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Systematic review of adjuvant external beam radiotherapy for hepatocellular carcinoma following radical hepatectomy

  • Author Footnotes
    1 Authors contributed equally in this study.
    Lei Wang
    Footnotes
    1 Authors contributed equally in this study.
    Affiliations
    Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
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  • Author Footnotes
    1 Authors contributed equally in this study.
    Lu Qiu
    Footnotes
    1 Authors contributed equally in this study.
    Affiliations
    Department of Radiation Oncology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China
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  • Author Footnotes
    1 Authors contributed equally in this study.
    Qiao Ke
    Footnotes
    1 Authors contributed equally in this study.
    Affiliations
    Department of Hepatopancreatobiliary Surgery, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
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  • Hongbing Ji
    Correspondence
    Corresponding authors at: Mengchao Hepatobiliary Hospital of Fujian Medical University. Fuzhou 350025, Fujian, China (H. Ji); Fujian Cancer Hospital. Fuzhou 350025, Fujian, China.
    Affiliations
    Department of Radiation Oncology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
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  • Junxin Wu
    Correspondence
    Corresponding authors at: Mengchao Hepatobiliary Hospital of Fujian Medical University. Fuzhou 350025, Fujian, China (H. Ji); Fujian Cancer Hospital. Fuzhou 350025, Fujian, China.
    Affiliations
    Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
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  • Author Footnotes
    1 Authors contributed equally in this study.
Open AccessPublished:August 20, 2022DOI:https://doi.org/10.1016/j.radonc.2022.08.019

      Highlights

      • The first review of EBRT following hepatectomy patients with high recurrence risk.
      • Silver markers should be retained in the procedure of hepatectomy.
      • Adjuvant EBRT (50-60Gy) should be carried out within 4-6 weeks after surgery.

      Abstract

      Background and aim

      Recurrence remains the main bottleneck hindering outcomes of hepatectomy for hepatocellular carcinoma (HCC). Owing to technological advances, external beam radiotherapy (EBRT) is being increasingly used in the management of HCC; however, there is no consensus on the role of adjuvant EBRT following hepatectomy.

      Methods

      A systematic review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. PubMed, MedLine, Embase, the Cochrane Library, Web of Knowledge were used to screen eligible studies (published as of May 1st, 2022) that evaluated the clinical safety and efficacy of EBRT for HCC receiving hepatectomy. The endpoints were disease-free survival (DFS), overall survival (OS), and adverse events (AEs).

      Results

      A total of ten studies were eligible (three randomized controlled trials, one phase II trial, and six retrospective comparative studies). The pooled hazard ratio (HR) for median DFS and OS were both in favor of adjuvant EBRT compared with surgery alone (all P < 0.05), and the advantage of adjuvant EBRT was also confirmed in subgroups stratified by different populations (narrow margin, P < 0.05; microvascular invasion, P < 0.05; portal vein tumor thrombus, P < 0.05) and study designs (prospective studies, P < 0.05; retrospective studies, P < 0.05). Adjuvant EBRT was also found to be superior to adjuvant TACE (P < 0.05). Pooled rates of overall AEs and severe AEs were 65.3% and 12.2%, but no fatal AEs were reported.

      Conclusion

      Adjuvant EBRT can be considered for HCC patients, especially those with a high risk of recurrence. Further studies are required for validation of these findings.

