信迪利单抗联合多西他赛治疗宫颈癌疗效及对实验室指标的影响

摘要/Abstract

摘要：

目的探究信迪利单抗联合多西他赛治疗宫颈癌的疗效及对实验室指标的影响。方法选取2019年7月至2022年6月在上海交通大学医学院附属新华医院治疗的86例晚期宫颈癌患者作为研究对象，按照治疗方法将患者分为研究组（n=43）和对照组（n=43）。研究组采用信迪利单抗联合多西他赛治疗，对照组采用多西他赛治疗。治疗6个周期后，比较两组临床疗效、血管内皮生长因子受体（VEGFR）水平、肿瘤标志物水平、免疫功能指标、程序性死亡受体1（PD-1）、程序性死亡受体配体1（PD-L1）水平以及治疗过程中的不良反应。比较两组患者1年无进展生存（PFS）率及总生存（OS）率。结果治疗6个周期后，研究组和对照组客观缓解率（ORR）分别为48.84%（21/43）、30.23%（13/43），差异无统计学意义（χ²=3.11，P=0.078）；两组疾病控制率（DCR）分别为86.05%（37/43）、62.79%（27/43），差异有统计学意义（χ²=6.11，P=0.013）。治疗前研究组VEGFR2、VEGFR3水平分别为（223.42±57.89）、（3.25±1.22）ng/L，对照组分别为（220.56±58.45）、（3.31±1.17）ng/L，差异均无统计学意义（t=0.23，P=0.820；t=0.23，P=0.817）；治疗后研究组VEGFR2、VEGFR3水平分别为（123.21±36.97）、（0.81±0.21）ng/L，对照组分别为（151.22±37.34）、（1.33±0.37）ng/L，差异均有统计学意义（t=3.50，P=0.001；t=8.02，P<0.001）；两组患者治疗后VEGFR2、VEGFR3水平均较治疗前下降（均P<0.05）。治疗前研究组癌胚抗原（CEA）、糖类抗原125（CA125）、鳞状细胞癌抗原（SCC-Ag）水平分别为（8.73±1.02）ng/ml、（29.73±5.88）U/ml、（7.23±1.34）ng/ml，对照组分别为（8.41±1.23）ng/ml、（30.12±5.93）U/ml、（7.37±1.43）ng/ml，差异均无统计学意义（t=1.31，P=0.193；t=0.31，P=0.760；t=0.47，P=0.641）；治疗后研究组CEA、CA125、SCC-Ag水平分别为（3.52±0.78）ng/ml、（13.28±1.82）U/ml、（2.33±0.49）ng/ml，对照组分别为（3.87±0.62）ng/ml、（14.12±1.72）U/ml、（2.65±0.54）ng/ml，差异均有统计学意义（t=2.30，P=0.024；t=2.20，P=0.031；t=2.88，P=0.005）；两组患者治疗后CEA、CA125、SCC-Ag水平均较治疗前下降（均P<0.05）。治疗前研究组T细胞亚群CD4⁺、CD8⁺和CD4⁺/CD8⁺分别为（27.53±2.23）%、（29.34±3.78）%、0.93±0.33，对照组分别为（28.32±2.31）%、（30.03±3.27）%、0.94±0.42，差异均无统计学意义（t=1.61，P=0.110；t=0.91，P=0.368；t=0.12，P=0.903）；治疗后研究组T细胞亚群CD4⁺、CD8⁺、CD4⁺/CD8⁺分别为（35.33±3.36）%、（44.32±4.33）%、0.80±0.22，对照组分别为（30.31±3.23）%、（42.21±4.31）%、0.71±0.19，差异均有统计学意义（t=7.06，P<0.001；t=2.27，P=0.026；t=2.03，P=0.046）；两组治疗后T细胞亚群CD4⁺、CD8⁺均高于治疗前，而CD4⁺/CD8⁺低于治疗前（均P<0.05）。治疗前研究组PD-1、PD-L1 mRNA分别为1.21±0.21、0.73±0.15，对照组分别为1.23±0.25、0.79±0.14，差异均无统计学意义（t=0.40，P=0.689；t=1.92，P=0.059）；治疗后研究组PD-1、PD-L1 mRNA分别为0.77±0.13、0.52±0.13，对照组分别为0.93±0.19、0.66±0.17，差异均有统计学意义（t=4.56，P<0.001；t=4.29，P<0.001）；两组患者治疗后PD-1、PD-L1 mRNA水平均较治疗前下降（均P<0.05）。研究组患者1年PFS率、OS率分别为60.47%、72.09%；对照组分别为51.16%、65.12%，差异均无统计学意义（χ²=1.31，P=0.253；χ²=0.82，P=0.365）。研究组消化系统反应、肝肾功能异常、血尿、骨髓抑制、皮疹发生率分别为39.53%（17/43）、13.95%（6/43）、13.95%（6/43）、23.26%（10/43）、37.21%（16/43），对照组分别为32.56%（14/43）、9.30%（4/43）、11.63%（5/43）、18.60%（8/43）、30.23%（13/43），差异均无统计学意义（χ²=0.45，P=0.500；χ²=0.45，P=0.501；χ²=0.10，P=0.747；χ²=0.28，P=0.596；χ²=0.47，P=0.494）。结论与多西他赛单药治疗相比，信迪利单抗联合多西他赛治疗晚期宫颈癌的DCR高，一定程度上有效降低了VEGFR、血清肿瘤标志物和外周血单核淋巴细胞中PD-1、PD-L1水平，改善患者的免疫功能，药物安全性相当，但两种治疗方案患者1年生存率相当。

