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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 2  |  Page : 243-249

A comparison between drug-eluting bead-transarterial chemoembolization and conventional transarterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis of six randomized controlled trials


1 Department of Lightning Scientific Research Lab, The First Clinical Medical School, Nanjing Medical University, Nanjing, China
2 Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3 Department of Lightning Scientific Research Lab, Clinical School of Imaging, Nanjing Medical University, Nanjing, China
4 Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, China
5 Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China

Date of Submission17-Jul-2019
Date of Decision07-Oct-2019
Date of Acceptance15-Nov-2019
Date of Web Publication28-May-2020

Correspondence Address:
Bo Zhai
Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai
China
Yihai Liu
Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_504_19

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 > Abstract 


Objective: Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate hepatocellular carcinoma. Drug-eluting beads (DEB)-TACE is a promising approach expected to improve the efficiency and safety of conventional (c) TACE. However, controversy remains whether DEB-TACE performs better than cTACE. This meta-analysis aimed to compare cTACE and DEB-TACE in terms of overall survival (OS), adverse events, and response rate. Literature search was performed in PubMed, Cochrane, Embase, and Web of Science. Complete response (CR), partial response (PR), disease control (DC), stable disease (SD), OS, and major complications were compared between these two modalities. The pooled relative risk and 95% confidence interval were calculated for assessment. Six randomized controlled trials were included for further analysis after a comprehensive search. No significant difference was found in overall response at 3, 6, 9, and 12 months, CR, PR, DC (SD), OS and complications between cTACE and DEB-TACE.
Conclusion: DEB-TACE had similar therapeutic effects to those of cTACE. Furthermore, major complications in both therapies were similar. The superiority of DEB-TACE over cTACE remains unclear, and further research with high-quality evidence is needed.

Keywords: Drug-eluting beads, hepatocellular carcinoma, transarterial chemoembolization


How to cite this article:
Wang H, Cao C, Wei X, Shen K, Shu Y, Wan X, Sun J, Ren X, Dong Y, Liu Y, Zhai B. A comparison between drug-eluting bead-transarterial chemoembolization and conventional transarterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis of six randomized controlled trials. J Can Res Ther 2020;16:243-9

How to cite this URL:
Wang H, Cao C, Wei X, Shen K, Shu Y, Wan X, Sun J, Ren X, Dong Y, Liu Y, Zhai B. A comparison between drug-eluting bead-transarterial chemoembolization and conventional transarterial chemoembolization in patients with hepatocellular carcinoma: A meta-analysis of six randomized controlled trials. J Can Res Ther [serial online] 2020 [cited 2020 Jul 16];16:243-9. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/243/285216

FNx01Hongye Wang, Cheng Cao and Xiyi Wei contributed equally to this work.





 > Introduction Top


Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide, responsible for approximately 1 million death/year.[1] Infection of hepatits B virus (HBV) and hepatitis C virus (HCV) is the leading cause of HCC in China. In addition, most patients suffer from infection-induced liver cirrhosis before it deteriorates to HCC.[2] More than 500,000 new cases are diagnosed each year, and most patients have already progressed to the advanced stage at diagnosis.[3] Despite the availability of curative therapies for early-stage HCC, such as liver transplantation, surgical resection, radiofrequency ablation, and percutaneous alcohol injection, the prognosis of intermediate HCC remains poor.[4]

According to the guidelines of the American Association for the Study of Liver Disease, one of the recommended therapies for unresectable intermediate HCC (Barcelona clinic liver cancer (BCLC) Stage B, multifocal HCC, or large carcinoma with no vascular invasion nor extra-hepatic metastasis and with a Child-Pugh score of A/B) is transarterial chemoembolization (TACE).[5],[6] Liver tumors are sensitive to hypoxia, and TACE utilizes gelatin for embolization of the blood vessels that nurture the tumor and for delivering lipiodol and epirubicin to increase the local drug concentration, leading to tumor infraction and necrosis.[7] Some randomized controlled trials (RCTs) have confirmed that patients can benefit from TACE, and that a combination of TACE and other therapies can improve patient survival.[8],[9],[10]

Although conventional (c) TACE has achieved remarkable results in clinical cases, a modified technique was developed to increase the efficiency and safety of this therapy. Drug-eluting bead (DEB)-TACE wasfirst introduced in 2006 and was included in the treatment criteria of some hepatology centers.[11] This novel embolization and drug delivery system adopts DEB, which can release doxorubicin slowly. It increases the local drug concentration while decreasing the peak serum drug concentration to 10%.[12] Some cohort studies found that the median survival period of patients who received DEB-TACE was more than 4 years.[13],[14]

