This study represents, to the authors’ knowledge, the first documentation of statistically significant improvements in LTP for patients with liver tumors treated with MWA in comparison to RFA based on the analysis of 3531 patients in 28 studies. Specifically, the risk of LTP was significantly reduced by 30% with MWA compared with RFA when analyzing all included studies. Furthermore, if only the three RCTs are considered, the LTP was significantly reduced by 45%. Additional analyses were performed using the fixed-effects model, with exclusion of poor-quality studies, and those using an open surgical approach for ablation. These analyses demonstrated results that were congruent with the main analyses.
OS and DFS were not significantly different between the MWA and RFA treatment arms. This finding is not unexpected given the presence of underlying liver disease in the HCC population and the multimodal therapy required for colorectal liver metastasis. In fact, LTP is generally considered a better indicator of treatment effectiveness for ablative therapies than OS or DFS because of the aforementioned factors. There was one notable exception, in that one-year OS significantly favored RFA over MWA in patients with metastatic disease. This effect is driven by the results from the van Tilborg et al, 2016 study, in which patients were assigned to MWA based on tumor proximity to blood vessels or to RFA based on tumor proximity to the biliary tract, diaphragm, or intestine.25 This allocation bias may have affected our results. In addition to the current meta-analysis, Huo performed a subgroup analysis on tumor type (HCC and metastases) and found conflicting results.16 Notably, only a few studies were included in metastases populations; thus, future studies are required to further assess this subgroup effect.
Results of the subgroup analyses indicated significant differences between treatment modalities based on tumor size and tumor type. LTP was the same between MWA and RFA for tumors less than 2.5 cm, but MWA had a significant reduction of 37% in LTP when compared with RFA in tumors ≥2.5 cm. This finding is consistent with a previous meta-analysis (discussed below).18 This is also consistent with the physics of radiofrequency and microwave energies. The penetration with RFA is variable because of the heat sink effect and the insulative effect of charred tissue.8,11,58 MWA will achieve penetration of 2.0 cm, leading to larger ablation volumes than RFA.8 Thus, tumors approximately 2.0 cm in diameter should be adequately covered with margin if the tumor is precisely targeted in the center and the margin is kept to 5 mm, as is the case for HCC. Conversely, the advantages of MWA should be observed for tumors greater than 2–2.5 cm because of the greater tissue penetration. These findings raise the question of whether the overall significant results seen for LTP with MWA over RFA are solely the result of the large tumor effect. However, the present study does not completely exclude a benefit of MWA for smaller tumors since a nonsignificant reduction of 28% was observed for tumors less than 2.5 cm.
Despite the overall improvement in LTP for MWA over RFA, the risk of complications was not significantly different between groups. This finding is important since larger ablations could be perceived to have a higher risk of complications. The results of this study refute that viewpoint. Technical efficacy was also not significantly different between MWA and RFA, nor for any subgroup analysis. This result is not surprising given the limitations associated with measurement of technique efficacy by the inability of imaging to detect whether neoplastic cells within the ablation zone have been sufficiently ablated,11 by variability between assessors in such evaluations, the high rates (>80%) reported for techniques efficacy in both arms, and by continuing ablation until an adequate margin is determined. Unfortunately, this analysis was unable to assess the number of treatment courses per procedure to achieve similar technique efficacy in both treatment arms. However, in the RCT performed by Yu et al, the number of treatment courses per session (or procedure) was significantly lower in the MWA treatment arm versus the RFA arm.20 This suggests that despite similar technical efficacy rates, MWA is more efficient than RFA.