关键词:宫颈肿瘤,免疫检查点抑制剂,多西他赛,治疗结果,信迪利单抗

Abstract:

ObjectiveTo investigate the efficacy of the combination of sintilimab and docetaxel in the treatment of cervical cancer and its impact on laboratory indicators.MethodsA total of 86 patients with advanced cervical cancer treated at Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from July 2019 to June 2022 were selected as the study subjects. The patients were divided into a study group （n=43） and a control group （n=43） according to the treatment method. The study group was treated with a combination of sintilimab and docetaxel， while the control group was treated with docetaxel. After 6 cycles of treatment， the clinical efficacy， vascular endothelial growth factor receptor （VEGFR） levels， tumor marker levels， immune function indicators， programmed death-1 （PD-1）， programmed death-ligand 1 （PD-L1） levels， and adverse reactions during treatment between the two groups were compared. 1-year progression-free survival （PFS） rate and overall survival （OS） rate between the two groups of patients were compared.ResultsAfter 6 cycles of treatment， the objective response rates （ORR） of the study group and the control group were 48.84% （21/43） and 30.23% （13/43）， respectively， with no statistically significant difference （χ²=3.11，P=0.078）； the disease control rates （DCR） of the two groups were 86.05% （37/43） and 62.79% （27/43）， respectively， with a statistically significant difference （χ²=6.11，P=0.013）. Before treatment， the levels of VEGFR2 and VEGFR3 in the study group were （223.42±57.89），（3.25±1.22） ng/L， respectively， while those in the control group were （220.56±58.45），（3.31±1.17） ng/L， respectively， with no statistically significant differences （t=0.23，P=0.820；t=0.23，P=0.817）. After treatment， the VEGFR2 and VEGFR3 levels in the study group were （123.21±36.97），（0.81±0.21） ng/L， respectively， while those in the control group were （151.22±37.34），（1.33±0.37） ng/L， respectively， with statistically significant differences （t=3.50，P=0.001；t=8.02，P<0.001）. However， the levels of VEGFR2 and VEGFR3 in both groups of patients decreased after treatment compared to before treatment （allP<0.05）. Before treatment， the levels of carcinoembryonic antigen （CEA）， carbohydrate antigen 125 （CA125）， and squamous cell carcinoma antigen （SCC-Ag） in the study group were （8.73±1.02） ng/ml，（29.73±5.88） U/ml， and （7.23±1.34） ng/ml， respectively， while those in the control group were （8.41±1.23） ng/ml，（30.12±5.93） U/ml， and （7.37±1.43） ng/ml， respectively， with no statistically significant differences （t=1.31，P=0.193；t=0.31，P=0.760；t=0.47，P=0.641）. After treatment， the CEA， CA125， and SCC-Ag levels in the study group were （3.52±0.78） ng/ml，（13.28±1.82） U/ml， and （2.33±0.49） ng/ml， respectively， while those in the control group were （3.87±0.62） ng/ml，（14.12±1.72） U/ml， and （2.65±0.54） ng/ml， respectively， with statistically significant differences （t=2.30，P=0.024；t=2.20，P=0.031；t=2.88，P=0.005）. However， the levels of CEA， CA125， and SCC-Ag in both groups of patients decreased after treatment compared to before treatment （allP<0.05）. Before treatment， the T cell subsets CD4⁺， CD8⁺， and CD4⁺/CD8⁺in the study group were （27.53±2.23） %，（29.34±3.78） %， and 0.93±0.33， respectively， while those in the control group were （28.32±2.31） %，（30.03±3.27） %， and 0.94±0.42， respectively， with no statistically significant differences （t=1.61，P=0.110；t=0.91，P=0.368；t=0.12，P=0.903）. After treatment， the T cell subsets CD4⁺， CD8⁺， and CD4⁺/CD8⁺in the study group were （35.33±3.36） %，（44.32±4.33） %， and 0.80±0.22， respectively， while those in the control group were （30.31±3.23） %，（42.21±4.31） %， and 0.71±0.19， respectively， with statistically significant differences （t=7.06，P<0.001；t=2.27，P=0.026；t=2.03，P=0.046）. After treatment， the CD4⁺and CD8⁺T cell subsets in both groups were higher than before treatment， while the CD4⁺/CD8⁺was lower than before treatment （allP<0.05）. Before treatment， the levels of PD-1 and PD-L1 mRNA in peripheral blood mononuclear lymphocytes of the study group were 1.21±0.21 and 0.73±0.15， respectively， while those in the control group were 1.23±0.25 and 0.79±0.14， respectively， with no statistically significant differences （t=0.40，P=0.689；t=1.92，P=0.059）. After treatment， the levels of PD-1 and PD-L1 mRNA in peripheral blood mononuclear lymphocytes of the study group were 0.77±0.13 and 0.52±0.13， respectively， while those in the control group were 0.93±0.19 and 0.66±0.17， respectively， with statistically significant differences （t=4.56，P<0.001；t=4.29，P<0.001）. However， the levels of PD-1 and PD-L1 mRNA in both groups of patients decreased after treatment compared to before treatment （allP<0.05）. The 1-year PFS rate and OS rate of the study group patients were 60.47% and 72.09%， respectively； while those in the control groups were 51.16% and 65.12%， respectively， with no statistically significant differences （χ²=1.31，P=0.253；χ²=0.82，P=0.365）. The incidences of digestive system response， abnormal liver and kidney function， hematuria， bone marrow suppression， and rash in the study group were 39.53% （17/43）， 13.95% （6/43）， 13.95% （6/43）， 23.26% （10/43）， and 37.21% （16/43）， respectively， while those in the control group were 32.56% （14/43）， 9.30% （4/43）， 11.63% （5/43）， 18.60% （8/43）， and 30.23% （13/43）， respectively， with no statistically significant differences （χ²=0.45，P=0.500；χ²=0.45，P=0.501；χ²=0.10，P=0.747；χ²=0.28，P=0.596；χ²=0.47，P=0.494）.ConclusionsCompared with monotherapy with docetaxel， the combination of sintilimab and docetaxel has a higher DCR in the treatment of advanced cervical cancer. To a certain extent， it effectively reduces the expression levels of VEGFR， serum tumor markers， and PD-1， PD-L1 in peripheral blood mononuclear lymphocytes， improves the immune function of patients， and has comparable drug safety. However， the two treatment options have comparable 1-year survival rates.

