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Comparison of radiofrequency ablation and ablative external radiotherapy for the treatment of intrahepatic malignancies: a hybrid meta-analysis

Open AccessPublished:September 21, 2022DOI:https://doi.org/10.1016/j.jhepr.2022.100594

      Highlights

      • Radiofrequency ablation (RFA) is the most widely used non-surgical local modality for the treatment of small intrahepatic malignancies.
      • Ablative radiotherapy (RT) yields a curative effect by focusing high doses on small targets using computerized planning.
      • Ablative RT provided higher local control (OR: 0.458, p<0.001) and overall survival (OR: 1.204, p=0.194) than RFA.
      • RT can be more effective than RFA for tumors larger than 2-3 cm or for specific sublocation of the liver (e.g., subphrenic or perivascular sites), with moderate quality of evidence.

      Abstract

      Background&Aims

      Radiofrequency ablation (RFA) and ablative external beam radiotherapy (ablative RT) are commonly used to treat small intrahepatic malignancies. We meta-analyzed oncologic outcomes and systematically reviewed the clinical consideration of tumor location and size.

      Methods

      PubMed, Medline, Embase, and Cochrane Library databases were searched on February 24, 2022. Studies comparing RFA and ablative RT, providing one of the endpoints (local control or survival), and encompassing ≥5 patients in each arm were included.

      Results

      Twenty-one studies involving 4,638 patients were included. Regarding survival, the odds ratio (OR) was 1.204 (p=0.194, favoring RFA, not statistically significant) among all studies, 1.253 (p=0.153) among hepatocellular carcinoma (HCC) studies, and 1.002 (p=0.996) among colorectal cancer metastasis studies. Regarding local control, the OR was 0.458 (p<0.001, favoring ablative RT) among all studies, 0.452 (p<0.001) among HCC studies, favoring the ablative RT arm, and 0.649 (p=0.484) among colorectal cancer metastasis studies. Pooled one- and two year survival rates of HCC studies were 91.8% and 77.7% after RFA, and 89.0% and 76.0% after ablative RT, respectively; of metastasis studies were 88.2% and 66.4% after RFA and 82.7% and 60.6% after RT, respectively. Literature analysis suggests that ablative RT can be more effective than RFA for tumors larger than 2-3 cm or for specific sublocation of the liver (e.g., subphrenic or perivascular sites), with moderate quality of evidence.
      Reference to the grading system of the American Society for Radiation Oncology Primary Liver Cancer Clinical Guidelines.
      The pooled grade ≥3 complication rates were 2.9% and 2.8% in the RFA and ablative RT arms, respectively (p=0.952).

      Conclusion

      Our study shows that ablative RT can yield oncologic outcomes similar to RFA;and suggests that it can be more effective for the treatment of tumors in locations where RFA is difficult to perform or large-sized tumors.

      Lay summary

      RFA and ablative RT are non-surgical modalities for the treatment of small intrahepatic malignancy. Ablative RT showed oncologic outcomes at least similar to those of RFA, and was more effective and feasible at specific locations (e.g. perivascular or subphrenic locations).

      Graphical abstract

      Keywords

      Introduction

      Surgical resection is the most reliable curative treatment for small-sized, localized hepatic malignancies (
      • Galle P.R.
      • Forner A.
      • Llovet J.M.
      • Mazzaferro V.
      • Piscaglia F.
      • Raoul J.-L.
      • et al.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      KLCA
      2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma.
      ). Compared to surgery, radiofrequency ablation (RFA) is a simpler modality that inflicts less damage to the liver. Therefore, it has been used as a surrogate radical modality for localized liver malignancies (
      • Galle P.R.
      • Forner A.
      • Llovet J.M.
      • Mazzaferro V.
      • Piscaglia F.
      • Raoul J.-L.
      • et al.
      EASL clinical practice guidelines: management of hepatocellular carcinoma.
      ,
      KLCA
      2018 Korean Liver Cancer Association-National Cancer Center Korea Practice Guidelines for the Management of Hepatocellular Carcinoma.
      ,
      • van Amerongen M.J.
      • Jenniskens S.F.M.
      • van den Boezem P.B.
      • Fütterer J.J.
      • de Wilt J.H.W.
      Radiofrequency ablation compared to surgical resection for curative treatment of patients with colorectal liver metastases – a meta-analysis.
      ). On the other hand, external beam radiation therapy (EBRT) has gained popularity in the treatment of intrahepatic malignancies, especially with the advent of CT-based computerized planning, which enables precise targeting and normal liver sparing (
      • Rim C.H.
      • Seong J.
      Application of radiotherapy for hepatocellular carcinoma in current clinical practice guidelines.
      ). Recent comparative studies have reported that the local control rate of SBRT for intrahepatic malignancies is comparable to that of RFA (
      • Lee J.
      • Shin I.-S.
      • Yoon W.S.
      • Koom W.S.
      • Rim C.H.
      Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: Meta-analyses and a systematic review.
      ). In order to make clinical decisions pertaining to the most suitable treatment modality, consideration of the tumor location and size is necessary. RFA has been most efficient in treating small tumors (<2-3cm) (
      • Lee H.
      • Heo J.S.
      • Cho Y.B.
      • Yun S.H.
      • Kim H.C.
      • Lee W.Y.
      • et al.
      Hepatectomy vs radiofrequency ablation for colorectal liver metastasis: a propensity score analysis.
      ,
      • Xu Q.
      • Kobayashi S.
      • Ye X.
      • Meng X.
      Comparison of hepatic resection and radiofrequency ablation for small hepatocellular carcinoma: a meta-analysis of 16,103 patients.
      ), but has difficulty in treating specific sublocations (e.g. subphrenic or perivascular sites) (
      • Lee D.H.
      • Kim J.W.
      • Lee J.M.
      • Kim J.M.
      • Lee M.W.
      • Rhim H.
      • et al.
      Laparoscopic Liver Resection versus Percutaneous Radiofrequency Ablation for Small Single Nodular Hepatocellular Carcinoma: Comparison of Treatment Outcomes.
      ,
      • Kang T.W.
      • Lim H.K.
      • Lee M.W.
      • Kim Y-s
      • Rhim H.
      • Lee W.J.
      • et al.
      Aggressive intrasegmental recurrence of hepatocellular carcinoma after radiofrequency ablation: risk factors and clinical significance.
      ). EBRT is able to deliver a prescribed dose efficiently to relatively large tumors, and can be less affected by locational difficulties (
      • Rim C.H.
      • Lee H.Y.
      • Kim J.S.
      • Kim H.
      Radiofrequency ablation and stereotactic body radiotherapy for hepatocellular carcinoma: should they clash or reconcile?.
      ). Therefore we have systematically reviewed the literature on clinical considerations of tumor location and size to aid in clinical decision making; we have also performed a comparative meta-analysis of the oncologic outcomes of RFA and ablative EBRT in the treatment of intrahepatic malignancies.

      Methods

      Study design

      We conducted our systematic review and meta-analysis in accordance with the PRISMA guidelines (
      • Page M.J.
      • McKenzie J.E.
      • Bossuyt P.M.
      • Boutron I.
      • Hoffmann T.C.
      • Mulrow C.D.
      • et al.
      The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.
      ), and also referred to the Cochrane Handbook for methodological aspects. We employed PICO to frame the main hypothetical question, “Does ablative RT have oncologic outcomes (e.g., survival and local control) and toxicity profiles comparable to RFA for the treatment of patients with localized liver malignancies?” We then conducted a systematic review with formal meta-analyses. The auxiliary hypothetical question was “Is ablative RT more efficient than RFA for the treatment of large-sized (>2-3 cm) liver malignancies present in locations that are difficult to access (e.g., perivascular, liver dome)?” A narrative review with evidence grading was performed on the auxiliary question because the criteria for tumor size and difficult locations varied in different studies, and it was necessary to subjectively evaluate the details of the treatment (i.e., a hybrid systematic review, figure 1). The primary endpoint was local control (LC) and the secondary endpoint was overall survival (OS). Grade ≥3 complications were investigated as the secondary endpoints. This study was registered with PROSPERO (Protocol No: CRD42022332997).
      Figure thumbnail gr1
      Figure 1Flow diagram of a hybrid systematic review.

      Study inclusion and data collection

      Four databases, including PubMed, MEDLINE, Embase, and Cochrane Library, were searched until February 24, 2022. The studies that fulfilled the following inclusion criteria were included: 1) clinical studies comparing RFA and ablative RT for treatment of liver malignancies; 2) data for at least one endpoint (LC or OS); and 3) each arm (RFA and ablative RT) should encompass five or more patients with HCC or liver metastases. Studies regarding thermal ablation which include cases of both RFA and microwave ablation (MWA) were also included. The reference lists of the included studies were also checked to identify potentially missing studies. Language restrictions were not applied, and external consultation was performed when language translation was necessary. Conference abstracts were included if they met the inclusion criteria. Multiple studies from a single institution were included if they did not have overlapping patient data. Otherwise, the study was selected using the following criteria prioritized in numerical order: 1) larger sample size, 2) data on more endpoints, and 3) time elapsed since publication. Two independent reviewers searched the literature, and any disagreement was resolved through mutual discussion and re-investigation. Search terms and strategies according to the databases are shown in Supplementary Data 1. We used pre-designed sheets including 1) general information, including author name, publication source, patient recruitment period, affiliation, type of study, and study design; and 2) clinical information including number of patients, target patients, follow-up periods, LC rates, overall survival rates, rate and detail of grade ≥3 complications, and differential clinical outcomes according to tumor size and location. OS and LC data were acquired from a descriptive graph in the absence of numerical data.