      Keywords

      Hepatectomy is still the most cost-effective curative treatment for hepatocellular carcinoma (HCC), but local recurrence remains the dominant pattern of treatment failures, with 5-year recurrence rate as high as 70% [
      • Benson A.B.
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      Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition).
      ]. In addition, with the improvement of perioperative management, promotion of neoadjuvant treatment, and rise of conversion therapy, an increasing number of patients with lesions adjacent to major vessel or those with BCLC III stage disease have received hepatectomy, with an increased risk of marginal resection and local recurrence [
      • Zheng K.
      • He D.
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      • Wu H.
      • Yang J.
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      Laparoscopic segmentectomy IV using hepatic round ligament approach combined with fluorescent negative staining method.
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      • Komatsu S.
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      Impact of hepatectomy for advanced hepatocellular carcinoma with major portal vein tumor thrombus.
      ,
      • Chen Z.H.
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      • Guo W.X.
      • et al.
      Liver resection versus intensity-modulated radiation therapy for treatment of hepatocellular carcinoma with hepatic vein tumor thrombus: a propensity score matching analysis.
      ]. Consequently, it is imperative to search for efficacious adjuvant treatments for patients receiving hepatectomy.
      However, there is no clear consensus on the management of adjuvant therapy (AT) for HCC. Radiotherapy (RT) is widely used to treat cancers [
      • Le Pechoux C.
      • Pourel N.
      • Barlesi F.
      • Lerouge D.
      • Antoni D.
      • Lamezec B.
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      ,
      • Supiot S.
      • Vaugier L.
      • Pasquier D.
      • Buthaud X.
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      • Peiffert D.
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      OLIGOPELVIS GETUG P07, a multicenter phase II trial of combined high-dose salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses in prostate cancer.
      ], and liver is no longer a contraindication for RT due to the advances in RT techniques and improved understanding of liver tolerance to RT [
      • 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.
      ]. Novel external beam RT (EBRT) techniques such as three-dimensional conformal RT (3D-CRT), intensity-modulated radiation therapy (IMRT), and stereotactic body RT (SBRT) have helped to achieve satisfactory local control rates (71.4–93.8%) in patients with unresectable HCC [
      • Park H.C.
      • Seong J.
      • Han K.H.
      • Chon C.Y.
      • Moon Y.M.
      • Suh C.O.
      Dose-response relationship in local radiotherapy for hepatocellular carcinoma.
      ,
      • Lim D.H.
      • Lee H.
      • Park H.C.
      • Lee J.A.
      • Kim S.W.
      • Yoo B.C.
      • et al.
      The efficacy of high-dose 3-dimensional conformal radiation therapy in patients with small hepatocellular carcinoma not eligible for other local modalities.
      ]. On the other hand, adjuvant EBRT has been recommended as the standard treatment for patients receiving radical surgery, but with high risk of recurrence in many types of malignant cancers [
      • Krug D.
      • Baumann R.
      • Krockenberger K.
      • Vonthein R.
      • Schreiber A.
      • Boicev A.
      • et al.
      Adjuvant hypofractionated radiotherapy with simultaneous integrated boost after breast-conserving surgery: results of a prospective trial.
      ,
      • Shimoyama R.
      • Nakagawa K.
      • Ishikura S.
      • Wakabayashi M.
      • Sasaki T.
      • Yoshioka H.
      • et al.
      A multi-institutional randomized phase III trial comparing postoperative radiotherapy to observation after adjuvant chemotherapy in patients with pathological N2 Stage III non-small cell lung cancer: Japan Clinical Oncology Group Study JCOG1916 (J-PORT study).
      ]. Internal radiation therapy (IRT) has long been used as a postoperative adjuvant treatment for HCC with promising results, including 131I-lipiodol radioembolization [
      • Lau W.Y.
      • Lai E.C.
      • Leung T.W.
      • Yu S.C.
      Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial-update on 5-year and 10-year survival.
      ], 131I-metuximab for radioimmunotherapy [
      • Li J.
      • Xing J.
      • Yang Y.
      • Liu J.
      • Wang W.
      • Xia Y.
      • et al.
      Adjuvant (131) I-metuximab for hepatocellular carcinoma after liver resection: a randomised, controlled, multicentre, open-label, phase 2 trial.
      ], and iodine-125 for brachytherapy [
      • Chen K.
      • Xia Y.
      • Wang H.
      • Xiao F.
      • Xiang G.
      • Shen F.
      Adjuvant iodine-125 brachytherapy for hepatocellular carcinoma after complete hepatectomy: a randomized controlled trial.
      ]. However, there is a paucity of data on adjuvant EBRT.
      Yu et al [
      • Yu W.
      • Wang W.
      • Rong W.
      • Wang L.
      • Xu Q.
      • Wu F.
      • et al.
      Adjuvant radiotherapy in centrally located hepatocellular carcinomas after hepatectomy with narrow margin (<1 cm): a prospective randomized study.
      ] first reported the feasibility of adjuvant 3D-CRT for centrally-located HCC with narrow margin in a single center randomized controlled trial (RCT). However, they found no significant differences in disease-free survival (DFS) and overall survival (OS) between patients receiving adjuvant 3D-CRT or not. However, in an open-label RCT by Sun et al [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ], adjuvant IMRT was found to significantly improve the recurrence-free survival (RFS) and OS of HCC patients with portal vein tumor thrombus (PVTT) compared with surgery alone. Similarly, Shi et al [
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ] identified the anti-recurrence efficacy of adjuvant IMRT following marginal resection for HCC patients with microvascular invasion (MVI) in a superiority RCT. Nonetheless, adjuvant EBRT is not commonly used in clinical settings owing to the uncertain efficacy and concerns pertaining to toxicity [
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ]. Hence, we conducted a systematic review and meta-analysis to synthesize the evidence of the safety and efficacy of adjuvant EBRT for HCC patients receiving hepatectomy.

      Materials and methods

      This systematic review was conducted according to the preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), which was also registered at https://www.crd.york.ac.uk/PROSPERO/ (Review registry CRD42022332532).

      Literature search

      A comprehensive literature search was performed using PubMed, MedLine, Embase, Web of Science, and the Cochrane Library to screen eligible studies published in English language as of May 1st, 2022. All studies evaluating the safety and efficacy of adjuvant EBRT for HCC receiving hepatectomy were eligible regardless of whether they were retrospective or prospective.

      Eligibility criteria

      Inclusion criteria: (i) patients with a pathological diagnosis of HCC; (ii) patients receiving hepatectomy; (iii) arms must include patients receiving adjuvant EBRT, regardless of the modality; and (iv) endpoints must include at least one of the following: DFS, OS, and adverse events (AEs).
      Exclusion criteria: (i) population included cholangiocarcinoma or metastatic liver cancer; (ii) patients receiving other adjuvant treatment modality; (iii) duplicate report derived from the same RCT; (iv) data unavailable; and (v) reviews, comments, case reports, or case-series reports.

      Definition of endpoints

      DFS was defined as the time from resection to recurrence or last follow-up, while OS was the time from resection to death or last follow-up.
      Severe AEs were defined as AEs grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

      Data extraction

      According to the predefined protocols, information of each study, including the surname of the first author, year of publication, study period, and baseline characteristics in each arm (sample size, age, sex, population characteristics, and radiation schedule) were independently extracted by two researchers (Lei Wang and Lu Qiu). The hazard ratios (HRs) for DFS or OS were extracted from multivariate analysis or calculated from the Kaplan-Meier curves using Engauge Digitizer 4.1 software [
      • Tierney J.F.
      • Stewart L.A.
      • Ghersi D.
      • Burdett S.
      • Sydes M.R.
      Practical methods for incorporating summary time-to-event data into meta-analysis.
      ,
      • Parmar M.K.
      • Torri V.
      • Stewart L.
      Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.
      ]. In case of any disagreement, the final decision was reached with participation of a third investigator, Qiao Ke.

