信迪利单抗联合同步放化疗对晚期宫颈癌患者肿瘤标志物及程序性死亡受体-1/程序性死亡配体1的影响

Effect of sintilimab combined with synchronous radiochemotherapy on tumor markers and PD-1/PD-L1 in patients with advanced cervical cancer

目的观察信迪利单抗联合同步放化疗对晚期宫颈癌患者肿瘤标志物及程序性死亡受体-1(programmed death-1,PD-1)/程序性死亡配体-1(programmed death ligand-1,PD-L1)的影响,探讨其临床疗效及安全性。方法晚期宫颈癌患者94例,随机分为观察组和对照组各47例。对照组给予同步放化疗,放疗采用体外适形放疗并腔内照射,放疗第1周给予紫杉醇+卡铂或紫杉醇+顺铂方案化疗,每21 d为1个化疗周期,共6个周期。观察组在对照组治疗基础上于每个化疗周期第1天静脉滴注信迪利单抗。放化疗结束后1个月评定2组疗效,记录治疗期间不良反应发生情况;分别于治疗前1 d及治疗结束第2天检测2组血清癌胚抗原(carcinoembryonic antigen,CEA)、糖类抗原125(carbohydrate antigen 125,CA125)、鳞状细胞癌抗原(squamous cell carcinoma antigen,SCC-Ag)、人附睾蛋白4(human epididymis protein 4,HE4)、血管内皮生长因子(vascular endothelial growth factor,VEGF)-A、VEGF受体2(VEGF receptor 2,VEGFR2)水平及外周血单核淋巴细胞PD-1、PD-L1 mRNA相对表达量;随访观察治疗后1、2年总生存率。结果观察组疾病控制率(95.74%)高于对照组(80.85%)(χ^(2)=5.045,P=0.025),治疗期间骨髓抑制、消化道反应、放射性膀胱炎、放射性直肠炎发生率与对照组比较差异均无统计学意义(P>0.05)。治疗前1 d观察组血清CEA[(4.69±0.89)μg/L]、CA125[(32.97±6.52)u/mL]、SCC-Ag[(11.87±2.65)μg/L]、HE4[(69.85±11.26)pmol/L]、VEGF-A[(805.24±147.36)ng/L]、VEGFR2[(435.26±89.38)ng/L]水平及外周血单核淋巴细胞PD-1 mRNA(1.24±0.29)、PD-L1 mRNA(0.76±0.17)相对表达量与对照组[(4.78±1.02)μg/L、(34.08±7.15)u/mL、(12.14±3.07)μg/L、(72.03±12.73)pmol/L、(792.09±135.42)ng/L、(441.47±95.32)ng/L、1.28±0.31、0.74±0.16]比较差异均无统计学意义(P>0.05);治疗结束第2天血清CEA、CA125、SCC-Ag、HE4、VEGF-A、VEGFR2水平及外周血单核淋巴细胞PD-1、PD-L1 mRNA相对表达量在观察组[(2.25±0.63)μg/L、(14.84±4.36)u/mL、(1.97±0.72)μg/L、(49.57±8.64)pmol/L、(598.49±126.38)ng/L、(305.76±79.43)ng/L、0.79±0.22、0.55±0.12]和对照组[(2.61±0.71)μg/L、(18.28±5.75)u/mL、(2.48±0.93)μg/L、(53.38±9.07)pmol/L、(651.28±115.32)ng/L、(346.87±82.46)ng/L、0.92±0.26、0.63±0.15]均低于治疗前(P<0.05),且观察组均低于对照组(P<0.05)。随访至2022年3月,观察组失访1例,对照组失访2例,观察组治疗后1、2年总生存率[78.26%(36/46)、43.48%(20/46)]与对照组[73.91%(34/46)、40.00%(18/45)]比较差异均无统计学意义(χ^(2)=0.239,P=0.625;χ^(2)=0.113,P=0.737)。结论晚期宫颈癌患者行信迪利单抗联合同步放化疗可降低血清肿瘤标志物水平,下调外周血单核淋巴细胞PD-1、PD-L1表达,且安全性良好。