      Quality assessment

      According to a preliminary search, the majority of candidate studies were observational studies. We used the Newcastle–Ottawa scale (

      Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2011.

      ), as recommended in the Cochrane handbook for the assessment of observational studies (

      JPT H, J T, J C, M C, T L, MJ P, et al. Tools for assessing methodological quality or risk of bias in non-randomized studies; Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

      ). A study with a score of 8-9 was evaluated as high quality, that with a score of 6-7 as medium quality, and a study with a score of 5 or less as low quality. Since observational studies with a high risk of bias are not recommended for meta-analysis, as referenced by the Cochrane handbook, (

      JPT H, J T, J C, M C, T L, MJ P, et al. Chapter 24: Including non-randomized studies on intervention effects; Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

      )we excluded low-quality studies from the present systematic review, if the authors agreed.

      Effect measures and data synthesis

      The main effect measure to assess the primary and secondary endpoints was the pooled odds ratio (OR) of OS and LC rates, in comparison of RFA and SBRT. Considering the possible heterogeneity in response evaluation (e.g. complete or partial response), LC was set as an endpoint and acquired either reported LC rate or non-local failure rate. Pooled analyses of OS were weighted using the number of patients, and those of LC were based on the patient or tumor number as reported by individual studies. The pooled percentiles of LC and OS were also calculated for clinical reference. Regarding complications, the pooled percentile rate of grade ≥3 complications was calculated and subjectively reviewed. Since the vast majority of candidate studies were observational studies from different institutions, there would be a possible heterogeneity with regard to treatment detail and clinical characteristics; thus, a random-effects model was used for the pooled analysis of the endpoints, in accordance with the Cochrane handbook (
      • Duan X.Z.T.
      • Xie H.
      • Sun J.
      • He W.
      • Xu H.
      Stereotactic body radiotherapy vs. radiofrequency ablation in the Treatment of small hepatocellular carcinoma.
      ).
      Subgroup analyses were also performed for comparability. The studies were regarded as having reliable comparability if they were randomized studies, performed intentional statistical matching (e.g., propensity scoring matching, inverse-probability weighting), or reported no significant difference regarding known clinical factors (including but not limited to age, tumor size, Child–Pugh class, and tumor location). Studies without available comparative information or those with SBRT arms having inferior clinical profiles (e.g., p<0.05, or >20% difference) were regarded as not having reliable comparability. The stepwise-hierarchical pooled analysis by Shin et al (
      • Shin I.S.
      • Rim C.H.
      Stepwise-Hierarchical Pooled Analysis for Synergistic Interpretation of Meta-analyses Involving Randomized and Observational Studies: Methodology Development.
      ). was referred to for the stepwise analysis methods and interpretation of the subject owing to scarce randomized literature. Subgroup analyses were also performed according to the disease, including HCC and colorectal cancer (CRC) with liver metastases.
      We performed the Cochran Q test (
      • Cochran W.G.
      The Combination of Estimates from Different Experiments.
      ) and I2 statistics (
      • Higgins J.P.T.
      • Thompson S.G.
      Quantifying heterogeneity in a meta-analysis.
      ) to assess heterogeneity in the pooled analyses, and I2 values of 25%, 50%, and 75% were regarded as low, moderate, and high heterogeneity, respectively. Publication bias assessments for pooled analyses involving >10 studies were performed using a visual funnel plot assessment and quantitative Egger’s test (
      • Egger M.
      • Smith G.D.
      • Schneider M.
      • Minder C.
      Bias in meta-analysis detected by a simple, graphical test.
      ). Possible publication bias was considered to exist if the funnel plots showed asymmetry and the two-tailed p value was <0.1 in the Egger’s test. Duval and Tweedie’s trim-and-fill method (
      • Duval S.
      • Tweedie R.
      Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis.
      ) was used for analyses with possible publication bias to yield the adjusted reference values. All statistical analyses were performed using the Comprehensive Meta-Analysis version 3 (Biostat Inc., Englewood, NJ, USA).
      The advantages of a specific modality according to tumor location and size were assessed by referencing to the grading system of the liver cancer practice guidelines of the American Society of Radiation Oncology (ASTRO) (
      • Apisarnthanarax S.
      • Barry A.
      • Cao M.
      • Czito B.
      • DeMatteo R.
      • Drinane M.
      • et al.
      External Beam Radiation Therapy for Primary Liver Cancers: An ASTRO Clinical Practice Guideline.
      ). The evidence grading system is summarized in Supplementary Table 1.

      Results

      Study selection and characteristics

      A total of 1438 studies were initially searched. Those duplicated among databases and having irrelevant formats (e.g., reviews, letters, conference abstracts, editorials, case reports, trial protocols, and lab studies) were machine-filtered. Eventually, 544 studies were screened using the abstracts and citations. After excluding 500 articles for various reasons, 44 studies underwent full-text review, and 21 studies involving 4638 patients (RFA 2807, ablative RT 1831) that met all inclusion criteria were finally included (
      • Ahuja C.K.Y.
      • Chadha M.
      • McLarty J.
      • Kaufman J.A.
      • Farsad K.
      • Marquez C.
      • Kolbeck K.J.
      Comparison of transarterial chemoembolization with radiofrequency ablation versus transarterial chemoembolization followed by stereotactic body radiation therapy for hepatocellular carcinoma.
      ,
      • Shiozawa K.
      • Watanabe M.
      • Ikehara T.
      • Matsukiyo Y.
      • Kogame M.
      • Kishimoto Y.
      • et al.
      Comparison of percutaneous radiofrequency ablation and CyberKnife((R)) for initial solitary hepatocellular carcinoma: A pilot study.
      ,
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Duan X.Z.T.
      • Xie H.
      • Sun J.
      • He W.
      • Xu H.
      Stereotactic body radiotherapy vs. radiofrequency ablation in the Treatment of small hepatocellular carcinoma.
      ,
      • Feng M.U.-S.
      • MV D.
      • Parikh N.
      Use of radiofrequency ablation and stereotactic body radiotherapy for the treatment of hepatocellular carcinoma: An analysis of the SEER-Medicare database.
      ,
      • Rajyaguru D.J.
      • Borgert A.J.
      • Smith A.L.
      • Thomes R.M.
      • Conway P.D.
      • Halfdanarson T.R.
      • et al.
      Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database.
      ,
      • Hara K.T.A.
      • Tsurugai Y.
      • Sanuki N.
      • Saigusa Y.
      • Maeda S.
      • Tanaka K.
      • Numata K.
      Clinical outcomes after treatment for hepatocellular carcinoma, stereotactic body radiotherapy vs radiofrequency ablation: A propensity score-matched analysis.
      ,
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Stintzing S.
      • Grothe A.
      • Hendrich S.
      • Hoffmann R.T.
      • Heinemann V.
      • Rentsch M.
      • et al.
      Percutaneous radiofrequency ablation (RFA) or robotic radiosurgery (RRS) for salvage treatment of colorectal liver metastases.
      ,
      • Vigano L.
      • Pedicini V.
      • Comito T.
      • Carnaghi C.
      • Costa G.
      • Poretti D.
      • et al.
      Aggressive and Multidisciplinary Local Approach to Iterative Recurrences of Colorectal Liver Metastases.
      ,
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ,
      • Ji R.
      • Ng K.K.
      • Chen W.
      • Yang W.
      • Zhu H.
      • Cheung T.-T.
      • et al.
      Comparison of clinical outcome between stereotactic body radiotherapy and radiofrequency ablation for unresectable hepatocellular carcinoma.
      ,
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Der Liang J.
      • Shih Y.L.
      • Huang W.-Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial.
      ,
      MULTICENTER COHORT STUDY OF THERMAL ABLATION VERSUS STEREOTACTIC BODY RADIATION THERAPY FOR HEPATOCELLULAR CARCINOMA.
      ,
      • Chen L.
      • Hung S.
      • Lin H.
      • Lee M.
      • Chiou W.
      • Huang L.
      • et al.
      Comparing Radiofrequency Ablation with Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma: Analysis of 108 Cases from a Single Academic Radiotherapy Center.
      ,
      • Nieuwenhuizen S.
      • Dijkstra M.
      • Puijk R.S.
      • Timmer F.E.
      • Nota I.M.
      • Opperman J.
      • et al.
      Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry.
      ,
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Gotohda N.
      • Nomura S.
      • Doi M.
      • Karasawa K.
      • Ohki T.
      • Shimizu Y.
      • et al.
      Clinical impact of radiofrequency ablation and stereotactic body radiation therapy for colorectal liver metastasis as local therapies for elderly, vulnerable patients.
      ). The inclusion process is illustrated in Figure 2.
      Among the 21 studies, 16 had full text and five were conference abstracts. Fourteen studies involved patients with HCC, and seven studies involved patients with colorectal cancer and liver metastases. With regard to radiation modalities, 18 studies investigated the results of SBRT, two of Cyberknife, and one of proton therapy. The majority (17 of 21) were observational studies that were retrospectively designed, two were studies based on US National cancer database, and there was one prospective observational and randomized study each. The general information of these studies is summarized in Table 1.
      Table 1General information of included studies.
      AuthorYear of publicationYears of patients recruitAffiliationCountryStudy typeSourceNo. of patientsStudy designsubject of study
      Ahuja2014Louisiana State Univ.USconference abstractCIRSETACE&RFA 32

