Traditional Chinese medicine combined with chemotherapy in the treatment of liver cancer:a meta-analysis

Juan Li,Zhu Yang,,#,Jing-Hui Wang,Bin Guo,Jie Chen,Qian Wang,Dong-Xin Tang,,#

1Guiyang College of traditional Chinese medicine,Guiyang,Guizhou,China.2The First Affiliated Hospital of Guiyang College of traditional Chinese medicine.Guiyang,Guizhou,China.

Abstract Objective:To analyze the clinical efficacy of traditional Chinese medicine(TCM)combined with chemotherapy in the treatment of primary liver cancer on the basis of meta-analysis software.Method:Retrieval randomized controlled trials(RCT)of TCM combined with chemotherapy in the treatment of the liver cancer from the network database(such as MEDLINE,EMBASE,PUBMED,Chinese CNKI database,Wanfang database,VIP database etc.).The retrieval period was from January 2011 to July 2017.Results:A total of 16 RCT studies were included and involving 1873 patients,with 949 patients in the treatment(TCM with chemotherapy)group and 924 patients in the control group(chemotherapy alone).Meta-analysis results suggest that TCM combined with chemotherapy in the treatment of primary hepatocellular carcinoma can improve curative effect,improve the degree of ascites of patients,improve the quality of life of patients and alleviate chemotherapy side effects.Conclusion:TCM combined with chemotherapy in the treatment of primary liver cancer is helpful to improve the short term curative effect,improve the quality of life of patients,and alleviate the toxic and side effects.

Key words:Primary liver cancer,Traditional Chinese medicine,Chemotherapy,Meta-analysis

Introduction

Primary Liver Cancer(PLC)is a common malignant tumor in the digestive system.The morbidity and mortality in developing countries are increasing year by year[1,2].Traditional Chinese medicine(TCM)in the treatment of cancer can reduce toxicity and increase efficiency,improve the quality of life of patients,and delay the survival of patients[3].According to the clinical features of liver cancer,it belongs to the category of"liver cancer"in Chinese medicine.Generaltreatise on the cause and symptoms of diseases recorded that:accumulation is the disharmony of Yin and Yang,companied with weakness of viscera,which could be affected by wind pathogen and the fight in the organs of Qi.This explained that deficiency is the essence for the cause and pathogenesis of cancer.As Qi deficiency and organs dysfunction may lead to qi stagnation,blood stasis,phlegm coagulation and poison accumulation[4].The symptoms of liver cancer were described in detail in Sheng Ji Zong Lu.Professor Liu Shangyi,a professor of TCM,attributed the cancer etiology to three aspects:phlegm,asthenia and stasis.Different drugs were selected according to the course of each course of disease[5].He emphasize the enhancement of immune function,and aim to support healthy energy,tonify Qiand Yin and activate blood circulation to dissipate blood stasis,detoxicate and resolve tumor.The therapeutic principle for tumor is balancing Yin-Yang,clearing heat,activating blood circulation,tonifying deficiency and so on[6].

Data and Methods

Diagnostic Criteria for Western Medicine

The standard of diagnosis and treatment of common cancer in China and the diagnostic criteria of liver cancer(1999 edition)were used[7].(1)Pathological diagnosis:(a)Liver histological examination confirmed as primary liver cancer.(b)Histological examination of extrahepatic tissues confirmed as primary liver cancer.(2)clinical diagnosis:(a)if there is no evidence of other liver cancer,AFP convection method is positive or radioimmunoassay≥ 400 μg/L,Lasts more than 4 weeks,eliminate pregnancy,Active liver disease,Germ cell tumor of the gonads And metastatic hepatic carcinoma,(b)the imaging examination showed clear hepatic parenchymal occupying lesions.Hepatic hemangioma and metastatic liver cancer can be excluded,and included One ofthe following conditions:①AFP≥200/L,②Imaging features of typical primary liver cancer,③No jaundice,while ALP or GGT increased obviously,④There is a definite metastatic lesion or bloody ascites in the distance or cancer cells found in ascites,⑤Definite hepatitis B positive cirrhosis[7].

