【作者】 张菁；

【导师】 李宝生；

【作者基本信息】 山东大学 ， 肿瘤学（专业学位）， 2021， 硕士

【摘要】 研究背景与目的:ⅢA-N2期非小细胞肺癌(non small-cell lung cancer,NCSLC)患者是异质性很强的群体。对于可切除的ⅢA-N2期NSCLC患者,首选手术切除。然而,纵隔或隆突下淋巴结的受累使这部分患者术后局部复发及远处转移可能性增加,预后差,5年总生存率仅为19-24%。因此,ⅢA-N2期NSCLC患者术后应进行辅助治疗。目前标准的辅助治疗是术后化疗(postoperativechemotherapy,POCT)。作为局部治疗的直接载体,术后放疗(postoperativeradiotherapy,PORT)是辅助治疗的重要组成部分,一直被认为可以降低ⅢA-N2期NSCLC的局部复发风险,然而,这种局部无病的获益能否转化为整体生存的获益,在当前阶段尚存在争议。因此,本研究旨在评估PORT对ⅢA-N2期NSCLC生存的作用。研究方法:本研究共两部分,第一部分从美国国立癌症研究所“检测、流行病学和结果数据库”(the Surveillance,Epidemiology and End Results,SEER)收集 2010-2015年接受术后化疗的ⅢA-N2期NSCLC患者的临床和随访数据,并将其分为术后化放疗组(postoperative chemoradiotherapy,POCRT)和术后化疗组。皮尔森卡方检验用于基线比较,倾向性匹配分析(propensity score matching,PSM)用于病例匹配和基线校正。单因素及多变量Cox 比例危险回归模型用于筛选对预后有影响的独立预后因素。Kaplan-Meier生存曲线及log-rank检验用于评估PORT对接受辅助化疗的ⅢA-N2期非小细胞肺癌患者总生存(overall survival,OS)及肿瘤特异性生存(cancer special survival,CSS)的影响。为行进一步验证,第二部分收集山东省肿瘤医院接受PORT的ⅢA-N2期NSCLC患者的临床与随访数据,并增加淋巴结状态相关变量及DFS的随访数据。采用与第一部分类似的统计学方法以评估PORT对OS及无病生存(disease-free survival,DFS)的影响,并验证及筛选受益亚组。研究结果:从SEER数据库中共确定了 1857例ⅢA-N2期NSCLC病例,其中1005例(54.1%)接受了 POCRT,而852例(45.9%)只接受POCT。原发部位(p=0.011)、阳性淋巴结个数(numberofpositivelymphnodes,PLN,p=0.003)和手术方式(p=0.002)共3个变量失衡。PSM后共828对,1656例病例,基线较前平衡。单因素及多因素COX回归分析显示,男性、年龄≥60岁、T3期及PLN≥5为预后危险因素(p均<0.05)。PORT与预后无显著相关性(p=0.191,0.148)。POCRT组与POCT组的OS(48 vs 44个月,p=0.365)及CSS无显著差异(57 vs 50个月,p=0.333)。但PORT可改善PLN≥5的患者的生存(p=0.021,p=0.070)。随着T分期的增加,PORT为病例带来的生存获益也显著增加。在第二部分,共纳入249例患者,其中179例(71.9%)接受POCT,而70例(28.1%)接受 POCRT。PORT 是与 OS(HR 0.550,95%CI 0.352-0.860,p=0.009)及 DFS(HR 0.613,95%CI 0.428-0.878,p=0.008)改善相关的独立预后因素。PORT为ⅢA-N2期肺癌患者带来显著OS和DFS获益(p=0.009,0.042)。针对淋巴结状态,PORT可改善PLN≥3及N2 PLN≥2患者的OS及DFS(p均<0.05)。PORT对T2及T3期患者有积极影响。研究结论:综合两部分研究,我们认为对于接受辅助化疗的ⅢA-N2期NSCLC患者,PORT可显著改善整体患者的DFS,对OS的积极作用适用于特定亚组。随着T分期的升级,ⅢA-N2期NSCLC患者从PORT中获益的可能性增加。T2及T3期患者是PORT的受益亚组。淋巴结状态是重要的预后因素。PLN≥3及N2PLN≥2是可通过PORT获益的优势亚组。更多还原

