Transarterial chemoembolization combined with radiofrequency ablation in the treatment of hepatocellular carcinomas larger than 5 cm

Aim: This meta-analysis was designed to compare the effectiveness of the combination of transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) vs. that of TACE alone in hepatocellular carcinoma (HCC) tumors larger than 5 cm. Methods: PUBMED, CNKI, and CBM were searched for all related randomized controlled trials (RCTs) up until October 22, 2018. Eleven studies were identified that compared TACE with RFA vs. TACE alone for HCC treatment. Tumor response rate, the proportion of patients with either complete or partial shrinkage of tumors, and survival rate were the major evaluation indices. Results: Meta-analysis data revealed that TACE with RFA showed significantly better tumor response rate (risk ratio (RR) = 1.452, 95% confidence interval (CI): 1.308-1.610, P < 0.001) and 1-year overall survival rate (RR = 1.412, 95% CI: 1.249-1.596, P < 0.001) than that of TACE alone treatment. Conclusion: The data of our study indicates that TACE combined with RFA in the treatment of HCC larger than 5 cm is an effective comprehensive interventional therapy.


INTRODUCTION
Hepatocellular carcinoma (HCC) is one of the most common and malignant tumor in the world, with an annual incidence of over 700,000 patients worldwide [1] .As the symptoms of HCC often do not present in the early stages, most patients are in the middle and late stage at the time of diagnosis, among which only 20%-30% of patients have the chance to receive surgical resection or liver transplantation [2] .Patients with large tumors that cannot undergo surgical resection or liver transplantation are usually offered comprehensive treatment based on transarterial chemoembolization (TACE) [3,4] .However, the long-term outcome of treating HCC with TACE alone is not ideal, due to incomplete tumor necrosis [5,6] .Studies have shown that TACE combined with RFA in the treatment of HCC is more efficacious than either TACE or RFA alone [7,8] .Nevertheless, some studies have reported contradictory results [9,10] .Of note, the sample sizes of these studies are small and the observations need further validation.Additionally, it is unknown whether this combined treatment is more effective than single modality treatment for HCC tumors larger than 5 cm.Therefore, in order to determine whether TACE plus RFA is more effective in patients with HCC than TACE alone, this current meta-analysis was performed to compare the efficacy of TACE plus RFA with TACE monotherapy.This comparison is expected to provide more convincing evidence for HCC patients having to choose between two methods.In this study, the clinical efficacy of TACE combined with RFA was compared with that of TACE alone in the treatment of HCC larger than 5 cm, to provide evidence to guide clinical practice.

Search methods and quality assessment
As of October 22, 2018, randomized controlled trials (RCT) comparing the clinical efficacy of TACE with RFA vs. TACE alone in the treatment of HCC was performed using a computerized search on PUBMED, Chinese Journal Full-text Database (CKNI), and CBM.Search terms include "Liver Neoplasms/therapy" [Mesh], "Chemoembolization, Therapeutic" [Mesh], "TACE", "Radiofrequency ablation".The literature language is limited to Chinese and English.
Evaluation of literature quality (including literature data extraction and quality scoring) was carried out by the authors.According to the Jadad quality standard, the scoring method is as follows.Whether it is randomly assigned: 2 points is awarded for detailed random allocation, 1 point when it was not specifically described, and 0 point if it was not mentioned.Whether analysis was blinded, 2 points for double-blind, 1 point for blinding without detailed description, 0 point for open trial.Whether there was a detailed reason for loss of follow-up: 1 point for yes, 0 point for no.High quality research literatures are those that received 3 to 5 points; and low quality literatures are those that received 0 to 2 points.

Inclusion criteria
Literature reports were eligible for inclusion if: (1) they are domestic or international publications, that compared the clinical efficacy of TACE combined with RFA vs. TACE alone in the treatment of intermediate and advanced staged HCC; (2) they report complete case data; (3) the results of the study include tumor response rate; (4) the maximum diameter of tumor lesions is greater than 5 cm; (5) the clinical study design is consistent with that of a RCT.

