【作者】 李楠；

【导师】 王丽萍；

【作者基本信息】 郑州大学 ， 肿瘤学（专业学位）， 2020， 硕士

【摘要】 背景及目的随着社会进步、医学诊断技术的提高、人均寿命的延长及饮食结构改变,恶性肿瘤的发病率呈现逐年升高的趋势,其中肺癌的发病率和死亡率均位于恶性肿瘤的首位,严重威胁人类的生命健康。因肺癌早期症状隐匿,患者确诊时大部分处于晚期或出现远处器官转移,失去手术机会,只能接受化疗,由于传统化疗药物的细胞毒性作用和客观反应率不高的特点,使得晚期肺癌的治疗处于平台期。随着分子检测技术的提高,尤其是EGFR(epidermal growth factor receptor)基因的发现,以及相应的靶向药物的研发成功,各项大型临床试验均证实吉非替尼较传统化疗治疗敏感突变的晚期非小细胞肺癌(non small cell lung cancer,NSCLC)患者,存在明显的生存获益,且因副反应小、耐受性好的特点,迅速成为存在EGFR敏感突变的晚期非小细胞肺癌的首选治疗方案。但是口服靶向药物受益时间有限,服药后期均不可避免的出现获得性耐药问题,限制了晚期肺腺癌患者的长期生存。由于分子靶向药物和细胞毒性药物的作用机理不同,目前关于如何将传统化疗与分子靶向药物相结合以延缓耐药的发生,成为.晚期肺腺癌治疗的争议问题。本课题通过大样本的病例对照研究,回顾性分析联合化疗后吉非替尼维持治疗对敏感突变的晚期肺腺癌患者的临床治疗效果和安全性。资料及方法无选择性收集2015年1月至2018年1月于郑州大学第一附属医院连续入院的初诊肺腺癌患者8796例,且均经本院活检病理确诊肺腺癌,筛选存在EGFR基因19外显子和21外显子L858R突变的患者。1.根据治疗方案的不同,将吉非替尼单药设对照组121例,将联合化疗后吉非替尼维持治疗设为观察组93例,根据正态性检验和方差齐性检验结果,对两治疗组间的临床数据,定量资料采用两独立样本t检验或秩和检验,定性资料采用卡方检验。2.对两治疗组间的无进展生存时间(progress free survival,PFS)和总生存时间(overall survival,OS)进行统计,两组间生存资料的比较采用Kaplan-Meier法及log-rank 比较两组生存的差异。3.对可能影响患者无进展生存时间和总生存时间的一般资料,通过COX回归模型进行单因素和多因素分析。4.两治疗组间的总不良反应通过采用卡方检验比较,组间三级以上不良反应的比较通过采用卡方的连续校正法及Fisher精确概率法。以上统计学分析均通过SPSS22.0统计软件处理,以α=0.05为检验水准,P<0.05为差异有统计学意义。结果1.缓解率:观察组CR 0例,PR 40例,SD 43例,PD 10例,疾病控制率(DCR)为89.2%,客观缓解率(ORR)为43%。对照组CR 0例,PR 34例,SD 73例,PD 14例,疾病控制率为88.43%,客观缓解率为28.1%。疾病控制率方面组间差异无统计学意义(P>0.05),客观缓解率在两组间差异有统计学意义(P<0.05)。2.生存分析:观察组的中位PFS为15个月,中位OS为52个月;对照组中位PFS为9个月,中位OS为36个月,两组间差异具有统计学意义(P<0.05)。3.单因素及多因素分析发现:基因突变类型是影响患者PFS的独立影响因素,其中EGFR19外显子突变是延长PFS的保护性因素(HR=0.688,95%CI 0.538-0.879,P=0.003)。4.根据基因突变类型进行分层分析发现,无论19外显子突变还是21外显子L858R突变亚组中,两治疗组间对PFS影响的差异均具有统计学意义(P<0.05)。5.不良反应情况:观察组常见的不良反应是消化道反应(40.9%)和骨髓抑制(62.3%),对照组的常见不良反应是皮疹(12.4%)和消化道反应(12.4%),在骨髓抑制、消化道反应、肝肾功能损伤方面组间差异具有统计学意义(P<0.05),但三级以上不良反应组间差异无统计学意义(P>0.05)。结论联合化疗后吉非替尼维持治疗EGFR敏感突变的晚期肺腺癌可以获得较好的临床效果,在不良反应可以耐受并可控的条件下,明显延长患者的PFS和OS,延缓吉非替尼耐药的发生,尤其在EGFR19外显子突变的患者中的疗效格外显著。更多还原

