Tatiana Chernyshenko
Roman Polkin
Ekaterina Dvoinikova1,2
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- 1Department of Surgery, Far Eastern Federal University, Vladivostok, Russia
- 2Medical Center, Far Eastern Federal University, Vladivostok, Russia
- 3Department of Neurosurgery, 1477th Naval Clinical Hospital, Vladivostok, Russia
Study design: Systematic review and update meta-analysis.
Purpose: The present systematic review and meta-analysis were conducted to compare the efficacy and safety of the two approaches for HCC in adult patients (DEB-TACE vs cTACE).
Overview of literature: The TACE procedure is indicated for the treatment of HCC with intermediate (BCLC B) and early (BCLC A). Conflicting data obtained from earlier meta-analyses comparing DEB-TACE with cTACE prompted the updated meta-analysis.
Methods: The study included adult patients over the age of 18 with HCC. MEDLINE conducted a literature search using Pubmed and Google Scholar up to May 2024. The following parameters were evaluated: the effectiveness of the tumor response to treatment according to the mRECIST criteria (CR, PR, SD, PD), overall survival, progression-free survival, and complication rate. 32 retro- and prospective studies were analyzed.
Results: The study included 4,367 patients. The radiological response of the tumor in all four CR, PR, SD, and PD parameters in the DEB-TACE group showed the best response. The overall survival rate during the DEB-TACE procedure was higher by 3.54 months (p <0.00001), and progression-free survival (PFS) by 3.07 months (p <0.0001), respectively. The incidence of complications was comparable in both groups.
Conclusions: The results of the meta-analysis revealed clinically significant advantages of DEB-TACE in comparison with cTACE. Being comparable in terms of the frequency of complications, DEB-TACE demonstrated the best result in the radiological response of the tumor to the therapy, in terms of overall survival and progression-free survival.
1 Introduction
Liver cancer is the sixth most common in the world and ranks third as the cause of death from malignant neoplasms (MNP) (1).
Hepatocellular carcinoma (HCC) and cholangiocarcinoma are the two most common primary liver MNPs. Hepatocellular carcinoma develops from hepatocytes, and cholangiocarcinoma develops from bile duct cells (2).
HCC accounts for 75-85% of all primary liver MNPs, leading to the fourth most common cause of cancer-related death in the world (3).
Existing methods of treating HCC, such as surgical resection, transplantation, systemic drug therapy, and stereotactic irradiation, are complemented by the use of minimally invasive methods. One of these options is transarterial chemoembolization (TACE), which consists of the administration of chemotherapeutic drugs directly into the artery feeding the tumor under conditions of digital subtraction angiography.
TACE is performed in the treatment of HCC with intermediate (BCLC B) and early (BCLC A) stages according to the BCLC classification (4). Classical transarterial chemoembolization (cTACE) and transarterial chemoembolization using drug-eluting beads (DEB-TACE) are the two main options for locoregional treatment (5).
cTACE is a procedure that involves the sequential delivery of a chemotherapeutic drug and lipidol into the vessels feeding the tumor, followed by an embolic agent (6).
DEB-TACE is another type of TACE that contains beads saturated with the drug. The use of this technique makes it possible to increase the concentration of the drug in the tumor and reduce its systemic concentrations compared to cTACE (4). However, the disadvantages of DEB-TACE are the constant occlusion of the artery feeding the tumor due to non-degradable beads and a limited choice of therapeutic agents for loading (7, 8).
At the moment, the algorithms for selecting a chemotherapeutic drug and the method of its delivery based on the morphological subtype of the tumor and the stage of the disease remain the subject of active discussions. Conflicting data obtained from previously conducted meta-analyses (16–19) comparing DEB-TACE with cTACE led to the publication of new clinical studies, which prompted the implementation of an updated meta-analysis.