      Quality assessment

      The quality of non-randomized studies was determined according to the modified Newcastle-Ottawa Scale (NOS) [
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      ]. Briefly, a study with 0–3 stars was considered to be of low quality, 3–6 stars was considered indicative of medium quality, and ≥7 stars was considered indicative of high quality. The quality of RCTs was determined based on the Cochrane Handbook [

      Higgins JP, Altman DG. Assessing risk of bias in included studies; 2008.

      ], and a trial with a total score of 0–2 was regarded as low-quality, whereas  >2 was considered indicative of high-quality.

      Statistical analysis

      The primary endpoints in this meta-analysis were DFS and OS, which were determined by HR with 95% confidence interval (CI); the secondary endpoint was AEs, which were determined using odds ratio (OR) with 95% CI. Heterogeneity among the included studies was assessed using χ2 test and I2 statistic; P > 0.10 and I2 < 50% was considered indicative of no significant heterogeneity. In case of significant heterogeneity (P < 0.10 and I2 > 50%), the random-effect model was used to estimate the effect size; if not, the fixed-effect model was used [
      • Higgins T.J.P.
      Measuring inconsistency in meta-analyses.
      ]. Sensitivity analysis was carried out to verify the stability of the results. Publication bias was determined using Begg’s and Egger’s tests, and the “trim and fill” method was conducted in case there was apparent publication bias. All statistical analyses in this meta-analysis were performed using RevMan Version 5.3 and Stata 14, and two-tailed P values < 0.05 were considered indicative of statistical significance.

      Results

      A total of 968 records were identified using electronic database. Of these, 73 records were excluded because of duplication, and 895 were excluded after screening of titles and abstracts. Then, 33 were excluded due to the following reasons: 26 because of adjuvant international radiotherapy, one because the updated data was available in a latter publication, two because of use of concomitant internal radiotherapy, one for non-clinical study, and three were excluded because these were review articles or comments. Finally, 10 studies were found eligible for this systematic review [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ,
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      ,

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ], including one Abstract published in collection of the Asian Pacific Association for the Study of the Liver in 2022 (Fig. 1) [

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ].
      Figure thumbnail gr1
      Fig. 1Flowchart of study selection for systematic review.
      Among the included studies, one was single arm phase II study [
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      ], and the remaining nine were comparative studies including six comparing adjuvant EBRT versus surgery alone [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ,

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ], one comparing adjuvant EBRT versus TACE [
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      ], and two comparing adjuvant EBRT, TACE versus surgery alone [
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ], respectively. The study object was HCC with narrow margin, HCC with MVI, and HCC with PVTT. The baseline characteristics of the included studies are summarized in Table 1. Notably, all the included studies were conducted in China and almost all of them were single-center studies. Among all, eight were assessed as high-quality ones [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ,
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      ] and two were medium-quality ones [
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ].
      Table 1Clinicopathological characteristics of the included studies.
      StudiesYearDesignPopulationTreatmentPatientsAgeSexTumor sizeTumor numberMean DFSP-valueDFS RateMean OSP-valueOS RateQuality
      (years)(M/F)(cm)(S/M)(months)(1/2/3/5years)(months)(1/2/3/5years)
      Wang 2015
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      2007–2011RNarrow-margin

      Close to major vessels
      Adjuvant EBRT3355(27–74)31/231/2 (10 cm)31/2NA0.03881.8/72.7/64.2/–NA0.009100/93.9/89.1/–H
      Surgery only8354(31–79)68/1577/6 (10 cm)72/11NA61.4/54.2/52.2/–NA89.2/71.1/67.7/–
      Bai 2016
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      2009–2010RPVTT (I/II)Adjuvant EBRT1047 ± 169/111 ± 67/3 (≤2/>2)14.0 ± 2.40.004

      0.078*
      67.7/–/–/–14.5 ± 1.60.017 0.716*71.1/–/–/–M
      Adjuvant

      TACE
      3148 ± 1529/210 ± 425/6 (≤2/>2)14.0 ± 3.40.01428.8/–/–/–21.9 ± 3.6<0.00153.3/31.8/–/–
      Surgery only5149 ± 1145/612 ± 742/9 (≤2/>2)6.5 ± 1.49.9/–/–/–9.0 ± 1.019.6/6.1/–/–
      Wang 2017
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      2008–2015RMVIAdjuvant EBRT4451.3 ± 11.239/55.63 ± 2.7341/325.47<0.001

      0.011*
      66.7/52.8/45.5/–72.54<0.001

      0.034*
      90.2/80.6/72.9/–H
      Adjuvant TACE4251.4 ± 10.934/86.15 ± 3.6538/47.410.58936.2/30.7/26.8/–28.850.16486.7/53.0/43.7/–
      Surgery only5057.2 ± 11.145/55.71 ± 2.6046/49.2137.4/14.8/11.1/–25.3769.0/50.4/28.1/–
      Wang 2019
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      2008–2016R

      PSM
      MVIAdjuvant EBRT4650.98 ± 10.5343/35.39 ± 2.7442/425.74 ± 8.120.00371.7/56.2/44.0/–60.69 ± 7.360.26293.4/80.6/70.7/H
      Adjuvant

