【作者】 孙振；

【导师】 凌昌全； 梁水庭；

【作者基本信息】 第二军医大学 ， 中西医结合临床， 2010， 博士

【摘要】 目的：比较软肝方(原名软坚护肝片)与介入疗法治疗根治术后小肝癌的长期疗效差异,验证“根治术后小肝癌患者使用中医药预防其复发的效果会比介入疗法更好”的假说。方法：在导师治疗肝癌遣方用药经验总结和我研究中心前期临床研究的基础上建立“根治术后小肝癌患者使用中医药预防其复发的效果会比介入疗法更好”的假说。通过病案信息科计算机数据库,使用国际疾病分类(ICD)编码查询1987.1-2008.12期间在广西医科大学第一附属医院肝胆外科和微创肿瘤外科病房行手术切除的所有原发性肝癌患者,手术标本均经病理检查证实为肝细胞癌,最终将399例根治术后小肝癌患者纳入验证假说的队列,其中346例为男性患者,53例为女性患者。按照根治术后小肝癌患者接受TCM治疗的暴露程度不同分为四组：(1)TCMO组(2)TCM与介入治疗术联合组(TCM-IT)(3)介入治疗组(ITO)(4)单纯手术组(SO)。生存率评估采用Kaplan-Meier生存分析法,组间生存率的差异比较采用Log-rank检验,寿命表法估算逐年复发率。预后多因素分析采用Cox比例风险模型回归分析,通过最终长期生存率结果比较,验证假说的成立。结果：对住院行根治术的399例小肝癌患者进行回顾性队列研究,随访至2009-02-28。对所有患者的基线资料进行分析,仅在肿瘤位置上四组差异有统计学意义(P=0.036)。TCMO组与ITO组1,2,3,5、10、15年总生存率(OS)分别为94.76%vs91.85%、91.69% vs74.42%、89.27% vs55.74%、83.94% vs45.50%、71.22%vs33.34%、55.58% vs9.26%(p=0.000,HR=0.210,95%CI:0.126-0.348),两组1,2,3,5、10、15的无病生存率分别(DFS)为85.30% vs81.60%、81.40% vs73.10%、76.10% vs57.10%. 69.80% vs45.00%、54.00% vs30.80%、44.50% vs0%(p=0.001,HR=0.518,95%CI: 0.341-0.788);TCMOvsTCM-IT组1,2,3,5、10、15年总生存(OS)率分别为94.76%vs98.53%,91.69% vs93.38%,89.27% vs87.54%,83.94% vs74.16%,71.22% vs57.10%,55.58% vs0%(Log Rank检验x2=2.365,p=0.124)；两组1,2,3,5、10、15年无病生存(DFS)率85.30% vs92.50%,81.40% vs83.30%,76.10% vs83.30%,69.80% vs76.20%, 54.00% vs62.20%,44.50% vs0%, (Log Rank检验x2=0.710,p=0.399)。两组(OS)率和(DFS)率比较差异无统计学意义；TCM-IT组总生存率和无病生存期率均高于ITO组,差异有统计学意义(P<0.05);TCMO组总生存率、无病生存率均高于SO组,差异有统计学意义(P<0.05)；ITO组总生存率高于SO组,差异有统计学意义(P<0.05)；ITO组vs SO组生存率无病生存率统计数据显示无明显差异(P>0.05)。总的中位生存时间分别是151.20月(TCM-IT组)、43.87月(ITO组)、20.77月(SO),而TCMO组由于各时间段对应的生存率均大于50%。中位无病生存时间分别是152.900月(TCMO组),51.733月(ITO组),76.667月(SO组)(P<0.0001),而TCM-IT组由于各时间段对应的无病生存率均大于50%; TCMO组vs ITO组1,2,3,5年逐年复发率为15% vs19%、5% vs100%、4% vs12%、5%vs4%(P=0.002),两组差异有统计学意义。单因素分析显示与总生存期(OS)相关的预后因素分析是：家族史、球蛋白、肿瘤个数、血管侵犯、肿瘤位置、child分级、TNM分期、治疗方式(P<0.05)。Cox多因素分析结果显示治疗方式、肿瘤大小、就医方式、TNM分期、家族史、性别6个变量为影响根治术后小肝癌患者生存期(OS)的独立风险因素；Cox多因素分析显示就医方式、性别、以及group 1 (TCMO group versus ITO group) (HR=0.210,95%CL 0.126-0.348)、group3 (TCM-IT group vs ITO group) (HR=0.294,95%CL 0.174-0.496)的回归系数均<0是保护因素,其中ITO组的死亡风险均高于TCMO组、TCM-IT组,分别是TCMO组,TCM-IT组的4.76倍、3.40倍。而group2 (SO group versus ITO group) (HR=2.613,95%CL 1.663-4.106)、肿瘤大小、TNM分期、家族史的回归系数>0是危险因素,其中SO组死亡风险是ITO组的2.613倍。单因素显示与无病生存期(DFS)相关的预后因素具体为：年龄、AFP、肿瘤包膜、TNM分期、治疗方式(P＜0.05); Cox多因素分析结果显示治疗方式和TNM分期2个变量为影响肝癌无病生存期的独立风险因素,其中group1 (TCMO versus ITO group)属保护性因素(P=0.002,HR=0.518,95%CL0.341-0.788),显示介入治疗组复发风险是TCMO组1.93倍；group2(SO group versus ITO group) (HR=1.107,95%CL0.609-2.011)是危险因素,显示单纯手术组复发风险是介入治疗组的1.107倍；：group3 (TCM-IT group vs ITO group)属保护性因素(P=0.001,HR=0.401,95%CL0.233-0.690),介入治疗组复发风险是联合治疗组的2.49倍。结论：长期口服软肝方能够明显延长根治术后小肝癌患者的无病生存时间和总生存时间、降低复发率,其结果有待于进一步前瞻性随机对照研究验证。更多还原