Exclusion criteria
Literature reports were excluded if: (1) they are review articles or case reports, are of poor literature quality as evaluated by the above method, or have no proper controls; (2) they are animal studies; (3) there are duplicate reports of similar content by the same author, or if there are too few patients and unclear data; (4) the maximum diameter of tumor lesions is less than 5 cm.

Data acquisition
The literature and extracted the data were screened independently by authors.After articles were screened by their titles and abstracts, they were filtered by reading the full text.During the screening process, the literature was selected in strict accordance with the set inclusion and exclusion criteria.After the screening was completed, the articles were read again to verify that they meet the requirements.

Statistical methods
Statistical analysis was performed using Comprehensive Meta Analysis V2.Before the meta-analysis, the heterogeneity I 2 test of each test result was performed.If the homogeneity of each test included in the study was good (P > 0.05), the fixed effect model was used.If heterogeneity existed, the random effect model was used.A funnel chart was used to evaluate the bias risk of the inclusion test, and asymmetric funnel charts suggest that there may be publication bias.

Literature search results
Manual search of electronic databases identified a total of 1,487 studies.After checking for duplicates, there were 1,304 remaining.A large number of these studies were excluded based upon our inclusion and exclusion criteria, leaving only 11 articles to be included in the meta-analysis [Figure 1 and Table 1].

Tumor response rate
There were 11 reports with tumor response rate data comparing TACE with RFA vs. TACE alone.Tumor response rate was measured by the proportion of patients with either complete or partial shrinkage of tumors.Since the heterogeneity test had a P = 0.983, the fixed-effects model was used.The results showed that the tumor response rate of TACE with RFA in the treatment of HCC was significantly superior to TACE alone [risk ratio (RR) = 1.452, 95%CI: 1.308-1.610,P < 0.001, I 2 = 0%] [Figure 2].
HCC is a serious global health problem and the third most common cause of cancer death.Most patients with HCC are diagnosed with intermediate or advanced stage, with baseline liver dysfunction, intrahepatic metastasis or excessive load, and are not suitable for surgical resection.The established local treatment options include TACE, RFA, ethanol injection, and microwave coagulation; however, it is still unclear which method is the most efficacious [23][24][25] .In the 2018 NCCN Clinical Practice Guidelines for Malignancies, TACE is recommended as a first-line palliative treatment for unresectable HCC.However, the tumor response rate and survival rate of patients treated with TACE alone are not ideal.Therefore, the treatment of TACE combined with other local treatment options such as RFA for comprehensive treatment is gradually being adopted.Based on our meta-analysis, combination therapy of TACE with RFA is an effective method for HCC treatment.HCC is mainly supplied by the hepatic artery.Even when the hepatic artery blood flow is blocked by TACE, the thermal coagulation effect of RFA is not affected.Thus, it increases the area of necrosis induced by RFA.Additionally, the effects of expanded ablation zones and anticancer agents on liver cancer cells during treatment may reduce the chance of tumor recurrence [26] .
This meta-analysis has some limitations.Firstly, the complications and adverse reactions of combination therapy cannot be assessed fully due to the lack of original research data.Therefore, future studies can further evaluate these indicators.Secondly, the sample size of this current meta-analysis is limited; largescale randomized controlled trials of long-term follow-up are needed to validate this result.
In conclusion, our study suggests that TACE combined with RFA is superior to TACE alone in the treatment of HCC larger than 5 cm.Patients in the combined treatment group showed significantly increased tumor response rate and survival rates compared with those treated with TACE alone.This article provided clinical and systematic evidence for the improved treatment of HCC larger than 5 cm.

Figure 2 .Figure 3 .
Figure 2. Tumor response rate of comparison TACE with RFA vs. TACE alone

Figure 4 .
Figure 4. One-year survival rate of TACE with RFA vs. TACE alone

Figure 7 .
Figure 7. Incidence of fever in the TACE with RFA group vs. TACE alone group