|Year : 2020 | Volume
| Issue : 2 | Page : 379-386
Microwave ablation versus other interventions for hepatocellular carcinoma: A systematic review and meta-analysis
Rui Cui1, Jie Yu2, Ming Kuang3, Feng Duan4, Ping Liang2
1 Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853; Department of Ultrasonography, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510000, China
2 Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
3 Division of Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road 2, Guangzhou 510080, China
4 Department of Interventional Radiology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853, China
|Date of Submission||11-Jun-2019|
|Date of Decision||09-Nov-2019|
|Date of Acceptance||15-Nov-2019|
|Date of Web Publication||28-May-2020|
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853
Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing 100853
Source of Support: None, Conflict of Interest: None
We aim to evaluate the efficacy and safety of microwave ablation (MWA) versus other treatment modalities for hepatocellular carcinoma (HCC). This study was registered in Prospero (registration number CRD42017057046). A complete electronic search was conducted for studies on MWA versus other interventions for HCC using PubMed, EMBASE, Cochrane Library databases, and ISI Web of Science. Randomized and non-randomized clinical trials were included. Data on technical efficacy, local tumor progression (LTP), overall survival (OS), progression-free survival (PFS), and major complications were extracted from included studies and combined to be analyzed via random effects models. OS was set as the primary outcome measure. Fifteen clinical studies were identified. When comparing MWA with radiofrequency ablation (RFA), no significant difference was found in 3-year OS rates (odds ratio [OR] 0.94, 95% confidence interval [CI] 0.66–1.34, P = 0.74), 5-year OS rates (OR 0.83, 95% CI 0.58–1.18, P = 0.29), 3-year PFS rates (OR 1.05, 95% CI 0.77–1.43, P = 0.74), 1-year LTP rate (OR 1.28, 95% CI 0.52–3.18,P = 0.59), technical efficacy rate (OR 1. 35, 95% CI 0. 85–2.15, P = 0.20), and major complication rate (OR 1.04, 95% CI 0.56–1.93, P = 0.90). When comparing MWA with hepatic resection, the 3-year OS rate was not significantly different (OR 0.89, 95% CI 0.59–1.35, P = 0.59). Compared with RFA and hepatic resection, MWA showed similar safety and efficacy for HCC, especially in OS rate and PFS. However, high-quality clinical trials are needed to validate the superiority of MWA.
Keywords: Hepatocellular carcinoma, meta-analysis, microwave, overall survival, progression-free survival
|How to cite this article:|
Cui R, Yu J, Kuang M, Duan F, Liang P. Microwave ablation versus other interventions for hepatocellular carcinoma: A systematic review and meta-analysis. J Can Res Ther 2020;16:379-86
|How to cite this URL:|
Cui R, Yu J, Kuang M, Duan F, Liang P. Microwave ablation versus other interventions for hepatocellular carcinoma: A systematic review and meta-analysis. J Can Res Ther [serial online] 2020 [cited 2020 Jul 5];16:379-86. Available from: http://www.cancerjournal.net/text.asp?2020/16/2/379/285185
| > Introduction|| |
Hepatocellular carcinoma (HCC) has been a serious threat to human health for a long time due to its high morbidity and mortality. Although thefirst-line treatment option remains hepatic resection for patients with early-stage HCC, thermal ablation is becoming a widely accepted treatment modality. In the past two decades, with the advancement of technology, image-guided local thermal ablation has promoted an increase in the number of treatment modalities., Percutaneous microwave ablation (MWA), a thermal ablation techniquefirst described in 1994, showed promising results due to its satisfactory treatment controllability and overall coagulation performance. Until now, there have been 4 meta-analysis,,,, published between 2015 and 2017, comparing MWA with radiofrequency ablation (RFA) for HCC. However, these reviews included studies issued prior to October 2015. In recent years, 2 clinical trials, with large sample sizes comparing MWA with RFA for HCC were published, providing new evidence for the comparison. Regarding comparison between MWA and hepatic resection, although only one meta-analysis has been published, it includes a comparative study regardless of the guidance way in MWA (ultrasound, computed tomography, or during the operation), which leads to increase in heterogeneity of the included studies and affects the accuracy of the results. Moreover, there is a paucity of systematic reviews on the comparison of MWA versus transcatheter arterial chemoembolization (TACE) and other local therapies recommended in guidelines. Therefore, focusing on ultrasound-guided percutaneous MWA, we performed this meta-analysis and systematic review to make a more comprehensive and robust assessment of the comparison between MWA and other interventions for HCC.