      TACE&SBRT 32
      RHCC
      Shiozawa20152011-2014Toho Univ.Japanfull articleWorld J GastroenterolRFA 38, Cyberknife 35 (all solitary tumor)RHCC
      Wahl20162004-2012Univ. of MichiganUSfull articleJ Clin OncolRFA 161, SBRT 63 (tumors: RFA 249, SBRT 83)PHCC
      Duan20162011-2012Beijing 302 hositalChinaconference

      abstract
      HepatolRFA 40, SBRT 37RHCC
      Feng20162004-2011Univ. of MichiganUSconference

      abstract
      ASCORFA 78, SBRT 78 (after PSM)NCDBHCC
      Rajyaguru20182004-2013Gundersen Health SystemUSfull articleJ Clin OncolRFA 521, SBRT 296 (after PSM)NCDBHCC
      Kim20192012-2016Yonsei Cancer CenterKoreafull articleRadiother OncolRFA 95, SBRT 95 (after PSM)

      (tumor n =patient n)
      RHCC
      Hara20192012-2016Yokohama City Univ., Ofuno Chao Univ.Japanfull articleHepatologyRFA 106, SBRT-HFRT 106 (after PSM)RHCC
      Ji R20222008-2021Univ. of Hong KongHK SAR, Chinafull articleMedicineRFA 38 SBRT 22RHCC
      Ueno20212014-2019Kurashiki Central HospitalJapanfull articleJ Gastrointestinal OncolRFA 62 SBRT 31 (after PSM)RHCC
      Kim N20202010-2016East Asian MulticentersChina, Japan, HK SAR, Taiwan, and Koreafull articleJ HepatolRFA 313 SBRT 313 (after PSM)RHCC
      Kim T20212013-2017National Cancer CenterKoreafull articleJ HepatolRFA 56 PBT 80RCTHCC
      Moon20192006-2018Multicenters of USUSconference

      abstract
      AASLDRFA 529 (include 123 MWA) SBRT 387 lesionsRHCC
      Chen LC20192014-2017Dalin Tzu Chi Hospt.Taiwanconference

      abstract
      ASTRORFA 84 SBRT 24RHCC
      Stintzing20132005-2011Comprehensive Cancer CenterGermanyfull articleActa OncolRFA 30, cyberknife 30 (tumors: RFA 35, cyberknife 35)RCRC liver mets
      Viganò20182004-2013Humanitas Univ.Italyfull articleWorld J SurgRFA 19, SBRT 14RCRC liver only mets
      Jackson20182000-2015Univ. of MichiganUSfull articleInt J Radiat Oncol Biol PhysRFA 69, SBRT 92RCRC and other liver mets
      Nieuwenhuizen S2021from 2007Amsterdam registryNetherlandfull articleCancersRFA 144 (include 81 MWA) SBRT 55RCRC liver mets
      Jeong20212013Asan hospitalKoreafull articleJ Gastroenterol HepatolRFA 172 SBRT 87 (after IPTW)RCRC liver mets
      Yu J20212007-2014Asan hospitalKoreafull articleCancer Res TreatRFA 178 SBRT 44 (after IPTW)RCRC liver mets
      Gotohda20202010-2016Seven centers from JapanJapanfull articleJGH openRFA 42 SBRT 5RCRC liver mets
      Abbreviations: CIRSE, cardiovascular and interventional radiological society of Europe; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy; HCC, hepatocellular carcinoma; R, retrospective; P, prospective; ASCO, American Society of Clinical Oncology; NCDB, national cancer database; ASTRO, American Society for Radiation Oncology; LT, liver transplantation.
      Among HCC studies, the median 2-year OS rates were 78.5% (range:52.9-92.9) in the RFA arm and 77.6% (range:46.3-90.2) in the ablative RT arm; the median 2-year LC rates were 84.5% (63.8-94.7) in the RFA arm and 91.7% (74.9-100) in the ablative RT arm. Regarding CRC studies, the median 2-year OS rates were 64.3% (50.2-80) in the RFA arm and 65.4% (52.3-80) in the ablative RT arm; the median 2-year LC rates were 60.8% (56.4-93.3) in the RFA arm and 77.0% (71.5-88.2) in the ablative RT arm. Regarding comparability analysis methods, nine studies used intentional patient-matching methods (e.g., propensity score matching; inverse probability of weighting). Eight studies performed statistical comparisons; six of them showed that the ablative RT arm had inferior clinical factors (e.g., p<0.05, or >20% numeral difference), and two of them reported no statistically significant difference between the RT and the RFA arms regarding clinical factors. Clinical factors included, but were not limited to, age, Child–Pugh score, tumor size, and difficult location to be treated. Three studies did not provide relevant information. One study performed a randomized allocation. Supplementary Table 2 provides information regarding the clinical characteristics of the included studies.

      Quality and bias assessments

      According to the Newcastle–Ottawa scale, 10 of the 21 studies were regarded as having high quality (8 to 9 points) and 8 studies had medium quality (6 or 7 points). None of the studies were assessed as having low quality. Therefore, all studies that fulfilled the inclusion criteria were included in the present systematic review. Details of scoring and the reasons according to each scoring category are shown in Supplement Table 3.

      Synthesis of clinical endpoints

      With regard to OS, the OR was 1.204 (95% CI:0.910-1.594, p=0.194) among all studies, 1.253 (95% CI:0.920-1.707, p=0.153) among HCC studies, and 1.002 (95% CI:0.515-1.947, p=0.996) among CRC metastases studies. Among studies with reliable comparability, the OR was 1.149 (95% CI:0.821-1.610, p=0.417) for all studies, 1.201 (95% CI:0.844-1.710, p=0.309) among HCC studies, and 0.746 (95% CI:0.247-2.258, p=0.64) among CRC metastases studies. These results are summarized in Table 2 and are shown in Figure 3 as forest plots. With regard to LC, the OR was 0.458 (95% confidence interval [CI]:0.368-0.570, p<0.001) among all studies and 0.452 (95% CI:0.362-0.565, p<0.001) among HCC studies, favoring the ablative RT arm, and 0.649 (95% CI:0.193-2.179, p=0.484) among CRC metastasis studies. Among studies with reliable comparability (e.g., randomized studies, studies performed with intentional statistical matching, no significant differences in known clinical factors), the OR was 0.466 (95% CI:0.357-0.609, p<0.001) among all studies, 0.421 (95% CI:0.227-0.779, p<0.001) among HCC studies, and 0.459 (95% CI:0.359-0.586, p=0.006) among CRC metastases studies, all favoring the ablative RT arm.
      Table 2Pooled rate of odds ratio regarding local control and survival.
      Studies(Subject)No. of studiesNo. of casesHeterogeneity pI2 (%)Heterogeneity assessmentOR (95% CI)RFA Vs SBRT (p value)
      All studies (local control)
       All173670<0.00164.8Moderate to high0.458 (0.368-0.570)<0.001
       HCC1129740.555∼0Very low0.452 (0.362-0.565)<0.001
       CRC mets6696<0.00188.2High0.649 (0.193-2.179)0.484
      Studies with reliable comparability (local control)
       All1021090.838∼0Very low0.466 (0.357-0.609)<0.001
       HCC818170.68∼0Very low0.421 (0.227-0.779)<0.001
       CRC mets22920.87∼0Very low0.459 (0.359-0.586)0.006
      All studies (overall survival)
       All193504<0.00160.10%Moderate to high1.204 (0.910-1.594)0.194
       HCC1428750.00260.1Moderate to high1.253 (0.920-1.707)0.153
       CRC mets56290.01766.7Moderate to high1.002 (0.515-1.947)0.996
      Studies with reliable comparability (overall survival)
       All122856<0.00167.5Moderate to high1.149 (0.821-1.610)0.417
       HCC1026340.00168.1Moderate to high1.201 (0.844-1.710)0.309
       CRC mets22220.0671.7Moderate to high0.746 (0.247-2.258)0.604
      Abbreviations: RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy; LC, local control; CI confidence interval; OR, odds ratio; HCC, hepatocellular carcinoma; CRC, colorectal cancer.
      Figure thumbnail gr3
      Figure 3Forest plots of (A) local control comparison of all included studies (upper) and of studies with reliable comparability (lower); (B) overall survival comparison of all included studies (upper) and of studies with reliable comparability (lower).
      Pooled analyses of the LC percentile included all studies, and pooled analyses of the OS percentile included HCC and CRC metastasis studies separately. Among HCC studies, the pooled 1-, 2-, and 3-year OS rates were 91.8% (95% CI:87.2-94.9), 77.7% (70.7-83.4), and 76.0% (64.4-84.7) in the RFA arm, respectively; the corresponding rates for the ablative RT arm were 89.0% (95% CI:83.6-92.7), 76.0% (64.4-84.7), and 65.9% (53.7-76.3), respectively. Among CRC metastases studies, pooled 1-, 2-, and 3-year OS rates were 88.2% (95% CI:77.9-94.0), 66.4% (50.9-79.0), and 52.1% (41.1-62.8) in RFA arm; the corresponding rates for the ablative RT arm were 82.7% (95% CI:61.6-93.4), 60.6% (50.7-69.6), and 43.6% (26.6-62.1), respectively. Pooled 1-, 2-, and 3-year LC percentile rates were 82.3% (95% CI: 77.2-86.4), 80.1% (72.7-85.8), and 92.4% (89.2-94.7) in RFA arms, and 92.4% (95% CI: 89.2-94.7), 86.5% (81.7-90.2), 83.9% (77.7-88.7) in ablative RT arms, respectively.
      Pooled results of OS and LC percentiles are summarized in Table 3.
      Table 3Pooled percentile of clinical endpoints.
      Subject

