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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 5  |  Page : 60-64

A meta-analysis of Cinobufacini combined with transcatheterarterial chemoembolization in the treatment of advanced hepatocellular carcinoma


1 Department of Interventional Radiology, The First Hospital Affiliated to Henan University, Henan, China
2 Department of Operation Room, The First Hospital Affiliated to Henan University, Henan, China
3 Department of Gastroenterology, The First Hospital Affiliated to Henan University, Henan, China
4 Department of Oncology, The First Hospital Affiliated to Henan University, Henan, China

Date of Web Publication30-Aug-2014

Correspondence Address:
Zhijun Zhao
Department of Interventional Radiology, The First Hospital Affiliated to Henan University, Henan - 475 001
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.139763

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 > Abstract 

Objective: The aim of this meta-analysis is to evaluate the clinical efficacy of cinobufacini combined with transcatheter arterial chemoembolization (TACE) in the treatment of advanced hepatocellular carcinoma.
Materials and Methods: By searching Medline, the Cochrane central register of controlled trials, EMBSE, ESMO, Wanfang and Chinese National Knowledge Infrastructure (CNKI) databases, the open published clinical trials compared the clinical efficacy of cinobufacini plus TACE versus TACE only in patients with advanced hepatocellular carcinoma were collected. The pooled objective response rate (ORR) and 1 or 2 year survival rate were calculated by Stata11.0 statistical software.
Results: Nine studies including a total of 659 subjects (333 in cinobufacini plus TACE and 326 in TACE only) were finally included in this meta-analysis. The pooled analysis demonstrated that cinobufacini plus TACE can significant increase the objective response rate (ORR) compared with TACE only with an relative risk of 1.28 (P = 0.006); The 1-year survival rate in cinobufacini plus TACE group was not significant difference compared with TACE only by pooling the data (RR = 1.24, P = 0.13); But the 2-year survival rate in cinobufacini plus TACE group was much higher than that of TACE only group with an RR of 2.0, (P = 0.001).
Conclusion: This meta-analysis demonstrated that cinobufacini combined with TACE can significantly increase the objective response rate and 2-year survival rate compared with TACE only in patients with advanced hepatocellular carcinoma.

Keywords: Advanced hepatocellular carcinoma, cinobufacini, meta-analysis, transcatheter arterial chemoembolization


How to cite this article:
Wu T, Sun R, Wang Z, Yang W, Shen S, Zhao Z. A meta-analysis of Cinobufacini combined with transcatheterarterial chemoembolization in the treatment of advanced hepatocellular carcinoma. J Can Res Ther 2014;10, Suppl S1:60-4

How to cite this URL:
Wu T, Sun R, Wang Z, Yang W, Shen S, Zhao Z. A meta-analysis of Cinobufacini combined with transcatheterarterial chemoembolization in the treatment of advanced hepatocellular carcinoma. J Can Res Ther [serial online] 2014 [cited 2020 Feb 29];10:60-4. Available from: http://www.cancerjournal.net/text.asp?2014/10/5/60/139763

Tao Wu and Ruimin sun contribute equally to this work



 > Introduction Top


Hepatocellular carcinoma is the second most common malignant tumors which results in 360,000 incident cases, and 350,000 deaths a year in China. [1] Hepatitis B virus (HBV) and aflatoxins have been identified as major causal factors, that act individually and synergistically of hepatocellular carcinoma in the etiology. Other agents such as Hepatitis C virus (HCV), genetic susceptibility or genetic polymorphisms may also play important roles in the development of hepatocellular carcinoma. Early stage primary hepatocellular carcinoma can be treated by surgery with acceptable prognosis but most of patients with advanced hepatocellular carcinoma lost the opportunity of operation. These patients were always recommended for receiving system chemotherapy, radiotherapy or transcatheter arterial chemoembolization (TACE) which could prolong the life expectancy.

Cinobufacini, an aqueous extract from the skins of Bufo bufo gargarizans Cantor, is a well-known traditional Chinese medicine (TCM) widely used in clinical cancer therapy especially for hepatocellular carcinoma in China and some Asian pacific countries. [2] Some studies demonstrated that cinobufacini plus TACE could enhance the antitumor effect as well as prolonged the patient's life expectancy. However, the small number of patients included in each study made the statistical power limited. Thus, we performed this meta-analysis by pooling the data together in order to figure out the clinical efficacy of cinobufacini combined with TACE in the treatment of advanced hepatocellular carcinoma.


 > Materials and methods Top


Trials identification

By searching Medline, the Cochrane central register of controlled trials, EMBSE, ESMO, Wanfang and Chinese National Knowledge Infrastructure (CNKI) databases, the open published clinical trials compared the clinical efficacy of cinobufacini plus TACE versus TACE only in patients with advanced hepatocellular carcinoma were collected. The searching strategy was performed using "hepatocellular carcinoma", "liver carcinoma", "hepatocellular carcinoma/cancer" AND "Cinobufacini," as the Medical Subject Headings (MeSH) and corresponding free text word searching term. The title and abstract of initial identified articles were evaluated for appropriateness to the inclusion criteria.