| > Materials and Methods|| |
A protocol for literature search, study selection, and analysis methods was explicitly designed in advance and can be accessed in Prospero (http://www.crd.york.ac.uk/prospero, registration number CRD42017057046). This meta-analysis was conducted based on the Cochrane Handbook and the PRISMA guidelines. In view of the nature of this study, which was a meta-analysis, it was exempt from obtaining informed consent and Institutional Review Board Approval.
Criteria for including studies
Eligible studies were randomized and nonrandomized clinical trials comparing treatment effects of MWA with those of any other interventions in HCC. Language, publication status, and blinding were not limited. All HCC patients without extrahepatic malignant manifestation, vascular invasion, or contraindications for MWA were included. Studies without comparative analysis involving MWA were excluded. For two included studies with overlapping patient population, only the one providing complete data of survival was included.
Search strategy, study selection, and assessment of studies
A systematic electronic literature search was conducted using the databases of Pubmed, Embase, Cochrane Library, and ISI Web of Science (Science Citation Index Expanded) from 1994 to 15 February 2017. To identify comparative trials involving MWA in a comprehensive, appropriate text words and subject headings were used including “microwave,” “radiofrequency,” “hepatectomy,” “liver transplantation,” “high-intensity focused ultrasound,” “laser,” “cryoablation,” “ethanol,” “acetic acid,” “TACE,” “radiotherapy,” “chemotherapy,” and “HCC.” The entire search strategy can be accessed on Prospero (http://www.crd.york.ac.uk/prospero, registration number CRD42017057046) on request. Conference abstracts of 5 oncological and hepatological societies (AASLD, APASL, ASCO, EASL, and ESMO) were also manually searched. One researcher collected all the potentially relevant studies. Two other researchers independently selected eligible trials, and disagreements were solved by discussion.
The quality of the eligible trial was evaluated via the Downs and Black quality assessment scale. This scale contains 27 evaluative criteria on reporting, power, and validity (including risk of bias) for each study.
A data extraction list was designed, pilot-tested, and refined accordingly. One researcher extracted the data from included studies, while another researcher verified these data. Missing data were supplemented after contacting the authors of the relevant studies. Extracted data included: (1) characteristics of patients in the study (including age, sex, Child-Pugh Class, nodule number, maximal diameter), diagnostic criteria, inclusion criteria and exclusion criteria; (2) therapeutic approach and relevant device system; (3) outcome measurement including technical efficacy, local tumor progression (LTP), overall survival (OS), progression-free survival (PFS), major complications, and duration of hospitalization. Technical efficacy was defined as the achievement of “complete ablation” according to contrast-enhanced computed tomography (CT) or contrast-enhanced ultrasound after the last course of the planned protocol. LTP was defined as the appearance of carcinoma on the edge of the ablation area after adequate ablation, confirmed via imaging criteria. Major complications included events leading to morbidity that substantially increased the level of care or lengthened hospital stay. For combining and analyzing the extracted data, percentages in the included studies were converted to whole numbers.
