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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 133-138

Efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization for hepatocellular carcinoma: A meta-analysis


Department of Interventional Radiology and Vascular Surgery, Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province, People's Republic of China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Zhibin Bai
Department of Interventional Radiology and Vascular Surgery, Zhongda Hospital of Southeast University, Dingjiaqiao 87, Nanjing, Jiangsu Province 210009
People's Republic of China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1261_16

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 > Abstract 

Objectives: This study was aimed to evaluate the efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC).
Materials and Methods: Studies were searched in Embase, PubMed, and Springer until August 10, 2016. All the studies were screened with inclusion and exclusion criteria. The quality assessment of the eligible studies was performed with the Newcastle-Ottawa Scale and the Jadad Scale. Response rate, recurrence, mortality, and thrombocytopenia were evaluated with risk ratios (RRs) with 95% confidence intervals (CIs). The heterogeneity and publication bias were assessed.
Results: Ten eligible studies were included with a total of 993 objects. The data were extracted and summarized. The overall results were calculated including response rate (RR = 0.98, 95% CI: 0.83–1.15), recurrence (RR = 0.75, 95% CI: 0.58–0.96), mortality (RR = 0.71, 95% CI: 0.39–1.28), and thrombocytopenia (RR = 0.42, 95% CI: 0.09–1.93), without significant heterogeneity. There was a significant heterogeneity for mortality; thus, the random effects model was used. No publication bias was observed in this study.
Conclusions: The results of meta-analysis indicated that epirubicin applied in TACE has an obvious efficacy for the treatment of HCC, with significantly decreased recurrence while without superiority of safety.

Keywords: Epirubicin, hepatocellular carcinoma, meta-analysis, transcatheter arterial chemoembolization


How to cite this article:
Bai Z, Qin Y, Zhu G, Zhao G, Deng G, Guo J, He S. Efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization for hepatocellular carcinoma: A meta-analysis. J Can Res Ther 2018;14:133-8

How to cite this URL:
Bai Z, Qin Y, Zhu G, Zhao G, Deng G, Guo J, He S. Efficacy and safety of epirubicin applied in transcatheter arterial chemoembolization for hepatocellular carcinoma: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Nov 16];14:133-8. Available from: http://www.cancerjournal.net/text.asp?2018/14/1/133/226736


 > Introduction Top


Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, leading to numbers of cancer-related death worldwide.[1],[2],[3],[4] More than 700,000 HCC cases have been diagnosed each year.[5] Despite surgical resection, 80% of HCC patients developed intrahepatic recurrence.[6] Furthermore, the mortality rate almost equaled to the incidence rate in most countries.[7],[8] In addition, the majority of patients were diagnosed during advanced stage and lost the opportunities for surgery.[9] Therefore, the improved prognosis of HCC would be critical for the treatment of advanced or relapsed HCC.

Transcatheter arterial chemoembolization (TACE) has been considered to be a standard therapy for patients with unresectable or relapsed HCC.[10],[11] TACE could contribute to tumor necrosis and shrinkage, thus improving the survival of those patients.[12],[13] However, in some cases, repeated TACE has generally lead to hepatic artery damage, thus affecting treatment success rate and clinical outcomes.[14] Fortunately, TACE combined with the injection of anticancer agent into the segmental or subsegmental arteries of the liver has attracted people's attention in clinical application.[15]

Recently, epirubicin has been widely applied as anticancer agent for TACE in HCC.[10] Several previous studies suggested that epirubicin might be an active and tolerable therapeutic option for patients with unresectable HCC, either used alone or combined with other drugs.[16],[17] Seki et al. indicated that epirubicin combined with TACE would be an effective and safe treatment for unresectable HCC. In addition, both damage to the hepatic artery and the frequency of postembolization syndrome could be reduced.[14] However, some studies show that epirubicin could lead to arteritis, hepatic artery occlusion, and development of extrahepatic collateral pathways. It would also interfere with repetitive TACE at the next session and limit the long-term efficacy of TACE.[10],[18] Therefore, the efficacy and safety of epirubicin applied in TACE for HCC has been still controversial.

In the present study, a systematic meta-analysis of the relevant publications was conducted to assess the efficacy and safety of epirubicin applied in TACE for the treatment of HCC. The overall results of response rate, recurrence, mortality, and thrombocytopenia were calculated. Our results could provide a new and synthetical insight for understanding the efficacy and safety of epirubicin applied in TACE for HCC.