      TACE
      4651.52 ± 11.4037/95.50 ± 3.0741/59.18 ± 1.6739.1/25.0/20.836.53 ± 5.3481.4/61.3/48.4
      Sun 2019
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      2013–2016RCTPVTT(I/II/III/IV)Adjuvant EBRT2649.6 ± 7.724/222/4 (5 cm)25/19.1 ± 1.60.00115.3/7.7/7.7/–18.9 ± 1.80.00576.9/19.2/11.5/–H
      Surgery only2651.1 ± 10.824/225/1 (5 cm)24/24.1 ± 0.53.8/0/0/–10.8 ± 1.326.9/11.5/3.8/–
      Wang 2020
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      2005–2018CCTMVIAdjuvant EBRT2955.90 ± 8.0524/54.75 ± 2.1527/241.770.00686.2/70.5/63.4/–38.110.00496.6/80.7/80.7/–H
      Surgery only3056.57 ± 9.4325/54.50 ± 2.9828/210.2646.4/36.1/36.1/–25.4479.7/58.3/50/–
      Rong 2020
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      2007–2012RCTNarrow-margin

      Central HCC
      Adjuvant EBRT5853.1 ± 10.551/74.7 ± 2.652/6NA0.03081.0/70.8/60.3/43.9NA0.26096.6/84.5/79.3/54.7H
      Surgery only6155.5 ± 10.748/135.6 ± 3.753/8NA71.7/50.8/44.2/35.8NA90.2/70.5/67.2/55.1
      Chen 2021
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      2008–2016Phase 2Narrow-marginAdjuvant EBRT7653(27–90)67/94.2(1–15)74/2NA-85.5/71.1/68.1/51.6NA-100/94.7/88.2/72.2H
      Shi 2022
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      2015–2016RCTMVI

      Narrow-margin
      Adjuvant EBRT3856.42 ± 10.4433/54.87 ± 2.03NANA0.00592.1/71.1/65.8/56.1NA0.053100/97.4/89.5/75H
      Surgery only3855.74 ± 10.1932/64.88 ± 2.46NANA76.3/57.9/36.8/26.3NA100/89.5/68.4/53.7
      Gou 2022

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      2011–2020R

      PSM
      Narrow-marginAdjuvant EBRT78NANANA61/1737.30.01189.7/65.4/47.4/12.872.50.02897.4/85.9/70.5/35.9M
      Surgery only78NANANA65/1324.074.4/51.3/38.5/14.152.596.2/70.5/62.8/24.3
      Notes: HCC, hepatocellular carcinoma; EBRT, external beam radiotherapy; R, Retrospective; RCT, randomized controlled trial; CCT, controlled clinical trial; PSM, propensity score matching; MVI, microvascular invasion; PVTT, portal vein tumor thrombus; M, male; F, female; S, single; M, multiple; DFS, disease-free survival time; OS, overall survival time; *, the p-value for adjuvant EBRT versus adjuvant TACE; NA, not available; M, medium; H, high.
      DFS was evaluated in all the included studies, as well as OS [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ,
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      ,

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ]. The median DFS and OS were reported in six comparative studies [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      ,

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ], including one study on narrow margin [

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ], three studies on MVI [
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      ], and two studies on PVTT [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ]. Significant difference in terms of DFS between adjuvant EBRT and surgery alone was reported in all the included six studies, regardless of presence of narrow margin, MVI, or PVTT (P < 0.05 for all, Table 1). The clinical results of the studies are exhibited in Table 1.
      Table 2 presents the regimens and parameters of adjuvant EBRT in each of the included study, including the modality, interval time between RT and surgery, dose/fractions, clinical tumor volume (CTV), planned tumor volume (PTV), and dose limitation of organs at risk (OAR). Of note, SBRT was adopted in one RCT, the majority interval time was 4–6 weeks after surgery, and the biologically effective dose (BED) on CTV ranged from 60 to 72 Gy.
      Table 2The regimes and parameters of adjuvant external beam radiotherapy in included studies.
      StudiesType for EBRTInitial timeDosesCTVPTVDose limitation of OAR
      Wang 2015
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      IMRT4–6 weeks after surgery50–60 Gy, and been given in daily dose fractions of 2 Gy, 5 days per week, BED of 64.8–72 Gytumour bed (indicated by silver markers) plus a 1.0-cm marginexpanding the clinical target volume by 0.5 cm in the anterior–posterior and left–right directions and by 1.0 cm in the cranial–caudal directionnormal liver (total liver volume minus gross tumour volume): mean dose ≤ 23 Gy stomach and duodenum: <54 Gy

      colon: <55 Gy

      Cord: <40 Gy

      Kidney: The volume receiving a dose ≥ 20 Gy (V20) was < 50%
      Bai 2016
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      3DCRT4 weeks after surgeryTotal radiation dose was around

      40 Gy (range 32–48 Gy)

      A daily fraction of 2.0–3.0 Gy was delivered four times per week
      resection margin and portal veinNANA
      Wang 2017
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      IMRT/3DCRT8 weeks after surgery54–60 Gy

      2 Gy/fraction, 5 fractions, BED of 64.8–72 Gy
      tumor cutting bed expands a 1-cm marginCTV added by 0.5 to 1 cmNA
      Wang 2019
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      IMRT/3DCRT8 weeks after surgery54–60 Gy

      2 Gy/fraction, 5 fractions, BED of 64.8–72 Gy
      tumor cutting bed expands a 1-cm marginCTV added by 0.5 to 1 cmNA
      Sun 2019
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      IMRT4 weeks after surgery50 Gy

      200 cGy/fraction, 5 days per week, BED of 60 Gy
      liver parenchymal transection bed plus a 1-cm margin, plus the main trunk of the right and left portal veins0.5 cm margin in the left–right and anterior–posterior directions, and by 1.0 cm in the cranial–caudal direction on the basis of CTVNormal liver: A mean dose was limited to <23 Gy and no more than 30% of the normal liver was exposed to > 30 Gy.