The primary outcome measure was OS. The Mantel-Haenszel test was chosen to compare data between different intervention groups. Statistical heterogeneity of trial results was tested by Cochrane's Chi-square test (P = 0.10 being set as the significance threshold) and I2 statistic (value higher than 50% suggesting significant heterogeneity). In order to confirm the assumption of our approach, sensitivity analysis was conducted with data from studies with relatively higher quality (scored ≥20 on the quality assessment scale). All the data were analyzed with the use of Review Manager 5.0 (Copenhagen, the Nordic Cochrane Centre, the Cochrane Collaboration).
| > Results|| |
In 2454 identified references, 872 duplicates were removed. After a preliminary screening of the remaining references from titles and abstracts, 80 references were selected. Then 65 references were excluded because of insufficient data, overlapping recruitment periods, or involvement of laparoscopic thermal ablation. Finally, 15 clinical studies were included in this meta-analysis,,,,,,,,,,,,,, and no additional studies were identified from the manual search [Figure 1].
Characteristics of included studies
We included 15 trials involving 2458 participants in this review. Characteristics of these studies are shown in [Table 1]. Four of them were randomized control trials (RCTs) and 11 of them were nonrandomized trials. In terms of comparing MWA versus laser, cryoablation, radiotherapy, chemotherapy, liver transplantation, high-intensity focused ultrasound or percutaneous acetic acid injection, no trial was identified. Eleven trials with 1892 participants compared MWA with RFA, two trials with 414 participants compared MWA with hepatic resection, one trial with 90 participants compared MWA with ethanol ablation (EA), one trial with 62 participants compared MWA with TACE. Except for 3 studies,, including HCC patients in Barcelona Clinic Liver Cancer (BCLC) stage A-B, the other 13 studies recruited HCC patients in BCLC stage 0-A.
The mean quality score was 20 based on the Downs and Black assessment scale. These studies scored relatively poorly due to failure to blind patients to received treatment (15/15), failure to state the method of concealing intervention assignment (14/15), and insufficient power in detecting clinical effects (13/15).
Therefore, we summarized the intervention effects of the comparison between MWA and RFA, MWA and hepatic resection, MWA and TACE, and MWA with EA.
Microwave ablation versus radiofrequency ablation
When comparing between MWA and RFA, 11 trials, were eligible. Technical efficacy was reported in nine trials. No significant heterogeneity was identified among these trials (I2 = 0%, P = 0.64). The odds ratio (OR) of the RCTs and non-RCTs group both suggested similar technical efficacy between MWA and RFA [Figure 2], yielding an overall OR of 1.35 (95% confidence interval [CI] 0.85–2.15, P = 0.20). Via visual examination of the funnel plot [Figure S1]a, there was no significant publication bias. Sensitivity analysis of 6 studies [Figure 3] with higher quality showed no significant trend in favor of the MWA group (OR 1.12, 95% CI 0.64–1.97, P = 0.69) and the heterogeneity is not significant (I2 = 0%, P = 0.71).
|Figure 2: Forest plot of technical effectiveness (MWA = Microwave ablation; RFA = Radiofrequency ablation)|
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|Figure 3: Forest plot of technical effectiveness rate from sensitivity analysis|
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Only 3 studies,, reported 1-year LTP rate. Heterogeneity was not significant among these studies (I2 = 8%, P = 0.34) and the OR was not significantly in favor of RFA (OR 1.28, 95% CI 0.52–3.18, P = 0.59).
In terms of 3-year OS, seven studies were available [Figure 4]. OR obtained by random effect model (OR 0.94, 95% CI 0.66–1.34, P = 0.74) showed no significant trend in favor of RFA with acceptable heterogeneity (I2 = 40%, P = 0.12). As shown in [Figure S1]b, the funnel plot is symmetrical without bias. In sensitivity analysis with higher quality, OR was 0.93 (95% CI 0.65–1.33, P = 0.69) with mild heterogeneity (I2 = 27%, P = 0.25). As for 5-year OS rates, only 3 studies,, were available and overall OR from meta-analysis was 0.83 (95% CI 0.58–1.18, P = 0.29) with nonsignificant heterogeneity (I2 = 23%, P = 0.27).
