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Efficacy of drug-eluting bead transarterial chemoembolization (DEB-TACE) combined with radiofrequency ablation versus DEB-TACE alone in Chinese hepatocellular carcinoma patients

Abstract To compare the efficacy of drug-eluting bead transarterial chemoembolization combined with radiofrequency ablation (DEB-TACE+RFA) versus DEB-TACE alone in Chinese hepatocellular carcinoma (HCC) patients. The 28 patients receiving DEB-TACE+RFA and 74 HCC patients receiving DEB-TACE were recruited in this study. Treatment responses, progression-free survival (PFS), and overall survival (OS) were evaluated. One to 3 months after treatments, the proportion of patients achieving complete response (CR) (78.6% vs 33.8%, P <.001) and objective response rate (ORR) (92.9% vs 78.4%, P =.010) were elevated in DEB-TACE+RFA group compared with DEB-TACE group. Multivariate logistic regression displayed that DEB-TACE+RFA was an independently predicting factor for better CR (P = .006). Subgroup analysis of CR achievement illuminated that DEB-TACE+RFA disclosed better CR achievement in patients with history of cirrhosis (P <.001), tumor located in right liver (P = .003), bilobar disease (P = .013), tumor size <3.3 cm (P = .001), no portal vein invasion (P = .001), no hepatic vein invasion (P <.001), Child-pugh stage A (P <.001), Barcelona Clinic Liver Cancer (BCLC) stage 0, A-B (P <.001), abnormal alpha-fetoprotein (AFP) (P = .001) and normal AFP (P = .016). The PFSs were similar between 2 groups (P = .112), however, the OS was more prolonged in DEB-TACE+RFA group (P = .025) compared with DEB-TACE group. And subgroup analysis displayed that PFS of patients with largest nodule size >3.3 cm (P = .025) was longer and patients with unilobar disease (P = .009), and patients with no hepatic invasion (P = .019) and Child-pugh stage A (P = .037) had more favorable OS in DEB-TACE+RFA group compared with DEB-TACE group. DEB-TACE+RFA achieved better treatment responses and OS compared with DEB-TACE alone in Chinese HCC patients.


Introduction
Hepatocellular carcinoma (HCC), displaying declining incidence among younger adults (0-49) in the developed countries, is still the most frequent primary liver cancer also in younger population (below 60) in China. [1,2] As one of the top cancers with worst prognosis due to lacking symptoms at early stage, most patients are at intermediate and advanced stages at diagnosis, who can only be treated with non-potential curative therapies. [3] The management of HCC patients in addition to early stage in clinical practice now includes chemotherapy, radiotherapy, chemoradiation, local regional therapy and sorafenib, among which transarterial chemoembolization (TACE) is recommended as a standard therapy for HCC patients in Barcelona Clinic Liver Cancer (BCLC) B stage. [4] For the purpose of eliminating systemic toxicity, better standardizing the operation procedure and improving treatment responses, TACE using drug-eluting bead (DEB-TACE) is developed and applied in HCC patients since 2006, presenting better efficacy and less chemotherapy-related systemic toxicity compared with conventional TACE (cTACE). [5,6] Radiofrequency ablation (RFA) is a potential curative therapy with minimal invasion for HCC patients in early stage who are not able to receive liver transplantation or hepatectomy due to poor liver function or diffuse tumors, disclosing good tumor ablation rate, mild adverse events (AEs) and good costeffectiveness in clinical practice. [7][8][9][10] Previous studies elucidate that RFA combined with TACE is efficacious in HCC patients, nonetheless, effort and evidence of whether DEB-TACE combined with RFA (DEB-TACE+RFA) is more effective than the single use of DEB-TACE is still scarce. [11][12][13] Therefore, our study aimed to compare the efficacy of DEB-TACE+RFA versus DEB-TACE alone in Chinese HCC patients.

Patients
The 28 patients receiving DEB-TACE+RFA and 74 HCC patients receiving DEB-TACE were recruited in this study from July, 2016 to May, 2017 at the Department of Liver Cancer in Ningbo No.2 Hospital. The inclusion criteria were: (1) patients diagnosed as primary HCC following the American Association for the Study of the Liver Diseases (AASLD) guidelines; (2) age above 18 years old; (3) about to receive DEB-TACE or DEB-TACE+RFA on demand. Meanwhile, the exclusion criteria were: (4) contraindications to magnetic resonance image (MRI), computerized tomography (CT), ultrasonic technique, hepatic artery puncture or the use of Epirubicin; (5) invisible tumor; (6) ascites; (7) cardiac disease, including congestive heart failure, recent myocardial infarction, or uncontrolled arrhythmias; (8) severe liver or renal failure; (9) coagulopathy; (10) severe infection or sepsis; (11) women who were pregnant or nursing.
This study was approved by the Ethical Committee of Ningbo No.2 Hospital and conducted strictly following the Declaration of Helsinki. Written informed consents were obtained from all participants.

