56例局部进展期胃癌术后中药防治复发转移临床研究及系统综述

【作者】 王玥；

【导师】 侯丽；

【作者基本信息】 北京中医药大学 ， 中西医结合临床（专业学位）， 2021， 硕士

【摘要】 目的:(1)通过Meta分析探索中医药联合化疗防治局部进展期胃癌(locally advanced gastric cancer,LAGC)术后复发转移的有效性及安全性,评价中医药提高辅助化疗期间患者生活质量、免疫功能、减轻毒副反应的作用以及防治LAGC术后复发转移的疗效。(2)通过分析临床相关资料对LAGC术后无瘤生存期(disease-free survival,DFS)的影响,从包括中医药干预在内的多项相关因素中筛选出LAGC术后DFS的危险因素及保护因素,为今后更好地应用中医药防治LAGC术后复发转移提供思路。方法:(1)Meta 分析:计算机检索 CNKI、wanfang、VIP、PubMed、Cochrane Library等数据库,检索时间截至2021年2月,检索“中药防治胃癌术后复发转移”相关随机对照临床研究,研究人群为已行标准胃癌根治术的LAGC患者,对照组应用标准术后化疗≥4周期,治疗组在对照组的基础上联合应用中药治疗≥8周。结局指标包括术后复发转移率、DFS、免疫功能、生活质量及不良反应发生情况。对研究文献进行筛选与数据提取,应用Cochrane提供的review manager 5.3软件进行Meta分析。(2)临床研究:收集2015年01月01日至2019年12月31日就诊于北京中医药大学东直门医院血液肿瘤科、河南省肿瘤医院中西医结合科、中日友好医院肿瘤科、中国中医科学院肿瘤医院中医科应用中医药治疗的LAGC患者术后2年内的一般资料、临床疾病资料、中医治疗资料等,对基线资料所有变量的有关数据做统计性描述及分析。采用Kaplan-Meier法进行单因素分析,筛选出LAGC术后DFS相关的因素(P<0.05)作复发转移曲线图,然后将相关影响因素纳入Cox风险回归模型作多因素分析,筛选出影响LAGC术后DFS的独立危险因素及保护因素。结果:(1)Meta分析:共纳入18个RCTs,经Meta分析显示,在辅助化疗期间疗效方面,对比单纯化疗,中医药联合化疗可以提高LAGC术后KPS评分(MD=7.24,95%CI[5.17,9.31],P<0.00001),提高 CD3+指标水平(MD=9.52,95%CI[5.90,13.15],P<0.00001),提高 CD4+/CD8+指标水平(MD=0.49,95%CI[0.32,0.66],P<0.00001),降低术后白细胞减少发生率(RR=0.55,95%CI[0.35,0.86],P=0.01),降低血红蛋白减少发生率(RR=0.60,95%CI[0.39,0.93],P=0.02),降低血小板减少发生率(RR=0.70,95%CI[0.57,0.87],P=0.001),降低恶心呕吐症状发生率(RR=0.54,95%CI[0.41,0.70],P<0.00001),降低腹泻发生率(RR=0.61,95%CI[0.46,0.81],P=0.0007),降低神经系统毒性反应发生率(RR=0.42,95%CI[0.19,0.93],P=0.03)。在术后QLQ-C30 评分(MD=7.22,95%CI[-8.54,22.98],P=0.37)以及肝功能异常发生率(RR=0.67,95%CI[0.29,1.58],P=0.37)、肾功能异常发生率(RR=0.57,95%CI[0.17,1.90],P=0.36)方面,中医药联合化疗与单纯化疗疗效相当,无统计学差异;在防治LAGC术后复发转移疗效方面,对比单纯化疗,中医药联合化疗可以降低LAGC术后1年累计复发转移率(RR=0.61,95%CI[0.44,0.85],P=0.003),2年累计复发转移率(RR=0.62,95%CI[0.44,0.86],P=0.005),3 年累计复发转移率(RR=0.59,95%CI[0.48,0.73],P<0.00001),5 年累计复发转移率(RR=0.60,95%CI[0.38,0.95],P=0.03),延长 DFS(MD=2.61,95%CI[1.38,3.83],P<0.0001)。(2)临床研究:共纳入符合入组标准患者62例,脱落6例,最终进入统计分析56例,截止2021年2月,入组的56例LAGC患者均已到达术后2年观察期。术后1年内3例患者发生复发或转移,1年累计复发转移率5.35%;术后2年内16例患者发生复发或转移,2年累计复发转移率28.57%;截止2021年2月,入组的56例LAGC术后患者发生复发转移32例,占比57.14%。统计发生复发转移患者DFS,结果显示:32例患者术后复发/转移时间范围为9-70个月,平均术后复发转移时间28.72±16.78个月,中位DFS 24个月。①单因素Cox回归显示:TNM分期(95%CI:0.21-0.97,P=0.041)、术后血清白蛋白水平(95%CI:0.18-0.96,P=0.04)、中医辨证治疗是否<1 年(95%CI:3.77-20.02,P<0.001)是LAGC术后DFS的影响因素。②多因素Cox回归显示:Ib-Ⅱ期(相较Ⅲ期)是LAGC术后DFS的独立保护因素(95%CI:0.119-0.712,P=0.007),中医治疗时间<1 年 LAGC 术后 DFS 的独立危险因素(95%CI:3.587-23.631,P<0.0001)。结论:(1)Meta分析:中医药联合化疗对比单纯化疗在辅助化疗期间疗效方面,可以提高LAGC术后患者免疫水平及KPS评分,降低白细胞减少、血红蛋白减少、血小板减少、恶心呕吐、腹泻、神经系统毒性反应的发生率。在QLQ-C30评分及肝、肾功能异常发生率方面,与单纯术后化疗无统计学差异;防治复发转移远期疗效方面,可以降低LAGC术后1年、2年、3年、5年的累计复发转移率,提高DFS。(2)临床研究:中医药联合化疗下,更早的TNM分期(Ib-Ⅱ期)以及更长的中医辨证治疗时间(1年以上)是LAGC术后DFS的独立保护因素。更多还原