      Stomach and duodenum: <54 Gy

      Colon: <55 Gy

      Spinal cord: <40 Gy
      Wang 2020
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      IMRT4–6 weeks after surgery54–60 Gy

      2 Gy per fraction for 5 days (fraction) per week, BED of 64.8–72 Gy
      the tumor cutting bed, indicated by postoperative CT/MR, with a 1-cm margin in three dimensionsa margin of 1.0 cm was added in cranial-caudal directions and 0.5 cm in other directions to generate the planning target volume (PTV) by expanding CTVNormal liver: A mean dose was limited to <24 Gy; Stomach and duodenum: <54 Gy

      Colon: <55 Gy

      Spinal cord: <40 Gy;

      Kidney: V20 of left and right kidney was ≤30%
      Rong 2020
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      3DCRT4–6 weeks after surgery60 Gy delivered using 2 Gy/fraction, 5 d per weektumor cutting bed plus a 1-cm marginexpanded by 0.5 to 1 cmNA
      Chen 2021
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      IMRT4–6 weeks after surgery50–60 Gy in 25–30 fractions over 5–6 weeks, BED of 60–72 Gytumor bed (indicated by silver markers and changes of postoperative imaging) plus a 1.0-cm margin and a 1.5-cm margin in regions where the tumor adhered to major vascular structuresincluded a 0.5-cm margin in the anterior–posterior and left–right directions and a 1.0-cm margin in the cranial–caudal direction around the CTVwhole liver, mean dose ≤ 24 Gy; stomach and duodenum, maximum dose ≤ 54 Gy, V50 ≤ 10 mL; colon, maximum dose ≤ 55 Gy, V52 ≤ 10 mL; spinal cord planning risk volume, maximum dose ≤ 40 Gy; and left and right kidney, V20 ≤ 30%.
      Shi 2022
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      SBRT4 weeks after surgeryA total dose of 35 Gy was delivered in a week, BED of 59.5 Gymarginal parenchyma with width of 1–3 cm, and the tumour bed was includedmargin of 5 mm to the CTVNormal liver: least 700 ml of the normal liver total dose ≤ 15 Gy;

      Spinal cord, the maximum dose ≤ 23 Gy and 14.5 Gy to 1.2 ml or less of irradiated volume. Oesophagus, the maximum dose should ≤ 30 Gy and 19.5 Gy to 5 ml or less of irradiated volume;

      Duodenum, the maximum dose ≤ 32 Gy and 18 Gy to 5 ml or less of irradiated volume;

      Small intestine, stomach, and kidneys: the doses were restricted to the lowest level possible.
      Gou 2022

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      NANANANANANA
      Notes: EBRT, external beam radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy; SBRT, stereotactic body radiotherapy; BED; CTV, clinical target volume; PTV, planning target volume; OAR, organ at risk; NA, not available.
      Among all, eight were comparative studies [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ,

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ], including three RCTs [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ] and one retrospective study involving propensity score matching (PSM) [

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ]. Owing to lack of significant heterogeneity among the studies (I2 = 0, P = 0.93; I2 = 0, P = 0.52; respectively), the fixed-effect model was used for meta-analysis; the pooled HR for median DFS and OS were both in favor of adjuvant EBRT to surgery alone (HR = 0.36, 95% CI = 0.28–0.46, P < 0.001, Fig. 2A; HR = 0.36, 95% CI = 0.28–0.47, P < 0.001, Fig. 2B, respectively). Sensitivity analysis showed no significant change in the results after sequential exclusion of one study at a time from the analysis (Fig. 3A, B). The advantage of adjuvant EBRT over surgery alone was also observed in terms of 1-, 2-, and 3-year DFS (P < 0.05 for all, Table 3), but not in terms of 5-year DFS (P = 0.78, Table 3). Similar findings were observed in terms of 1-, 2-, 3-, and 5-year OS (Table 3).
      Figure thumbnail gr2
      Fig. 2Forest plots of disease-free survival and overall survival rates between adjuvant EBRT and surgery alone (A, disease-free survival; B, overall survival).
      Figure thumbnail gr3
      Fig. 3Forest plots of disease-free survival and overall survival rates between adjuvant EBRT and adjuvant TACE (A, disease-free survival; B, overall survival).
      Table 3Comparing the 1-, 2-, 3-, and 5-year disease-free survival and overall survival rates of adjuvant EBRT versus surgery alone.
      SubgroupsDisease-free survivalOverall survival
      Studies includedPatientsEffect modelI2OR (95%CI)PStudies includedPatientsEffect modelI2OR (95%CI)P
      1-year8733Fixed0%3.27(2.24–4.80)<0.0018733Fixed0%5.56(3.09–10.00)<0.001
      2-year7672Fixed2%2.31(1.64–3.23)<0.0017672Fixed0%3.01(2.03–4.45)<0.001
      3-year7672Fixed0%2.14(1.52–3.00)<0.0017672Random51%2.24(1.29–3.88)0.004
      5-year3351Fixed0%0.19(0.61–1.94)0.7803351Fixed0%1.08(0.66–1.76)0.770
      Notes: OR, odds ratio; CI, confidence interval.
      Among the included studies, four were on patients with narrow margin [
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ,

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ]. The adjuvant EBRT modality was IMRT in one study [
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ], 3DCRT in one [
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ], SBRT in one [
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ], and unknown in one [

      Gou XX, Shi HY, Yao LQ, Chen ZL, Ouyang W, Shen F, et al. Adjuvant radiotherapy was independently associated with favorable overall and recurrence-free survival following narrow-margin hepatectomy for hepatocellular carcinoma: a multicenter propensity-matched study from China; 2022 APASL, OP-0530.