【Abstract】 Background:Patients with ⅢA-N2 non-small cell lung cancer(NSCLC)have high heterogeneity.For patients with resectable ⅢA-N2 NSCLC,surgical resection is preferred.However,mediastinal or subcarinal lymph nodes metastasis increases the probability local recurrence and distant metastasis after surgery.ⅢA-N2 NSCLC patients have a poor prognosis with a 5-year overall survival(OS)rate of only 19-24%.Therefore,adjuvant therapy should be performed after surgery.The current standard adjuvant therapy is postoperative chemotherapy(POCT).As a direct vehicle for local treatment,postoperative radiotherapy(PORT)is an important component of adjuvant therapy and has been considered to reduce the risk of local recurrence in stage ⅢA-N2 NSCLC.However,whether this local disease-free benefit translates into an OS benefit is controversial.Therefore,the aim of our study was to evaluate the role of PORT on survival in stage ⅢA-N2 NSCLC.Methods:In Part Ⅰ,we collected clinical and follow-up data from 2010-2015 from the Surveillance,Epidemiology and End Results(SEER)database for patients with stageⅢA-N2 NSCLC treated with POCT.Patients were divided into postoperative chemoradiotherapy(POCRT)and POCT groups.Pearson’s chi-square test was used for baseline comparisons.Propensity score matching(PSM)analysis was used for case matching and baseline correction.Univariate and multivariate Cox proportional hazards regression models were used to screen for independent prognostic factors that had an impact on prognosis.Kaplan-Meier survival curves and log-rank tests were used to assess the effect of PORT on OS and cancer specific survival(CSS).For further validation,clinical and follow-up data of stage ⅢA-N2 NSCLC patients at Shandong Cancer Hospital were collected in the second part.Lymph node status related variables and disease-free survival(DFS)were added.Statistical methods similar to those used in first part were used to assess the effect of PORT on OS and DFS and to validate and screen for beneficiary subgroups.Results:A total of 1857 cases were identified from the SEER database,of which 1005(54.1%)received POCRT,while 852(45.9%)received POCT.3 variables,primary site,number of positive lymph nodes(PLN)and surgical approach were imbalanced(all p<0.05).A total of 828 pairs and 1656 cases were balanced after PSM.Male,age ≥60 years,T3 stage and PLN≥5 were prognostic risk factors(all p<0.05).There was no significant correlation between PORT and OS or CSS(p=0.191,0.148).OS(48 vs 44 months,p=0.365)and CSS were not significantly different between the POCRT and POCT groups(57 vs 50 months,p=0.333).However,PORT improved survival in patients with PLN≥ 5(p=0.021,0.070).The survival benefit of PORT increased with increasing T stage.In Part Ⅱ,249 patients were included,of whom 179(71.9%)received POCT,while 70(28.1%)received POCRT.PORT was an independent prognostic factor associated with improved OS(HR 0.550,95%CI 0.352-0.860,p=0.009)and DFS(HR 0.613,95%CI 0.428-0.878,p=0.008).PORT provided significant OS and DFS benefits forⅢA-N2 patients(p=0.037,0.024).For lymph node status,PORT improved OS and DFS in patients with PLN≥3 and N2 PLN≥2(all p<0.05).PORT also has a positive impact on patients with T2 stage.Conclusions:For patients with ⅢA-N2 NSCLC and POCT,PORT significantly improved DFS while the positive effect on OS was applicable to specific subgroups.Patients with T2 and T3 stage were the beneficiary subgroups of PORT.PLN≥3 and N2 PLN≥2 were dominant subgroups.更多还原