2 Materials and methods
This review was conducted in accordance with the recommendations of The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (9) and Assessment of Multiple Systematic Reviews AMSTAR. A systematic search was conducted via MEDLINE, PubMed, and Google Scholar. A highly sensitive search strategy using keywords was used for the search: hepatocellular carcinoma AND transarterial chemoembolization, hepatocellular carcinoma, AND chemoembolization, drug-eluting beads AND hepatocellular carcinoma. Irrelevant studies were excluded and duplicates were deleted. Only original articles from 2010 to 2024 were selected. Additional links were found by manually searching the literature lists of relevant studies, conference abstracts, and registered clinical trials. The search was limited to publications in English.
2.1 Selection criteria
All articles were selected using previously specified keywords. The data were independently selected by two authors (TC, RP), who checked all relevant titles and abstracts of publications to exclude irrelevant ones. The researchers independently evaluated the complete reports, after which each selected article was independently evaluated by the entire author’s team using PICOS (Population, Intervention, Comparison, Outcome, Study Design) (10) inclusion and exclusion criteria (Table 1).
Table 1
Table 1. PICOS. Inclusion and exclusion criteria.
2.2 Data extraction and quality assessment
The two above-mentioned authors independently extracted data using standardized forms. From publications that meet the inclusion criteria, information on the year, study design, type of emboli, intervention, comparative control, overall survival, mean and standard deviations (SD) or confidence interval (CI), as well as sample sizes were obtained. Modified scales were used to assess the methodological quality of research: Newcastle-Ottawa, NIH quality assessment tool for case series studies, and Cochrane Risk of Bias (ROB) 2.0 tool (11).
2.3 Evaluation of outcomes
The study primarily analyzed the following parameters: (1) median overall survival, (2) progression-free survival, (3) radiological response to treatment, according to the recommendations of the “Criteria for Evaluating Response in Solid Tumors” (RECIST) (12), the frequency of complications during hospitalization.
2.4 Statistical analysis
To analyze the data, we used the Review Manager ver. 5.4 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). Risk ratio (RR), odds ratio (OR), and 95% confidence interval (CI) were calculated for dichotomous variables; standardized mean differences (SMD) and their 95% CI were used for continuous variables. The degree of heterogeneity was estimated using the coefficient I2. The fixed effects model was used for the absence of heterogeneity, and the random effects model was used if I2 was greater than 40%. A funnel-shaped graph was constructed and an Egger’s test was performed to assess the systematic error of the publication. A value of p <0.05 was used to indicate statistical significance. The standard deviations were calculated using the Cochrane Handbook for Systematic Reviews of Interventions (13).
3 Results
3.1 Systematic search results
Figure 1 shows a brief description of the research selection process. In total, 1,365 articles were found in the databases of MEDLINE via PubMed, and Google Scholar. A total of 1,189 studies were excluded because they were duplicates, irrelevant studies, case reports, and reviews. A total of 176 potential articles were received for further full-text evaluation. Of these, 157 articles were excluded for non-compliance with the inclusion criteria. The final synthesis included 32 studies. 11 of them were added as a result of an updated systematic search. Table 2 summarizes the main characteristics of the included studies
Figure 1
Figure 1. Flow diagram of the studies included in the systematic review according to PRISMA.
Table 2
Table 2. General characteristics of the studies included in the systematic review and meta-analysis.
3.2 Initial characteristics and quality assessment
32 studies were included in this meta-analysis. These studies were published between 2010 and 2024. We have discovered and added 11 new studies. 3 scales were used to assess the methodological quality of articles: Newcastle-Ottawa, NIH quality assessment tool for case series studies and Cochrane Risk of Bias (ROB) 2.0 tool. The presented research quality was predominantly low and average (Table 2).
3.3 Clinical trial
3.3.1 Evaluation of the effectiveness of the procedure according to the mRECIST criteria
The effectiveness was assessed according to the mRECIST criteria: Complete Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD). And was analyzed in two groups (455 patients with DEB-TACE and 502 cTACE patients).
The complete response in the DEB-TACE group was obtained in most cases compared to cTACE (310/1248) versus (260/1365) (RR, 1.77; 95% CI, 1.32 to 2.37; p=0.0001; I2 = 64%; random effects model (Figure 2).
Figure 2
Figure 2. Forest plot of the complete response rate (CR) according to the mRECIST criteria.