【Abstract】 Objective:(1)To explore the efficacy and safety of traditional Chinese medicine combined with chemotherapy in the prevention and treatment of postoperative recurrence and metastasis of locally advanced gastric cancer(LAGC)by meta-analysis,and to evaluate the efficacy of traditional Chinese medicine on quality of life,immune indexes,toxic and side effects during adjuvant chemotherapy,as well as the prevention and treatment of recurrence and metastasis after LAGC.(2)To analyze the influence of clinical data on disease-free survival(DFS)after LAGC,and screen out the risk factors and protective factors of multiple related factors including TCM Intervention on DFS after LAGC,so as to provide ideas for the better application of TCM in the prevention and treatment of recurrence and metastasis after LAGC in the future.Methods:(1)CNKI,Wanfang,VIP,PubMed,Cochrane Library and other databases were searched by computer until February 2021.Randomized controlled trials(RCTs)related to"prevention and treatment of recurrence and metastasis of gastric cancer with traditional Chinese medicine" were searched.The study population was LAGC patients who had undergone standard radical gastrectomy.The control group was treated with standard postoperative chemotherapy for more than 4 cycles,On the basis of the control group,the treatment group was treated with traditional Chinese medicine for more than 8 weeks.The outcome measures included recurrence and metastasis rate,DFS,immune function,quality of life and adverse reactions.The research literature screening and data extraction.The Review Manager 5.3 software provided by Cochrane was used for meta-analysis.(2)The general data,clinical disease data and TCM treatment data of LAGC patients treated with TCM in 4 hosptials within 2 years after operation were collected,The relevant data of all variables in the baseline data were statistically described.The results were analyzed according to the location,stage and operation method of the primary lesion.Kaplan Meier method was used in univariate analysis to screen out the factors related to postoperative DFS(P<0.05)for recurrence and metastasis curve,and then the related factors were included in Cox risk regression model for multivariate analysis to screen out the independent risk factors and protective factors of postoperative DFS.Results:(1)A total of 18 RCTs were included.Meta analysis showed that compared with chemotherapy alone,traditional Chinese medicine combined with chemotherapy could improve KPS score(MD=7.24,95%CI[5.17,9.31],P<0.00001),CD3+index level(MD=9.52,95%CI[5.90,13.15],P<0.00001)and CD4+/CD8+index level(MD=0.49,95%Cl[0.32,0.66]),The incidence of postoperative leucopenia(RR=0.55,95%CI[0.35,0.86],P=0.01),hemoglobin reduction(RR=0.60,95%CI[0.39,0.93],P=0.02),thrombocytopenia(RR=0.70,95%CI[0.57,0.87],P=0.001),nausea and vomiting(RR=0.54,95%CI[0.41,0.70],P<0.00001)and diarrhea(RR=0.61,P<0.00001)were reduced,95%CI[0.46,0.81],P=0.0007),incidence of neurotoxicity(RR=0.42,95%CI[0,19,0.93],P=0.03).In