The inclusion criteria and data extraction

The inclusion criteria of this meta-analysis was: The patients were limited to advanced hepatocellular carcinoma; The intervention in the experiment group was cinobufacini combined with TACE and the treatment procedure in the control group was TACE only; The outcomes should included the objective response rate or the survival rate in each individual study. The general characteristic of first author, year of publication, treatment regimen and year of follow up were extracted for each include individual trial.

The quality assessments

The methodological qualities of the included studies were evaluated by two authors (Tao Wu and Ruimin Sun) according to the Cochrane Reviews Handbook. The concealment of the sequence, randomization, blinding, incomplete outcome date address and selective reports were evaluated in each of individual studies, which generally represent the quality of the randomized control trial (RCT). [3]

Statistical analysis

STATA/SE 11.0 (StataCorp LP, http://www.stata.com) were used for statistical analysis. Statistical heterogeneity across studies was assessed by Chi-square (χ2 ) test, [4] and the inconsistency was calculated by I 2 . [5] If heterogeneity was significant (χ2 , P < 0.1 or I 2 > 50%), the random-effect method (Dersimonian-Laird method) was used to pool the data. Inversely, without significant heterogeneity across the individual studies, fixed-effect method was used.


 > Results Top


Study characteristics

A total of nine studies [6],[7],[8],[9],[10],[11],[12],[13],[14] including a total of 659 subjects (333 in cinobufacini plus TACE and 326 in TACE only) were finally included in this meta-analysis. Of the included nine trials, all of the them reported the objective response rate, seven reported the 1 or 2 year survival rate, five reported the quality of live, three reported the toxicity and only one reported the change of liver function [Table 1].
Table 1: The general characteristics of included trials


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Quality evaluation of each study

The quality of each individual study was showed in [Table 2], which demonstrated that the quality was relative low for each individual trial included in this meta-analysis.
Table 2: The quality of included studies


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The pooled ORR

Seven trials reported the individual data of objective response rate, the pooled results demonstrated that cinobufacini plus TACE can significant increase the ORR compared with TACE only with an relative risk of 1.28 (P = 0.006) with no statistical heterogeneity across the studies [Figure 1].
Figure 1: The forest plot of ORR for cinobufacini combined with transcatheter arterial chemoembolization versus TACE only in the treatment of advanced liver cancer

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The pooled survival rate

Of the included nine studies, five trials provide the 1 or 2-year survival rate in each arm. The 1-year survival rate in cinobufacini plus TACE group was not significant difference compared with TACE only by pooling the data (RR = 1.24, P = 0.13); But the 2-year survival rate in cinobufacini plus TACE group was much higher than that of TACE only group with an RR of 2.0, (P = 0.001) [Figure 2].
Figure 2: The forest plot of 1 or 2-year survival rate for cinobufacini combined with transcatheter arterial chemoembolization (TACE) versus TACE only in the treatment of advanced liver cancer

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Publication bias

Egger's test were used to evaluate possible publication bias. No significant publication bias was found in the pooled analysis of ORR 1 or 2 year survival rate with a P value of 0.08, 0.14 and 0.22 [Figure 3].
Figure 3: The begg's funnel plot of publication (a: For effects size of ORR; b: For effect size of 1-year survival rate; c: For 2-year survival rate)

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 > Discussion Top


Primary hepatocellular carcinoma or hepatocellular carcinoma is the sixth most common malignant tumors worldwide in terms of numbers of cases of 626,000, and the third most common cause of death from cancer (598,000 deaths annually). [15] China is one of the most affected countries by hepatocellular carcinoma, with an age-standardized incidence rate of 37.9 per 100,000 for men, and of 14.2 per 100,000. [15] In the mainland of China, hepatocellular carcinoma is the second major cause of cancer related deaths, with a mortality rate of 26.26 per 100,000 (males: 37.55 and females: 14.45 per 100,000), accounting for 19.33% of all sites of cancers. For the patients with early stage of hepatocellular carcinoma and without remote metastasis, the best treatment strategy was surgery with or without assistant chemotherapy. But for patients with advanced stage, the surgery procedure was always not suitable. They always turn for the chemotherapy or radiotherapy.

Recently, the Barcelona Clinic Liver Cancer (BCLC) classification was deemed as the standard classification system for clinical management of patients with hepatocellular carcinoma. [16] And according to the BCLC staging system, TACE was the standard treatment for patients with advanced or unresectable liver carcinoma. Some trials has demonstrated that TACE can reduced the symptoms caused by hepatocellular carcinoma and prolonged the life expectancy.