A partial response was also more often recorded in the DEB-TACE group (509/1248) versus (440/1365) (RR, 1.29; 95% CI, 1.17 to 1.43; p <0.00001; I2 = 33%; fixed effects model) (Figure 3).
Figure 3
Figure 3. Forest plot of partial response rate (PR) according to mRECIST criteria.
Stabilization of the disease prevailed in the cTACE group (238/1248) than in the DEB-TACE 355/1365 group (RR, 0.72; 95% CI, 0.57 to 0.91; p=0.006; I2 = 58%; random effects model) (Figure 4).
Figure 4
Figure 4. Forest plot of the frequency of Stable Disease (SD) according to mRECIST criteria.
Disease progression was 310/1365 (22.7%) in the cTACE group and 191/1248 (15.3%) in the DEB-TACE group (RR, 0.63; 95% CI, 0.54 to 0.74 p <0.00001; I2 = 20%; fixed effects model) (Figure 5).
Figure 5
Figure 5. Forest plot of the frequency of Progressive Disease (PD) according to the mRECIST criteria.
3.3.2 Overall survival rate
Information on overall survival is presented in 22 studies. The analysis obtained a statistically significant result in the form of better overall survival in the DEB-TACE group over cTACE (MD, 3.54; 95% CI, 2.10 to 4.98; p <0.00001; I2 = 41%; random effects model) (Figure 6).
Figure 6
Figure 6. Forest plot of overall survival.
3.3.3 Progression-free survival
The analysis obtained a statistically significant result in the form of better progression-free survival in the DEB-TACE group over cTACE (MD, 3.07; 95% CI, 1.66 to 4.49; p <0.0001; I2 = 51%; random effects model) (Figure 7).
Figure 7
Figure 7. Forest plot of progression-free survival.
3.3.4 Complications
17 studies reported complications after treatment 284/1122(25.31%) in the DEB-TACE group and 317/1117 (28.38%) in the cTACE group (RR, 0.93; 95% CI, 0.72 to 1.19; p=0.55; I2 = 72%; random effects model (Figure 8).
Figure 8
Figure 8. Forest plot of complications identified after hospitalization.
3.4 Evaluation of the publication bias
The estimation of the publication bias for each research parameter was performed using a visual analysis of the funnel diagram. The studies were almost symmetrically distributed on both sides of the vertical line, which indicates a relatively small distortion of publications (Figures 9, 10).
Figure 9
Figure 9. Funnel-shaped diagrams of tumor efficacy. (A) Complete Response. (B) Partial Response. (C) Stable Disease. (D) Progressive Disease .
Figure 10
Figure 10. Funnel-shaped diagrams of OS (A), PFS (B), complications after treatment (C).
4 Discussion
In recent years, indications for the TACE procedure have expanded. Starting from treatment as a first-line for the intermediate stage of HCC and ending with palliative care for late-stage patients (14). Various embolic agents for transarterial embolization have been developed, the improvement of the properties of which improved clinical results (7) and dictated the need to study the dependence of the drug delivery method and its effectiveness. Previous meta-analyses (15–18) did not demonstrate definitive conclusions and led to the continuation of the publication of comparative clinical studies (19–21). Our meta-analysis is a summary of the intermediate outcome of these efforts.
According to the results of our study, it was revealed that patients in the DEB-TACE group had a clinically and statistically significantly better radiological tumor response according to the mRECIST criteria compared with cTACE. The overall survival and progression-free survival rates were significantly higher in the DEB-TACE group. At the same time, DEB-TACE did not have an increased complication rate compared to cTACE. The results obtained in the DEB-TACE group may influence the selection of patients for surgical resection, transplantation and chemotherapy line.