Diagnostic Standard of traditional Chinese medicine

Referring to the diagnostics of TCM published by Chinese Medicine Publishing House of diagnostic criteria for liver cancer in the second edition：mass/masses in right hypochondrium,with pain or not;jaundice(yellowish eyes or skin);abdominal swelling;varicose veins;epigastric distension;anorexia;dry mouth;irritability;night sweat;emaciation;waistand knee aching and limp;constipation;dark tongue with ecchymosis or red;yellow greasy or thin white,or less moss;taut and uneven pulse or slippery or thin pulse.

Inclusion Criteria

(1)The subjectswere clinically diagnosed as malignant tumor cases,(2)randomized controlled trial of TCM combined with chemotherapy versus chemotherapy alone,(3)Outcome indicators include the following aspects:a solid tumor or short-term effect,b KPS score or quality of life,c Remission of clinical symptoms,d Analysis of adverse reaction indexes(Including the patient's blood routine,nausea,vomiting,diarrhea,liver function,neurotoxicity and other aspects of analysis),e the repeated or similar publications and consistent with the above criteria,the literature is only included in recent or more cases.

Retrieval Method

Retrieve TCM combined with chemotherapy in compared with chemotherapy alone for liver cancer Internet databases(such as MEDLINE,EMBASE,PUBMED,Chinese CNKIdatabase,Wanfang database,VIP database etc.).Retrieve from January 2011 to July 2017.Chinese and English search keywords are“traditional Chinese medicine,traditional Chinese medicine therapy,Chemotherapy,liver Cancer,hepatocellular carcinoma,liver tumor,Clinical efficacy observation,randomized controlled trial.

Literature Screening,General Data Extraction,Quality Evaluation

(1)Literature screening:After repeated reading the title,abstract,and even the full text of the literature,the literature was eventually included in the study.The literature screening process was shown in Figure 1.(2)General data extraction:The general literature included in the study included the first author,the year of publication,the gender(male/female)of the subjects,the age range or average age of the subjects,the intervention,the course of treatment/week,and the outcome measures(e.g.,three line Table 1).(3)Outcome:indicators include the following aspects:a solid tumor or short-term effect,b KPS score or quality of life,c Remission of clinical symptoms,d Analysis of adverse reaction indexes(including the patient's blood routine,nausea,vomiting,diarrhea,liver function,neurotoxicity and other aspects of analysis).(4)Quality evaluation:use the bias risk assessment tool in RevMan 5.3 software to evaluate the literature and draw a bias risk map(Figure 2,3)Risk assessment was conducted from 7 aspectes:the generation of random allocation scheme,covert grouping,whether patients and doctors were double-blind,single-blind,or unblinded,whether evaluate the studies in a blinded,random fashion,whether the outcome data is complete,whether to selectively report the results,whether there are other biases[8].According to these aspects,five types of bias can be divided,namely,selection bias,implementation bias,measurement bias,loss of access bias,and reporting bias.Forthe risk assessmentof the inclusion of literature,the following conclusionsare obtained(Figure2):election bias were associated with a low bias risk of about 75%,Hidden allocation was 55%,Patients and physicians were blinded and with a low risk of bias of 90%,Measurement bias was 100%,Reporting bias were 75%,The risk of follow-up bias were 80%,The risk of other bias was low(100%).

Data Statistics

Revman 5.3 software was used to calculate the final extracted data.Theeffectsoftreatmentswere evaluated by Odds Ratio(OR).The results of the merger were estimated by the effect measure and its 95%confidence interval(95%CI).The heterogeneity of the included studies was evaluated by the Chi2 test.When P＞0.1 and I2＜50%(no significant heterogeneity among researches)meta-analysis was performed using the fixed effects model.Funnel plots were drawn for publication bias.

Outcome

According to WHO standard,the curative effect of primary liver cancer was judged by the following indicators[7]:(1)complete remission(CR):the tumor completely disappeared and no new lesions occurred for at least 4 weeks.(2)Partial remission(PR):tumor volume shranked by more than 30%and no new lesions were present for at least 4 weeks.(3)Progress(PD):tumor volume increased by 20%and over,or a new lesion or metastasis occurs.(4)Stability(SD):tumor volume was between PD and PR.

Results

Characteristics of Included Study

A total of 95 Chinese literatures from the CNKI database(n=53),the VIP database(n=23)and Wanfang database(n=19)were retrieved.After reading the title,abstract and full text of the literature,16 articles were included in this study[9-24],with a totalof1873cases,949cases in treatment(chemotherapy+TCM)group and 924 cases in the controlgroup(chemotherapy alone).Literature general information was showed in Table 1.