Five studies reported the 3-year PFS [Figure 5] and the OR from the analysis was 1.05 (95% CI 0.77–1.43, P = 0.74) with mild heterogeneity (I2 = 35%, P = 0.19).
Eight studies evaluated the major complication rate [Figure 6]. OR obtained by random effect model was 1.04 (95% CI 0.56–1.93, P = 0.90) without significant heterogeneity (I2 = 0%, P = 0.47). Funnel plot for publication bias is shown in [Figure S1]c and no significant publication bias was found. Sensitivity analysis conducted on 6 studies that scored 20 or more points showed OR did not remain significantly in favor of RFA (OR 1.08, 95% CI 0.52–2.24, P = 0.83) without significant heterogeneity (I2 = 5%, P = 0.39).
Only one trial reported a lower hospitalization cost in MWA group (T RMB 43.2 ± 14.5 vs. 50.3 ± 9.8, P < 0.001).
Microwave ablation versus hepatic resection
Only 2 nonrandomized studies, made the comparison between MWA and hepatic resection. Meta-analysis of the two studies showed no significant difference between the two treatment modalities in 3-year OS rate (OR 0.89, 95% CI 0.59–1.35, P = 0.59) and no significant heterogeneity was found (I2 = 0%, P = 0.91). Although the lengths of follow-up of LTP rate are different in the two studies, both of them supported that LTP rate were significantly higher in MWA group compared with hepatic resection (Zhang's, 16.2% vs. 4.9%, P = 0.006; Shi's, 10.3% vs. 2.8%, P = 0.026). Moreover, Zhang's study reported that compared with the MWA group, major complications were more common in the hepatic resection group (22.1% vs. 5.9%, P = 0.004).
Microwave ablation versus other interventions
In terms of the comparison between MWA versus EA and MWA versus TACE, only one study was available. In Seki's study comparing MWA and EA, subgroup analysis was conducted for patients with well and poor differentiation degrees. Although the overall 5-year OS rate were not significantly different between the two groups for patients with well-differentiated HCC, for patients with moderately or poorly differentiated HCC, 5-year OS rate in the MWA group was significantly higher (78% vs. 35%, P = 0.03).
In Abdelaziz's study comparing MWA and TACE, MWA showed a higher rate in both technique efficacy (75% vs. 40.6%, P = 0.005) and 1-year OS rate (OR 3.15, 95% CI 1.06–9.36, P = 0.004).
| > Discussion|| |
During the last two decades, several techniques for local ablation have been developed and accepted for clinical application. For early-stage HCC patients ineligible for surgical resection, local tumor ablation is recommended., In recent years, with the increasing number of published studies, MWA has been proposed in the guidelines,, as an effective intervention for HCC patients. However, prior to MWA, other interventions, including resection, liver transplantation, image-guided RFA, and TACE, were all effective therapies recommended in the guidelines. Hence, in order to obtain better evidence on the effectiveness of MWA for HCC compared to other interventions, we conducted a meta-analysis.
In view of the few relevant RCTs, this meta-analysis included both RCTs and non-RCTs. Unlike previous meta-analyses, we did not use the Newcastle–Ottawa scale for quality assessment, since it is only used for quality assessment of non-RCTs. In order to ensure proper quality assessment, we applied the Downs and Black quality assessment scale. It was regarded as a suitable assessment tool to simultaneously assess the quality of RCTs and non-RCTs.
Regarding technical efficacy, our results showed that the differences between MWA and RFA were not significant. According to previous research, MWA showed several advantages over RFA, including better heating, larger ablation volume, and less susceptibility to heat-sink effects., However, results from this study seemed insufficient to demonstrate the higher thermal efficacy of MWA. Possible reasons are as follows:
First, in different clinical trials, the energy delivery system equipment for MWA and RFA is different. Second, comparative analysis for relatively larger tumors group (such as 3–4 cm, 4–5 cm or 3–5 cm) between both the thermal ablation techniques are absent.