【Abstract】 Background and ObjectiveWith the advancement of society,the improvement of medical diagnostic,the extension of life expectancy and changes in diet structure,the incidence of malignant tumors has a tendency of increasing.The morbidity and mortality of lung cancer are the highest in all cancer,which bitterly threatens human health.Because the early symptoms about lung cancer were not obvious,most patients were already in advanced stage or had distant organ metastasis when they are diagnosed,then they will lose the opportunity of surgery and have to receive chemotherapy.Due to the cytotoxic effect and low objective response rate of traditional chemotherapeutic drugs,the treatment of advanced lung cancer was in the plateau stage.With the improvement of molecular detection technology,especially the discovery of the EGFR(Epidermal growth factor receptor)gene,and the development of targeted drugs,various large clinical trials have confirmed that gefitinib has obvious survival benefits compared with traditional chemotherapy for advanced non-small cell lung cancer(NSCLC).Because of the good tolerance and weak side effects have quickly made gefitinib as the standard treatment for advanced non-small cell lung cancer with EGFR sensitive mutation.But oral targeted drugs have limited benefit time,and will have unavoidable acquired drug resistance in the later treatment,which limits the long-term survival of advanced patients.Due to the different mechanisms of molecular targeted drugs and cytotoxic drugs,how to combine traditional chemotherapy with molecular targeted drugs has became a controversial question in the treatment of advanced lung adenocarcinoma,in order to delay the occurrence of drug resistance.This project retrospectively analyzed the clinical effect and safety of gefitinib followed by chemotherapy in advanced lung adenocarcinoma with sensitive mutations,through a large sample case-control study.Masterials and methodsWe collect 8796 newly diagnosed lung adenocarcinoma patients,who were consecutively admitted to the First Affiliated Hospital of Zhengzhou University between January 2015 and January 2018.All patients were diagnosed with adenocarcinoma by pathological biopsy.Patients with EGFR exon 19 and exon 21 L858R mutation were selected.1.According to different treatment regimen,121 patients were set as the control group recepted gefitinib alone,93 received chemotherapy and gefitinib maintenance,which were set as the observation group.According to the results of normality test and homogeneity test of variance,quantify clinical data between the two treatment groups use two independent sample t-tests or rank sum tests,qualitative data use Chi-square test.2.Statistics of progress free survival(PFS)and overall survival(OS)between the two groups,Comparison of survival data between the two groups using Kaplan-Meiermrethod,log-rank is used to compare the difference in survival between the two groups.3.General clinical data that may be affected patients’ PFS or OS,we get univariate and multivariate analysis by using COX regression models.4.Adverse reactions were compared between the two treatment groups by using Chi-square test,Grade 3 adverse reactions or obove between the two groups were analysed by Chi-square continuous correction method and Fisher’s exact probability method.The above statistical analysis is processed by SPSS22.0 statistical software,Withα=0.05 as the inspection level,β<0.05 is considered statistically significant.Results1.Remission rate:In the observation group,0 cases were CR,40 cases were PR,43 cases were SD,and 10 cases were PD.The disease control rate(DCR)was 89.2%,and the objective response rate(ORR)was 43.0%.In the control group,0 cases were CR,34 cases were PR,73 cases were SD,and 14 cases were PD.The disease control rate was 88.4%and the objective response rate was 28.1%.The disease control rate was not statistically significant between the two groups(P>0.05),and the objective response rate was significantly different between two groups(P<0.05).2.Survival analysis:The median PFS in the observation group was 15 months,the median OS was 52 months.The median PFS in the control group was 9 months,and the median OS was 36 months.The difference between the two groups was statistically significant(P<0.05).3.Univariate and multivariate analysis:Genetic mutation type is an independent influencing factor for PFS,and EGFR exon 19 mutation is a protective factor in prolonging patients’ PFS(HR=0.688,95%CI 0.538-0.879,P=0.003).4.According to subgroup analysis,regardless of exon 19 mutation or exon 21 L858R mutation,the difference in PFS between the two groups was statistically significant(P<0.05).5.Adverse reactions:Common adverse reactions in the observation group were gastrointestinal reactions(40.9%)and bone marrow suppression(62.3%).Common adverse reactions in the control group were rash(12.4%)and gastrointestinal reactions(12.4%).There were statistically significant differences between the groups about bone marrow suppression,gastrointestinal reactions,liver and kidney function damage(P<0.05),but there were no significant differences between the groups of Grade 3 adverse reactions or obove(P>0.05).ConclusionChemotherapy followed by Gefitinib maintenance therapy in advanced lung adenocarcinoma with EGFR-sensitive mutation can achieve better clinical efficacy.Under conditions where the adverse reactions can be tolerated and controlled,significantly prolongs patients’ PFS and OS and delays the occurrence of gefitinib resistance,especially in patients with EGFR exon 19 mutations,the effect is particularly significant.更多还原