      Modality
      No. of cohortsNo. of casesEffect size % (95% CI)RFA Vs ablative RT (p value)Heterogeneity pI2 (%)
      One year LC rate (HCC and CRC mets)
      All32368787.2 (84.2-89.7)<0.00183.3%
      RFA16217282.3 (77.2-86.4)<0.00180.0%
      RT16151592.4 (89.2-94.7)<0.001<0.00163.9%
      Two year LC rate
      All28254984 (80.0-87.3)<0.00184.8%
      RFA14146480.1 (72.7-85.8)<0.00188.2%
      RT14108486.5 (81.7-90.2)0.094<0.00166.4%
      Three year LC rate
      All26280979.6 (74.9-83.6)<0.00187.4%
      RFA13164975.7 (68.6-81.7)<0.00188.7%
      RT13116083.9 (77.7-88.7)0.062<0.00180.4%
      One-year OS (HCC)
      All24287590.3 (87.0-92.9)<0.00181.8%
      RFA12168691.8 (87.2-94.9)<0.00185.6%
      RT12118989.0 (83.6-92.7)0.333<0.00179.7%
      Two-year OS (HCC)
      All22280277.2 (71.4-82.2)<0.00190.6%
      RFA11164877.7 (70.7-83.4)<0.00188.2%
      RT11115476.0 (64.4-84.7)0.775<0.00192.7%
      Three-year OS (HCC)
      All18251867.5 (60.3-74.0)<0.00191.1%
      RFA9144968.5 (59.3-76.5)<0.00190.7%
      RT9106965.9 (53.7-76.3)0.718<0.00192.4%
      One-year OS (CRC mets)
      All862986.6 (77.7-92.3)<0.00186.0%
      RFA443388.2 (77.9-94.0)0.00181.8%
      RT419682.7 (61.6-93.4)0.5070.00181.1%
      Two-year OS (CRC mets)
      All862962.2 (54.0-69.8)<0.00180.8%
      RFA443366.4 (50.9-79.0)<0.00188.2%
      RT419660.6 (50.7-69.6)0.5170.19536.3%
      Three-year OS (CRC mets)
      All862949.9 (40.5-59.3)<0.00183.7%
      RFA443352.1 (41.1-62.8)0.00378.5%
      RT419643.6 (26.6-62.1)0.4440.00279.5%
      Grade ≥3 complication
      All2646982.9 (1.9-4.4)<0.00172.5%
      RFA1334152.9 (1.4-6.1)<0.00173.0%
      RT1312832.8 (1.6-4.9)0.952<0.00173.2%
      Abbreviations: CI, confidence interval; RFA, radiofrequency ablation; RT, radiotherapy; LC, local control; HCC, hepatocellular carcinoma; CRC, colorectal cancer; OS, overall survival.

      Heterogeneity analyses and publication bias assessment

      Heterogeneity in the pooled analyses of LC was moderate to high (I2=64.8%), very low (I2=∼0%), and high (I2=88.2%), including all studies, HCC studies, and CRC metastases studies. In the subgroup analyses, including studies with reliable comparability, heterogeneity was very low in pooled analyses of all HCC and CRC metastasis studies. With regard to OS, heterogeneity was moderate to high in all pooled analyses (Table 2). No publication bias was identified in the pooled analyses of local control (p=0.824) and overall survival (p=0.468). The funnel plots are shown in Supplementary Fig. 1.

      Complications

      Thirteen studies provided comparative complication data (
      • Shiozawa K.
      • Watanabe M.
      • Ikehara T.
      • Matsukiyo Y.
      • Kogame M.
      • Kishimoto Y.
      • et al.
      Comparison of percutaneous radiofrequency ablation and CyberKnife((R)) for initial solitary hepatocellular carcinoma: A pilot study.
      ,
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Stintzing S.
      • Grothe A.
      • Hendrich S.
      • Hoffmann R.T.
      • Heinemann V.
      • Rentsch M.
      • et al.
      Percutaneous radiofrequency ablation (RFA) or robotic radiosurgery (RRS) for salvage treatment of colorectal liver metastases.
      ,
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ,
      • Ji R.
      • Ng K.K.
      • Chen W.
      • Yang W.
      • Zhu H.
      • Cheung T.-T.
      • et al.
      Comparison of clinical outcome between stereotactic body radiotherapy and radiofrequency ablation for unresectable hepatocellular carcinoma.
      ,
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial.
      ,
      • Nieuwenhuizen S.
      • Dijkstra M.
      • Puijk R.S.
      • Timmer F.E.
      • Nota I.M.
      • Opperman J.
      • et al.
      Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry.
      ,
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ). The Common Terminology Criteria for Adverse Events by the National Cancer Institute of the US was used in most studies except the study by Ji et al (
      • Ji R.
      • Ng K.K.
      • Chen W.
      • Yang W.
      • Zhu H.
      • Cheung T.-T.
      • et al.
      Comparison of clinical outcome between stereotactic body radiotherapy and radiofrequency ablation for unresectable hepatocellular carcinoma.
      ). of which used the Clavien-Dindo classification. Pooled grade ≥3 complication rates were 2.9% (95% CI:1.4-6.1) and 2.8% (1.6-4.9) in the RFA and ablative RT arms, respectively (p=0.952 for difference). The vast majority of complications in RFA arms were due to mechanical damage from the procedures (e.g., bleeding, perforation, and pneumothorax). Among 20 grade ≥3 complication events from the ablative RT arms of 13 studies, 55% were hepatic damage (e.g., ascites, biliary stricture, liver function worsening), whereas 45% were gastrointestinal damage (e.g., bleeding or ulcer). Table 4 summarizes the reported complications.
      Table 4Complications according to treatment modalities.
      AuthorSourceSubject of studyNo. of patients (No. of tumors)Complications of grade ≥3
      Shiozawa, 2015World J GastroenterolHCCRFA 38, Cyberknife 35No late adverse effect in RFA

      11.4% (4 cases of ascites, 2 of them liver-related death) in SBRT

      1yr CPC score in SBRT higher than RFA group (p=0.003)
      Wahl, 2016J Clin OncolHCCRFA 161, SBRT 63>G3 complication: RFA 11% Vs. SBRT 5%. (p=0.31) two G5 bleeding in RFA arms
      Kim, 2019Radiother OncolHCCRFA 668, SBRT 105 (before PSM)3.7% in RFA group had grade 3 or 4 toxicities no G≥3 toxicity in SBRT arm, however RILD in 7 cases (6.7%)
      Hara, 2019HepatologyHCCRFA 231, SBRT-HFRT 143 (before PSM)One G5 peritonitis and one G5 gastric hemorrhage in RFA
      Ji R, 2022MedicineHCCRFA 38 SBRT 22No severe (Clavien–Dindo ≥III) complication in both arms
      Ueno, 2021J Gastrointestinal OncolHCCRFA 62 SBRT 31 (after PSM)No serious complication noted in both arms
      Kim N, 2020J HepatolHCCRFA 1568 SBRT 496 (before PSM)No difference in grade 3-4 toxicity (2.6% vs 1.6%, p=0.268)

      CPC score change of >2 point was higher in SBRT arm at 3 months (4.7 vs 11.2%, p<0.001) but restored at 6 months (8.1% vs 6.3%, p=0.278)
      Kim T, 2021J HepatolHCCRFA 56 PBT 80G3 LFT increase (14.3%) and G3 bleeding (1.8%) in RFA arm

      No grade 3/4 Cx in PBT arm
      Jeong, 2021HCCHCCRFA 172 SBRT 87 (after IPTW)G4 hemorrhage in RFA arm (0.6%); G3 biliary stricture in SBRT arm (1.1%)
      Stintzing, 2013Acta OncolCRC liver metsRFA 30, cyberknife 30No > G3 complication in both arms
      Jackson, 2018Int J Radiat Oncol Biol PhysCRC and other liver metsRFA 69, SBRT 92>G3 complication: RFA 4.3% Vs. SBRT 4.3% (p=ns)
      Nieuwenhuizen, 2021CancersCRC liver metsRFA 144 SBRT 556.3% in RFA arm (all procedure related damage) vs 0 cases
      Yu J, 2021Cancer Res TreatCRC liver metsRFA 178 SBRT 44 (after IPTW)no G3 or higher complication in both arms
      Abbreviations: HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy; HR, hazard ratio; CRC, colorectal cancer; LT, liver transplantation.