      ] study. Meta-analysis showed that adjuvant EBRT decreased the risk of recurrence by 63% compared to surgery alone (HR = 0.37, 95% CI = 0.23–0.60, Table 4), as well as decreased the all-cause mortality (HR = 0.32, 95% CI = 0.19–0.55, Table 4). Three studies were on patients with MVI including one study of adjuvant SBRT [
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ]. The pooled HR for median DFS and OS in adjuvant EBRT group was 0.28 (95% CI = 0.23–0.70, Table 4) and 0.28 (95% CI = 0.17–0.46, Table 4), respectively, compared with surgery alone. Two studies were on patients with PVTT [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ], and the advantage of adjuvant EBRT was also identified in terms of the median DFS (HR = 0.40, 95% CI = 0.28–0.57, Table 4) and OS (HR = 0.42, 95% CI = 0.30–0.60, Table 4).
      Table 4Subgroups analysis comparing adjuvant EBRT versus surgery alone.
      SubgroupsDisease-free survivalOverall survival
      Studies includedPatientsEffect modelI2HR (95%CI)PStudies includedPatientsEffect modelI2HR (95%CI)P
      Narrow margin4467Fixed0%0.37(0.23–0.60)<0.0014467Fixed0%0.32(0.19–0.55)<0.001
      MVI3229Fixed0%0.28(0.19–0.44)<0.0013229Fixed30%0.28(0.17–0.46)<0.001
      PVTT2113Fixed0%0.40(0.28–0.57)<0.0012113Fixed0%0.42(0.30–0.60)<0.001
      Prospective study4306Fixed0%0.36(0.24–0.52)<0.0014306Fixed23%0.36(0.23–0.55)<0.001
      Retrospective study4427Fixed0%0.36(0.26–0.49)<0.0014427Fixed0%0.37(0.26–0.51)<0.001
      Notes: HR, hazard ratio; CI, confidence interval.
      Four prospective controlled studies including three RCTs were eligible in this study [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ]. The pooled HR for median DFS and OS were both in favor of adjuvant EBRT compared with surgery alone (HR = 0.36, 95% CI = 0.24–0.52, P < 0.001; HR = 0.36, 95% CI = 0.23–0.55, P < 0.001; respectively, Table 4). Moreover, the results did not change greatly in the subgroup of retrospective controlled studies (P < 0.001 for both, Table 4).
      Three studies had compared the efficacy of adjuvant EBRT versus TACE [
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang L.
      • Chen B.
      • Li Z.
      • Yao X.
      • Liu M.
      • Rong W.
      • et al.
      Optimal postoperative adjuvant treatment strategy for HBV-related hepatocellular carcinoma with microvascular invasion: a propensity score analysis.
      ]. The median DFS in patients receiving adjuvant EBRT was significantly longer than that in patients receiving surgery alone in the two studies on patients with MVI (P < 0.05 for both, Table 1), but comparable DFS was reported in adjuvant EBRT and TACE arms in the study enrolling patients with PVTT (14.0 ± 2.4 months vs 14.0 ± 3.4 months, Table1). Nonetheless, there was no significant heterogeneity among these three studies (I2 = 0, P > 0.05). The pooled HR for median DFS and OS was in favor of adjuvant EBRT compared with TACE (HR = 0.42, 95% CI = 0.28–0.65, P = 0.001, Fig. 4A). Likewise, the advantage of adjuvant EBRT was also observed in terms of OS (HR = 0.55, 95% CI = 0.33–0.93, P = 0.020, Fig. 4B).
      Figure thumbnail gr4
      Fig. 4Sensitivity analysis for the pooled disease-free survival and overall survival rates between adjuvant EBRT and surgery alone (A, disease-free survival; B, overall survival).
      Intrahepatic recurrence was reported in five comparative studies [
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ]. Meta-analysis showed that adjuvant EBRT decreased the risk of intrahepatic recurrence by 66% compared to surgery alone (OR = 0.34, 95% CI = 0.23–0.50, P < 0.001, Table 5), as well as extrahepatic recurrence (OR = 0.50, 95% CI = 0.26–0.97, P = 0.04, Table 5). Not as expected, adjuvant EBRT was found to decrease the risk of non-marginal recurrence (OR = 0.50, 95% CI = 0.31–0.79, P = 0.003, Table 5) but not that of marginal recurrence (OR = 0.51, 95% CI = 0.20–1.29, P = 0.15, Table 5). Likewise, the divergence was also observed in terms of single lesion (OR = 1.06, 95% CI = 0.50–2.22, P = 0.88, Table 5) and multiple lesions (OR = 0.41, 95% CI = 0.22–0.75, P = 0.004, Table 5).
