图1 PSM前后两组OS和DFS比较
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探析益气养精方对Ⅰ~ⅢA期肺腺癌根治术后患者生存预后的影响。
以2012年1月1日至2015年12月31日上海交通大学医学院附属胸科医院中西医结合科收治的Ⅰ~ⅢA期肺腺癌根治术后患者为研究对象,根据是否接受过益气养精方为主的中药治疗,分为中药组和对照组;采用倾向性评分匹配(PSM)平衡组间混杂因素,Kaplan-Meier法分析比较两组总生存期(OS)和无病生存期(DFS),Cox回归模型分析预后风险因素。
①共纳入357例Ⅰ~ⅢA期肺腺癌根治术后患者,按1∶1进行PSM后,成功匹配204例,中药组和对照组均为102例。②PSM前,中药组5年OS率高于对照组(79.7% vs 64.2%,P=0.001),且5年DFS率较对照组更高(60.6% vs 47.2%,P=0.005);PSM后,中药组5年OS率高于对照组(68.6% vs 52.5%,P=0.038),5年DFS率较对照组高但差异无统计学意义(49.0% vs 43.1%,P=0.176)。③PSM后的Cox单因素分析显示,组织学亚型是否含有高危病理因素(P=0.009)和是否服用中药(P=0.046)与OS显著相关;组织学亚型是否含有高危病理因素(P=0.031)和TNM分期(P=0.002)与DFS显著相关。④Cox多因素分析显示,是否含有高危病理因素(P=0.002)和是否服用中药(P=0.030)是影响Ⅰ~ⅢA期肺腺癌根治术后患者OS的独立预后因素;而是否含有高危病理因素(P=0.027)和临床TNM分期(P=0.001)是影响Ⅰ~ⅢA期肺腺癌根治术后患者DFS的独立预后因素。
Ⅰ~ⅢA期肺腺癌根治术后尤其是组织学亚型有高危病理因素的患者,在西医治疗基础上服用益气养精方为主的中药,可达到延长生存期的治疗效果。
To retrospectively analyze the effect of the Yiqi Yangjing (benefiting qi and nourishing essence) Prescription on the survival prognosis of patients with stage Ⅰ-ⅢA lung adenocarcinoma after radical surgery.
We included patients with stage Ⅰ-ⅢA non-small cell lung adenocarcinoma after radical surgery who were admitted to the Department of Integrative Medicine, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 1, 2012 to December 31, 2015, and these study subjects were divided into traditional Chinese medicine (TCM) and control groups depending on whether they had received Yiqi Yangjing Prescription-based TCM treatment. The propensity score matching (PSM) was used to exclude the confounding factors and bias, the Kaplan-Meier method was used to compare the overall survival (OS) and disease-free survival (DFS) between the two groups, and the Cox Proportional-Hazards Model was used to analyze the prognostic risk factors.
①A total of 357 patients with stage Ⅰ-ⅢA lung adenocarcinoma after radical surgery were included. After conducting a 1∶1 propensity score matching procedure, we got 204 successfully matched cases, with 102 cases in each group. ②Before PSM analysis, the 5-year OS rate was higher in the TCM group than that in the control group (79.7% vs. 64.2%, P=0.001), and the 5-year DFS rate was higher than that in the control group (60.6% vs. 47.2%, P=0.005); after PSM analysis, the 5-year OS rate was higher in the TCM group than that in the control group (68.6% vs. 52.5%, P=0.038), and the 5-year DFS rate was higher than that in the control group, but the difference was not statistically significant (49.0% vs 43.1%, P=0.176). ③The Cox univariate analysis after PSM showed that the presence of high-risk pathological factors in histological subtypes (P=0.009) and the administration of TCM (P=0.046) were significantly associated with OS; and the presence of high-risk pathological factors in histological subtypes (P=0.031) and TNM stage (P=0.002) were significantly associated with DFS. ④The Cox multifactorial analysis showed that the presence of high-risk pathological factors (P=0.002) and the administration of TCM (P=0.030) were independent prognostic factors affecting OS in patients with stage Ⅰ-ⅢA lung adenocarcinoma after radical surgery; while the presence of high-risk pathological factors (P=0.027) and clinical TNM stage (P=0.001) were independent prognostic factors affecting DFS in patients with stage Ⅰ-ⅢA lung adenocarcinoma after radical surgery.
