炎性指标及CA199与免疫检查点抑制剂治疗晚期胃癌患者疗效及预后的预测价值分析

Analysis of Predictive Value of the Efficacy and Prognosis of Inflammatory Indicators and CA199 with Immune Checkpoint Inhibitors in the Treatment of Advanced Gastric Cancer Patients

摘要: 目的：本研究旨在评估外周血炎性指标中性粒细胞与淋巴细胞比率(NLR)、血小板与淋巴细胞比率(PLR)、系统免疫炎症指数(SII)及肿瘤标志物糖类抗原199 (CA199)在预测接受免疫检查点抑制剂(ICIs)治疗的晚期胃癌患者疗效响应和预后结局中的价值。方法：本研究为一项回顾性队列分析，纳入2021年4月至2025年2月期间在安徽医科大学第四附属医院接受ICIs (主要为PD-1/PD-L1抑制剂)治疗的149例晚期胃癌患者，随访时间截止至2025年5月，收集患者的一般病例资料及治疗前的外周血液学相关指标。近期治疗效果依据实体瘤疗效评价标准(RECIST 1.1)进行判定，以疾病进展(PD)或死亡作为终点事件，构建受试者工作特征(ROC)曲线以评估各检测指标(NLR、PLR、SII、CA199)的预测效能，并确定其最佳临界值(cut-off值)。依据此临界值，将患者划分为高值组与低值组，通过Kaplan-Meier生存分析法评估不同分组患者的预后差异，并采用Cox回归进行单因素和多因素生存分析，确定影响经ICIs治疗的晚期胃癌患者无进展生存期(PFS)的危险因素。结果：149例入组患者中，截至末次随访，观察到的最佳总体疗效为完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)共57例，而疾病进展(PD)或死亡共92例。通过ROC曲线确定NLR、PLR、SII、CA199的临界值分别为3.57、159.75、466.17、30.75 U/ml，基于临界值将患者分为高NLR组(n = 48)、低NLR组(n = 101)、高PLR组(n = 74)、低PLR组(n = 75)、高SII组(n = 78)、低SII组(n = 71)、高CA199组(n = 73)、低CA199组(n = 76)。Kaplan-Meier分析显示，高NLR、PLR、SII、CA199组中位PFS分别为5.6月、5.97月、5.6月、6.37月，低NLR、PLR、SII、CA199组中位PFS分别为9.6月、13.4月、14.77月、15.57月，各组别Log-Rank检验显示，组间比较差异均具有统计学意义(P < 0.05)。单因素Cox回归分析表明，组织学低分化、存在淋巴结转移以及NLR、PLR、SII、CA199处于高值水平均与晚期胃癌患者接受ICIs治疗后较短的PFS显著相关(P < 0.05)。多因素Cox回归模型进一步筛选出三个独立危险因素：组织学低分化、SII高值及CA199高值，它们均显著预示ICIs治疗后患者PFS的缩短(P < 0.05)。结论：治疗前外周血炎性指标(NLR、PLR、SII)及肿瘤标志物CA199水平与晚期胃癌患者ICIs治疗的预后显著相关。其中，SII和CA199被证实是影响患者PFS的独立危险因素。动态监测这些生物标志物可为ICIs治疗的临床决策提供重要依据，有助于优化个体化治疗策略。

Abstract: Objective: The purpose of this study was to evaluate the value of peripheral blood inflammatory indicators, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and tumor marker carbohydrate antigen 199 (CA199), in predicting the efficacy response and prognostic outcomes of advanced gastric cancer patients receiving immune checkpoint inhibitors (ICIs) therapy. Methods: This retrospective cohort study enrolled 149 patients with advanced gastric cancer treated with ICIs (primarily PD-1/PD-L1 inhibitors) at the Fourth Affiliated Hospital of Anhui Medical University from April 2021 to February 2025. Follow-up was conducted until May 2025, during which we collected comprehensive clinical data and pre-treatment peripheral blood biomarkers. Treatment efficacy was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), with disease progression (PD) or death as primary endpoints. We constructed Receiver Operating Characteristic (ROC) curves to evaluate predictive performance of biomarkers (NLR, PLR, SII, CA199), identifying optimal cut-off values. Patients were stratified into high-risk and low-risk groups based on these thresholds. Kaplan-Meier survival analysis was performed to assess prognostic differences between subgroups, while Cox regression was employed for univariate and multivariate survival modeling to determine prognostic factors affecting Progression-Free-Survival (PFS) in ICIs-treated advanced gastric cancer patients. Results: Among 149 enrolled patients, 57 achieved the best overall response: complete response (CR), partial response (PR), or disease stabilization (SD) as of the final follow-up, while 92 experienced disease progression (PD) or death. ROC curves established cut-off values for NLR, PLR, SII, and CA199 at 3.57, 159.75, 466.17, 30.75 U/ml. Patients were categorized into high NLR (n = 48), low NLR (n = 101), high PLR (n = 74), low PLR (n = 75), high SII (n = 78), low SII (n = 71), high CA199 (n = 73) and low CA199 (n = 76) groups. Kaplan-Meier analysis showed median PFS of 5.6 months, 5.97 months, 5.6 months, and 6.37 months in high NLR/PLR/SII/CA199 groups versus 9.6 months, 13.4 months, 14.77 months, and 15.57 months in low groups. The Log-Rank test showed that the differences between groups were statistically significant (P < 0.05). Univariate Cox regression analysis demonstrated that histological low differentiation, lymph node metastasis and elevated NLR/PLR/SII/CA199 levels were significantly associated with shorter PFS in advanced gastric cancer patients receiving ICIs (P < 0.05). Multivariate Cox regression model further screened out three independent risk factors: histological low differentiation, high SII value and high CA199 value, which were significantly associated with the shortening of PFS after ICIs treatment (P < 0.05). Conclusion: Pre-treatment peripheral blood inflammatory markers (NLR, PLR, SII) and tumor marker CA199 levels were significantly associated with the prognosis of advanced gastric cancer patients undergoing ICIs therapy. Notably, SII and CA199 were identified as independent prognostic factors influencing progression-free survival (PFS). Dynamic monitoring of these biomarkers provides critical evidence for clinical decision-making in ICIs treatment, facilitating the optimization of personalized therapeutic strategies.