Key words:Uterine cervical neoplasms,Immune checkpoint inhibitors,Docetaxel,Treatment outcome,Sintilimab

李锦鑫, 顾芬芬. 信迪利单抗联合多西他赛治疗宫颈癌疗效及对实验室指标的影响[J]. 国际肿瘤学杂志, 2025, 52(6): 366-373.

Li Jinxin, Gu Fenfen. Efficacy of sintilimab combined with docetaxel in the treatment of cervical cancer and its impact on laboratory indicators[J]. Journal of International Oncology, 2025, 52(6): 366-373.

图/表10

基因位点	引物序列
PD-1正向引物	5'-GCGTGACTTCCACATGAGC-3'
PD-1反向引物	5'-GCAGGCTCTCTTTGATCTGC-3'
PD-L1正向引物	5'-CTATGGTGGTGCCGACTACA-3'
PD-L1反向引物	5'-TGCTTGTCCAGATGACTTCG-3'
U6正向引物	5'-ATGGAACGACAGAGAAGAT-3'
U6反向引物	5'-GGAACGCTTCACGAATTTG-3'

表1

表2

两组晚期宫颈癌患者一般临床资料比较（例）"

一般临床资料	研究组（n=43）	对照组（n=43）	χ²/Z值	P值
年龄（岁）
<50	15	16	0.05	0.822
≥50	28	27	0.05	0.822
既往放疗史
有	40	39	<0.01	>0.999
无	3	4	<0.01	>0.999
肿瘤最大径（cm）
<4	22	23	0.05	0.829
≥4	21	20	0.05	0.829
病理类型
鳞状细胞癌	29	26	0.46	0.793
腺癌	8	10
腺鳞癌	6	7
分化程度
低分化	18	16	0.54	0.762
中分化	15	14
高分化	10	13
KPS评分（分）
<70	8	10	0.28	0.596
≥70	35	33	0.28	0.596
FIGO分期
ⅢA	12	10	0.59	0.938
ⅢB	16	17
ⅣA	10	12
ⅣB	5	4