      Evidence grading review considering tumor location

      Seven studies reported treatment efficacy related to tumor location in comparison with the two arms. Among them, two studies (
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ) reported that difficult location was a factor affecting inferior LC in RFA arms, whereas it was not a factor in ablative RT arms. Kim et al. (
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ) reported that SBRT showed better LC in the treatment of subphrenic and segment 8 tumors. Two studies (

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ) reported that LC was higher in the SBRT arm, although the SBRT arm included more tumors in difficult locations. Two studies (
      • Ji R.
      • Ng K.K.
      • Chen W.
      • Yang W.
      • Zhu H.
      • Cheung T.-T.
      • et al.
      Comparison of clinical outcome between stereotactic body radiotherapy and radiofrequency ablation for unresectable hepatocellular carcinoma.
      ,
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ) reported that although the majority of the SBRT arm included tumors in difficult locations, as different from the RFA arm, LC was higher or non-inferior. To summarize, all the above studies (
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Ji R.
      • Ng K.K.
      • Chen W.
      • Yang W.
      • Zhu H.
      • Cheung T.-T.
      • et al.
      Comparison of clinical outcome between stereotactic body radiotherapy and radiofrequency ablation for unresectable hepatocellular carcinoma.
      ,
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ) consistently reported that SBRT could be more effective in the treatment of tumors in difficult locations, and four studies (
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ) reported better LC with SBRT (Table 5) than with RFA. This corresponds to a moderate quality of evidence in the grading system judging literature on HCC by ASTRO (Supplement Table 1).
      Table 5Complications and size considerations in treatment efficacy.
      AuthorSubject of studyNo. of patients (No. of tumors)Consideration of size in treatment efficacy
      Wahl, 2016HCCRFA 161, SBRT 63 (tumors: RFA 249, SBRT 83)Favoring SBRT with tumors > 2 cm (HR 3.35, p=0.025), no difference in LC with tumors <2 cm (HR 2.50, p=0.15)
      Kim, 2019HCCRFA 668, SBRT 105Favoring SBRT with tumors > 2 cm (HR 2.18, p=0.012), no difference in LC with tumors ≤2 cm (HR 2.25, p=0.061) (before PSM)
      Jackson, 2018CRC and other liver metsRFA 69, SBRT 92 (tumors: RFA 122, SBRT: 170)Favoring SBRT with tumors > 2 cm (HR 3.54, p<0.01), no difference in LC with tumors <2 cm (HR 2.18, p=0.4)
      Yu J, 2021CRC liver metsRFA 178 SBRT 44Favoring SBRT with tumors > 2 cm (HR 0.153, p<0.001), no difference in LC with tumors <2 cm (HR 0.648, p=0.1) (IPTW cohort)
      Kim N, 2020HCCRFA 1568 SBRT 496>3 cm size related to inferior LC with RFA (HR 1.26, p=0.030) of which was not related with SBRT (HR 1.01, p=0.960) (before PSM)
      Nieuwenhuizen, 2021CRC liver metsRFA 144 SBRT 55>3 cm size related to inferior LC with RFA (p<0.001) of which was not related with SBRT (p=0.361)
      Kim T, 2021HCCRFA 56 PBT 80All ≤3 cm in size

      LC 83.9/77.6% vs. 94.8/88.3% (RFA vs. SBRT) at 2/3 years (p=0.123)
      Hara, 2019HCCRFA 106 SBRT-HFRT 106All ≤3 cm in size

      LC: 79.8% vs 93.2% (RFA vs. SBRT) at 3 years (p<0.01)

      (PSM cohort)
      Ueno, 2021HCCRFA 62 SBRT 31All ≤3 cm in size

      LC 93/87% vs 100/100% (RFA vs. SBRT) at 2/3 years (p=0.024)

      (PSM cohort)
      Jeong, 2021HCCRFA 172 SBRT 87All ≤3 cm in size

      LC 90.6% vs. 96.3% (RFA vs. SBRT) at 4 years (p=0.167)

      (IPTW cohort)
      Moon, 2019HCCRFA 529 SBRT 387 lesionsFor ≤2 cm tumors, 1 year LC was 87 vs. 93.4%; for >2 cm tumors, 1-year LC was 71.4 vs. 84.8% (RFA vs SBRT)
      Location consideration in treatment efficacy
      Kim, 2019HCCRFA 668, SBRT 105Subphrenic location related to inferior LC with RFA (HR 1.53, p=0.003), which was not related with SBRT (HR 1.00, p = .996).

      (before PSM)
      Jeong, 2021HCCRFA 172 SBRT 87Perivascular location related to inferior LC with RFA (4-year LC: 72% vs. 97%, <0.001), which was not related with SBRT (4-year LC: 94.7% vs. 95.5%, p=0.872)

      (IPTW cohort)
      Kim N, 2020HCCRFA 1568 SBRT 496Favoring SBRT with subphrenic tumors (2-year LC 77% vs. 84.7%, p=0.005)

      Favoring SBRT with segment 8 tumors (2-year LC 77.4% vs 85.5% p=0.014)

      (before PSM)
      Hara, 2019HCCRFA 106 SBRT-HFRT 106More tumors in difficult location (attaching organs) in SBRT arm (42% vs. 100%)

      LC: 79.8% vs 93.2% (RFA vs. SBRT) at 3 years (p<0.01)

      (PSM cohorts)
      Yu J, 2021CRC liver metsRFA 178 SBRT 44More tumors in difficult location in SBRT arm (60.7% vs 90.9%, p=.0.001)

      LC 58% vs. 76% (RFA vs. SBRT) at 3 years

      (IPTW cohort)
      Ueno, 2021HCCRFA 62 SBRT 31Vast majority of SBRT arm had difficult location compared to few difficult locations in RFA arm (p<0.001) cumulative LC 90.3 vs. 100% (RFA vs. SBRT) (p=0.024)

      (PSM cohort)
      Ji R, 2022HCCRFA 38 SBRT 22Majority in SBRT arm had difficult locations whereas there were no difficult locations for patients in RFA arm.

      LC (overall): 94.7 vs 90.6 (p=0.566)
      Abbreviations: HCC, hepatocellular carcinoma; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy; HR, hazard ratio; LC, local control; PSM, propensity score matching; CRC, colorectal cancer; PBT, proton beam therapy; IPTW, inverse probability of treatment weighting; HFRT, hypofractionated radiotherapy.

      Evidence grading review considering tumor size

      Eleven studies reported treatment efficacy related to size consideration in the two arms. In four studies, LC did not differ between the arms in the treatment of tumors <2 cm in size, but SBRT was preferred with regard to LC in the treatment of tumors >2 cm in size (
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ). Two studies reported that tumor size >3 cm was related to inferior LC in RFA arm but not in the SBRT arm (
      • Nieuwenhuizen S.
      • Dijkstra M.
      • Puijk R.S.
      • Timmer F.E.
      • Nota I.M.
      • Opperman J.
      • et al.
      Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry.
      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ). Four studies included only patients with tumors ≤3 cm in size, and two of them reported no difference between the arms, while the other two reported better LC rates in SBRT arms (
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial.
      ,
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ). Moon et al. (
      MULTICENTER COHORT STUDY OF THERMAL ABLATION VERSUS STEREOTACTIC BODY RADIATION THERAPY FOR HEPATOCELLULAR CARCINOMA.
      ) showed that the 1-year LC rates were 87% vs. 93.4% for tumors ≤ 2 cm and 71.4% vs. 84.8% for tumors > 2 cm (RFA vs. SBRT). In summary, five studies (
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ,
      MULTICENTER COHORT STUDY OF THERMAL ABLATION VERSUS STEREOTACTIC BODY RADIATION THERAPY FOR HEPATOCELLULAR CARCINOMA.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ) consistently suggested more efficient LC of SBRT compared to RFA for larger tumors (>2–3 cm), and nine studies (
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Der Liang J.
      • Shih Y.L.
      • Huang W.-Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,
      MULTICENTER COHORT STUDY OF THERMAL ABLATION VERSUS STEREOTACTIC BODY RADIATION THERAPY FOR HEPATOCELLULAR CARCINOMA.
      ,
      • Nieuwenhuizen S.
      • Dijkstra M.
      • Puijk R.S.
      • Timmer F.E.
      • Nota I.M.
      • Opperman J.
      • et al.
      Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ,
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: A randomized phase III trial.
      ) consistently suggested at least non-inferior LC of SBRT compared to RFA for smaller tumors (<2–3 cm) (Table 5). This corresponds to a moderate quality of evidence in the grading system judging the literature on HCC by ASTRO (Supplement Table 1).

