Medication regularity and effect of Fuzheng Qingdu therapy for survival of patients with gastric cancer based on real world evidence
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摘要: 目的 评价真实世界环境下扶正清毒法(Fuzheng Qingdu therapy，FZQDT)治疗胃癌的临床疗效并分析其用药规律。方法 多中心收集2012年3月1日-2022年6月30日医院信息系统数据库中符合纳入、排除标准的胃癌患者，采用真实世界研究的方法，按有、无接受FZQDT治疗分为中医组和对照组。建立Cox回归模型进行生存预后分析。采用Kaplan-Meier法及log-rank检验比较两组患者的总生存期(overall survival，OS)及无进展生存期(progression-free survival，PFS)。使用Microsoft Excel 16.0、SPSS Modeler 18.0及Cytoscape 3.9.1软件对处方用药分别进行频次统计、关联规则分析及聚类分析。结果 共纳入479例胃癌患者，中医组200例，对照组279例。生存预后分析表明FZQDT是影响患者生存的独立保护因素(P < 0.001)。中医组较对照组显著延长OS(中位OS 37.30个月vs.12.77个月，HR=0.38，P < 0.001)和PFS(中位PFS 26.80个月vs.10.03个月，HR=0.59，P < 0.001)。亚组分析表明，不同TNM分期及手术情况的胃癌患者均能从中医治疗中获益(P < 0.05)。数据挖掘共纳入200首中药处方，涉及中药180味，使用频率≥50%的核心中药16味，如炙甘草、黄芪等。核心中药关联规则分析得到支持度>35%且置信度>95%的二联药对10对，如紫苏梗-藿香等。高频中药聚类分析得到6个聚类。结论 基于“扶正清毒”指导思想治疗胃癌，“扶正”重在健脾，兼顾养肝，“清毒”以祛除“水毒”为主，消化“食毒”和清解“热毒”为辅，契合胃癌“脾虚毒聚”的病机，在真实世界中能延长胃癌患者生存期，核心用药为炙甘草、黄芪、茯苓等。Abstract: Objective To evaluate the clinical efficacy of Fuzheng Qingdu therapy(FZQDT) in the treatment of gastric cancer(GC) in the real world environment and analyze its medication rules.Methods The clinical data of GC patients who met the inclusion and exclusion criteria in Hospital information system of multi-center from March 1, 2012 to June 30, 2022 were collected. Real world study was conducted. The patients were divided into the Traditional Chinese Medicine(TCM) group and the control group according to whether they received FZQDT or not. Cox regression model was used to analyze the survival prognosis. Kaplan-Meier survival curve and log-rank test were used to compare overall survival(OS) and progress-free survival(PFS). Microsoft Excel 16.0, SPSS Modeler 18.0 and Cytoscape 3.9.1 was used to carry out statistics of frequency, association rules and cluster analysis of prescription herbs respectively.Results The total of 479 enrolled GC patients were divided into TCM group(n=200) and control group(n=279). The result of prognostic analysis showed that the TCM treatment of FZQDT was an independent protective factor for OS of GC patients(P < 0.001). The median of OS(37.30 months vs. 12.77 months, HR=0.38, P < 0.001) and PFS(26.80 months vs. 10.03 months, HR=0.59, P < 0.001) of TCM group were significantly longer than those of control group. Subgroup analysis showed that the OS of GC patients, regardless of TNM stage and surgical history, in TCM group were longer than those in the control group(P < 0.05). The total of 200 prescriptions and 180 herbs were included. There were 16 core herbs with utilization rate ≥50%, such as Glycyrrhiza uralensis Fisch, Astragalus membranaceus(Fisch) Bunge. Ten pairs of two herbs with support rate >35% and confidence rate >95%, such as Perilla frutescens(L) Britton-Agastache rugosa(Fisch. et Mey.) O. Kuntze, were found. The results of cluster analysis showed that the core herbs could be clustered into 6 categories.Conclusion FZQDT is consistent with the pathogenesis of "spleen deficiency and toxic accumulation" of GC. "Fuzheng" emphasizes spleen strengthening, followed by liver nourishing. "Qingdu" focuses on removing "water poison", followed by "food poison" and "heat poison". FZQDT could prolong the survival of GC patients in the real world, the core herbs of which were Glycyrrhiza uralensis Fisch, Astragalus membranaceus(Fisch) Bunge, Poria cocos(Schw.), etc.
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Key words:
- gastric cancer /
- survival time /
- Fuzheng Qingdu therapy /
- medication regularity /
- real world
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表 1 两组患者的临床特征比较
X±S，例(%) 临床特征 对照组
(n=279)中医组
(n=200)P 临床特征 对照组
(n=279)中医组
(n=200)P 年龄/岁 68.9±5.9 68.7±6.4 0.390 组织分化程度 0.539 性别 0.854 中/高分化 49(17.6) 37(18.5) 男 210(75.3) 152(76.0) 低/未分化 127(45.5) 81(40.5) 女 69(24.7) 48(24.0) 不详 103(36.9) 82(41.0) 原发肿瘤部位 0.070 TNM分期 0.064 胃窦 18(6.5) 19(9.5) Ⅰ 9(3.2) 18(9.0) 胃体 41(14.7) 25(12.5) Ⅱ 38(13.6) 27(13.5) 贲门 105(37.6) 68(34.0) Ⅲ 95(34.1) 63(31.5) 其他部位 25(9.0) 18(9.0) Ⅳ 71(25.4) 40(20.0) 多个部位 57(20.4) 29(14.5) 不详 66(23.7) 52(26.0) 不详 33(11.8) 41(20.5) 根治性手术 0.057 病理类型 0.704 是 154(55.2) 114(57.0) 腺癌 209(74.9) 152(76.0) 否 120(43.0) 75(37.5) 印戒细胞癌 8(2.9) 9(4.5) 不详 5(1.8) 11(5.5) 腺癌含印戒细胞 21(7.5) 12(6.0) 化疗 0.107 成分 是 220(78.9) 145(72.5) 其他 7(2.5) 7(3.5) 否 59(21.1) 55(27.5) 不详 34(12.2) 20(10.0) 放疗 0.213 是 10(3.6) 12(6.0) 否 269(96.4) 188(94.0) 
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表 2 FZQDT对不同亚组患者OS的影响
指标 对照组例数/中医组例数 中位生存期(95%CI)/月 P 对照组 中医组 TNM分期 Ⅰ 9/18 29.57(16.01~43.13) 0.002 Ⅱ 38/27 31.73(26.20~37.26) < 0.001 Ⅲ 95/63 16.87(8.72~25.02) 39.43(19.02~59.84) < 0.001 Ⅳ 71/40 8.40(7.54~9.26) 13.90(8.64~19.16) < 0.001 根治性手术 是 154/114 21.87(18.27~25.47) < 0.001 否 120/75 8.40(7.58~9.22) 19.70(13.98~25.43) < 0.001
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表 3 FZQDT治疗胃癌核心中药的关联规则
药对 共现频次/次 支持度/% 置信度/% 炙甘草-陈皮 157 78.50 95.54 炙甘草-神曲 153 76.50 95.42 紫苏梗-藿香 141 70.50 97.16 黄芪-藿香 141 70.50 96.45 炙甘草-藿香 141 70.50 95.74 白术-枳壳 97 48.50 95.88 黄芪-当归 78 39.00 96.15 炙甘草-蜀羊泉 73 36.50 100.00 黄芪-蜀羊泉 73 36.50 100.00 白花蛇舌草-蜀羊泉 73 36.50 95.89
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