表2

组别	CR	PR	SD	PD	客观缓解	疾病控制
研究组（n=43）	6	15	16	6	21	37
对照组（n=43）	3	10	14	16	13	27
χ²值					3.11	6.11
P值					0.078	0.013

表3

组别	VEGFR2
研究组（n=43）	223.42±57.89	123.21±36.97^a	3.25±1.22	0.81±0.21^a
对照组（n=43）	220.56±58.45	151.22±37.34^a	3.31±1.17	1.33±0.37^a
t值	0.23	3.50	0.23	8.02
P值	0.820	0.001	0.817	<0.001

表4

组别	CEA（ng/ml）			SCC-Ag（ng/ml）
研究组（n=43）	8.73±1.02	3.52±0.78^a	29.73±5.88	13.28±1.82^a	7.23±1.34	2.33±0.49^a
对照组（n=43）	8.41±1.23	3.87±0.62^a	30.12±5.93	14.12±1.72^a	7.37±1.43	2.65±0.54^a
t值	1.31	2.30	0.31	2.20	0.47	2.88
P值	0.193	0.024	0.760	0.031	0.641	0.005

表5

组别	CD4⁺（%）			CD4⁺/CD8⁺
研究组（n=43）	27.53±2.23	35.33±3.36^a	29.34±3.78	44.32±4.33^a	0.93±0.33	0.80±0.22^a
对照组（n=43）	28.32±2.31	30.31±3.23^a	30.03±3.27	42.21±4.31^a	0.94±0.42	0.71±0.19^a
t值	1.61	7.06	0.91	2.27	0.12	2.03
P值	0.110	<0.001	0.368	0.026	0.903	0.046

表6

组别	PD-1 mRNA
研究组（n=43）	1.21±0.21	0.77±0.13^a	0.73±0.15	0.52±0.13^a
对照组（n=43）	1.23±0.25	0.93±0.19^a	0.79±0.14	0.66±0.17^a
t值	0.40	4.56	1.92	4.29
P值	0.689	<0.001	0.059	<0.001

表7

图1

图2

不良反应	研究组（n=43）	对照组（n=43）	χ²值	P值
消化系统反应	17（39.53）	14（32.56）	0.45	0.500
肝肾功能异常	6（13.95）	4（9.30）	0.45	0.501
血尿	6（13.95）	5（11.63）	0.10	0.747
骨髓抑制	10（23.26）	8（18.60）	0.28	0.596
皮疹	16（37.21）	13（30.23）	0.47	0.494