Cinobufacini, an aqueous extract from the skins of Bufo bufo gargarizans Cantor, is a well-known TCm widely used in clinical cancer therapy especially for hepatocellular carcinoma in China and some Asian pacific countries. [2] Some studies demonstrated that cinobufacini plus TACE could enhance the antitumor effect as well as prolonged the patient's life expectancy. [6],[7],[10] But with small number cases in each individual studies and inconclusive results, the exact effects of cinobufacini combined with TACE in the treatment of hepatocellular carcinoma was not very clear. Thus, we performed this meat-analysis about cinobufacini combined with TACE in the treatment of advanced hepatocellular carcinoma based on randomized controlled trials. The pooled results showed that that cinobufacini plus TACE can significant increase the ORR compared with TACE only with an relative risk of 1.28 (P = 0.006); The 1-year survival rate in cinobufacini plus TACE group was not significant difference compared with TACE only by pooling the data (RR = 1.24, P = 0.13); But the 2-year survival rate in cinobufacini plus TACE group was much higher than that of TACE only group with an RR of 2.0, (P = 0.001). This meta-analysis demonstrated that cinobufacini combined with TACE can significantly increase the objective response rate and 2-year survival rate compared with TACE only in patients with advanced hepatocellular carcinoma.

However, several limitations required consideration for this meta-analysis. Firstly, the general quality of the included individual studies was relative low; Secondly, the mean number of subjects included in each studies was small, and without multiple center RCTs were included in this meta-analysis. Thirdly, the survival data was not completely in each studies which lead to the hazard ratio could not be calculated.

In conclusion, existing data indicated that cinobufacini combined with TACE can significantly increase the objective response rate and 2-year survival rate compared with TACE only in patients with advanced hepatocellular carcinoma. But for lacking huge multiple centers prospective RCTs comparing the two treatment regiments, the results should be interpreted cautiously.

 
 > References Top

1.Chen JG, Zhang SW. Liver cancer epidemic in China: Past, present and future. Semin Cancer Biol 2011;21:59-69.  Back to cited text no. 1
    
2.Cui X, Inagaki Y, Xu H, Wang D, Qi F, Kokudo N, et al. Anti-hepatitis B virus activities of cinobufacini and its active components bufalin and cinobufagin in HepG2.2.15 cells. Biol Pharm Bull 2010;33:1728-32.  Back to cited text no. 2
    
3.Zafarmand MH, van der Schouw YT, Grobbee DE, de Leeuw PW, Bots ML. The M235T polymorphism in the AGT gene and CHD risk: Evidence of a Hardy-Weinberg equilibrium violation and publication bias in a meta-analysis. PLoS One 2008;3:e2533.  Back to cited text no. 3
    
4.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.  Back to cited text no. 4
[PUBMED]    
5.Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.  Back to cited text no. 5
    
6.Dong HT, Zhao W, Lu WP, He YH. A clinical study of cinobufacini combined with transcatheter arterial chemoembolization (TACE) in the treatment of 38 cases with primary hepatocellular carcinoma. Chin J Inf Tradit Chin Med 2008;15:66-7.  Back to cited text no. 6
    
7.Liang Y, Long JZ, Liu H, Feng J. Study of cinobufotalin and interferon combined with transcatheter hepatic arterial chemoembolization on primary hepatocellular carcinoma. Mod J Integr Tradit Chin West Med 2008;17:1628-30.  Back to cited text no. 7
    
8.Li Q, Sun BM, Peng YM, Fan ZZ, Sun Y. Clinical Study on the Treatment of Primary Liver Cancer by Cinobufotain Combined with Transcatheter Arterial Chemoembolization. Acta Univ Tradit Med Sinensis Pharmacol Shanghai 2008;22:32-4.  Back to cited text no. 8
    
9.Liu XH, Fu H, Zhu QH, Pan PS, Yang L. cinobufacini combined with transcatheter arterial chemoembolization (TACE) in the treatment of liver cancer. Chin J Mod Drug Appl 2009;134-5.  Back to cited text no. 9
    
10.Yang YG, Li J, Ma YH, Liu JS. Cinobufacini combined with transcatheter arterial chemoembolizationin in the treatment of advanced liver carcinoma. Chin Rural Health Serv Adm 2006;22:20.  Back to cited text no. 10
    
11.Zhou JS, Lu H, Wu XD, Xu X. Effects of huachan-shu injection combined with transcatheter arterial chemombolization on patients with advanced unresectable hepatocelluler carcinoma. Chin J Prim Med Pharm 2006;13:571-2.  Back to cited text no. 11
    
12.Xue S, Lu LQ, Yuan GR, Zhao TW. Cinobufacini combined with transcatheter arterial chemoembolization (TACE) in the treatment advanced liver cancer: Report of 32 cases. Jiangsu J Tradit Chin Med 2010;42:22-4.  Back to cited text no. 12
    
13.Liu YQ, Yu ZH, Shao ZH, Jiang ZY, Liu XW. Cinobufacini combined with transcatheter arterial chemoembolization (TACE) in the treatment advanced liver cancer. Chin Rural Health Serv Adm 2010;30:402-4.  Back to cited text no. 13
    
14.Transcatheter arterial chemoembolization (TACE) in the treatment advanced liver cance. Mod Dig Interv 2013;18:32-3.  Back to cited text no. 14
    
15.Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.  Back to cited text no. 15
    
16.Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: The BCLC staging classification. Semin Liver Dis 1999;19:329-38.  Back to cited text no. 16
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]



 

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