Existing studies showed that patients may benefit from either cTACE or DEB-TACE. Nevertheless, controversy remains whether one is superior to the other. Some retrospective studies pointed out obvious advantages of fewer adverse events and longer overall survival (OS) in the DEB-TACE group.[15],[16],[17] However, other studies showed comparable efficiency between these two modalities.[18],[19],[20] Thus, the purpose of this systemic review and meta-analysis was to evaluate the efficiency and safety of cTACE and DEB-TACE for HCC by analyzing six RCTs.[21],[22],[23],[24],[25]


 > Materials and Methods Top


Literature search strategy

The searching strategy strictly followed the review protocols and guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) group. Four medical databases, namely PubMed, Embase, Cochrane, and Web of Science, were used. A total of 1752 relevant studies were included. The search strategy was performed using the following terms: (“DEB” overall response [OR] “drug-eluting microsphere” OR “doxorubicin eluting” OR “drug-eluting”) AND (“TACE” OR “transcatheter arterial chemoembolization” OR “transarterial chemoembolization”) AND (“HCC”) OR (“carcinoma” OR “neoplasm” OR “cancer” OR “tumour” OR “tumor”). Quality tests were conducted by two reviewers independently.

Inclusion criteria

The inclusion criteria were: (i) RCTs; (ii) tripatients diagnosed as inoperable HCC >18 years old as subjects; (iii) data available regarding at least one of the following indicators: OS, objective response, disease control (DC), and adverse events.

Exclusion criteria

The exclusion criteria were: (i) prospective and retrospective trials; (ii) duplicates; (iii) animal experiments; (iv) commentaries or editorials, reviews, case reports, and meta-analyses; (v) studies that did not offer any result regarding the following indicators: OS, objective response, DC, and adverse events.

Data extraction

Data extraction was conducted by two reviewers (Cheng Cao and Hongye Wang) independently. The following information was extracted from the journal article: authors, year of publication, regions of the studies, types of the beads, chemotherapeutic drugs, research design, duration of the research, sample size, subject number of males and females, mean age of patients, tumor size, Child-Pugh score, Eastern Cooperative Oncology Group (ECOG) score, Barcelona clinic liver cancer (BLCL) stages, etiology of HCC, complete response (CR), partial response (PR), objective response, stable disease (SD), DC, progressive disease, adverse events, progression-free survival, and OS.

Disagreements about data extraction and study eligibility were resolved by consulting a third reviewer.

Statistical analysis

Relative risks (RR) and 95% confidence intervals (CI) were used to evaluate the statistics for dichotomous variables, including CR, PR, objective response, SD, and DC. If there was heterogeneity across the studies, the RRs corresponding to all outcomes were pooled using a random model (the Der Simonian and Laird method) or a fixed model (the Mantel–Haenszel method). The heterogeneity of these studies was evaluated by Higgins I2 statistic and Cochrane's Q test. An I2 >50% or P < 0.01 suggested significant heterogeneity. Sensitivity analysis was used to seek the origin of the heterogeneity if significant heterogeneity existed. Begg's test was applied to estimate publication bias. In addition, significant publication bias was considered when a P < 0.05. All data analyses were conducted using the STATA version 12.0 (STATA Corporation, College Station, TX, USA).


 > Results Top


Identification and methodology quality of included studies

A total of six RCTs were included in our studies at the final stage using the strict selection criteria. The flowchart of the search process is presented in [Figure 1]. Items including year, time of publication, region, authors, drug, sample size, tumor size, Child-Pugh score, ECOG score, and BCLC stage were recorded according to the PRISMA guidelines [Table 1]. A total of 660 patients that met the criteria were enrolled in this study. The quality test was conducted by two researchers (Cheng Cao and Yihai Liu) independently. All Newcastle-Ottawa Scale (NOS) results showed that the studies included were of good quality.
Figure 1: Flowchart of the search strategy

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Table 1: Characterization of six selected randomized controlled trials