      Discussion

      Brief review of literature

      According to a recent meta-analysis, the survival outcomes of RFA were comparable to that of surgical resection among HCC patients within the Milan criteria (
      • Wang Q.
      • Tang M.
      • Zhang S.
      Comparison of radiofrequency ablation and surgical resection for hepatocellular carcinoma conforming to the Milan criteria: a meta-analysis.
      ). For liver metastases, RFA has been used in the treatment of patients with adverse clinical conditions as a lesser invasive surrogate with fewer complications (
      • van Amerongen M.J.
      • Jenniskens S.F.M.
      • van den Boezem P.B.
      • Fütterer J.J.
      • de Wilt J.H.W.
      Radiofrequency ablation compared to surgical resection for curative treatment of patients with colorectal liver metastases – a meta-analysis.
      ). Regarding EBRT, the ablative role by precisely targeting and delivering high dose of external radiation to localized lesions has emerged. SBRT, which delivers a high-dose of X-ray beams (70-100 Gy in equivalent dose, 2 Gy per fraction scheme (EQD2)) within 1-2 weeks, and precise radiotherapy which delivers particle beams at doses within the ablative range, have both yielded local control comparable to that of other ablative modalities (
      • Lee J.
      • Shin I.-S.
      • Yoon W.S.
      • Koom W.S.
      • Rim C.H.
      Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: Meta-analyses and a systematic review.
      ,
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial.
      ,
      • Rim C.H.
      • Kim H.J.
      • Seong J.
      Clinical feasibility and efficacy of stereotactic body radiotherapy for hepatocellular carcinoma: A systematic review and meta-analysis of observational studies.
      ). Since two modalities have overlapping role in treating localized intrahepatic malignancies, several researchers reported comparative oncologic outcomes (
      • Lee J.
      • Shin I.-S.
      • Yoon W.S.
      • Koom W.S.
      • Rim C.H.
      Comparisons between radiofrequency ablation and stereotactic body radiotherapy for liver malignancies: Meta-analyses and a systematic review.
      ,
      • Rim C.H.
      • Lee H.Y.
      • Kim J.S.
      • Kim H.
      Radiofrequency ablation and stereotactic body radiotherapy for hepatocellular carcinoma: should they clash or reconcile?.
      ). Notably, Kim et al. (
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: A randomized phase III trial.
      ) reported non-inferior local control in the treatment of small HCCs by delivery of proton beam therapy in ablative doses (91.3 Gy in EQD2) in a phase 3 randomized study. Certain studies based on national database reported that RFA yields favorable survival outcomes compared to those of SBRT (
      • Rajyaguru D.J.
      • Borgert A.J.
      • Smith A.L.
      • Thomes R.M.
      • Conway P.D.
      • Halfdanarson T.R.
      • et al.
      Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database.
      ); while no significant difference was noted in studies with matched cohorts (
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Der Liang J.
      • Shih Y.L.
      • Huang W.-Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ). RFA is most efficient in treating tumors <2 cm in size (
      • Lee H.
      • Heo J.S.
      • Cho Y.B.
      • Yun S.H.
      • Kim H.C.
      • Lee W.Y.
      • et al.
      Hepatectomy vs radiofrequency ablation for colorectal liver metastasis: a propensity score analysis.
      ,
      • Xu Q.
      • Kobayashi S.
      • Ye X.
      • Meng X.
      Comparison of hepatic resection and radiofrequency ablation for small hepatocellular carcinoma: a meta-analysis of 16,103 patients.
      ); however, it is less efficient in the treatment of tumors larger than 2-3 cm or for specific sublocation of the liver (e.g., subphrenic or perivascular sites), and may even pose a risk of complications (
      • Lee D.H.
      • Kim J.W.
      • Lee J.M.
      • Kim J.M.
      • Lee M.W.
      • Rhim H.
      • et al.
      Laparoscopic Liver Resection versus Percutaneous Radiofrequency Ablation for Small Single Nodular Hepatocellular Carcinoma: Comparison of Treatment Outcomes.
      ,
      • Kang T.W.
      • Lim H.K.
      • Lee M.W.
      • Kim Y-s
      • Rhim H.
      • Lee W.J.
      • et al.
      Aggressive intrasegmental recurrence of hepatocellular carcinoma after radiofrequency ablation: risk factors and clinical significance.
      ). EBRT is less affected by the location of the tumor, and it is possible to deliver a sufficient radiation dose covering tumors >2-3 cm with clinical margins (
      • Rim C.H.
      • Lee H.Y.
      • Kim J.S.
      • Kim H.
      Radiofrequency ablation and stereotactic body radiotherapy for hepatocellular carcinoma: should they clash or reconcile?.
      ). Several investigators reported that SBRT showed higher local control when treating tumors >2-3 cm in matched cohort studies, and can be advantageous for treating tumors in difficult locations (

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ).

      Local control and survival

      Our study reported that ablative RT has a better efficacy with regard to LC than RFA. Comparative OR was significant in the pooled analyses of all studies (OR:0.458, p<0.001) and HCC studies (OR:0.452, p<0.001). Similarly, the comparative OR was significant in the pooled analyses of all studies (OR:0.466, p<0.001), HCC studies (OR:0.421, p<0.001), and CRC metastasis studies (OR:0.459, p=0.006) with very low heterogeneity (I2: ∼0% in all above analyses), among studies with reliable comparability. Although not as rigid as the pooled analysis of RCT, the pooled results of studies with reliable comparability have very low heterogeneity and are consistently valid, increasing the reliability of hypothesis testing (
      • Shin I.S.
      • Rim C.H.
      Stepwise-Hierarchical Pooled Analysis for Synergistic Interpretation of Meta-analyses Involving Randomized and Observational Studies: Methodology Development.
      ). While both RFA and ablative RT confer a high LC probability for small intrahepatic malignancies, RFA might yield suboptimal LC for tumors near major vessels or the diaphragm, or those exceeding 2–3 cm in size.(
      • Lee M.W.
      • Kang D.
      • Lim H.K.
      • Cho J.
      • Sinn D.H.
      • Kang T.W.
      • et al.
      Updated 10-year outcomes of percutaneous radiofrequency ablation as first-line therapy for single hepatocellular carcinoma < 3 cm: emphasis on association of local tumor progression and overall survival.
      ,
      • Kang T.W.
      • Lim H.K.
      • Lee M.W.
      • Kim Y.S.
      • Rhim H.
      • Lee W.J.
      • et al.
      Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation: Risk Factors and Clinical Significance.
      ,
      • Lee S.
      • Kang T.W.
      • Cha D.I.
      • Song K.D.
      • Lee M.W.
      • Rhim H.
      • et al.
      Radiofrequency ablation vs. surgery for perivascular hepatocellular carcinoma: Propensity score analyses of long-term outcomes.
      ,
      • Kim Y.S.
      • Lim H.K.
      • Rhim H.
      • Lee M.W.
      • Choi D.
      • Lee W.J.
      • et al.
      Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: analysis of prognostic factors.
      ). On the other hand, ablative RT is less limited by tumor location because it does not cause mechanical damage and can provide a prescribed dose within a relatively wide range (
      • Rim C.H.
      • Lee H.Y.
      • Kim J.S.
      • Kim H.
      Radiofrequency ablation and stereotactic body radiotherapy for hepatocellular carcinoma: should they clash or reconcile?.
      ,
      • Miften M.
      • Vinogradskiy Y.
      • Moiseenko V.
      • Grimm J.
      • Yorke E.
      • Jackson A.
      • et al.
      Radiation dose‐volume effects for liver SBRT.
      ). In clinical practice, ablative RT is considered less preferred than RFA and is applied more often in recurrent settings (
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,
      • Chen L.
      • Hung S.
      • Lin H.
      • Lee M.
      • Chiou W.
      • Huang L.
      • et al.
      Comparing Radiofrequency Ablation with Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma: Analysis of 108 Cases from a Single Academic Radiotherapy Center.
      ,
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ). In some studies, patients who underwent ablative RT had less favorable clinical parameters than those who underwent RFA (
      • Shiozawa K.
      • Watanabe M.
      • Ikehara T.
      • Matsukiyo Y.
      • Kogame M.
      • Kishimoto Y.
      • et al.
      Comparison of percutaneous radiofrequency ablation and CyberKnife((R)) for initial solitary hepatocellular carcinoma: A pilot study.
      ,
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ,
      • Ji R.
      • Ng K.K.
      • Chen W.
      • Yang W.
      • Zhu H.
      • Cheung T.-T.
      • et al.
      Comparison of clinical outcome between stereotactic body radiotherapy and radiofrequency ablation for unresectable hepatocellular carcinoma.
      ,
      MULTICENTER COHORT STUDY OF THERMAL ABLATION VERSUS STEREOTACTIC BODY RADIATION THERAPY FOR HEPATOCELLULAR CARCINOMA.
      ,
      • Chen L.
      • Hung S.
      • Lin H.
      • Lee M.
      • Chiou W.
      • Huang L.
      • et al.
      Comparing Radiofrequency Ablation with Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma: Analysis of 108 Cases from a Single Academic Radiotherapy Center.
      ,
      • Nieuwenhuizen S.
      • Dijkstra M.
      • Puijk R.S.
      • Timmer F.E.
      • Nota I.M.
      • Opperman J.
      • et al.
      Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry.
      ). Considering the above, we assume that the difference in LC between modalities was due to the characteristics of the modalities rather than due to clinical differences.
      Controversy has existed on the effect on survival, of selection between RFA and ablative RT. A study based on a national database reported favorable OS in the RFA arm (
      • Rajyaguru D.J.
      • Borgert A.J.
      • Smith A.L.
      • Thomes R.M.
      • Conway P.D.
      • Halfdanarson T.R.
      • et al.
      Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database.
      ). However, it had a limitation—the data of liver fibrosis was missing in nearly 70% of patients; furthermore, many of the factors used for propensity matching were social but not clinical factors (e.g., race, location of treatment facility, etc.). In a randomized study by Kim et al. (
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial.
      ), no difference in OS was reported between ablative proton therapy and RFA. There was no difference in OS between the RFA and SBRT arms in a study that involved propensity matching in approximately 2,000 patients from five countries (
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ). In the present study, pooled analyses did not reveal a comparative difference in the overall and subgroup analyses according to the primary disease (Table 2). The survival of HCC patients is affected by several clinical factors including liver function, biological profile, previous treatment, and local control (
      • Rajyaguru D.J.
      • Borgert A.J.
      • Smith A.L.
      • Thomes R.M.
      • Conway P.D.
      • Halfdanarson T.R.
      • et al.
      Radiofrequency Ablation Versus Stereotactic Body Radiotherapy for Localized Hepatocellular Carcinoma in Nonsurgically Managed Patients: Analysis of the National Cancer Database.
      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Der Liang J.
      • Shih Y.L.
      • Huang W.-Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ). In addition, both treatment methods were effective, with a 2-year LC rate >80% in the pooled analyses (Table 3). Therefore, investigating OS differences based only on the selection of local modalities might be difficult. Although the pooled analyses and the majority of individual studies reported no significant difference, future randomized studies are needed to define the effect of selection between the two modalities on OS.