The treatment effect of prolonging survival can be achieved by using Yiqi Yangjing Prescription-based TCM treatment in addition to Western medicine conventional treatment in patients with stage Ⅰ-ⅢA lung adenocarcinoma after radical surgery, especially those with high-risk pathological factors in histological subtypes.
肺癌是近年来最常见的恶性肿瘤,在人群中的发病率和病死率均居于高位,而非小细胞肺癌(non-small cell lung cancer,NSCLC)在肺癌中占比超过80%[
1.1.1 纳入标准
①已完成肺癌根治性手术;②术后病理为肺腺癌[
1.1.2 排除标准
①对本研究药物过敏者;②同时患有其他恶性肿瘤者;③临床资料缺失或不完整者;④存在精神障碍或其他严重的伴随疾病者。
本研究纳入的病例均为2012年1月1日至2015年12月31日上海交通大学医学院附属胸科医院中西医结合科收治的Ⅰ~ⅢA期肺腺癌根治术后患者。根据是否接受过1个月及以上益气养精方为主的中药治疗,分为中药组和对照组。
1.3.1 基线资料
收集纳入研究病例的临床资料,包括性别、年龄、吸烟史、脏层胸膜侵犯、伴随癌栓、高危病理因素、分化程度、TNM分期以及是否辅助化疗。
1.3.2 生存分析
主要观察终点为5年OS和DFS。OS定义为非小细胞肺腺癌确诊至任何原因导致死亡的时间,DFS定义为从根治性手术切除肿瘤到肿瘤局部/全身复发的时间。
1.3.3 预后相关因素分析
采集可能影响预后的因素,以OS和DFS为主要评价指标,进行Cox单因素和多因素分析。
研究数据采用SPSS26.0软件进行统计学分析。建立Logistic回归模型,对两组患者按1∶1进行PSM。计数资料采用 χ2检验,应用Kaplan-Meier法、Log-rank检验进行生存分析,建立Cox比例风险模型对预后进行单因素和多因素分析。以P<0.05为差异有统计学意义。
PSM前,纳入357例患者,其中中药组251例,对照组106例。两组性别(P=0.004)、脏层胸膜侵犯(P<0.001)、伴有癌栓(P=0.044)、高危病理因素(P=0.001)、分化程度(P<0.001)、TNM分期(P<0.001)以及辅助化疗(P=0.041)情况比较,差异具有统计学意义(P<0.05)。PSM后,中药组和对照组均为102例,两组基线资料差异均无统计学意义(P>0.05)。见
项目 | PSM前 | PSM后 | |||||
---|---|---|---|---|---|---|---|
中药组(n=251) | 对照组(n=106) | P | 中药组(n=102) | 对照组(n=102) | P | ||
性别 | |||||||
男 | 112 | 65 | 0.004 | 69 | 61 | 0.244 | |
女 | 139 | 41 | 33 | 41 | |||
年龄 | |||||||
≤60岁 | 124 | 56 | 0.554 | 46 | 53 | 0.327 | |
>60岁 | 127 | 50 | 56 | 49 | |||
吸烟史 | |||||||
无 | 198 | 75 | 0.098 | 69 | 73 | 0.543 | |
有 | 53 | 31 | 33 | 29 | |||
脏层胸膜侵犯 | |||||||
否 | 184 | 55 | <0.001 | 57 | 54 | 0.673 | |
是 | 67 | 51 | 45 | 48 | |||
伴随癌栓 | |||||||
否 | 214 | 81 | 0.044 | 76 | 80 | 0.509 | |
是 | 37 | 25 | 26 | 22 | |||
高危病理因素 | |||||||
否 | 142 | 40 | 0.001 | 39 | 38 | 0.885 | |
是 | 109 | 66 | 63 | 64 | |||
分化程度 | |||||||
G1-G2 | 133 | 34 | <0.001 | 65 | 68 | 0.659 | |
G3-G4 | 118 | 72 | 37 | 34 | |||
TNM分期 | |||||||
Ⅰ | 155 | 34 | <0.001 | 35 | 34 | 0.888 | |
Ⅱ | 35 | 28 | 24 | 27 | |||