DEB-TACE Procedure
The 100 to 300 mm CalliSpheres Beads (CBs) (Jiangsu Hengrui Medicine Co. Ltd., Jiangsu, China) were loaded with Epirubicin (80 mg) for each DEB-TACE procedure. To start with, Epirubicin was dissolved by water for injection into solution of concentration at 20 mg/mL and stored in a 10 mL syringe afterward. Subsequently, 1 bottle of CBs was shaken and the beads suspension was extracted by a 20 mL syringe, which stood at room temperature (RT) for 5 minutes. Discarding the supernatant in the syringe and mixed the remaining CBs with drug solution by a tee joint. Lastly, non-ionic contrast agent was added in the mixture at the ratio of 1:1, which stood for another 30 mins at RT for further application.
Each DEB-TACE procedure was performed on demand according to the evaluation of the multidisciplinary team in our hospital. The detection of tumor supplying vascular was performed by digital subtraction angiography (DSA). After the tumor supplying vascular was located, a microcatheter with diameter of 2.4F (Merit Maestro, Merit Medical System, Inc., UT) was super selectively catheterized leading by a microware, using Seldinger's technique. Then CBs loaded with Epirubicin mixed with non-ionic contrast agent was injected through microcatheter by the pulse injection method at the speed of 1 mL/min. The indication of the injection end was the stasis flow of contrast agent, and another time of angiography was performed to detect the blushed tumor post 5 minutes of the delivery, and the embolization was stopped if no more blushed tumor existed.

RFA procedure
RFA was performed if HCC patients who tolerated to RFA and still had residual tumor after 1 to 3 months post-DEB-TACE, which was confirmed by image examination. The RFA was conducted under the guidance of ultrasound, which was used to detect the size and location of residual tumor. Subsequently, under general anesthesia, monopole ablation electrode was punctured at intercostal area or costal margin post local disinfection, and overlay ablation was performed on each residual tumor for 10 to 20 minutes until complete ablation of the tumor existed, and the ablation area should reach over 5 cm from the edge of the tumor.

Evaluations of treatment responses and survival
Treatment responses were evaluated by MRI or CT post 1 to 3 months after DEB-TACE or DEB-TACE+RFA according to the criteria of modified Response Evaluation Criteria in Solid Tumors (mRECIST). [14] (1) complete response (CR): the loss of any intratumoral arterial enhancement in the target nodules; (2) partial response (PR): at least a 30% decline in the sum of diameters of viable (enhancement in the arterial phase) target nodules, taking as reference the baseline sum of the diameters of target nodules; (3) stable disease (SD): any cases that do not measure up either PR or progressive disease (PD); (4) PD: an elevation of at least 20% in the sum of the diameters of viable (enhancing) target nodules, taking as reference the smallest sum of the diameters of viable (enhancing) target nodules recorded since initiation of treatment.
Objective response rate (ORR) was the proportion of patients achieving CR and PR, and disease control rate (DCR) was the proportion of HCC patients were CR, PR, and SD.
The median follow up time was 220 (range: 2-465) days and the last follow up date was November 20, 2017. Progression free survival (PFS) was the duration from treatment time to the date of disease progression or death from any cause, and overall survival (OS) is the duration from treatment time to the date of death from any cause.

Statistical analysis
Statistical analysis of our study was performed by SPSS 22.0 software (IBM Co., NY) and Graphpad Prism 6.0 software (GraphPad Software Inc). Comparison between 2 groups was determined by t test,Chi-square testorWilcoxon rank sum test.Kaplan-Meiercurves were performed to evaluate the PFS and OS. Univariate and multivariate logistic regressions were conducted to assess independent predictive value of DEB-TACE+RFA for treatment responses, and univariate as well as multivariate Cox's regression analyses were carried out for evaluating the independent predicting value of DEB-TACE+RFA for survival. P <.05 was considered significant.

Discussion
In this study, the results showed that: (1) the CR and ORR were increased in DEB-TACE+RFA group compared with DEB-TACE group, and multivariate logistic regression revealed that DEB-TACE+RFA was independently associated with increased CR;   The results in our study suggest that DEB-TACE+RFA might have a more pleasant efficacy than using DEB-TACE alone in HCC patients. RFA is a potentially curative therapy for HCC patients and displays satisfying tumor control according to numerous previous studies, which might be able to explain why DEB-TACE+RFA achieved better treatment responses in our study. [23] As to the survival profile in our study, the OS in DEB-TACE +RFA group was prolonged (mean OS 380 days vs 320 days), and there was no difference of PFS between 2 groups. In a previous prospective single-center pilot study comparing DEB-TACE+FA and DEB-TACE alone in HCC patients with cirrhosis and single tumor, the OS rate is markedly higher in patients www.md-journal.com treated by DEB-TACE+RFA, which is in accordance with our study. [22] In another single arm retrospective study, the cumulating survival rates at 1, 3 and 5 years are 90%, 50%, 27%, and the median value of survival is 37.4 months. [24] In addition, the cumulating recurrence-free survival (RFS) rates at 1, 3, and 5 years are 48%, 16%, and 16%, and the median RFS time was 10.7 months. [24] Those studies suggest DEB-TACE+RFA might be able to accomplish a satisfying survival in HCC patients. Due to the relatively short follow up time, the long-term survival was not assessed in our study; however, the results regarding survival in our study might provide information to the future studies, which could extend the follow-up time of survival in the future. There were still several limitations to our study: (1) the short follow up time resulted in that the long-term efficacy was not assessed in our study; (2) as a retrospective cohort study, there were several confounding factors in our study, such as cirrhosis and the ALP level at baseline; (3) the sample size was relatively small, which could lead to less statistical power and the magnify of some bias in our study; (4) our study was conducted in a single center, which causes selection bias. In order to further validate our results, more clinical trials which could avoid the confounding factors and bias should be conducted. Thus, a multicenter, prospective study with larger sample size and increased follow up time, or a multicenter, randomized clinical trial with larger sample size and longer follow up duration are needed in the future.
In conclusion, DEB-TACE+RFA achieved better treatment responses and OS compared with DEB-TACE alone in Chinese HCC patients.