Previous meta-analyses comparing treatment responses between DEB-TACE and cTACE in HCC have yielded contradictory results (15–18), which is probably caused by differences between the included studies and population heterogeneity. The initial meta-analysis by Wang et al. (2020) (16) did not reveal any differences in overall survival, radiological response, and complication rates in the cTACE and DEB-TACE groups. Subsequently, Bzeizi et al. (2021) (17) evaluated the safety profile and found that DEB-TACE is associated with a better objective response (CR+PR) (OR: 1.33, 95% CI: 0.99–1.79, p<0.01), lower mortality (OR: 0.32, 95% CI: 0.16-1.17, p=0.04), fewer side effects (OR: 0.74, 95% CI: 0.24-2.24, p<0.01). However, the safety results were based on very limited data. In a meta-analysis by Wang et al. (2023) (15), the best tumor response (OR) was obtained in the DEB-TACE group (RR: 1.27, 95% CI: 1.08–1.48; p = 0.003). The overall survival time was slightly longer in the DEB-TACE group (RR: 1.05, 95% CI: 0.99–1.11, p=0.08), but the result was not statistically significant. The incidence of adverse events was slightly higher in the cTACE group (RR: 1.11, 95% CI: 0.99–1.26; p=0.08). Liang et al. (2021) (18) showed that patients who underwent DEB-TACE had the best complete response (CR) (OR: 2.00, 95% CI: 1.29–3.09, p=0.89), objective response (ORR) (OR: 2.87, 95% CI: 2.15–3.83, p=0,96). Four studies presented PFS and OS data and were included in the combined analysis. The combined results showed a tendency towards longer duration of PFS (HR: 0.86, 95% CI: 0.67–1.11, p=0.16) and OS (HR: 0.79, 95% CI: 0.59–1.07, p=0.58) with DEB-TACE compared to cTACE, although these differences did not reach statistical significance. The analysis of the safety profile revealed no differences in the frequency of adverse events.
Previous studies have not shown that DEB-TACE demonstrates a significant improvement in overall survival or tumor response rate compared to cTACE, calling into question the broader clinical benefits of this technique despite targeted drug delivery. However, the presence of a statistically significant advantage of DEB-TACE in overall survival and tumor response rate in some studies gave impetus to further research in this area, which led to the need to conduct an updated meta-analysis. Our work is the result of efforts and summarizing the results of previous research. The results obtained are statistically and clinically significant. The radiological response of the tumor in all four parameters CR, PR, SD, PD in the DEB-TACE group showed the best response (RR, 1.77; 95% CI, 1.32 to 2.37; p =0.0001; I2 = 64%; RR, 1.29; 95% CI, 1.17 to 1.43; p <0.00001; I2 = 33%; RR, 0.72; 95% CI, 0.57 to 0.91; p =0.006; I2 = 58%; RR, 0.63; 95% CI, 0.54 to 0.74 p <0.00001; I2 = 20%; respectively). The overall survival rate during the DEB-TACE procedure was higher by 3.54 months (p <0.00001), and progression-free survival (PFS) by 3.07 months (p <0.0001), respectively. At the same time, the incidence of complications was comparable in both groups. Although, in some cases DEB-TACE can cause more serious side effects such as bile duct damage (60, 61). Controlled, sustained drug release can lead to prolonged local toxicity, which should be considered when administering DEB-TACE (62).
The results obtained during the meta-analysis can significantly affect the practice of using TACE. Thus, when using TACE as a Bridge therapy, in order to reduce tumor progression and the frequency of patients dropping out of the waiting list for liver transplantation, the overall survival of the patient is crucial. Choosing DEB-TACE technology can clinically significantly increase the survival time and increase the chances of liver transplantation. The best radiological response in the DEB-TACE group can be used in down-standing therapy to lower the tumor stage, which can increase the patient’s chances of resection surgery. The radiological response and increased survival time in the DEB-TACE group can significantly affect the use of antitumor drug therapy, changing the choice of therapy line, the algorithm of further management and the timing of follow-up. And also better integrate the use of image segmentation with deep learning technologies in the evaluation of treatment results (58, 59).