ⅢA | 61 | 44 | 43 | 41 | |||
辅助化疗 | |||||||
否 | 117 | 37 | 0.041 | 32 | 35 | 0.655 | |
是 | 134 | 69 | 70 | 67 |
注: PSM为倾向性评分匹配,TNM为肿瘤分期。高危病理因素为手术后病理标本中组织学亚型含微乳头或实体成分超过10%,否则为不具有高危病理因素。G1为高分化⁃低级别,G2为中分化⁃中级别,G3为低分化⁃高级别,G4为未分化⁃高级别。
PSM前,中药组5年OS率高于对照组(79.7% vs 64.2%,P=0.001),且5年DFS率较对照组更高(60.6% vs 47.2%,P=0.005)。PSM后,中药组5年OS率高于对照组(68.6% vs 52.5%,P=0.038),中药组5年DFS率较对照组高但差异无统计学意义(49.0% vs 43.1%,P=0.176)。见
图1 PSM前后两组OS和DFS比较
注: OS为总生存期,DFS为无病生存期。A为PSM前两组OS比较(P=0.001),B为PSM前两组DFS比较(P=0.005),C为PSM后两组OS比较(P=0.038),D为PSM后两组DFS比较(P=0.176)。
2.3.1 Cox单因素分析
PSM后的Cox单因素分析结果显示,组织学亚型是否含有高危病理因素(P=0.009)和是否服用中药(P=0.046)与Ⅰ~ⅢA期肺腺癌根治术后患者OS显著相关;组织学亚型是否含有高危病理因素(P=0.031)和TNM分期(P=0.002)与Ⅰ~ⅢA期肺腺癌根治术后患者DFS显著相关。见
项目 | OS | DFS | |||||
---|---|---|---|---|---|---|---|
平均数/月 | HR(95% CI) | P | 平均数/月 | HR(95% CI) | P | ||
性别 | |||||||
男 | 47.208 | 1 | 0.786 | 37.977 | 1 | 0.622 | |
女 | 52.189 | 0.919(0.501~1.686) | 37.681 | 1.131(0.693~1.847) | |||
年龄 | |||||||
≤60岁 | 48.040 | 1 | 0.900 | 36.963 | 1 | 0.886 | |
>60岁 | 49.933 | 0.971(0.609~1.546) | 38.724 | 0.972(0.662~1.427) | |||
吸烟史 | |||||||
无 | 51.021 | 1 | 0.064 | 39.601 | 1 | 0.299 | |
有 | 44.419 | 1.689(0.970~2.941) | 33.903 | 1.286(0.800~2.065) | |||
脏层胸膜侵犯 | |||||||
否 | 49.486 | 1 | 0.518 | 38.562 | 1 | 0.427 | |
是 | 48.452 | 1.170(0.726~1.887) | 37.043 | 1.171(0.793~1.728) | |||
伴随癌栓 | |||||||
否 | 49.231 | 1 | 0.950 | 38.650 | 1 | 0.570 | |
是 | 48.313 | 0.983(0.573~1.686) | 35.333 | 1.135(0.733~1.756) | |||
高危病理因素 | |||||||
否 | 55.195 | 1 | 0.009 | 45.623 | 1 | 0.031 | |
是 | 45.268 | 2.126(1.206~3.748) | 33.169 | 1.595(1.043~2.438) | |||
分化程度 | |||||||
G1-G2 | 51.732 | 1 | 0.719 | 43.563 | 1 | 0.610 | |
G3-G4 | 47.564 | 1.100(0.655~1.846) | 34.830 | 0.895(0.585~1.370) | |||
TNM分期 | |||||||
Ⅰ | 50.971 | 1 | 0.149 | 43.101 | 1 | 0.002 | |
Ⅱ | 50.176 | 0.898(0.457~1.768) | 44.294 | 0.850(0.475~1.520) | |||
ⅢA | 46.702 | 1.512(0.817~2.797) | 29.671 | 2.105(1.271~3.485) | |||
辅助化疗 | |||||||
否 | 49.403 | 1 | 0.332 | 38.961 | 1 | 0.385 | |
