| Primary liver cancer(PLC)ranks 6th in morbidity and 2nd in mortality,which seriously threatens human life and health In the worldwide.The diagnosis and treatment of PLC should adopt the multi-disciplinary cooperation mode according to the stages of patients,and provide the best treatment for patients.Traditional Chinese medicine in the treatment of PLC can improve symptoms,improve the body’s resistance,reduce adverse reactions of radiotherapy and chemotherapy,improve the quality of life.Toxicity,blood stasis and deficiency are the main pathogenesis of PLC,several studies have reported the effectiveness of Fuzheng Huoxue Jiedu method in the treatment of PLC,professor Qianying,a well-known TCM doctor in China,composes Hu Qi Fang according to the principles of strengthening,promoting blood circulation and detoxifying.Wang Xuejiang et al.made a number of experimental studies on the prevention and treatment of liver cancer,which showed the blocking effect of this prescription on precancerous lesions of liver cancer.But at present,the clinical target of Hu Qi Fang in the treatment of liver cancer is not clear,whether the blood activating drugs can promote the metastasis of liver cancer is controversial,Therefore,this study intends to systematically evaluate the treatment of liver cancer by Fuzheng Huoxue Jiedu method.Through a retrospective study of the clinical data,we analyzed the clinical effective target of Hu Qi Fang in the treatment of liver cancer.Through in vitro experiments,we preliminarily discussed the influence of "Huoxue Method" in Fuzheng Huoxue Jiedu method and Huoxue medicine in Hu Qi Fang on the metastasis of liver cancer.Objective:Through the methods of literature evaluation,clinical retrospective study and laboratory study,this study discussed the theoretical basis of the treatment of primary liver cancer with the method of Fuzheng Huoxue Jiedu,and found the effective target of "Hu Qi Fang" clinical treatment with this method,and talked about the effect of blood activating drugs in the formula and method on the relevant indicators of liver cancer metastasis.We wanted to provide evidence-based basis for the establishment of the clinical application program of Fuzheng Huoxue Jiedu method in the treatment of primary liver cancer,and provide research ideas for the application of blood activating drugs in the treatment of liver cancer on the basis of liver cirrhosis.Methods:1.systematic review:We retrieved published articles on the treatment of PLC with method Fuzheng Huoxue Jiedu by CNKI,Wanfang Medical Network and PubMed,the studies are randomized controlled trial,the retrieval time was from January 1,1990 to June 30,2019,we took "Fuzheng Huoxue Jiedu","Fuzheng","Huoxue","Jiedu","stagnate","toxin","PLC" as the key words.The treatment group was treated with Chinese medicine which were used Fuzheng Huoxue Jiedu method combined with modern medical means for PLC,while the control group was treated only by modern medical means.We established inclusion and exclusion criteria,We systematically evaluated the short-term efficiency,survival time and quality of life and other aspects,RevMan 5.3 software was used for statistical analysis,methodological quality evaluation of the included literature through the Cochrane Systematic Evaluation Manual 5.1 Quality Evaluation Criteria were completed,we chose subgroup analysis and sensitivity analysis to determine outcome heterogeneity,we used forest map or funnel map to analyze the distribution status of research data and determine whether there is publication bias.2.clinical research:We retrospectively analysed 297 cases of primary liver cancer diagnosed in Youan Hospital Affiliated to Capital Medical University from January 2014 to June 2016,the patients were divided into treatment group and control group according to whether they were treated with Hu Qi Fang or not.Liver cancer staging was performed according to Barcelona staging criteria:stage A(early stage),stage B(medium stage),stage C(late stage)and stage D(end stage).The treatment group and the control group were stratified according to the staging of liver cancer.Patients in stage A and B were divided into A+B layers,while patients in stage C and D were divided into C+D layers.All patients were followed up.The deadline for follow-up was 30 June 2018.SPSS software is used for data processing,the differences of survival time,recurrence and metastasis rate,TCM syndromes,quality of life and liver function between the two groups were compared,we also analyzed the effect of Hu Qi Fang application on the prognosis of PLC.3.experimental research:We wanted to evaluate the effect of blood-activating drugs on metastasis of hepatocellular carcinoma,we took Tanshinone IIA as the research object and Huh7 as the intervention object.Different concentrations of Tanshinone IIA solution were used to interfere with Huh7 human hepatocellular carcinoma cells.Cell scratch test,CCK-8 test,PCR,Western blot were used to examine the effects of Tanshinone ⅡA on typical molecular markers related to proliferation and metastasis of hepatocellular carcinoma cells.We preliminarily explored the effect of Tanshinone IIA on metastasis of hepatocellular carcinoma