| 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.
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