Research Progress on Relation Between SII and Prognosis of Non-small Cell Lung Cancer Patients
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摘要:
肺癌是世界上常见的恶性肿瘤,其中非小细胞肺癌(NSCLC)占肺癌的大多数。虽然在手术、化学药物治疗、放射治疗、靶向治疗、免疫治疗中NSCLC患者的总体生存率在不断改善,但部分患者预后仍较差。炎性反应在肿瘤的发生、进展和转移中均起着重要作用。因此,与炎性反应相关的全血细胞计数将会是预测NSCLC预后的有效指标。由中性粒细胞、淋巴细胞、血小板系统组成的系统免疫炎症指数(SII)能全面反映宿主全身炎症及免疫状态,与其他炎症指标如C反应蛋白/白蛋白值(CAR)、晚期肺癌炎症指数(ALI)、预后营养指数(PNI)等的联合检测,可以增加对NSCLC患者预后的预测效能。此外,SII检测成本低廉、操作简单、获取方便,易于在临床中运用。本文就SII与NSCLC预后关系的研究进展综述如下。
Abstract:Lung cancer is a common malignant tumor in the world and NSCLC accounts for the majority. Although the overall survival rate of patients with NSCLC is improving through surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy, the prognosis of some patients is still poor. Inflammatory response plays an important role in the occurrence, progress and metastasis of tumors. Therefore, the whole blood cell count associated with inflammatory response will be an effective index to predict the prognosis of NSCLC. The systemic immune-inflammatory index (SII), composed of neutrophils, lymphocytes and platelet systems, can fully reflect the systemic inflammation and immune status of the host, and can be combined with other inflammatory indexes such as C-reactive protein/albumin value (CAR), advanced lung cancer inflammatory index (ALI) and prognostic nutritional index (PNI). It can increase the predictive efficacy of NSCLC patieats' prognosis. In addition, SII has the advantages of low cost, simple operation and convenient acquisition, and is easy to be used in clinic. This paper reviews the research progress of the relation between SII and the prognosis of NSCLC.
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0 引言
鼻咽癌是最常见的头颈部肿瘤之一。我国为鼻咽癌高发地区,每年的发病率约为20/10万[1],由于鼻咽解剖结构及生物学行为的特殊性,很难行手术治疗,目前鼻咽癌公认和有效的治疗手段为放射治疗或以放疗为主的综合治疗。虽然放疗技术不断进步与放疗设备的不断更新,鼻咽癌的生存率有了较大的提高,但5年生存率仍为60%~80%[2],部分患者仍未能获得长期生存。TNM分期系统是鼻咽癌预后判断和指导治疗的重要依据,但临床发现同一分期患者即使接受相同的治疗方案,预后却不同[3-4],这提示鼻咽癌生物学差异的存在,仅基于解剖学信息的TNM临床分期系统还不能准确地预测鼻咽癌患者的预后。虽然EB病毒滴度、表皮生长因子受体、microRNA也可提示鼻咽癌的预后[5-7],但检测成本高,需要多中心合作,临床上可行性差。所以,亟需检测方便、价格低廉可预测鼻咽癌预后的标志物。