是 | 48.825 | 0.782(0.476~1.285) | 37.336 | 0.828(0.541~1.267) | |||
服用中药 | |||||||
否 | 46.088 | 1 | 0.046 | 34.837 | 1 | 0.193 | |
是 | 51.941 | 0.623(0.391~0.992) | 40.902 | 0.972(0.662~1.982) |
注: OS为总生存期,DFS为无病生存期。高危病理因素为手术后病理标本中组织学亚型含微乳头或实体成分超过10%,否则为不具有高危病理因素。G1为高分化⁃低级别,G2为中分化⁃中级别,G3为低分化⁃高级别,G4为未分化⁃高级别。
2.3.2 Cox多因素分析
将上述单因素分析结果中差异有统计学意义的预后影响因素纳入Cox多因素分析中,结果显示,组织学亚型是否含有高危病理因素(P=0.002)和是否服用中药(P=0.030)是影响Ⅰ~ⅢA期肺腺癌根治术后患者OS的独立因素;组织学亚型是否含有高危病理因素(P=0.027)和临床TNM分期(P=0.001)是影响Ⅰ~ⅢA期肺腺癌根治术后患者DFS的独立因素。组织学亚型有高危病理因素患者5年OS的相对危险度是无高危病理因素患者的2.317倍[95%CI(1.359~3.950),P=0.002],服用中药患者5年OS的相对危险度低于未服用中药者[95% CI(0.382~0.952), P=0.030];组织学亚型有高危病理因素患者术后复发转移的相对危险度是无高危病理因素患者的1.579倍[95%CI(1.052~2.370),P=0.027],在高危病理因素不变的情况下,TNM分期越晚术后复发转移相对危险度增加1.552倍[95% CI(1.225~1.966),P=0.001]。见
预后因素 | β | SE | Wald | df | P | HR(95%CI) |
---|---|---|---|---|---|---|
高危病理因素(否/是) | 0.840 | 0.272 | 9.524 | 1 | 0.002 | 2.317(1.359~3.950) |
服用中药(否/是) | 0.506 | 0.233 | 4.713 | 1 | 0.030 | 0.603(0.382~0.952) |
注: OS为总生存期。高危病理因素为手术后病理标本中组织学亚型含微乳头或实体成分超过10%,否则为不具有高危病理因素。
预后因素 | β | SE | Wald | df | P | HR(95%CI) |
---|---|---|---|---|---|---|
高危病理因素(否/是) | 0.457 | 0.207 | 4.865 | 1 | 0.027 | 1.579(1.052~2.370) |
TNM分期(Ⅰ/Ⅱ/ⅢA) | 0.440 | 0.121 | 13.276 | 1 | 0.001 | 1.552(1.225~1.966) |
注: DFS为无病生存期,TNM为肿瘤分期。高危病理因素为手术后病理标本中组织学亚型含微乳头或实体成分超过10%,否则为不具有高危病理因素。
NSCLC中鳞状细胞癌预后较好,而微乳头状/实体成分腺癌复发的可能性明显高于其他组织学类型[
徐振晔教授认为肺癌的病因病机主要是精气亏虚、邪毒聚积所致的阴阳失调,采用益气养精、解毒散结法治之,总结并研制出益气养精方(主要由生黄芪、白术、七叶一枝花、干蟾皮、女贞子、黄精、淫羊藿等组成)。前期研究[
临床疗效是中医发展的基础与前提,除了开展临床试验,回顾性研究同样能提供科学有效的临床依据。本研究通过收集临床病例数据,运用PSM法使中药组和对照组间基线资料具有可比性。生存分析发现,PSM前,中药组5年OS率高于对照组(79.7% vs 64.2%,P=0.001),且5年DFS率较对照组更高(60.6% vs 47.2%,P=0.005);PSM后,中药组5年OS率高于对照组(68.6% vs 52.5%,P=0.038),5年DFS率较对照组高但差异无统计学意义(49.0% vs 43.1%,P=0.176)。预后相关因素分析证实,是否含有高危病理因素(P=0.002)和是否服用中药(P=0.030)是影响Ⅰ~ⅢA期肺腺癌根治术后患者OS的独立预后因素;而是否含有高危病理因素(P=0.027)和临床TNM分期(P=0.001)是影响Ⅰ~ⅢA期肺腺癌术后患者DFS的独立预后因素。上述结果提示,Ⅰ~ⅢA期肺腺癌根治术后尤其是组织学亚型有高危病理因素的患者,在西医治疗的基础上服用益气养精方为主的中药,可达到延长生存期的治疗效果。
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