terms of postoperative QLQ-C30 score(MD=7.22,95%CI[-8.54,22.98],P=0.37),abnormal liver function(RR=0.67,95%CI[0.29,1.58],P=0.37)and abnormal renal function(RR=0.57,95%CI[0.17,1.90],P=0.36),the incidence of TCM combined chemotherapy was similar to that of chemotherapy alone,with no statistical difference;Compared with chemotherapy alone,TCM combined chemotherapy can reduce the 1-year cumulative recurrence and metastasis rate(RR=0.61,95%CI[0.44,0.85],P=0.003),2-year cumulative recurrence and metastasis rate(RR=0.62,95%CI[0.44,0.86],P=0.005),3-year cumulative recurrence and metastasis rate(RR=0.59,95%CI[0.48,0.73],P<0.00001),The 5-year cumulative recurrence and metastasis rate(RR=0.60,95%CI[0.38,0.95],P=0.03)and the disease-free survival time(MD=2.61,95%CI[1.38,3.83],P<0.0001)were prolonged.(2)A total of 62 patients who met the inclusion criteria were included in the clinical study,including 6 cases of abscission,and finally 56 cases entered the statistical analysis.As of February 2021,all the 56 patients with LAGC had reached the 2-year observation period after operation.Recurrence or metastasis occurred in 3 patients within 1 year after operation,and the cumulative recurrence and metastasis rate was 5.35%;Recurrence or metastasis occurred in 16 patients within 2 years after operation,and the cumulative recurrence and metastasis rate was 28.57%.As of February 2021,32 cases of recurrence and metastasis occurred in 56 patients after LAGC,accounting for 57.14%.The results showed that the recurrence/metastasis time of 32 patients ranged from 9 to 70 months,with an average of 28.72 months ±78 months,the median DFS was 24 months.① Univariate Cox regression showed that TNM stage(95%CI:0.21-0.97,P=0.041),postoperative serum albumin level(95%CI:0.18-0.96,P=0.04)and TCM treatment<1 year(95%CI:3.77-20.02,P<0.001)were the influencing factors of postoperative DFS.② Multivariate Cox regression showed that IB-II stage(compared with III stage)was an independent protective factor for postoperative DFS(95%CI:0.119-0.712,P=0.007),and TCM treatment time<1 year was an independent risk factor for postoperative DFS(95%CI:3.587-23.631,P<0.0001).Conclusion:(1)Meta analysis:comparing the efficacy of traditional Chinese medicine combined chemotherapy with chemotherapy alone in adjuvant chemotherapy,the immune level and KPS score of patients after LACC can be improved,and the incidence of leucopenia,hemoglobin reduction,thrombocytopenia,nausea and vomiting,diarrhea and neurotoxicity can be reduced.There was no significant difference between QLQ-C30 score and the incidence of liver and kidney dysfunction compared with chemotherapy alone;In the long-term prevention and treatment of recurrence and metastasis,the recurrence and metastasis rate of LAGC can be reduced and DFS can be improved.(2)Clinical study:under the combination of traditional Chinese medicine and chemotherapy,earlier TNM stage(IB-II stage)and longer dialectical treatment time(more than 1 year)are independent protection factors of DFS after LAGC.更多还原