流行病学研究证实,约25%的肿瘤由炎性反应发展而来,其与肿瘤的发生发展密切相关并且影响肿瘤患者的预后[8]。炎性反应指标,如白细胞计数[9]、血小板计数[10-11]、中性粒淋巴细胞比(neutrophil-lymphocyte ratio, NLR)[12-13]、血小板淋巴细胞比(platelet-lymphocyte ratio, PLR)[14-15]被发现可作为肿瘤的独立预后因素。这些血液指标检测方便,价格低廉,可广泛应用于临床,评估患者预后。本研究通过对91例鼻咽癌患者临床资料进行回顾性分析,评价治疗前PLR和NLR与鼻咽癌患者预后的相关性,为评估预后提供客观依据。
1 资料与方法
1.1 临床资料
回顾性收集2009年1月至2013年9月期间于西安交通大学第一附属医院和陕西省人民医院初治的91例鼻咽癌患者,所有病例均经病理证实。临床资料完整。排除标准:(1)合并有免疫性疾病以及其他恶性肿瘤的患者;(2)治疗前合并有急性或慢性感染;(3)合并有血液系统疾病、血栓或出血性疾病;(4)合并有严重的肝、肾疾病;(5)治疗前曾接受过放疗或化疗;(6)无远处转移。记录患者治疗前的中性粒细胞计数、淋巴细胞计数及血小板计数结果。
1.2 治疗及随访方法
入选患者采用3D-CRT或IMRT根治性放疗(有或无化疗),Ⅰ期患者仅接受单纯放射治疗,Ⅱ、Ⅲ、Ⅳ期患者接受以顺铂和5-氟尿嘧啶为主的辅助或同步放化疗。鼻咽原发灶和颈部转移淋巴结剂量为(70~76)Gy/(7~8)w/(35~38)f,颈部预防区域剂量为(50~60)Gy/(5~6)w/(25~30)f。根据患者的临床分期及不良反应给予2~6周期的全身化疗,化疗方案为:顺铂25 mg/m2,第1~3天静脉滴注;5-氟尿嘧啶500 mg/m2,第1~5天静脉滴注,每21天重复1周期。患者治疗结束后均定期随访,治疗后前2年,每3月检查一次,2年后半年复查一次,5年后1年复查1次。随访截止时间为2016年9月。
1.3 统计学方法
采用SPSS19.0软件对数据进行统计学分析。绘制ROC曲线确定PLR和NLR与总生存期(overall survival, OS)及无进展生存期(progression-free survival, PFS)的相关性,选取截断值。应用Kaplan-Meier法进行生存分析并采用Log rank检验来检验。采用Cox比例风险回归模型分析多种因素对生存时间的影响。以P < 0.05为差异有统计学意义。
2 结果
2.1 鼻咽癌患者临床病理资料
91例患者的基本特征资料见表 1,中位年龄53岁(12~72)岁,女30例,男61例,男女比例2:1,Ⅰ、Ⅱ、Ⅲ、Ⅳ期患者分别为2、27、42、20例。单纯放疗患者9例,82例患者接受辅助或同步放化疗,所有患者均按期完成放化疗。中位随访时间为44月(6~87)月,其中44例出现复发或转移,39例患者死亡。患者的1、3、5年总生存率分别为92.3%、72.1%、56.8%,1、3、5年无进展生存率分别为82.4%、60.9%、53.3%。
表 1 91例鼻咽癌患者临床基本特征资料(n(%))Table 1 Basic clinical features of 91 nasopharyngeal carcinoma patients (n(%))2.2 ROC曲线选取PLR和NLR预后相关截断值
以OS作为终点,PLR、NLR为检测变量,绘制ROC曲线选取截断值分别为143.3、2.6,两者的曲线下面积分别为0.640、0.739,见图 1。
以PFS作为终点,PLR、NLR为检测变量,绘制ROC曲线选取截断值分别为143.3、2.6,两者的曲线下面积分别为0.657、0.694,见图 2。说明治疗前PLR、NLR与患者的预后存在相关性,利用ROC曲线选取的截断值进行进一步生存分析。
2.3 Kaplan-Meier生存分析、Cox单因素和多因素分析
PLR≥143.3组和PLR < 143.3组患者生存曲线比较,差异有统计学意义(P=0.022),见图 3~4。NLR≥2.6组和NLR < 2.6组患者生存曲线比较,差异有统计学意义(P=0.044),见图 5~6。
Cox单因素分析显示除性别、年龄以外,TNM分期、治疗前PLR≥143.3、NLR≥2.6均是影响鼻咽癌患者OS和PFS的不良预后因素(P < 0.05),见表 2。Cox多因素分析显示治疗前PLR≥143.3(RR=2.491, 95%CI=1.139~5.451, P=0.022)、NLR≥2.6(RR=2.186, 95%CI=1.021~4.682,P=0.044)是鼻咽癌患者OS的独立危险因素,而治疗前PLR≥143.3(RR=2.461,95%CI=1.242~4.874, P=0.010)是鼻咽癌患者PFS的独立危险因素,见表 3。
表 2 影响鼻咽癌患者生存预后的Cox单因素分析Table 2 Cox univariate analysis of prognostic factors for nasopharyngeal carcinoma patients表 3 影响鼻咽癌患者生存预后的Cox多因素分析Table 3 Cox multivariate analysis of prognostic factors for nasopharyngeal carcinoma patients3 讨论