There are a number of fundamental limitations in our work. Most of the studies were not randomized and were retrospective in nature, which can lead to a variety of systematic biases, including selection bias, attrition bias, reporting bias and other systematic and random errors. In the included trials, patients were selected according to the BCLC classification with stages A and B. Some studies included only patients in stage B, while others included both B and A. These selection criteria may influence the heterogeneity of the patient groups, which may affect prognosis and overall survival rates. Many aspects of the technical implementation of both types of chemoembolization were not taken into account in the meta-analysis process. The type of embolizing agent material leads to a different ability to adsorb the chemotherapy drug and retain it for a long time in the bloodstream during embolization, which affects the local concentration of the chemotherapy drug and systemic toxicity. In addition, DEB-TACE may require more precise planning and monitoring because of the sustained release mechanism of the beads and the possibility of embolization complications. Furthermore, the size of the emboli reflects the selectivity of delivery of the chemotherapy drug to the tumor, determining the degree of ischemia of healthy tissue. While DEB-TACE offers the advantage of customizable bead sizes, selecting the wrong size can lead to suboptimal outcomes, including inadequate embolization or excessive tissue ischemia (53, 54). However, given the different size of the emboli used, we did not consider this factor in our analysis. Further studies are needed to assess the risks of non-targeted obstruction (55). In addition, in some clinical cases, a differentiated approach to transarterial chemoembolization techniques is required. For example, DEB-TACE releases chemotherapeutic agents in a controlled manner, but this may limit the extent of drug distribution compared to the oil-based emulsions used in cTACE. It may also affect treatment efficacy in larger or more vascularized tumors (56, 57). The chemotherapy drug group also affects the level of response to HCC. Systemic administration of different groups of drugs causes a heterogeneous tumor response. Local administration of the same drugs can similarly lead to different changes in tumor cells, which can affect the overall survival and radiological response (22, 23). These features were not taken into account during the meta-analysis, and there was significant heterogeneity in the presented works with respect to the emboli and chemotherapeutic drugs used. In addition, DEB-TACE uses drug-eluting beads, which are more expensive than the materials used in cTACE. This may make it less affordable in resource-limited settings. This should be taken into account when comparing treatment effects and planning oncology programs. Another limitation of our research was the analysis of publications in English only.
5 Conclusion
The results of the meta-analysis revealed clinically significant advantages of DEB-TACE in comparison with cTACE. Being comparable in the frequency of complications, DEB-TACE demonstrated the best results in the radiological response of the tumor to the therapy, in terms of overall survival and progression-free survival, which may affect the selection of patients for surgical treatment, as well as the choice of a line of chemotherapy. Thus, DEB-TACE may have an advantage over сTACE in increasing the overall life expectancy of patients with HCC.
The data obtained as a result of the meta-analysis are subject to distortions and systematic errors due to the small sample size, lack of randomization and the predominantly retrospective nature of the studies. To improve the methodological quality of studies, as well as an objective comparison of the effectiveness of DEB-TACE and cTACE, it is necessary to conduct prospective randomized trials on a large cohort of patients comparing the effectiveness and safety of these procedures in patients with HCC.
Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Author contributions
TC: Investigation, Visualization, Writing – original draft. RP: Writing – original draft, Writing – review & editing. ED: Data curation, Project administration, Software, Writing – review & editing. VS: Conceptualization, Data curation, Supervision, Writing – review & editing. RG: Methodology, Project administration, Supervision, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.
Acknowledgments
We thank the academic committee of School of Medicine and Life Sciences Far Eastern Federal University.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
Publisher’s note
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Keywords: transarterial chemoembolization, drug-eluting beads, hepatocellular carcinoma, systematic review, meta-analysis
Citation: Chernyshenko T, Polkin R, Dvoinikova E, Shepelev V and Goncharuk R (2025) Drug-eluting beads transarterial chemoembolization vs conventional transarterial chemoembolization in the treatment of hepatocellular carcinoma in adult patients: a systematic review and update meta-analysis of observational studies. Front. Oncol. 14:1526268. doi: 10.3389/fonc.2024.1526268
Received: 11 November 2024; Accepted: 31 December 2024;
Published: 12 February 2025.
Edited by:
Francisco Tustumi, University of São Paulo, BrazilReviewed by:
David Sacerdoti, University of Verona, ItalySarada Prasad Dakua, Hamad Medical Corporation, Qatar
Copyright © 2025 Chernyshenko, Polkin, Dvoinikova, Shepelev and Goncharuk. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Roman Polkin, cm9tYW4ucG9sa2luQGdtYWlsLmNvbQ==