      Feasibility considering tumor location and size

      Overall grade ≥3 complication rates in the pooled analyses were <3% in both modalities (RFA:2.9%; ablative RT 2.8%, p=0.952), indicating their feasibility. The characteristics of the complications were different between the two methods: most of the toxicities caused by RFA were due to mechanical damage, whereas ablative RT mainly caused hepatic or gastrointestinal damage.
      Because RFA mainly causes mechanical complications, tumor location significantly affects treatment safety and efficacy. Cao et al. (
      • Cao S.
      • Lyu T.
      • Fan Z.
      • Guan H.
      • Song L.
      • Tong X.
      • et al.
      Long-term outcome of percutaneous radiofrequency ablation for periportal hepatocellular carcinoma: tumor recurrence or progression, survival and clinical significance.
      ) reported a major complication rate of 10.7% after RFA for periportal HCCs, which was higher than that of non-periportal controls (5.1%). Kang et al. (
      • Kang T.W.
      • Lim H.K.
      • Lee M.W.
      • Kim Y.S.
      • Rhim H.
      • Lee W.J.
      • et al.
      Aggressive Intrasegmental Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation: Risk Factors and Clinical Significance.
      ) reported that aggressive intrasegmental recurrence occurred in 15% of periportal tumors after RFA because of thermal damage to the intrahepatic vessels. Song et al. (
      • Song K.D.
      • Lim H.K.
      • Rhim H.
      • Lee M.W.
      • Kang T.W.
      • Paik Y.H.
      • et al.
      Hepatic resection vs percutaneous radiofrequency ablation of hepatocellular carcinoma abutting right diaphragm.
      ) reported 9.5% of peritoneal seeding after RFA for subphrenic tumors and a local tumor progression rate of 37.8% at 3 years. Lee et al. (
      • Lee M.W.
      • Kang D.
      • Lim H.K.
      • Cho J.
      • Sinn D.H.
      • Kang T.W.
      • et al.
      Updated 10-year outcomes of percutaneous radiofrequency ablation as first-line therapy for single hepatocellular carcinoma < 3 cm: emphasis on association of local tumor progression and overall survival.
      ) reported that the local recurrence risk was significantly higher after RFA for HCCs in the periportal location (HR:2.29) and subphrenic location (HR:2.25). The higher recurrence risk related to difficult locations and could be owing to suboptimal ablation to avoid possible complications or the heat-sink effect for perivascular tumors (i.e., ineffective thermal ablation hindered by blood flow) (
      • Lee S.
      • Kang T.W.
      • Cha D.I.
      • Song K.D.
      • Lee M.W.
      • Rhim H.
      • et al.
      Radiofrequency ablation vs. surgery for perivascular hepatocellular carcinoma: Propensity score analyses of long-term outcomes.
      ,
      • Cao S.
      • Lyu T.
      • Fan Z.
      • Guan H.
      • Song L.
      • Tong X.
      • et al.
      Long-term outcome of percutaneous radiofrequency ablation for periportal hepatocellular carcinoma: tumor recurrence or progression, survival and clinical significance.
      ,
      • Lin Z.-Y.
      • Li G.-L.
      • Chen J.
      • Chen Z.-W.
      • Chen Y.-P.
      • Lin S.-Z.
      Effect of heat sink on the recurrence of small malignant hepatic tumors after radiofrequency ablation.
      ).
      Ablative RT uses X-ray beams from multiple directions, which penetrate the body and accumulate in the target tumor (
      • Rubio C.
      • Morera R.
      • Hernando O.
      • Leroy T.
      • Lartigau S.E.
      Extracranial stereotactic body radiotherapy. Review of main SBRT features and indications in primary tumors.
      ). Since cell death by X-rays is biological death due to DNA damage, direct mechanical or thermal damage does not occur (
      • Rubio C.
      • Morera R.
      • Hernando O.
      • Leroy T.
      • Lartigau S.E.
      Extracranial stereotactic body radiotherapy. Review of main SBRT features and indications in primary tumors.
      ,

      Khan FM, Gibbons JP. Khan's the physics of radiation therapy: Lippincott Williams & Wilkins; 2014.

      ). Normal organs have various radiation tolerances; the major vessel can tolerate radiation doses as high as ≥90 Gy in EQD2 clinically, and partial fibrosis does not alter blood flow (
      • Xue J.
      • Kubicek G.
      • Patel A.
      • Goldsmith B.
      • Asbell S.O.
      • LaCouture T.A.
      Validity of Current Stereotactic Body Radiation Therapy Dose Constraints for Aorta and Major Vessels.
      ,
      • Rim C.H.
      • Yoon W.S.
      Leaflet manual of external beam radiation therapy for hepatocellular carcinoma: a review of the indications, evidences, and clinical trials.
      ,
      • Evans J.D.
      • Gomez D.R.
      • Amini A.
      • Rebueno N.
      • Allen P.K.
      • Martel M.K.
      • et al.
      Aortic dose constraints when reirradiating thoracic tumors.
      ). Application of ablative RT to subphrenic tumors rarely induces pulmonary plural toxicities because radiation can cause partial fibrosis or atrophy but not rupture (