Three systematic reviews and meta-analyses have recently been published of the comparison between MWA and RFA for the treatment of HCC and/or liver metastases.15,16,18 Huo and colleagues included metastatic liver cancer studies,16 whereas they were not included by Luo and Facciorusso. Luo found that MWA and RFA had similar rates of one- and three-year survival, complete tumor ablation, local tumor recurrence, and major complications,15 which generally aligns with the results reported here. Huo and colleagues reported similar findings in their meta-analysis of both HCC and metastatic patients.16 However, our meta-analysis showed that MWA was also associated with significantly lower LTP compared with RFA. In comparison to these two systematic reviews, the current meta-analysis included several additional studies. Facciorusso and colleagues,18 whose findings were generally aligned with the other two published reviews, included only seven studies in their meta-analysis (two RCTs and 5 observational studies) and only five were in common with the 28 included in our study.32,40,45,50,55 Regarding local recurrence, Facciorusso reported significantly lower odds with MWA over RFA (OR=0.46; P=0.02) in patients with high tumor burden (>1.2 tumors per patient and/or large tumors >2.5 cm in diameter).18
This meta-analysis had broad inclusion criteria allowing for a wide variety of subgroup analyses other than tumor size and type. The results of the frequency subgroup analysis showed that the benefit of MWA over RFA was most apparent for the 2450 MHz versus the 915 MHz frequency. These results may be explained by the ability of 2450 MHz MWA systems to deliver greater amounts of power and achieve larger ablation volumes.11 A recent observational study comparing 915 and 2450 MHz MWA for ablation of lung metastases found that ablation margin size was significantly associated with the local progression rate and that 2450 MHz MWA demonstrated a significantly better local progression-free survival curve than 915 MHz MWA (P=0.048).59 Liu and colleagues did not report any differences in treatment effect when comparing these two MWA frequencies.60 The results of the tumor type subgroup analysis on HCC and metastases showed that there were no differences between MWA and RFA in HCC or metastases for technique efficacy and complications.
There are a few limitations of this meta-analysis. First, most of the included studies are observational (primarily retrospective cohort studies) and present a potential for selection bias. RFA was often used for a longer time at institutions than MWA and had a longer follow-up duration than MWA. Despite this, most studies were well balanced for baseline covariates, and some of the studies used matching to control for differences or reported regression analyses that showed the minimal impact of potential effect modifiers on treatment outcome. To control for the effect of poor study quality, studies receiving lower quality assessment scores were excluded in a sensitivity analysis. The results of these sensitivity analyses remained aligned with the main analyses. Second, there was often variability between and within studies for follow-up time; this was handled in two ways: 1) a meta-regression was performed to determine whether follow-up time had a significant effect on LTP (results showed there was no effect) and 2) studies with ≥25% difference in mean follow-up time between arms were excluded from analyses of outcomes potentially impacted by follow-up time. Third, significant heterogeneity was observed for certain outcomes, such as five-year DFS and LOS, which may have been due to variability in patient baseline characteristics, treatment parameters, and study designs across studies. As such, random-effects model, which accounts for heterogeneity, was used; sensitivity analyses were performed with a fixed-effects model. Fourth, due to the broad inclusion of this meta-analysis, there was some variability in the definitions of outcomes, particularly technique efficacy and LTP. Reporting guidelines recommend that technique efficacy (often called complete tumor ablation or complete response) should be assessed by imaging ideally one week to one month after the procedure and no later than three months afterwards.10 Thus, studies were included regardless of the terminology used to describe the outcome, as long as it was reported from one week to three months after treatment. It is unclear whether all the studies assessed treatment efficacy (ie, effective ablation of tumors) or if some assessed technical success (ie, tumors treated according to protocol),10 since these terms are sometimes used interchangeably. As well, the terminology used to define local tumor recurrence or LTP were sometimes variable. Here, we used the following definition for LTP: reappearance of tumors, within or adjacent to the ablation zone, based on that of Ahmed et al.10 This definition often allowed the inclusion of studies which labeled the outcome as LTP and studies which labeled it as local tumor recurrence (LTR). However, it is unclear whether minor variations in definition could have impacted overall results. Finally, 16 studies reported that patients underwent retreatment after initial ablation; however, it is difficult to assess how retreatment could have impacted outcomes due to lack of data availability (ie, outcomes were not reported separately for patients that did or did not receive retreatment or by type of retreatment).
Despite these limitations, this meta-analysis is strengthened by its broad inclusion of 28 studies in liver cancer which enrolled over 3500 patients. The time period for study inclusion was limited from 2006 to 2017 to control for the use of outdated ablation devices. A broad range of outcomes such as IDL and EHM were included, which have not been meta-analyzed previously. This meta-analysis also used several methods to control for heterogeneity and study quality including use of a random-effects model, subgroup and sensitivity analyses, study quality assessment, assessment of publication bias, and meta-regression analysis.
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