鼻咽癌对放射线高度敏感,因此放疗成为主要治疗手段。随着三维适形放疗和调强放射治疗的临床应用,鼻咽癌的生存率较前明显提高,但5年生存率仍仅为60%~80%。多项研究表明鼻咽癌患者预后与众多因素有关,包括患者年龄、临床分期、EB病毒感染及贫血等。此外,肿瘤的预后还与机体本身的炎性反应有关。炎性反应包含中性粒细胞、淋巴细胞、血小板、C反应蛋白等多种指标,其中PLR、NLR已受到越来越多专家的关注。本研究发现治疗前PLR和NLR可能成为鼻咽癌的独立预后因素。
恶性肿瘤患者常伴随血小板的升高,实验研究表明血小板参与肿瘤细胞生长、转移及血管生成[16]。临床研究表明血小板数目升高与肿瘤患者较差预后相关[11, 17]。此外研究表明中性粒细胞可促使机体产生多种促肿瘤生长因子和蛋白酶,促进肿瘤的发生、发展[18]。而淋巴细胞参与机体的免疫反应是抗肿瘤免疫的重要组成部分,淋巴细胞减少说明机体免疫机制异常,抗肿瘤免疫力下降,为肿瘤生长、浸润和转移提供条件。随着肿瘤进展,机体内炎性反应与肿瘤失去平衡,体内淋巴细胞降低,而血小板、中性粒细胞升高,相应的PLR和NLR比值也增高,机体内促进肿瘤炎性反应与抗肿瘤炎性反应的平衡状态被打破。因此PLR和NLR是反应机体免疫情况的重要指标,两者的升高能促进肿瘤进展,导致肿瘤患者预后不良。既往研究结果显示高PLR和NLR可影响宫颈癌、乳腺癌、结直肠癌等恶性肿瘤的预后[19-21]。而目前关于PLR、NLR与鼻咽癌患者预后相关性的研究较少,Sun等[21]分析了251例鼻咽癌患者治疗前PLR和NLR,结果证明治疗前两者水平是影响鼻咽癌患者生存独立预后因素。本研究结果显示治疗前PLR、NLR与鼻咽癌患者的总生存期和无进展生存期具有相关性。Cox多因素分析提示PLR≥143.3、NLR≥2.6和TNM分期是影响鼻咽癌患者治疗后的独立危险因素。PLR≥143.3组患者有较短OS和PFS,而NLR≥2.6组患者有较差的OS,和本研究结果相一致。因此,高PLR、NLR的鼻咽癌患者总生存率要低于低PLR、NLR的患者,且高PLR的患者复发或转移风险明显增加。据此,临床上或许可以通过提高鼻咽癌患者免疫功能及降低机体炎性反应,改善患者的预后。
但由于本研究是一个相对小样本的回顾性研究,不能代表大部分的鼻咽癌患者,且随访时间较短,存在一定的局限性,因此需要进行多中心、大样本的前瞻性研究来进一步证实。
本研究结果表明,治疗前PLR和NLR水平与鼻咽癌患者预后具有相关性,可能是影响鼻咽癌患者预后的独立危险因素,NLR和PLR的获取具有简便、经济的优点,可以作为鼻咽癌患者病情评估的一个有益补充,值得推广。目前鼻咽癌相关有效预后指标较多,笔者将在今后的临床研究工作中继续探索,将本研究指标与已有的有效预后指标进行比较,从而提高治疗前PLR和NLR水平这一预后指标应用于临床的合理性及可靠性。
Competing interests: The authors declare that they have no competing interests.作者贡献:陈晓博:论文构思、撰写及修改王倩:参与文献收集及整理李庆霞:论文构思、写作指导及审阅 -
[1] Ozkan EE, Kaymak Cerkesli ZA, Erdogan M. Predictive value of immune-inflammation indices in metabolic response and outcome after curative radi otherapy in patients with non-small cell lung cancer[J]. Clin Respir J, 2020, 14(9): 849-856. doi: 10.1111/crj.13217
[2] Guo D, Zhang J, Jing W, et al. Prognostic value of systemic immune-inflammation index in patients with advanced non-small-cell lung cancer[J]. Future Oncol, 2018, 14(25): 2643-2650. doi: 10.2217/fon-2018-0285
[3] Wang C, Jin S, Xu S, et al. High Systemic Immune-Inflammation Index (SⅡ) Represents an Unfavorable Prognostic Factor for Small Cell Lung Cancer Treated with Etoposide and Platinum-Based Chemotherapy[J]. Lung, 2020, 198(2): 405-414. doi: 10.1007/s00408-020-00333-6
[4] Nie D, Gong H, Mao X, et al. Systemic immune-inflammation index predicts prognosis in patients with epithelial ovarian cancer: A r etrospective study[J]. Gynecol Oncol, 2019, 152(2): 259-264. doi: 10.1016/j.ygyno.2018.11.034