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,
      • Sioshansi S.
      • Rava P.
      • Karam A.
      • Ding L.
      • FitzGerald T.
      Tolerance Dose of the Diaphragm With Liver SBRT.
      ); therefore, organ functions can be maintained. Therefore, ablative RT is often administered to tumors in locations where it is difficult to perform RFA. Several studies have reported that SBRT arms showed higher (
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Der Liang J.
      • Shih Y.L.
      • Huang W.-Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ) or similar LC (
      • Ji R.
      • Ng K.K.
      • Chen W.
      • Yang W.
      • Zhu H.
      • Cheung T.-T.
      • et al.
      Comparison of clinical outcome between stereotactic body radiotherapy and radiofrequency ablation for unresectable hepatocellular carcinoma.
      ) although they had more target tumors in difficult locations. Similarly, Kim et al. (
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ) and Jeong et al. (
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ) reported that difficult locations (e.g., subphrenic or perivascular) were related to inferior LC after RFA but not after SBRT.
      As tumor size increases, it might have a biologically aggressive profile, and the presence of microinvasion or subclinical satellite nodules is frequent (
      • Ke S.
      • Ding X.M.
      • Qian X.J.
      • Zhou Y.M.
      • Cao B.X.
      • Gao K.
      • et al.
      Radiofrequency ablation of hepatocellular carcinoma sized > 3 and ≤ 5 cm: is ablative margin of more than 1 cm justified?.
      ,
      • Ikeda K.
      • Seki T.
      • Umehara H.
      • Inokuchi R.
      • Tamai T.
      • Sakaida N.
      • et al.
      Clinicopathologic study of small hepatocellular carcinoma with microscopic satellite nodules to determine the extent of tumor ablation by local therapy.
      ). For large tumors, it is difficult to secure sufficient ablative margins because of the possible risk of damage to the heat-sink effects in adjacent organs (
      • Ke S.
      • Ding X.M.
      • Qian X.J.
      • Zhou Y.M.
      • Cao B.X.
      • Gao K.
      • et al.
      Radiofrequency ablation of hepatocellular carcinoma sized > 3 and ≤ 5 cm: is ablative margin of more than 1 cm justified?.
      ,
      • Dodd 3rd, G.D.
      • Frank M.S.
      • Aribandi M.
      • Chopra S.
      • Chintapalli K.N.
      Radiofrequency thermal ablation: computer analysis of the size of the thermal injury created by overlapping ablations.
      ). For HCCs ≥3 cm in size, the local recurrence rate of RFA has been reported to be 30–50% (
      • Kim Y.S.
      • Lim H.K.
      • Rhim H.
      • Lee M.W.
      • Choi D.
      • Lee W.J.
      • et al.
      Ten-year outcomes of percutaneous radiofrequency ablation as first-line therapy of early hepatocellular carcinoma: analysis of prognostic factors.
      ). When ablative RT is applied to liver tumors, the blood vessels or bile ducts can tolerate the radiation dose required for treatment (
      • Rim C.H.
      • Kim H.J.
      • Seong J.
      Clinical feasibility and efficacy of stereotactic body radiotherapy for hepatocellular carcinoma: A systematic review and meta-analysis of observational studies.
      ). Therefore, ablative RT could be performed with clinical margins covering subclinical disease for patients with preserved liver function and tumors with a distance of 1-2 cm from the small bowel, which is less affected by tumor size. Accordingly, in our systematic review, SBRT showed better LC for treatment of intrahepatic tumors >2 cm in size (
      • Wahl D.R.
      • Stenmark M.H.
      • Tao Y.
      • Pollom E.L.
      • Caoili E.M.
      • Lawrence T.S.
      • et al.
      Outcomes After Stereotactic Body Radiotherapy or Radiofrequency Ablation for Hepatocellular Carcinoma.
      ,
      • Kim N.
      • Kim H.J.
      • Won J.Y.
      • Kim D.Y.
      • Han K.H.
      • Jung I.
      • et al.
      Retrospective analysis of stereotactic body radiation therapy efficacy over radiofrequency ablation for hepatocellular carcinoma.
      ,
      • Jackson W.C.
      • Tao Y.
      • Mendiratta-Lala M.
      • Bazzi L.
      • Wahl D.R.
      • Schipper M.J.
      • et al.
      Comparison of Stereotactic Body Radiation Therapy and Radiofrequency Ablation in the Treatment of Intrahepatic Metastases.
      ,

      Yu J, Kim DH, Lee J, Shin YM, Kim JH, Yoon SM, et al. Radiofrequency Ablation versus Stereotactic Body Radiation Therapy in the Treatment of Colorectal Cancer Liver Metastases. Cancer Research and Treatment. 2021.

      ); however, tumor size > 3 cm showed inferior LC with RFA but not with SBRT (
      • Nieuwenhuizen S.
      • Dijkstra M.
      • Puijk R.S.
      • Timmer F.E.
      • Nota I.M.
      • Opperman J.
      • et al.
      Thermal Ablation versus Stereotactic Ablative Body Radiotherapy to Treat Unresectable Colorectal Liver Metastases: A Comparative Analysis from the Prospective Amsterdam CORE Registry.
      ,
      • Kim N.
      • Cheng J.
      • Jung I.
      • Liang J.
      • Shih Y.L.
      • Huang W.Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ). LC being similar between modalities for treatment of small tumors (<2–3 cm) was shown as well (
      • Ueno M.
      • Takabatake H.
      • Itasaka S.
      • Kayahara T.
      • Morimoto Y.
      • Yamamoto H.
      • et al.
      Stereotactic body radiation therapy versus radiofrequency ablation for single small hepatocellular carcinoma: a propensity-score matching analysis of their impact on liver function and clinical outcomes.
      ,
      • Kim T.H.
      • Koh Y.H.
      • Kim B.H.
      • Kim M.J.
      • Lee J.H.
      • Park B.
      • et al.
      Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial.
      ,
      MULTICENTER COHORT STUDY OF THERMAL ABLATION VERSUS STEREOTACTIC BODY RADIATION THERAPY FOR HEPATOCELLULAR CARCINOMA.
      ,
      • Jeong Y.
      • Lee K.J.
      • Lee S.J.
      • Shin Y.M.
      • Kim M.J.
      • Lim Y.S.
      • et al.
      Radiofrequency ablation versus stereotactic body radiation therapy for small (≤ 3 cm) hepatocellular carcinoma: a retrospective comparison analysis.
      ,
      • Hara K.
      • Takeda A.
      • Tsurugai Y.
      • Saigusa Y.
      • Sanuki N.
      • Eriguchi T.
      • et al.
      Radiotherapy for Hepatocellular Carcinoma Results in Comparable Survival to Radiofrequency Ablation: A Propensity Score Analysis.
      ).
      In summary, ablative RT could be more effective than RFA for treatment of tumors in difficult locations or with relatively large sizes. However, ablative RT should be cautiously applied to tumors near the small bowel or in patients with impaired liver function.

      Limitations and future perspectives

      Since most of the included studies were non-randomized, heterogeneity in clinical and methodological aspects could not be entirely overcome. For example, when analyzing the effectiveness of treatment modalities according to tumor size, the reference size was not constant among studies, and the statistical methods and effect measures were also different. The definition of difficult location was subjective, and only one study (
      • Kim N.
      • Cheng J.
      • Jung I.
      • Der Liang J.
      • Shih Y.L.
      • Huang W.-Y.
      • et al.
      Stereotactic body radiation therapy vs. radiofrequency ablation in Asian patients with hepatocellular carcinoma.
      ) provided values of oncologic outcome according to specific location. In addition, heterogeneity in treatment outcomes could exist between previously treated and treatment-naïve tumors. Although most studies did not report segregated results, future studies are expected to report separate results to enable subgroup analyses. Regarding RFA arms, we included the studies with subject of thermal ablation including both RFA and MWA. Although the two modalities are similar in applying thermal damage to the tissue using a needle, MWA is reported to be effective for relatively larger tumors and is less affected by the heat-sink effect (
      • Wang Z.
      • Liu M.
      • Zhang D.Z.
      • Wu S.S.
      • Hong Z.X.
      • He G.B.
      • et al.
      Microwave ablation versus laparoscopic resection as first-line therapy for solitary 3-5-cm HCC.
      ). MWA cases must be separated into subgroups and evaluated if the relevant literature increases.
      Many clinical decisions inevitably rely on information obtained from observational studies, particularly in the field of oncology. To the best possible extent, we performed an evidence-grading review for possible subjective outcomes, quantitative analyses for major oncologic outcomes, subgroup analyses, and formal heterogeneity assessments. Since sufficient information from randomized studies is lacking, integration of clinical outcomes through quantitative and qualitative meta-analysis could be an alternative route to help in clinical decision-making (
      • Frieden T.R.
      Evidence for health decision making—beyond randomized, controlled trials.
      ,
      • Shin I.-S.
      • Rim C.H.
      Updating Perspectives on Meta-Analyses in the Field of Radiation Oncology.
      ).
      Our study suggests that ablative RT can yield oncologic outcomes similar to that with RFA and that ablative RT can be more effective for tumors in locations where it is difficult to perform RFA or in cases of large-sized tumors. However, no standardized guidance exists to clarify the indications for RFA and ablative RT. Therefore, it is necessary to establish a decision criteria for selecting optimum modality between the two, considering the efficacy and feasibility according to specific location, tumor size, and other clinical circumstances. Since ablative RT has been commonly applied as salvage therapy, further studies are needed to compare the efficacy of the two modalities in recurrent and primary treatment settings. Since a randomized study has been limited to only one that compared proton therapy and RFA, future randomized trials involving SBRT and RFA arms are warranted to obtain more robust conclusions.

      Author contributions

      Conception and study design: J Seong.
      Data collection: Rim CH, Lee JS, Kim SY.
      Analysis: Rim CH.
      Drafting: Rim CH.
      Editing and supervision: J Seong.
      Final approval: All authors.

      Ethical Statement

      The authors are accountable for all aspects of the work and for ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

      Conflicts of Interest

      Conflict of interest relevant to this article was not reported.

      Data availability Statement

      Data available within the article or its supplementary materials.

      Acknowledgments

      This study was supported by the Research Supporting Program of the Korean Association for the Study of the Liver and the Korean Liver Foundation. This study was supported by National Research Fund of Korea (NRF-2021R1I1A2047475).

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

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