      Table 5Pattern of recurrence of HCC in included studies.
      FactorsStudies includedPatientsEffect modelI2OR (95%CI)P
      Intrahepatic recurrence5464Fixed41%0.34(0.23–0.50)<0.001
      Marginal recurrence4345Fixed14%0.51(0.20–1.29)0.150
      Non-marginal recurrence4345Fixed23%0.50(0.31–0.79)0.003
      Single lesion of intrahepatic recurrence4370Random55%1.06(0.50–2.22)0.880
      Multiple lesion of intrahepatic recurrence4370Fixed0%0.41(0.22–0.75)0.004
      Extrahepatic recurrence5464Fixed0%0.50(0.26–0.97)0.040
      AEs were reported in seven included studies [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ,
      • Shi C.
      • Li Y.
      • Geng L.
      • Shen W.
      • Sui C.
      • Dai B.
      • et al.
      Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial.
      ,
      • Chen B.
      • Wu J.X.
      • Cheng S.H.
      • Wang L.M.
      • Rong W.Q.
      • Wu F.
      • et al.
      Phase 2 study of adjuvant radiotherapy following narrow-margin hepatectomy in patients With HCC.
      ,
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ,
      • Wang W.H.
      • Wang Z.
      • Wu J.X.
      • Zhang T.
      • Rong W.Q.
      • Wang L.M.
      • et al.
      Survival benefit with IMRT following narrow-margin hepatectomy in patients with hepatocellular carcinoma close to major vessels.
      ,
      • Wang L.
      • Wang W.
      • Rong W.
      • Li Z.
      • Wu F.
      • Liu Y.
      • et al.
      Postoperative adjuvant treatment strategy for hepatocellular carcinoma with microvascular invasion: a non-randomized interventional clinical study.
      ,
      • Rong W.
      • Yu W.
      • Wang L.
      • Wu F.
      • Zhang K.
      • Chen B.
      • et al.
      Adjuvant radiotherapy in central hepatocellular carcinoma after narrow-margin hepatectomy: a 10-year real-world evidence.
      ], and none of these were fatal AEs. The proportion of overall AEs was 0.653 (95% CI = 0.405–0.865, Table 6), and the proportion of overall severe AEs was 0.122 (95% CI = 0.027–0.261, Table 6). The most common type of AEs was myeloid suppression (OR = 0.500, 95% CI = 0.236–0.764), and the most common kind of severe AEs was fatigue (OR = 0.039, 95% CI = 0.008–0.086). The details of severe AEs are presented in Table 6.
      Table 6Treatment-related adverse events of adjuvant external beam radiotherapy.
      EventsAll gradeGrade ≥ 3
      Included studiesParticipantsEffect modelProportion (95%CI)Included studiesParticipantsEffect modelProportion (95%CI)
      Total6237Random0.653 (0.405–0.865)7263Random0.122 (0.027–0.261)
      Nausea and vomiting6237Random0.167 (0.113–0.229)7263Fixed0.000 (0.000–0.011)
      RILD6237Random0.209 (0.044–0.442)7263Random0.024 (0.000–0.076)
      Myeloid suppression6237Random0.500 (0.236–0.764)6237Fixed0.039 (0.008–0.086)
      Fatigue5227Fixed0.192 (0.142–0.247)6253Random0.005 (0.000–0.036)
      Abdominal pain381Random0.164 (0.000–0.471)3810.000
      Anorexia4176Random0.162 (0.047–0.322)5202Random0.005 (0.000–0.038)
      Dermatitis4189Random0.122 (0.054–0.208)41890.000
      Hypoalbuminemia2109Fixed0.081 (0.034–0.142)21090.000
      Infections239Fixed0.042 (0.000–0.143)2390.000
      Notes: RILD, radiation induced liver disease; CI, confidence interval.
      We observed no significant effect of publication bias on the pooled HR for the median DFS using Egger’s (P = 1.000, Fig. 5A) and Begg’s test (P = 0.464). There was no significant effect of publication bias on the pooled HR for median OS using Egger’s test (P = 0.045, Fig. 5B), but not Begg’s test (P = 0.174). However, using the “trim and fill” analysis, the advantage of adjuvant EBRT over surgery alone remained (HR = 0.362, 95% CI = 0.279–0.471, P < 0.05), which indicated that the unpublished studies had no significant effect on the results.
      Figure thumbnail gr5
      Fig. 5Egger’s tests for publication bias (A, disease-free survival; B, overall survival).