through our results.Results:1.Systematic evaluation of the treatment of PLC with Fuzheng Huxue Jiedu methodA total of 622 articles were retrieved and 530 were duplicated.We excluded 346 articles by reading literature abstracts,160 articles by reading specific literature contents,and finally included 24 articles for meta-analysis.According to the quality evaluation criteria recommended by Cochrane Systematic Evaluation Manual 5.1,3 articles were rated as Grade B,21 as Grade C,and the quality of the included documents was generally low.the 12-month survival funnel plot showed asymmetry,suggesting a certain degree of publication bias Meta-analysis results showed that,on the basis of Western medicine treatment,the combination of Fuzheng Huoxue Jiedu Chinese herbal medicine in the treatment of primary hepatocellular carcinoma,compared with the control group of Western medicine alone,could improve short-term efficacy,6-month and 12-month survival rate,improve quality of life,reduce AST and AFP levels,reduce the incidence of digestive tract adverse reactions,improve the curative effect of TCM syndromes,improve liver pain,fatigue and abdomen.The clinical symptoms were obviously superior to those of the control group.2.Clinical study on the treatment of PLC with Fuzheng Huxue Jiedu method(1)Survival analysis:The cumulative survival rates of 6 months,12 months,18 months and 24 months in the treatment group were 80.4%,69.8%,58.5%and 55.7%respectively.The cumulative survival rates of 6 months,12 months,18 months and 24 months in the control group were 81.1%,64.7%,52.1%and 42.3%respectively.The cumulative survival rates in the treatment group were higher than those in the control group after 6 months.The decrease rate of 6-24 months in the treatment group was 24.7%.The decrease was 38.8%lower than that of the control group,suggesting that Hu Qi Fang can improve the cumulative survival rate of patients with primary hepatocellular carcinoma.The average survival time of the two groups was 17.3 months in the treatment group(95%CI,15.8-18.7 months)and 16.1 months in the control group(95%CI,14.7-17.5 months).The average survival time of the treatment group was longer than that of the control group,indicating that Hu Qi Fang can prolong the average survival time of patients with primary liver cancer.The median progression-free survival time of the treatment group was 11.4 months(95%Cl,8.3-14.5 months),while that of the control group was 4.1 months(95%CI,3.3-4.9 months),P<0.01.The difference was statistically significant.The progression-free survival time of the treatment group was longer than that of the control group,indicating that Hu Qi Fang can prolong the progression-free survival time of the patients with liver cancer.Comparing the recurrence and metastasis rates of the two groups,the cumulative recurrence rates of hepatocellular carcinoma in the treatment group were 56.4%and 64.9%in one year and two years,28.7%and 38.3%in one year and two years,90.3%and 95.7%in the control group,64.5%and 74.2%in one year and two years respectively.The cumulative recurrence and metastasis rates of the two groups at each time point were significantly different(P<0.01).The recurrence and metastasis rates of the treatment group were low.Hu Qi Fang could reduce the recurrence and metastasis rates of patients with primary liver cancer.Analysis of prognostic factors of hepatocellular carcinoma:Univariate analysis showed that hepatophilic virus infection history,baseline AFP level,Barcelona stage and Child-Pugh grade had significant influence on survival of patients(P<0.01).Cox multivariate regression analysis was carried out to determine the protective factors of PLC were the application of Hu Qi Fang(P<0.05,HR＝0.44)and the treatment of TACE(P<0.05,HR=0.33).(2)Analysis of TCM syndromes:The score of TCM syndromes in the treatment group was 7.0(5.0,11.0)at 24 weeks,14.0(10.0,19.5)in the control group,7.0(3.0,9.0)at 48 weeks in the treatment group and 16.0(12.0,20.0)at 48 weeks in the control group.The difference was statistically significant(P<0.01).The score of TCM syndromes in the treatment group was significantly improved compared with the previous one.The curative effect of TCM syndromes in the treatment group was 56.9%in 24 weeks and 12%in the control group.The difference between the two groups was statistically significant(P<0.01).The curative effect of TCM syndromes in the treatment group was 67%in 48 weeks and 11.6%in the control group in 48 weeks.The difference between the two groups was statistically significant(P<0.01).The curative effect of TCM syndromes in the treatment group was higher in 24 and 48 weeks(P<0.01).The results showed that Hu Qi Fang could improve the TCM syndromes(syndrome scores,syndromes efficacy)of patients with primary liver cancer.In terms of single TCM syndrome score,after 24 and 48 weeks of treatment,there were significant differences in body weight,fecal discharge and other syndrome scores between the treatment group and the control group(P<0.05).After stratification,there were significant differences in syndrome scores of belching and five-heart-upset fever(P<0.05).For patients with liver cancer in the early and middle stages,Hu