 > Materials and Methods Top


Data sources and retrieval strategy

A computerized literature searches were performed in PubMed, Embase, and Springer until August 10, 2016. Following keywords were applied for literature retrieval: TACE, epirubicin, cancer, carcinoma, hepatocellular, and liver. There was no restriction for languages. In addition, the reference lists of the retrieved papers were manually examined for additional relevant studies.

Inclusion and exclusion criteria

The inclusion criteria for this meta-analysis were as follows: (1) studies were designed as cohort studies or randomized controlled trials (RCTs); (2) the objects were patients suffering from HCC; (3) patients in the experimental group were administrated with epirubicin in TACE, while the control group was not administrated with epirubicin in TACE; (4) the outcomes were provided including response rate, mortality, recurrence, and thrombocytopenia.

The exclusion criteria were: (1) studies with incomplete data thus unavailable for statistical analysis; (2) studies in which the control groups were not treated with TACE; and (3) reviews, letters, or comments.

Data extraction and quality assessment

After literature selection, the data were independently extracted by two investigators with a standardized data collection form. For each study, the following data were collected: the first author's name, year of publication, region of original study, follow-up period, age and gender of the objects, sample sizes, and treatment outcomes. Then, they exchanged the data collection form. Any disagreements between them were resolved with discussion to reach a consensus.

The quality assessment of the included cohort studies was performed using the Newcastle-Ottawa Scale (NOS) with a total score of 9. NOS was an eight-item instrument that categorized into three dimensions: selection, comparability, and outcome of cohort studies.[19] The study was considered to be of high-quality when the score was not lower than 7; otherwise, it was considered as a study with poor quality. The quality of the included RCTs was assessed using the Jadad Scale [20] with a maximum score of 5. The quality of RCT was considered to be high if the score ranged from 3 to 5 and low with the score <3.

Statistical analysis

Risk ratios (RRs) with 95% confidence intervals (CIs) were applied in this meta-analysis to evaluate response rate, recurrence, mortality, and thrombocytopenia. The heterogeneity between studies was evaluated with Cochran Q-test and I2 statistic. When there was significant heterogeneity (P< 0.05, I2> 50%), the random effects model was applied to pool the effect size. Otherwise, the fixed effect model was performed. All statistical analyses were conducted using STATA vision 11.0 software (StataCorp LP, College Station, TX, USA).

Publication bias

The assessment of publication bias was performed with Begg's [21] and Egger's tests.[22]


 > Results Top


Literature selection

The process of literature retrieval and study selection was showed [Figure 1]. Seven hundred and eighty-six studies were obtained in the initial search of the database (Embase: 324, PubMed: 141, and Springer link: 321). After the exclusion of the duplicates, there were 594 studies. According to the inclusion and exclusion criteria, a total of 576 studies were excluded by title and abstract review. Then, eight studies (5 reviews and 3 without available data) were removed after full-text review. No additional articles were obtained during manual retrieval. At last, ten studies [23],[24],[25],[26],[27],[28],[29],[30],[31],[32] were included for analysis in this meta-analysis.
Figure 1: The flow diagram of the literature retrieval and study selection

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Characteristics of eligible articles

The characteristics of the included studies were summarized [Table 1]. There were nine cohort studies and one RCT published between 2004 and 2016. A total of 993 objects (539 in experimental group and 454 in control group) were included in these studies. The average age of each study was ranged from 54.3 to 75. There were no significant differences in baseline age and sex ratio between two groups. Among the ten studies, eight studies were from Japan, one study from China, and one study from Korea. The included studies were of high quality according to their scores.
Table 1: The characteristics of the included studies

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Meta-analysis

Response rate was provided in seven studies [Figure 2]a. No evidence of prominent heterogeneity was observed among studies (P = 0.588 and I2= 0.0%); therefore, the fixed effect model was applied. There was no significant difference in response rate between EP-TACE group and control group (RR = 0.98, 95% CI: 0.83–1.15, P = 0.799).
Figure 2: Meta-analysis of efficacy and safety. (a) The results of response rate. (b) The results of recurrence. (c) The results of mortality. (d) The results of thrombocytopenia. RR=Risk ratio

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Recurrence was reported in four studies [Figure 2]b. No significant heterogeneity was found between studies (P = 0.712 and I2= 0.0%); therefore, the fixed effect model was applied. The results showed that the recurrence rate in EP-TACE group was lower than that of in the control group (RR = 0.75, 95% CI: 0.58–0.96, P = 0.024).

Mortality rate was reported in four studies [Figure 2]c. Significant heterogeneity was found between studies (P = 0.034 and I2= 65.3%), so the random effects model was applied. No significant difference was observed in mortality rate between EP-TACE group and control group (RR = 0.71, 95% CI: 0.39–1.28, P = 0.251).