Figure 1 literature screening process

Table 1 Generl Information

Figure 2 Bias risk map

Figure 3 Bias risk map

Recent or Solid Tumor Remission

A total of 16 articles were included in the literature[9-24].Results of heterogeneous tests showed that:P=the two groups[OR=1.81,95%CI(1.48.2.22),P＜0.00001](as shown in Figure 4).effect model was used to calculate the combined effects.These results suggest 0.05,I2=41%and the fixed effect model used to calculate the combined effects.Meta-analysis showed that there was significant statistical difference between that[OR=2.69,95%,CI(2.02,3.60),P＜0.00001](Figure 5).

Figure 4 Recent remission

Figure 5 Improvement of lifequality

Adverse Reactions Incidence

The incidence of adverse events was analyzed from 7 aspects:leukocyte reduction,nausea and vomiting,liver function damage,fatigue,abdominal distension,liver pain,and thrombocytopenia.A total of 8 articles were included[9-12,16,18,23,24],as shown in Figure 6.The heterogeneity of adverse reactions showed that P=0.05,I2=0%and the pooled effects were calculated using a fixed effect model.The results of the analysis showed that there was a significant difference between the two groups[OR=0.41,95%CI(0.36,0.47),P＜0.00001];Subgroup results were analysed as follows:the decrease of WBC in subgroup showed that P=0.77,I2=0%and there was significant difference between the two groups[OR=0.37，95%CI(0.27,0.51),P＜0.00001].The heterogeneity of the incidence of nausea and vomiting showed that P=0.25,I2=25%and there was a significant difference between the two groups[OR=0.29，95%CI(0.22,0.39,P＜0.00001].The heterogeneity test of the liver function was damaged showed that P=0.93,I2=0%,[OR=0.36，95%CI(0.19,0.68),P=0.02].Lack of strength heterogeneity test showed that P=0.04,I2=69%,[OR=0.65，95%CI(0.48,0.88),P=0.005].The heterogeneity test showed that the abdominal distension was heterogeneous(P=0.93，I2=0%,[OR=0.36，95%CI(0.19,0.680),P=0.02]).The heterogeneity test of liver area pain showed that P=0.62,I2=0%,[OR=0.38,95%CI(0.22,0.64),P=0.0004].The heterogeneity testofthe thrombocytopenia was showed that P=0.54,I2=0%.There was significant statistical difference between the two groups([OR=0.45，95%CI(0.31,0.67),P＜0.0001])(As shown in Figure 6).

Figure 6 Adverse Reactions Incidence

Discussion

The purpose of this study is to investigate whether Chinese medicine combined with chemotherapy is more effective in the treatment of liver cancer than chemotherapy alone.The randomized controlled trials on the use of Chinese herbal medicine combined with chemotherapy and chemotherapy only for liver cancer were searched between January 2011 and July 2017.Revman 5.3 software was used to analyze the literature by Meta.The chemotherapy protocolsinvolved cis-platinum complexes(DDP);Gemcitabine(GEM);Adriacin(ADM);Fluorouracil(5-FU);Oxaliplatin(L-OHP);Carboplatin(CBP);Calcium folinate(LV).Observation indicators include:①solid tumorOrrecenteffective remission;②QOL improvement in quality of life/KPS Scoring status；③Adverse reactions;④Symptomatic relief.Compared with the control group,the TCM and chemotherapy treatment can improve the solid tumor situation and corresponding symptoms(P＜0.01).The toxic and side effects of the treatment group were significantly smaller than those of the control group.Moreover,TCM can reduce nausea and vomiting,liver function damage and three line decrease caused by chemotherapy(P＜0.01).To sum up,compared with the chemotherapy alone,the combination of Chinese herbalmedicine and chemotherapy has obvious advantages in improving the short-term curative effect of liver cancer,reducing the adverse reactions of chemotherapy and improving the quality of life of patients.But the literature is less,we can’t exactly analyze every subgroup of the study.There are problems with heterogeneity.The scope of traditional Chinese medicine is broader and cannot be explained by one example,the study should analysis a certain method or a certain medicine.