Qi Fang was mainly based on the syndrome of blood stasis and Qi stagnation.And Yin deficiency syndrome and Spleen deficiency syndrome were mixed.For patients with advanced and end-stage liver cancer,the distribution of each syndrome type is more average,and the deficiency and excess are mixed.The proportion of sinking pulse in 24 weeks in two groups was 15.4%and 66.4%,P<0.01,with significant difference,17.6%and 71.4%respectively in 48 weeks,P<0.01.The difference was significant.The proportion of sinking pulse in the treatment group was reduced,indicating that Hu Qi Fang can reduce the proportion of sinking pulse in patients with primary liver cancer and has the effect of delaying the disease in depth.The proportion of dark tongue in the treatment group was 12.1%,4.1%and 3.3%at 24,48 weeks,respectively.The proportion of dark tongue in the control group was 22.3%,24.8%and 24.1%at 24,48 weeks,respectively.The proportion of dark tongue in the treatment group decreased gradually,while the proportion of dark tongue in the control group did not change significantly.The proportions of sublingual vein lengthening were 21.5%,22.0%and 23.1%in the treatment group,24 weeks and 48 weeks respectively,and 21.6%,25.6%and 29.5%in the control group,respectively.The proportion of sublingual vein lengthening in the control group was slightly higher than that in the treatment group.The change trend of the proportion of dark tongue and sublingual vein lengthening showed that Hu Qi Fang could reduce the proportion of dark tongue and delay the progress of sublingual vein lengthening,and had definite blood-activating effect.(3)Quality of life score:The 24-week and 48-week QOL scores of the treatment group were 54.0(50.5,56.0)and 53.0(51.0,56.0),respectively.The 24-week and 48-week QOL scores of the control group were 45.0(39.3,44.8)and 43.0(36.8,45.3),respectively.The scores of the two groups were compared at 24 and 48 weeks,P<0.01.The scores of the treatment group were significantly improved compared with those before treatment.The results showed that Hu Qi Fang could improve significantly.Improve the quality of life of patients with primary liver cancer.(4)Laboratory indicators:Glutamyl transpeptidase(GGT)levels were 42.6(24.7,24.7,76.8)U/L,36.1(25.8,25.8,69.4)U/L,36.1(36.1,25.8,69.4)U/L at 24 weeks and 48 weeks in the treatment group,70.8(39.6,131.7,131.7)U/L and 62.9(35.6,35.6,138.3)U/L at 24 weeks and 48 weeks in the control group,70.8(39.6,131.7)U/L and 62.9(35.6,138.6,138.3)U/L at 24 weeks and 48 weeks in the treatment group,41.1(37.1(37.0,Right Albumin(ALB)levels were 38.4(34.3,42.6)g/L and 39.2(33.9,42.4)g/L at 24 and 48 weeks in the control group,75.3(59.0,100.2)U/L at 48 weeks in the treatment group and 109.1(73.7,152.7)U/L at 48 weeks in the control group,respectively.There were significant differences between the two groups(P<0.01).Hu Qi Fang can improve the level of ALB and reduce the level of GGT and ALP.The levels of alpha-fetoprotein(AFP)in the treatment group were 5.1(2.3,32.5)ng/ml,5.2(2.5,24.3)ng/ml,and 14.4(2.8,261.0)ng/ml,18.0(3.3,307.4)ng/ml,respectively,at 24 and 48 weeks in the control group.There was a significant difference between the two groups(P<0.05).The level of alpha-fetoprotein in the treatment group was lower than that in the control group.The results showed that Hu Qi Fang could reduce the level of alpha-fetoprotein in patients with primary liver cancer.3.Experimental study on the effect of blood activating drugs on the metastasis of liver cancerCell scratch test showed that Tanshinone IIA could inhibit the invasion and metastasis of Huh7 hepatocellular carcinoma cells directly;CCK-8 test showed that Tanshinone IIA could inhibit the activity of Huh7 hepatocellular carcinoma cells in a concentration-dependent manner;Fluorescence quantitative polymerase chain reaction and Western blot assay showed that Tanshinone IIA could inhibit the expression of genes and proteins of hepatocellular carcinoma proliferation,metastasis-related factors such as TGFbeta,Wnt and snail in a concentration-dependent manner.Conclusion:1.Low-level evidence shows that the application of Chinese medicine used Fuzheng Huoxue Jiedu method combined with modern medical means can be more effective in the treatment of PLC.2.Hu Qi Fang based on Fuzheng Huoxue Jiedu method has definite clinical efficacy in the treatment of PLC.3.Tanshinone ⅡA,an extract of Salvia miltiorrhiza,a blood-activating drug in Hu Qi Fang,can inhibit the proliferation and metastasis of Huh7 hepatocellular carcinoma cells.This effect may be mediated by the effect of EMT(epithelial-mesenchymal transformation)on Huh7 hepatocellular carcinoma cells.Significance:This study systematically evaluates the clinical effect of Fuzheng Huoxue Jiedu method in the treatment of PLC,retrospectively analyses the clinical efficacy of Hu Qi Fang with Fuzheng Huoxue Jiedu method,explores the anti-metastasis effect of Tanshinone IIA,an extract of Hu Qi Fang,the combination of theoretical research,clinical research and experimental research has promoted the clinical application of traditional Chinese medicine in the treatment of primary liver cancer. |
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