Regarding the major complication rate, no significant differences were found between MWA and RFA, suggesting that MWA is as safe as RFA. This is consistent with previous studies which reported the low major complication rate of thermal ablation., Only one trial reported a higher complication rate in the hepatic resection group compared with that in the MWA group. In fact, hepatic resection is not an optimal choice for patients with a deeply-located lesion or multi-lobar tumors considering the excess loss of normal liver tissues and increased amount of intraoperative blood loss.
As for the LTP rate, in studies comparing MWA and RFA, most of them (8/11) reported an overall LTP rate for their entire follow-up period, and the lengths of follow-up periods differed in these trials. In order to ensure the comparability of the data, we extracted the data from 3 trials reporting the 1-year LTP rate. Therefore, due to the limited information available, we do not consider the result be robust. In two studies comparing MWA and hepatic resection, both reported a higher LTP rate in MWA. A possible reason is the different safety margin of the two interventions. In hepatic resection, the safety margin is wider, which may reduce the chances of LTP.
Regarding OS, our result showed a comparable effect of MWA with hepatic resection and RFA in treating early-stage HCC. Besides, for the PFS rate, the result of this analysis also suggested the comparable effectiveness of MWA to that of RFA. This evidence may favorably support that MWA has potential to be incorporated into standard treatment guidelines for HCC.
There are several limitations in our study. First, the simultaneous analysis of both randomized and nonrandomized studies would inevitably lead to selection bias. Second, comparative studies with insufficient samples were not discarded. Since some of these studies were conducted in the early period of MWA application, it would have been nearly impossible for them to fulfill the ideal sample size. Third, we did carry out stratification analysis in terms of tumor size or location since related information is not available in most studies. Forth, due to the limited amount of relevant studies, we cannot definitely confirm the superiority of MWA compared to other interventions.
Despite these limitations, some insights from this systematic review should be noted. First, in the comparative study between MWA and RFA, an increase of sample size without improvement in statistical analysis will not contribute to the value of the study. Hence, for future large-sample RCTs, a better study design and more sufficient subgroup analysis should be prioritized. Second, despite the difficulty to conduct RCTs for comparison between MWA and other interventions, more prospective cohort studies with serious follow-up procedures should be initiated, and Propensity Score Analysis may be helpful to minimize defects of these studies and provide accurate comparisons by simulating RCTs. Third, to ensure the reliability and standardization of the comparative study, it is necessary to establish statistical indicators according to terminology and reporting criteria in the study design stage. Forth, outcome variables such as LTP rate and OS rate should be based on standardized length of follow-up to ensure the comparability of data. Fifth, according to research on surgery for HCC, underlying liver disease has been proved to have an influence on patients' prognosis.,,, Therefore, data on the etiological profile and hepatitis viral replication should be considered as indispensable clinical baseline information when conducting comparative studies on MWAs. Last, in order to provide better practical references for deciding the optimal management of HCC, in the context of sufficient sample cases, subgroup analysis should be conducted on the survival result taking into account different sizes and location of the tumor.
| > Conclusion|| |
MWA showed similar safety and technical efficacy compared with RFA in treating HCC. Moreover, for early-stage HCC patients, MWA was comparable to RFA and hepatic resection in OS rate and PFS. However, it is imperative to conduct higher quality clinical studies to validate the superiority of MWA, promote its clinical application, and broaden its indication.
This work was supported by Grants 81627803, 81971625 and 91859201 from the National Scientific Foundation Committee of China, Grant JQ18021 from the National Scientific Foundation Committee of Beijing and Fostering Funds of Chinese PLA General Hospital for National Distinguished Young Scholar Science Fund. Grant 2018ZX10723-204 from the National Key R&D Program of Ministry of Science and Technology of China.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]