【Abstract】 Objectives:To compare long-term effectiveness of ruanganfang (RGF), originally named ruanjianhugan (RJH) tablets,a form of traditional Chinese medicine (TCM), with interventional therapy (IT) after resection of small hepatocellular carcinoma (HCC), and provid a reliable proof for the hypothesis that TCM would be more effective than interventional therapy in preventing HCC recurrence and prolonging survival after curative resections for small HCC.Methods:On the basis of Professor Ling Changquan’s experience in treating primary liver cancer and previous research in Department of Traditional Chinese Medicine, Changhai Hospital,a hypothesis that TCM would be more effective than intervcntional therapy in prolonging survival after curative resections for small HCC was built up.From January 1987 to December 2008, all the consecutive patients with HCC underwent curative resection from the Department of Medical Records according to the International Classification of Diseases, tenth Revision, Clinical Modification (ICD-10) diagnosis Codes for HCC were included, the patients came from the Department of Hepatobiliary Surgery and Center of Minimally Invasive Surgery of the First Affiliated Hospital of Guangxi Medical University, Nanning,399 patients with small HCC were analyzed by a retrospective cohort study (346 men and 53 women). Subjects were separated into four groups based on different therapy modes:a TCM-only (TCMO) group, a TCM combined with interventional therapy (TCM-IT) group, an interventional therapy-only(ITO)group, and a simple operation (SO) group. Prognostic factors were correlated with disease-free survival (DFS) and overall survival (OS); DFS and OS rates were calculated with the Kaplan-Meier method, and multivariate analyses for factors affecting survival were evaluated by the Cox proportional hazard model. The accuracy of the former theories hypothesis was verified.Results:The retrospective cohort study of 399 patients with small HCC was stopped on February 28,2009. about the base-line information of the patients, Only tumor location was considered significant (P=0.036).Overall survival rates at1,2,3,5,10,and15 years of the TCMO patients and the ITO patients were 94.76% and 91.85%,91.69% and 74.42%,89.27% and 55.74%,83.94% and 45.50%,71.22% and 33.34%,55.58% and 9.26% respectively (risk ratio 0.210,95% confidence interval 0.126-0.348, P=0.000). There was a significant difference in DFS rates between the TCMO and ITO groups at 1,2,3,5,10, and 15 years (85.30% vs 81.60%,81.40%vs73.10%,76.10%vs57.10%,69.80%vs45.00%,54.00%vs30.80%, 44.50%vs0%, respectively; risk ratio 0.518,95% confidence interval 0.341-0.788, P= 0.001);1,2,3,5,10,15-year OS rates in patients with TCMO group and in TCM-IT group were 94.76% vs98.53%,91.69% vs93.38%,89.27% vs87.54%,83.94% vs74.16%, 71.22% vs57.10%,55.58% vs 0%, respectively (log-rank test,χ2=2.365; P=0.124), while 1,2,3,5,10,15-year DFS rates in patients with TCMO group and TCM-IT group were 85.30% vs92.50%,81.40% vs83.30%,76.10% vs83.30%,69.80% vs76.20%, 54.00% vs62.20%,44.50% vs0%, respectively (log-rank test,χ2=0.710, P=0.399), there was no significant difference between the two groups;The OS and DFS rates in TCM-IT patients were higher compared with ITO patients, and the difference was significant (P＜0.05)The OS rates in TCMO patients were higher compared with SO patients, and the difference was significant (P＜0.05),While the difference