Thrombocytopenia was reported in three studies [Figure 2]d. No evidence of prominent heterogeneity was present these studies (P = 0.887 and I2= 0.0%); therefore the fixed effect model was applied. The results showed no significant difference in thrombocytopenia between EP-TACE group and control group (RR = 0.42, 95% CI: 0.09–1.93, P = 0.264).

Publication bias

Publication bias was assessed based on response rate because the number of included studies was maximum. No publication bias was explored by Begg's (P = 0.368) and Egger's tests (P = 0.677).


 > Discussion Top


HCC has been a highly lethal cancer and the third most frequent cause of cancer-related death.[33],[34] In the present study, a quantitative meta-analysis of relative studies was performed to examine the efficacy and safety of epirubicin applied in TACE for the treatment of HCC. A total of ten studies were included in our meta-analysis, involving 539 objects in epirubicin group and 454 controls. The results suggested a significantly decreased recurrence rate in epirubicin group compared to that of in control group. However, no significant differences were observed in response rate, mortality, and thrombocytopenia between the two groups.

The response rate, as an indicator of efficacy, was provided in most of the studies included in this meta-analysis. Jang et al.[29] found that the response rate in epirubicin group was significantly higher than that of in control group; however, the outcome of response rate in other studies showed no significant difference between epirubicin group and control group. In this study, the seven included studies providing response rate showed no significant difference between two groups. Besides, in the study of Yamanaka et al.,[23] epirubicin used in TACE was more effective than cisplatin (control) for single HCC, while cisplatin provided a stronger efficacy than epirubicin in multiple HCC. Thus, we inferred that, for response rate, the efficacy of epirubicin may be associated with the confounding factors in HCC patients.

The efficacy of epirubicin applied in TACE for the treatment of HCC was associated with the recurrence of HCC as well. In the study of Sahara et al.,[27] no significant difference was observed between the groups for the recurrence assessed by the frequency of repeat TACE. However, it revealed that the local recurrence rate in epirubicin group (43.1%) was obviously lower than that of in control group (71.2%) in the study of Handa et al.[30] Similarly, Miyayama et al.[25] found that the local recurrence in the epirubicin group was significantly less than that of in other groups. In our meta-analysis, the overall results of recurrence indicated a remarkable reduction of recurrence in epirubicin group compared with that of in control group. Thereby, our results suggested that a high efficacy could be provided by epirubicin used in TACE for the treatment of HCC, resulted from the significantly decreased recurrence.

The overall results of mortality (applied as an index of safety) in our meta-analysis suggested that there was no significant difference between epirubicin group and control group. The index of mortality was considered to be effective when the number of patients was >50 with the follow-up time longer than 1 year.[35] For the included studies in this meta-analysis, the number of patients was 38 in the study of Sahara et al.[27] The follow-up time was <1 year in two included studies,[26],[27] in which no significant difference in mortality was observed between epirubicin group and control group. To the contrary, significantly higher overall mortality in epirubicin group was observed by Yodono et al.[28] Two hundred and two objects were involved in their study, with a follow-up time of 32 months. Therefore, superiority of safety may not be provided by epirubicin based on the outcome of mortality, and further studies with larger sample size and longer follow-up time would be needed for the mortality of patients treated with epirubicin.

The overall results of thrombocytopenia were also obtained in our meta-analysis to assess the safety of epirubicin. The results indicated that there was no significant difference for thrombocytopenia between two groups. Thus, we speculated that no significant safety could be provided with epirubicin when applied in TACE for the treatment of HCC because the risk of thrombocytopenia could not be reduced.

Noticeably, there are some advantages in this meta-analysis. First, the included studies were of high quality. Second, there was no significant heterogeneity for response rate, recurrence, and thrombocytopenia among studies. Third, no publication bias was observed in the meta-analysis.

Oppositely, there were several limitations in our study. First, the included studies were observational studies except for one study of Sahara et al.[27] This may contribute to the undemanding control of confounding factors, which may affect our results. Therefore, further study with massive RCTs with high-quality should be required to verify our preliminary findings. Second, both the number of included studies and the sample sizes were limited, and more samples with high quality should be included to enhance the stability. Third, the meta-analysis of mortality showed a significant heterogeneity, which may be resulted from short follow-up time and small sample size.


 > Conclusions Top


Epirubicin applied in TACE may provide a high efficacy for the treatment of HCC due to the significantly decreased recurrence, while there was no superiority of safety based on the overall mortality and thrombocytopenia. Further studies with more high-quality trails and larger sample sizes are warranted to verify the efficacy and safety of epirubicin in TACE for HCC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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