生存期,下调血清HE4、CA125和CTC水平,不良反应发生率低。

关键词: 卵巢肿瘤, 复发, 治疗结果, 奥拉帕尼, 贝伐珠单抗

Abstract:

Objective To observe the efficacy and safety of olaparib combined with bevacizumab in patients with recurrent platinum-sensitive ovarian cancer, and the effect on serum levels of human epididymis protein 4 (HE4), carbohydrate antigen 125 (CA125) and circulating tumor cells (CTCs). Methods A total of 96 patients with recurrent platinum-sensitive ovarian cancer admitted to Dongfeng Hospital Affiliated to Hubei Medical College from June 2018 to June 2019 were selected and divided into control group (n=48) and study group (n=48) according to the random number table method. The control group was given doxorubicin liposomes combined with carboplatin chemotherapy for 6 cycles, and the study group was given olaparib combined with bevacizumab, continuous olaparib, and bevacizumab for 6 cycles. The median progression-free survival (PFS), the objective effective rate (ORR), disease control rate (DCR) of the two groups were evaluated, the changes of serum HE4, CA125 and CTCs levels of the two groups after treatment were compared, and the adverse drug reactions of patients during treatment were observed. Results The median PFS of the study group was 8.3 months, which was longer than 5.5 months of the control group, with a statistically significant difference (χ ²=5.134, P=0.025). The ORR and DCR of the study group were 52.08% (25/48) and 81.25% (39/48), which were significantly higher than 31.25% (15/48) and 62.50% (30/48) of the control group, with statistically significant differences (χ²=4.286, P=0.038; χ²=4.174, P=0.041). After 6 cycles treatment, serum HE4 [(123.60±31.52) pmol/L vs. (178.01±46.22) pmol/L], CA125 [(33.52±10.61)U/L vs. (50.32±11.09) U/L] and CTCs [(2.19±0.24) pcs/5 ml vs. (3.25±0.31) pcs/5 ml] of the study group were significantly lower than those of the control group, with statistically significant differences (t=8.489, P=0.025; t=7.562, P=0.032; t=9.341, P=0.017). The incidences of gastrointestinal reactions [35.42% (17/48) vs. 64.58% (31/48)], bone marrow suppression [18.75% (9/48) vs. 41.67% (20/48)], liver and kidney function damage [2.08% (1/48) vs. 14.58% (7/48)], cardiotoxicity [4.17% (2/48) vs. 18.75% (9/48)], allergy reaction [0 (0) vs. 8.33% (4/48)], neurotoxicity [2.08% (1/48) vs. 16.67% (8/48)] and other adverse reactions of the study group were significantly lower than those of the control group, with statistically significant differences (χ²=8.167, P=0.004; χ²=7.584, P=0.006; χ²=4.909, P=0.027; χ²=5.031, P=0.025; χ²=4.174, P=0.041; χ²=6.008, P=0.014). Conclusion For patients with recurrent platinum-sensitive ovarian cancer, olalapril combined with bevacizumab has better curative effect than doxorubicin liposome combined with carboplatin chemotherapy, and can prolong the survival period of patients, down-regulate serum HE4, CA125 and CTCs levels, with low incidence of adverse reactions.

Key words: Ovarian neoplasms, Recurrence, Treatment outcome, Olapani, Bevacizumab

权瑞泉, 张丽, 匡黎, 李洪波, 肖梅仙. 奥拉帕尼联合贝伐珠单抗治疗复发性铂类敏感卵巢癌患者的疗效及对血清HE4、CA125、CTC水平的影响[J]. 国际肿瘤学杂志, 2020, 47(10): 606-610.

Quan Ruiquan, Zhang Li, Kuang Li, Li Hongbo, Xiao Meixian. Efficacy of olaparib combined with bevacizumab in the treatment of patients with recurrent platinum-sensitive ovarian cancer and its effect on serum HE4, CA125 and CTC levels[J]. Journal of International Oncology, 2020, 47(10): 606-610.