[5] Wang D, Guo D, Shi F, et al. The predictive effect of the systemic immune-inflammation index for patients with small-cell lung cancer[J]. Future Oncol, 2019, 15(29): 3367-3379. doi: 10.2217/fon-2019-0288
[6] Hu B, Yang XR, Xu Y, et al. Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepato cellular carcinoma[J]. Clin Cancer Res, 2014, 20(23): 6212-6222. doi: 10.1158/1078-0432.CCR-14-0442
[7] Zhang H, Shang X, Ren P, et al. The predictive value of a preoperative systemic immune-inflammation index and prognostic nutritional index in patients with esophageal squamous cell carcinoma[J]. J Cell Physiol, 2019, 234(2): 1794-1802. doi: 10.1002/jcp.27052
[8] Tecchio C, Cassatella MA. Neutrophil-derived cytokines involved in physiological and pathological angiogenesis[J]. Chem Immunol Allergy, 2014, 99: 123-137. http://www.karger.com/Article/Pdf/353358
[9] Teramukai S, Kitano T, Kishida Y, et al. Pretreatment neutrophil count as an independent prognostic factor in advanced non-small-cell lung cancer: an analysis of Japan Multinational Trial Organisation LC00-03[J]. Eur J Cancer, 2009, 45(11): 1950-1958. doi: 10.1016/j.ejca.2009.01.023
[10] Yang R, Chang Q, Meng X, et al. Prognostic value of Systemic immune-inflammation index in cancer: A meta-analysis[J]. J Cancer, 2018, 9(18): 3295-3302. doi: 10.7150/jca.25691
[11] Zhang Q, Qu Y, Liu H, et al. Initial platelet-to-lymphocyte countas prognostic factor in limited-stage small cell lung cancer[J]. Biomark Med, 2019, 13(4): 249-258. doi: 10.2217/bmm-2018-0415
[12] Mezouar S, Frère C, Darbousset R, et al. Role of platelets in cancer and cancer-associated thrombosis: Experimental and clinical evidences[J]. Thromb Res, 2016, 139: 65-76. doi: 10.1016/j.thromres.2016.01.006
[13] Zhang T, Jiang Y, Qu X, et al. Evaluation of preoperative hematologic markers as prognostic factors and establishment of novel risk stratification in resected pN0 non-small-cell lung cancer[J]. PLoS One, 2014, 9(10): e111494. doi: 10.1371/journal.pone.0111494
[14] Shoji F, Kozuma Y, Toyokawa G, et al. Complete Blood Cell Count-Derived Inflammatory Biomarkers in Early-Stage Non-Small-Cell Lung Cancer[J]. Ann Thorac Cardiovasc Surg, 2020, 26(5): 248-255. doi: 10.5761/atcs.oa.19-00315