between the TCMO and SO patients was not significant (P>0.05)The overall median survival time was 151.20 months (TCM-IT),43.87 months (ITO), and 20.77 months (SO). While the survival rates of TCMO group were higher than 50%, the median survival time of the TCMO group can not be calculated.The median DFS times were 152.900 months (TCMO),51.733 months (ITO), and 76.667 months (SO), respectively.The median DFS times of the SO and TCMO groups were both longer than the median DFS times of the ITO, the median survival time of the TCM-IT group can not be calculated.The 1-,2-,3-, and 5-year recurrence rates in patients with TCMO group and the ITO groupwere 15% and 19%,5% and 10%,4% and 12%, and 5% and 4%, respectively; the difference was significant (P=0.002).Univariate analysis for OS were calculated for patient showed the significant prognostic factors were family history, globulin, tumor number, vascular invasion, tumor location, Child-Pugh classification, TNM staging, and therapy mode (P< 0.05).Multivariate survival analysis by Cox proportional hazard model, the six independent factors were as follows:therapy mode, tumor size, seeking behavior, TNM staging, family history, sex. Results of the multivariate survival analysis also showed group 2 (so group versus ITO group), tumor size, TNM staging, and family history were major risk factors of recurrence for small HCC tumors (P< 0.05, regression coefficient>0, relative risk 2.613,1.210,1.365,2.104), while seeking behavior, sex, the group 1(TCMO group versus ITO group) and group 3 (TCM-IT group vs ITO group) using different therapy mode were protective factors (P<0.05, regression coefficient<0, relative risk 0.659,0.431, 0.210,0.294).The results showed that the risk of death from HCC in ITO was 4.76 times and 3.40 times higer than the TCMO and TCMO-ITgroup.Univariate analysis for DFS were performed on the patients with different group,and results showed the significant prognostic factors (P<0.05)including age, AFP,Tumor capsule,TNM staging, therapy mode.Multivariate survival analysis showed the two independent factors were therapy mode and TNM staging. Results of the multivariate survival analysis also showed group 1(TCMO versus ITO group) was major protective factor of recurrence for small HCC tumors (P=0.002,HR=0.518,95%CL0.341-0.788), The results of the multivariate survival analysis showed that the risk of recurrence in ITO patients was 1.93 times than in TCMO patients. While group 2 (SO group versus ITO group)was major risk factor, the risk of recurrence in SO patients was 1.107 times than in ITO. While Group3 (TCM-IT group vs ITO group) was the protective factor (P=0.001,HR= 0.401,95%CL0.233-0.690), showed that the risk of recurrence of IT group was 2.49 than TCM-IT group.Conclusions:Long-term oral use of ruanganfang (RGF) (originally named ruanjianhugan tablets) can improve significantly DFS and OS for small-HCC after resection compared with interventional therapy. Randomized, controlled trials are needed to confirm the findings of this study.更多还原