图/表 5

表1

图1

表2

表3

表4

参考文献 15

[1]	张凤喜, 常玉梅, 崔允巍, 等. TRAIL与上皮性卵巢癌中耐药相关基因的关系[J]. 河北医药, 2020,42(11):1620-1623, 1628. DOI: 10.3969/j.issn.1002-7386.2020.11.004.
[2]	中华医学会妇科肿瘤学分会. 卵巢癌PARP抑制剂临床应用指南[J]. 中国医学前沿杂志(电子版), 2020,12(5):29-37. DOI: 10.12037/YXQY.2020.05-06.
[3]	葛丽, 吴令英. 循环肿瘤细胞检测在卵巢上皮性癌中应用的研究进展[J]. 中华妇产科杂志, 2017,52(12):853-856. DOI: 10.3760/cma.j.issn.0529-567x.2017.12.012.
[4]	牛星燕, 张冬萍, 李飞霞, 等. 卵巢恶性肿瘤化疗研究进展[J]. 国际妇产科学杂志, 2020,47(2):125-128.
[5]	徐富. PARP抑制剂奥拉帕尼用于前列腺癌精准治疗的研究进展[J]. 医学研究杂志, 2018,47(7):17-20. DOI: 10.11969/j.issn.1673-548X.2018.07.005.
[6]	马小莲, 郑德友, 何吉庆. 贝伐珠单抗注射液联合紫杉醇注射液和顺铂注射液治疗卵巢癌的临床研究[J]. 中国临床药理学杂志, 2018,34(23):2697-2699, 2703. DOI: 10.13699/j.cnki.1001-6821.2018.16.005.
[7]	喻喆, 刘泓若, 蒋葵. 依维莫司维持治疗原发性铂类耐药卵巢透明细胞癌一例[J]. 中华肿瘤杂志, 2017,39(8):634-635. DOI: 10.3760/cma.j.issn.0253-3766.2017.08.014.
[8]	冀培刚, 刘永, 刘竞辉, 等. 贝伐珠单抗联合替莫唑胺剂量密度方案治疗复发胶质瘤的疗效分析[J]. 现代肿瘤医学, 2019,27(12):2084-2087. DOI: 10.3969/j.issn.1672-4992.2019.12.012.
[9]	赵海波, 徐翔, 丁佳佳, 等. 卵巢癌患者循环肿瘤细胞中ERCC1表达与铂类药物敏感性的关系[J]. 解放军医学院学报, 2018,39(4):279-282. DOI: 10.3969/j.issn.2095-5227.2018.04.003.
[10]	李飞霞, 田刚, 余婷, 等. 血清CA125、HE4联合PLR、NLR、MLR诊断上皮性卵巢癌的临床价值[J]. 山东医药, 2020,60(10):70-72. DOI: 10.3969/j.issn.1002-266X.2020.10.018.
[11]	Kim HS, Park NH, Kang S, et al. Comparison of the efficacy between topotecan- and belotecan-, a new camptothecin analog based chemotherapies for recurrent epithelial ovarian cancer: a single institutional experience[J]. J Obstet Gynaecol Res, 2010,36(1):86-93. DOI: 10.1111/j.1447-0756.2009.01101.x. pmid: 20178532
[12]	陈本川. 治疗晚期卵巢癌新药—奥拉帕尼(olaparib)[J]. 医药导报, 2015,34(6):846-849. DOI: 10.3870/yydb.2015.06.043.
[13]	樊蓓, 吴玉梅. PARP抑制剂—奥拉帕尼应用于卵巢癌治疗的研究进展[J]. 北京医学, 2016,38(11):1206-1209. DOI: 10.15932/j.0253-9713.2016.11.022.
[14]	Domchek SM, Aghajanian C, Shapira-Frommer R, et al. Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy[J]. Gynecol Oncol, 2016,140(2):199-203. DOI: 10.1016/j.ygyno.2015.12.020. doi: 10.1016/j.ygyno.2015.12.020 pmid: 26723501
[15]	Penson RT, Valencia RV, Cibula D, et al. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 Mutation (SOLO3): a randomized phase Ⅲ trial[J]. J Clin Oncol, 2020,38(11):1164-1174. DOI: 10.1200/JCO.19.02745.

临床病理特征	对照组 (n=48)	研究组 (n=48)	χ²值	P值
年龄(岁)
≤60	22	25	0.375	0.540
>60	26	23
病理类型
浆液性腺癌	18	15
黏液性腺癌	12	13
透明细胞癌	6	4
子宫内膜样癌	5	6	1.446	0.963
乳头状腺癌	3	5
移行细胞癌	3	4
混合型腺癌	1	1
临床分期
Ⅱ期	15	12	0.464	0.496
Ⅲ期	33	36
复发部位
盆腔	23	26
腹腔	11	10	0.385	0.825
腹盆腔	14	12

组别	CR	PR	SD	PD	客观有效	疾病控制
对照组(n=48)	0(0)	15(31.25)	15(31.25)	18(37.50)	15(31.25)	30(62.50)
研究组(n=48)	1(2.08)	24(50.00)	14(29.17)	9(18.75)	25(52.08)	39(81.25)
χ²值					4.286	4.174
P值					0.038	0.041

组别	HE4(pmol/L)		CA125(U/L)		CTC(个/5 ml)
组别	治疗前	治疗后	治疗前	治疗后	治疗前	治疗后
对照组(n=48)	349.55±79.02	178.01±46.22	112.55±18.55	50.32±11.09	6.75±1.38	3.25±0.31
研究组(n=48)	343.26±72.11	123.60±31.52	119.78±20.37	33.52±10.61	7.35±1.19	2.19±0.24
t值	1.826	8.489	2.125	7.562	2.006	9.341
P值	0.085	0.025	0.073	0.032	0.079	0.017