METHODS

Search strategy

This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.30 A systematic search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials was conducted for systematic reviews, randomized controlled trials (RCTs), and observational studies (prospective or retrospective cohort and case–control studies) using a search strategy developed by a medical information specialist that involved controlled vocabulary and keywords related to our research question (eg, “Liver Neoplasms”, “Microwave”, “Ablation Techniques”) (Appendix A). The search strategy was not limited by time or language; however, only English language articles published on or after January 1, 2006, were screened. The strategy was peer-reviewed by another senior information specialist prior to execution using the PRESS Checklist.31 Searches for the systematic reviews and RCTs were performed on October 29, 2017. A supplementary search for non-RCTs was performed on November 24, 2017. Reference lists of retrieved articles and relevant reviews were hand-searched. As this meta-analysis examined existing data from published studies, it was exempted from Institutional Review Board (IRB) approval.


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Study selection

Specific inclusion criteria were defined according to PICOS (ie, population, intervention, comparator, outcomes, and study design). Studies were considered for inclusion in the meta-analysis if they were RCTs or observational studies comparing MWA with RFA in adults (≥18 years) with confirmed HCC or liver metastasis who either refused or were ineligible for surgery. Based on the inclusion criteria, the eligibility of each publication was evaluated in the title and abstract review. If the title and abstract suggested potential eligibility, a full-text screening followed. Reviewers were not blinded to the names of the authors or the institutions of the studies considered for inclusion, but no criteria were applied to include or exclude studies based on these parameters. Systematic reviews and meta-analyses were reviewed for insight and reference retrieval. Articles published before January 1, 2006, were excluded given the high likelihood that outdated technologies were used. Records were evaluated for eligibility by two independent reviewers and discrepancies were resolved either through consensus or by adjudication from a third reviewer.

Data extraction

Details (ie, baseline characteristics and outcomes) from the included studies were extracted using a standardized data extraction form developed in Microsoft Excel. The following study details were retrieved: study authors, publication year, study time frame, study design, country of origin, sample size, key patient characteristics (eg, age, diagnosis, average tumor size, average number of ablated tumors, duration of follow-up, etc.), intervention and comparator details [eg, microwave system, frequency, utilization of transarterial chemoembolization (TACE), transarterial embolization (TAE) etc.], and detailed outcomes data. Some studies did not report percentages in text for LTP, OS, and DFS, but did present Kaplan–Meier curves, which were utilized instead (extracted using DigitizeIt 2.2.2, Braunschweig, Germany). If studies did not report the number at risk at each time point, the denominator for number treated was assumed to be the initial sample size. Data were extracted by one reviewer and then checked for accuracy by a second reviewer with discrepancies resolved by consensus, or by adjudication from a third reviewer.

Study outcomes

LTP was defined as reappearance of tumors within or adjacent areas to the ablation zone.10 This definition aligned with many study definitions of “local recurrence”. If a study reported “recurrence” but did not specify whether it was local or distant, it was assumed to be local (only two studies).21,32 If more than one LTP value was reported, the latest value in the study was used in the meta-analysis. Other outcomes were 1) technique efficacy (typically defined as complete tumor ablation), measured at one week to three months post ablation;10 2) one-, three-, and five-year OS; 3) one-, three-, and five-year DFS; 4) IDL, defined as appearance of a new tumor at a new focus within liver (sometimes referred to in studies as “de novo lesions,” “intrahepatic metastasis,” or “distant recurrence”); 5) EHM, defined as appearance of a new tumor outside the liver; 6) length of hospital stay (days); and 7) overall complications, including any major or minor adverse events that were reported by the studies. For outcomes that were not typically measured at defined time points within the study (ie, LTP, IDL, EHM, and complications), study data were excluded if the study reported a large difference in mean follow-up time (ie, ≥25% difference) between treatment arms.

Risk of bias assessment

The quality of studies included in the meta-analyses was assessed using the Cochrane Risk of Bias (RoB) tool33 for RCTs and the Newcastle–Ottawa quality assessment Scale (NOS)34 for observational studies. The RoB tool assessed the following domains: sequence generation, allocation concealment, blinding, selective reporting, and other sources of bias. Each study was assigned a rating for each domain (ie, low, unclear, or high risk of bias).