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Meta-analysis results

CR, PR, DC, and SD in 6 months after conventional TACE and DEB-TACE were compared. No significant difference was found between these two treatments (6M CR: Pooled RR: 1.06 95% CI: (0.84, 1.34) P = 0.170, 6M PR: Pooled RR: 1.05 95% CI: (0.75, 1.46) P = 0.609, 6M DC: Pooled RR: 1.06 95% CI: (0.93, 1.20) P = 0.113, 6M SD: Pooled RR: 1.14 95% CI: (0.65, 2.00) P = 0.251) [Figure 2]. In addition, OR at 3, 6, 9, and 12 months were also compared, and the results showed no significant difference between the two treatment modalities (3M OR: Pooled RR: 1.04 95% CI: (0.87, 1.25) P = 0.491, 6M OR pooled RR: 1.06 95% CI: (0.91, 1.23) P = 0.093, 9M OR: Pooled RR: 1.11 95% CI: (0.89, 1.38) P = 0.105, 12M OR: Pooled RR: 1.06 95% CI: (0.97, 1.25) P = 0.707) [Figure 3]. Furthermore, there was no significant difference in OS and major complications (OS: Pooled RR: 0.96, 95% CI: 0.69, 1.32 P = 0.715, Complications: Pooled RR: 1.22 95% CI: 0.87, 1.71 P = 0.255) [Figure 4].
Figure 2: Forest plot of complete response, partial response, disease control, stable disease

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Figure 3: Forest plot of overall response in 3, 6, 9, and 12 months

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Figure 4: Forest plot of overall survival and major complication

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 > Discussion Top


To date, most HCC patients have no choice but to receive surgical resection owing to the advanced stage of the disease. However, only 30% of patients are suitable for surgical operation and nearly 50% of patients will progress to intrahepatic metastasis.[26] TACE is considered the standard therapy for patients with intermediate-stage HCC. Nevertheless, many studies have found that HCC cannot be completely eradicated with TACE alone.[27],[28] As a novel therapy, DEB-TACE shows promising prospect in clinical use by increasing patients' median survival up to 3 years.[29] However, it remains a controversy whether DEB-TACE has higher efficiency and safety than cTACE.

This meta-analysis was conducted to estimate the safety and efficiency of cTACE compared with DEB-TACE in patients with HCC. Six randomized clinical trials were included in the analysis. CR, PR, DC, and SD in 6 months and OR in 3, 6, and 9 months were compared. OS and major complications were also compared between cTACE and DEB-TACE. There were no significant differences in these variables between the two treatment groups, which indicated that DEB-TACE had similar safety and efficiency to those of cTACE.

The active components of cTACE include lipiodol and doxorubicin for embolization. High incidence of systemic adverse reactions can be expected owing to the wide distribution of chemotherapeutic drugs, but a weaker therapeutic effect of embolization. Moreover, low drug concentration in the tumor microenvironment promotes tumor survival and drug-resistance development, contributing to tumor metastasis.[30] As a newly-developed technology, DEB-TACE releases the chemotherapeutic drugs slowly, thus sustaining the drug concentration for a much longer period. Furthermore, owing to their flexibility, the DEBs can adapt and adhere to the target blood vessels, further depriving tumors of oxygen. The size of DEBs and the dose of chemotherapy agents may attribute to different clinical outcomes. Some studies have confirmed that lower drug dosage and DEBs with sizes within a certain range lead to low adverse events and improved treatment efficiency.[21],[22],[31],[32] Theoretically, DEB-TACE is supposed to have better curative effects and fewer side effects than cTACE. However, there were no significant differences between the two treatment modalities in this study. Thus, more multi-center clinical trials are required for further analysis.

Several meta-analyses also evaluated the effects of DEB-TACE and cTACE for patients with late-stage HCC. In contrast to our results, Zhou et al. showed better OS, DC, and objective rate in the DEB-TACE-treated group with 830 patients than in the cTACE group.[33] Similar to the results observed by Zhou et al., Martin et al. found a significant advantage of DEB-TACE compared with cTACE.[12] Another systemic review conducted by Huang et al. found no disparity between these two treatments in terms of objective response at 6 months and survival rate at 3 years.[34] Taken together, all three meta-analyses indicated that DEB-TACE was correlated with fewer side effects. However, these meta-analyses collected retrospective studies for analysis, which might lead to selection bias.

It should be noted that our systemic analysis had some limitations. First, the small size of the study might have caused selection bias. Second, only six RCTs were included in the analyses, and each analysis contained only three to four studies. More RCTs are required to confirm our findings. Third, the population of patients might have had heterogeneity, and the procedures of TACE in different institutions might have varied. Fourth, subgroup analyses were not conducted owing to lack of information. Despite these limitations, this systemic review may contribute to the comprehensive assessment of DEB-TACE, which can facilitate doctors to make feasible decisions.

Acknowledgment

We thank all authors who contributed to the included studies. This research was funded by the National Science and Technology Major Project (No. 2017ZX10203206-006-002).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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