[15] Ocana A, Nieto-Jiménez C, Pandiella A, et al. Neutrophils in cancer: prognostic role and therapeutic strategies[J]. Mol Cancer, 2017, 16(1): 137. doi: 10.1186/s12943-017-0707-7
[16] 史美祺, 陶如. 迈向早期非小细胞肺癌的免疫治疗[J]. 医学研究生学报, 2019, 32(8): 785-790. https://www.cnki.com.cn/Article/CJFDTOTAL-JLYB201908002.htm Shi MQ, Tao R. Immunotherapy: Towards on early non-small cell lung cancer[J]. Yi Xue Yan Jiu Sheng Xue Bao, 2019, 32(8): 785-790. https://www.cnki.com.cn/Article/CJFDTOTAL-JLYB201908002.htm
[17] Guo W, Cai S, Zhang F, et al. Systemic immune-inflammation index (SⅡ) is useful to predict survival outcomes in patients with surg ically resected non-small cell lung cancer[J]. Thorac Cancer, 2019, 10(4): 761-768. doi: 10.1111/1759-7714.12995
[18] Gao Y, Zhang H, Li Y, et al. Preoperative increased systemic immune-inflammation index predicts poor prognosis in patients with operable non-small cell lung cancer[J]. Clin Chim Acta, 2018, 484: 272-277. doi: 10.1016/j.cca.2018.05.059
[19] Li X, Hu P, Liu J, et al. Systemic immune-inflammation index predicted overall survival and radiosensitivity in advanced non-small-cell lung cancer[J]. Future Oncol, 2020, 16(5): 103-115. doi: 10.2217/fon-2019-0761
[20] Fortunato O, Boeri M, Moro M, et al. Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction[J]. Cell Death Dis, 2014, 5(12): e1564. doi: 10.1038/cddis.2014.507
[21] Tong YS, Tan J, Zhou XL, et al. Systemic immune-inflammation index predicting chemoradiation resistance and poor outcome in patients with stage Ⅲ non-small cell lung cancer[J]. J Transl Med, 2017, 15(1): 221. doi: 10.1186/s12967-017-1326-1
[22] Deng C, Zhang N, Wang Y, et al. High systemic immune-inflammation index predicts poor prognosis in advanced lung adenocarcinoma patients treated with EGFR-TKIs[J]. Medicine (Baltimore), 2019, 98(33): e16875. doi: 10.1097/MD.0000000000016875
[23] Liu J, Li S, Zhang S, et al. Systemic immune-inflammation index, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio can predict clinical outcomes in patients with metastatic non-small-cell lung cancer treated with nivolumab[J]. J Clin Lab Anal, 2019, 33(8): e22964.