表8

参考文献23

[1]	Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants[J].Chin Med J (Engl),2022,135(5): 584-590. DOI:10.1097/CM9.00000000000 02108.
[2]	Kokka F, Bryant A, Olaitan A, et al. Hysterectomy with radiotherapy or chemotherapy or both for women with locally advanced cervical cancer[J].Cochrane Database Syst Rev,2022,8(8): CD010260. DOI:10.1002/14651858.CD010260.pub3.
[3]	Abu-Rustum NR, Yashar CM, Arend R, et al. NCCN guidelines^®insights: cervical cancer, version 1.2024[J].J Natl Compr Canc Netw,2023,21(12): 1224-1233. DOI:10.6004/jnccn.2023.0062.
[4]	Nishiyama M, Wada S. Docetaxel: its role in current and future treatments for advanced gastric cancer[J].Gastric Cancer,2009,12(3): 132-141. DOI:10.1007/s10120-009-0521-z. pmid:19890692
[5]	中国抗癌协会肿瘤内分泌专业委员会, 周琦. 妇科恶性肿瘤免疫治疗中国专家共识(2023年版)[J].中国癌症杂志,2023,33(10): 954-968. DOI:10.19401/j.cnki.1007-3639.2023.10.008.
[6]	中国优生科学协会阴道镜和宫颈病理学分会(CSCCP)专家委员会. 中国子宫颈癌筛查及异常管理相关问题专家共识(二)[J].中国妇产科临床杂志,2017,18(3): 286-288. DOI:10.13390/j.issn.1672-1861.2017.03.041.
[7]	刘秋华, 林榕波. 实体瘤疗效评价标准(RECIST)指南1.1版[C]//第十二届全国临床肿瘤大会暨2009年CSCO学术年会论文集. 厦门: 中国抗癌协会,2009: 451.
[8]	Zhang S, Zhang M, Wu WW, et al. Preclinical characterization of sintilimab, a fully human anti-PD-1 therapeutic monoclonal antibody for cancer[J].Antib Ther,2018,1(2): 65-73. DOI:10.1093/abt/tby005.
[9]	Galluzzi L, Humeau J, Buqué A, et al. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors[J].Nat Rev Clin Oncol,2020,17(12): 725-741. DOI:10.1038/s41571-020-0413-z.
[10]	Feng J, Zhang X, Li D, et al. Effect of docetaxel+tigio capsule on serum tumor markers and immune level in patients with advanced cervical cancer[J].Panminerva Med,2024,66(1): 83-84. DOI:10.23736/S0031-0808.21.04581-X.
[11]	Monk BJ, Colombo N, Tewari KS, et al. KEYNOTE-826: final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab+chemotherapy vs placebo+chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer[J].J Clin Oncol,2023,41(16):5500-5500. DOI:10.1200/JCO.2023.41.16_suppl.5500.
[12]	Han L, Husaiyin S, Ma C, et al. Association study between the polymorphisms of angiogenesis-related genes and cervical cancer susceptibility in Chinese Uygur population[J].Mol Genet Genomic Med,2019,7(10): e00899. DOI:10.1002/mgg3.899.
[13]	Nayarisseri A, Abdalla M, Joshi I, et al. Potential inhibitors of VEGFR1, VEGFR2, and VEGFR3 developed through deep learning for the treatment of cervical cancer[J].Sci Rep,2024,14(1): 13251. DOI:10.1038/s41598-024-63762-w.
[14]	何端端, 韩衍永. 信迪利单抗联合含卡铂化疗方案治疗复发转移性宫颈癌的近期疗效[J].临床合理用药,2024,17(18): 125-128. DOI:10.15887/j.cnki.13-1389/r.2024.18.035.
[15]	Bai X, Liu B, Wu Y, et al. Differential expressions of carcinoem-bryonic antigen and squamous cell carcinoma antigen in patients with advanced cervical cancer undergoing chemotherapy[J].Am J Transl Res,2021,13(10): 11875-11882.
[16]	Ran C, Sun J, Qu Y, et al. Clinical value of MRI, serum SCCA, and CA125 levels in the diagnosis of lymph node metastasis and para-uterine infiltration in cervical cancer[J].World J Surg Oncol,2021,19(1): 343. DOI:10.1186/s12957-021-02448-3.
[17]	Huang XD, Huo LQ, Luo YS, et al. Clinical utility of pretreatment serum squamous cell carcinoma antigen for prognostication and decision-making in patients with early-stage cervical cancer[J].Ther Adv Med Oncol,2023,15: 17588359231165974. DOI:10.1177/17588359231165974.
[18]	郝晓慧, 张志林, 卢秀荣, 等. 信迪利单抗静注联合全身化疗治疗复发转移宫颈癌的临床疗效观察[J].山东医药,2022,62(5): 78-81. DOI:10.3969/j.issn.1002-266X.2022.05.019.
[19]	Wang Y, Zhao J, Liang H, et al. Efficacy and safety of sintilimab plus albumin-bound-paclitaxel in recurrent or metastatic cervical cancer: a multicenter, open-label, single-arm, phase Ⅱ trial[J].EClinicalMedicine,2023,65: 102274. DOI:10.1016/j.eclinm.2023.102274.
[20]	Liu C, Ran X, Wang Z, et al. Efficacy and safety of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer with pelvic and/or para-aortic lymph node metastases: a retrospective cohort study[J].Chin Clin Oncol,2023,12(4): 38. DOI:10.21037/cco-23-70.
[21]	Yang B, Chen J, Teng Y. TNPO1-mediated nuclear import of FUBP1 contributes to tumor immune evasion by increasing NRP1 expression in cervical cancer[J].J Immunol Res,2021,2021: 9994004. DOI:10.1155/2021/9994004.
[22]	Ishikawa M, Nakayama K, Nakamura K, et al. High PD-1 expression level is associated with an unfavorable prognosis in patients with cervical adenocarcinoma[J].Arch Gynecol Obstet,2020,302(1): 209-218. DOI:10.1007/s00404-020-05589-0. pmid:32435885
[23]	Dyer BA, Feng CH, Eskander R, et al. Current status of clinical trials for cervical and uterine cancer using immunotherapy combined with radiation[J].Int J Radiat Oncol Biol Phys,2021,109(2): 396-412. DOI:10.1016/j.ijrobp.2020.09.016.