Objective To observe the effect of sintilimab combined with synchronous radiochemotherapy on tumor markers and programmed death-1(PD-1)/programmed death ligand-1(PD-L1)in patients with advanced cervical cancer,and to explore their clinical efficacy and safety.Methods Ninety-four patients with advanced cervical cancer were randomly divided into observation group and control group,with 47 patients in each group.Control group was given synchronous radiochemotherapy,and radiation therapy was performed with external conformal radiation therapy and intracavitary radiation.Paclitaxel+carboplatin or paclitaxel+cisplatin chemotherapy was given in the first week of radiotherapy,21 d as one cycle,totally for 6 cycles.Observation group was given intravenous injection of sintilimab by day 1 of every cycle in addition to the therapy in control group.The efficacy was evaluated in one month after radiochemotherapy,and the incidence of adverse reactions were recorded during therapy.The levels of carcinoembryonic antigen(CEA),carbohydrate antigen 125(CA125),squamous cell carcinoma antigen(SCC-Ag),human epididymis protein 4(HE4),vascular endothelial growth factor(VEGF)-A,VEGF receptor 2(VEGFR2),and the relative expressions of PD-1 and PD-L1 mRNAs in peripheral blood mononuclear cells were detected one day before therapy and on the second day after therapy in two groups.The 1-and 2-year survival rates were followed up.Results The disease control rate was higher in observation group(95.74%)than that in control group(80.85%)(χ^(2)=5.045,P=0.025),and there were no significant differences in the incidences of bone marrow suppression,gastrointestinal reactions,radiation cystitis and radiation proctitis between two groups(P>0.05).There were no significant differences in serum CEA[(4.69±0.89)μg/Lvs.(4.78±1.02)μg/L],CA125[(32.97±6.52)u/mLvs.(34.08±7.15)u/mL],SCC-Ag[(11.87±2.65)μg/L vs.(12.14±3.07)μg/L],HE4[(69.85±11.26)pmol/L vs.(72.03±12.73)pmol/L],VEGF-A[(805.24±147.36)ng/L vs.(792.09±135.42)ng/L],VEGFR2[(435.26±89.38)ng/L vs.(441.47±95.32)ng/L],PD-1mRNA(1.24±0.29 vs.1.28±0.31),and PD-L1mRNA(0.76±0.17 vs.0.74±0.16)between two groups one day before therapy(P>0.05).On the second day after therapy,the levels of CEA,CA125,SCC-Ag,HE4,VEGF-A,VEGFR2,PD-1 mRNA and PD-L1 mRNA were lower in observation group[(2.25±0.63)μg/L,(14.84±4.36)u/mL,(1.97±0.72)μg/L,(49.57±8.64)pmol/L,(598.49±126.38)ng/L,(305.76±79.43)ng/L,0.79±0.22,0.55±0.12]than those in control group[(2.61±0.71)μg/L,(18.28±5.75)u/mL,(2.48±0.93)μg/L,(53.38±9.07)pmol/L,(651.28±115.32)ng/L,(346.87±82.46)ng/L,0.92±0.26,0.63±0.15](P<0.05),and all above indexes were lower than those before therapy in both groups(P<0.05).Till March,2022,one patient was lost in observation group and two patients were lost in control group in follow-up survey.There were no significant differences in 1-and 2-year overall survival rates between observation group[78.26%(36/46),43.48%(20/46)]and control group[73.91%(34/46),40.00%(18/45)](2χ=0.239,P=0.625;2χ=0.113,P=0.737).Conclusion Sintilimab combined with synchronous radiochemotherapy can lower the levels of serum tumor markers and down-regulate the PD-1 and PD-L1 levels,and it is safe.