[24] Wang Y, Li Y, Chen P, et al. Prognostic value of the pretreatment systemic immune-inflammation index (SⅡ) in patients with non-small cell lung cancer: a meta-analysis[J]. Ann Transl Med, 2019, 7(18): 433. doi: 10.21037/atm.2019.08.116
[25] Lindenmann J, Fink-Neuboeck N, Taucher V, et al. Prediction of Postoperative Clinical Outcomes in Resected Stage Ⅰ Non-Small Cell Lung Cancer Focusing on the Preoperative Glasgow Prognostic Score[J]. Cancers (Basel), 2020, 12(1): 152. doi: 10.3390/cancers12010152
[26] Nie D, Zhang L, Wang C, et al. A high Glasgow prognostic score (GPS) or modified Glasgow prognostic score (mGPS) predicts poor prognosis in gynecologic cancers: a systematic review and meta-analysis[J]. Arch Gynecol Obstet, 2020, 301(6): 1543-1551. doi: 10.1007/s00404-020-05581-8
[27] Li X, Hu P, Liu J, et al. Systemic immune-inflammation index predicted overall survival and radiosensitivity in advanced non-small-cell lung cancer[J]. Future Oncol, 2020, 16(5): 103-115. doi: 10.2217/fon-2019-0761
[28] 张辉, 施仲义, 胡一迪, 等. 术前系统免疫炎症指数和反应蛋白/血清白蛋白比值与非小细胞肺癌预后的相关性[J]. 中国卫生检验杂志, 2019, 29(5): 573-576. https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ201905021.htm Zhang H, Shi ZY, Hu YD, et al. Prognostic values of preoperative systematic immue-inflammation index and CRP/Alb in non-small cell lung cancer patients[J]. Zhongguo Wei Sheng Jian Yan Za Zhi, 2019, 29(5): 573-576. https://www.cnki.com.cn/Article/CJFDTOTAL-ZWJZ201905021.htm
[29] Ni XF, Wu J, Ji M, et al. Effect of C-reactive protein/albumin ratio on prognosis in advanced non-small-cell lung cancer[J]. Asia Pac J Clin Oncol, 2018, 14(6): 402-409. doi: 10.1111/ajco.13055
[30] Zhang Y, Chen B. Prognostic Value of the Advanced Lung Cancer Inflammation Index in Patients with Lung Cancer: A Meta- Analysis[J]. Dis Markers, 2019, 2019: 2513026. http://www.researchgate.net/publication/334167794_Prognostic_Value_of_the_Advanced_Lung_Cancer_Inflammation_Index_in_Patients_with_Lung_Cancer_A_Meta-Analysis
[31] Tomita M, Ayabe T, Maeda R, et al. Comparison of Inflammation-Based Prognostic Scores in Patients undergoing Curative Resection for Non-small Cell Lung Cancer[J]. World J Oncol, 2018, 9(3): 85-90. doi: 10.14740/wjon1097w
[32] Shiroyama T, Suzuki H, Tamiya M, et al. Pretreatment advanced lung cancer inflammation index (ALI) for predicting early progression in nivolumab-treated patients with advanced non-small cell lung cancer[J]. Cancer Med, 2018, 7(1): 13-20. doi: 10.1002/cam4.1234
[33] Wang Y, Lin L, Ji Y, et al. Prognostic value of the advanced lung cancer inflammation index in early-stage non-small cell lung ca ncer patients undergoing video-assisted thoracoscopic pulmonary resection[J]. Ann Palliat Med, 2020, 9(3): 721-729. doi: 10.21037/apm.2020.03.18
[34] Mirili CY, Lmaz A, Demirkan S, et al. Clinical significance of prognostic nutritional index (PNI) in malignant melanoma[J]. Int J Clin Oncol, 2019, 24(10): 1301-1310. doi: 10.1007/s10147-019-01461-7
[35] Wang D, Hu X, Xiao L, et al. Prognostic Nutritional Index and Systemic Immune-Inflammation Index Predict the Prognosis of Patients with HCC[J]. J Gastrointest Surg, 2021, 25(2): 421-427. doi: 10.1007/s11605-019-04492-7
[36] Zhang Y, Chen B, Wang L, et al. Systemic immune-inflammation index is a promising noninvasive marker to predict survival of lung cancer: A meta-analysis[J]. Medicine (Baltimore), 2019, 98 (3): e13788. doi: 10.1097/MD.0000000000013788
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