The NOS assessed the following categories: selection (ie, representativeness of exposed cohort, selection of non-exposed cohort, ascertainment of exposure, demonstration that the outcome of interest was not present at the start of the study), comparability (comparability based on design and analysis), and outcome (assessment of the outcome, follow-up long enough for the outcome to occur, and adequacy of follow-up of cohorts). When assessing cohort representativeness, the studies received a star if they were representative of the HCC population: BCLC stage 0 or A (Child–Pugh A or B, single tumor ≤3 cm, or up to three nodules ≤3 cm).2 For studies of liver metastasis, no restrictions were placed on the source of the primary tumor. For comparability, studies received a star if treatment groups were balanced on the potential effect modifiers of Child–Pugh class (HCC studies) and tumor size and primary origin (metastatic studies). Studies also received a star if they used a matching design, or regression analyses indicated that Child–Pugh class or tumor size and primary origin were not predictors of outcomes. Studies received an additional star if they were balanced on additional potential effect modifiers [ie, age, gender, tumor size (for HCC), surgical approach, tumor location], or they used a matching design, or regression analyses indicated that these variables were not predictors of outcomes. For outcome assessment, a study received a star if the follow-up time was at least six months. Studies also received a star if loss to follow-up was less than 20%.33 In total, each observational study could obtain a maximum of nine stars. The quality of included studies was assessed by two reviewers and reconciled by a third reviewer, if required.

Data synthesis and statistical methods

The DerSimonian–Laird random-effects model was used for the meta-analyses and forest plots were generated. For continuous outcomes (ie, LOS), the weighted mean difference (WMD) and its corresponding 95% CI were calculated. For dichotomous outcomes (all outcomes except LOS), the relative risk (RR) and the corresponding 95% CIs were calculated. As follow-up times varied across studies, a random-effects meta-regression analysis was completed to assess the association between mean study follow-up time and the treatment effect for LTP. All analyses were conducted for RCTs alone, observational studies alone, and the combination of RCTs and observational studies.

An I2 value was generated to describe the percentage of variance attributable to heterogeneity among studies.33 The following ranges were used to interpret I2 values: 0–40% represented minimal heterogeneity, 30–60% represented moderate heterogeneity, 50–90% represented substantial heterogeneity, and 75–90% represented considerable heterogeneity.33 The following subgroup analyses were conducted for LTP, one-year OS, complications, and technique efficacy outcomes: 1) tumor size (<2.5 versus ≥2.5 cm); 2) type of liver tumor (HCC versus metastasis); 3) impact of adding another treatment to both arms (MWA and RFA versus MWA+TACE and RFA+TACE); and 4) MWA frequency (915 versus 2450 MHz). For the subgroup analysis assessing the effects of the type of liver tumor, any study that included patients with metastatic tumors was classified as a metastatic study. Additionally, several sensitivity analyses were performed to assess the impact of alternative methods (ie, fixed-effects model), study quality (ie, exclusion of lower quality studies, defined as any RCT with high risk for any domain of the RoB tool or any observational study with ≤7 stars on the NOS), and surgery type (ie, exclusion of open surgical approach). Publication bias was examined using funnel plots for outcomes reported by 10 or more studies.35 Data were analyzed using STATA (Version 15.1, Texas, USA).

RESULTS

A total of 1379 citations were identified from database searching. After removing duplicates, 1137 unique records were screened. Of these, 1064 studies were excluded at the abstract screening phase for several reasons (eg, non-human, not English, not liver cancer, etc.) (Figure 1). Seventy-three articles were screened at the full-text stage. Of these, 45 articles were further excluded if the studies were systematic or narrative reviews (n=22), were published prior to 2006 (n=9), reported irrelevant outcomes (n=4), utilized non surgical modalities other than RFA as the comparator (n=4), did not report outcomes by treatment arm (n=3), were duplicates (n=2), and were comparing MWA frequencies (n=1). The four studies that utilized non surgical modalities other than RFA (not included in the meta-analysis) compared MWA to TACE,36 IRE,37 RFA+TACE (did not include TACE in the intervention arm),38 and systemic chemotherapy.39 Twenty-eight studies, consisting of a total of 3531 patients, that compared MWA versus RFA (24 studies) or MWA+TACE/TAE versus RFA+TACE/TAE (4 studies) were included in the meta-analyses.19–29,32,40–55 The demographics of the included studies followed historical patterns for gender56 and geography.57

Study characteristics are presented in Table 1. The sample size of the included studies (four RCTs and 24 observational studies) ranged from 19 to 460 patients and study follow-up duration ranged from five to 62 months. The average age across studies ranged from 50.4 to 69.4 years. In total, most studies (n=10) originated from China. Other regions included USA (n=7), Egypt (n=3), Italy (n=3), Japan (n=2), Australia (n=1), Belgium (n=1), and the Netherlands (n=1). Retreatment after the initial ablation session was reported by 16 studies (Table S1).19,23–29,42,48–51,53–55 Of these 16 studies, ten reported retreatment with the same type of thermal ablation that the patient initially received,26,42,50,51,54,55 but only seven of them reported the number of patients that received retreatment.19,25,26,29,51,54,55 Other types of retreatments with chemotherapy,28,49 TACE,19,23,29,48 resection,19,25 MWA or RFA,19 and radiotherapy19,25 were reported by eight studies. The number of retreated patients were generally similar for MWA and RFA across most studies (n=14), with a few notable exceptions.26,54 Four studies reported patients receiving liver transplants after thermal ablation.24,26,27,53

(To view a larger version of Table 1, click here.)

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