      Discussion

      Recurrence is still the bottleneck of HCC management, but there is no consensus over the role of adjuvant treatment in these patients [
      • Benson A.B.
      • D'Angelica M.I.
      • Abbott D.E.
      • Anaya D.A.
      • Anders R.
      • Are C.
      • et al.
      Hepatobiliary cancers, version 2.2021, NCCN clinical practice guidelines in oncology.
      ,
      • Reig M.
      • Forner A.
      • Rimola J.
      • Ferrer-Fabrega J.
      • Burrel M.
      • Garcia-Criado A.
      • et al.
      BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.
      ,
      • Zhou J.
      • Sun H.
      • Wang Z.
      • Cong W.
      • Wang J.
      • Zeng M.
      • et al.
      Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition).
      ]. To the best of our knowledge, this was the first systematic review evaluating the feasibility and efficacy of adjuvant EBRT following hepatectomy for HCC. A total of 10 studies enrolling 974 patients were eligible for this study, which included three RCTs, one phase II trial, and one retrospective comparative study using PSM. The results showed that adjuvant EBRT decreased the risk of recurrence and conferred oncological benefit for HCC patients receiving hepatectomy, but without increasing severe radiation-related AEs. Our results suggest that adjuvant EBRT can be considered for a selected subset of HCC patients, such as combined with narrow margin, MVI, and PVTT.
      MVI is generally regarded as the primary origin of intrahepatic recurrence [
      • Lim K.C.
      • Chow P.K.
      • Allen J.C.
      • Chia G.S.
      • Lim M.
      • Cheow P.C.
      • et al.
      Microvascular invasion is a better predictor of tumor recurrence and overall survival following surgical resection for hepatocellular carcinoma compared to the Milan criteria.
      ,
      • Sumie S.
      • Kuromatsu R.
      • Okuda K.
      • Ando E.
      • Takata A.
      • Fukushima N.
      • et al.
      Microvascular invasion in patients with hepatocellular carcinoma and its predictable clinicopathological factors.
      ], and is one of the most important adverse prognostic risk factors. MVI has been a key concern in the recent decade with the incidence rates ranging from 15.0% to 57.1% [
      • Rodriguez-Peralvarez M.
      • Luong T.V.
      • Andreana L.
      • Meyer T.
      • Dhillon A.P.
      • Burroughs A.K.
      A systematic review of microvascular invasion in hepatocellular carcinoma: diagnostic and prognostic variability.
      ], although there is no clear consensus on its definition. Wang et al [
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ] first identified that adjuvant EBRT can result in better oncological outcomes for patients with MVI compared with adjuvant TACE or surgery alone. This systematic review included three studies that were conducted on patients with MVI, and the pooled HR for median DFS and OS were both in favor of adjuvant EBRT over surgery alone (P < 0.001 for both), regardless of conventional fractions or SBRT. Hence, patients with MVI may potentially benefit from adjuvant EBRT.
      Narrow margin is also one of the most important risk factors for recurrence and adverse prognosis [
      • Shi M.
      • Guo R.P.
      • Lin X.J.
      • Zhang Y.Q.
      • Chen M.S.
      • Zhang C.Q.
      • et al.
      Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: a prospective randomized trial.
      ,
      • Liu L.
      • Shui Y.
      • Yu Q.
      • Guo Y.
      • Zhang L.
      • Zhou X.
      • et al.
      Narrow-margin hepatectomy resulted in higher recurrence and lower overall survival for R0 resection hepatocellular carcinoma.
      ], although the optimal margin distance is still not clear. With the advances in surgical technique, increasingly complex hepatectomy including mesohepatectomy are being carried out worldwide [
      • Zheng K.
      • He D.
      • Liao A.
      • Wu H.
      • Yang J.
      • Jiang L.
      Laparoscopic segmentectomy IV using hepatic round ligament approach combined with fluorescent negative staining method.
      ]. The extended indications for hepatectomy have conferred oncological benefit compared with conservative therapy; however, this also results in increased risk of narrow margin and recurrence [
      • Komatsu S.
      • Kido M.
      • Kuramitsu K.
      • Tsugawa D.
      • Gon H.
      • Fukushima K.
      • et al.
      Impact of hepatectomy for advanced hepatocellular carcinoma with major portal vein tumor thrombus.
      ,
      • Chen Z.H.
      • Zhang X.P.
      • Feng S.
      • Feng J.K.
      • Chai Z.T.
      • Guo W.X.
      • et al.
      Liver resection versus intensity-modulated radiation therapy for treatment of hepatocellular carcinoma with hepatic vein tumor thrombus: a propensity score matching analysis.
      ]. In a prospective randomized study, Yu et al [
      • Yu W.
      • Wang W.
      • Rong W.
      • Wang L.
      • Xu Q.
      • Wu F.
      • et al.
      Adjuvant radiotherapy in centrally located hepatocellular carcinomas after hepatectomy with narrow margin (<1 cm): a prospective randomized study.
      ] first reported the feasibility and safety of adjuvant EBRT for centrally located HCC receiving narrow-margin hepatectomy, although significant between-group difference was not observed in terms of DFS and OS (P > 0.05 for both). In the present systematic review, four studies were conducted on patients with narrow margin, and meta-analysis identified the advantage of adjuvant EBRT, both with respect to DFS and OS (P < 0.001 for both). Consequently, adjuvant EBRT may also be considered for patients with narrow margin.
      HCC with PVTT, staged at BCLC-C, was earlier considered as a contraindication for hepatectomy [
      • Reig M.
      • Forner A.
      • Rimola J.
      • Ferrer-Fabrega J.
      • Burrel M.
      • Garcia-Criado A.
      • et al.
      BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update.
      ]. Chen et al [
      • Chen X.P.
      • Huang Z.Y.
      Surgical treatment of hepatocellular carcinoma in China: surgical techniques, indications, and outcomes.
      ] first identified the feasibility of surgical resection for patients with PVTT. Subsequent studies and a meta-analysis have confirmed the oncological benefit of hepatectomy plus thrombectomy over conservative therapy [
      • Liang L.
      • Chen T.H.
      • Li C.
      • Xing H.
      • Han J.
      • Wang M.D.
      • et al.
      A systematic review comparing outcomes of surgical resection and non-surgical treatments for patients with hepatocellular carcinoma and portal vein tumor thrombus.
      ]. Nonetheless, the median DFS in patients with PVTT was significantly shorter than those without PVTT, and the 2-year DFS rate was as low as 16.1% [
      • Chen Z.H.
      • Zhang X.P.
      • Lu Y.G.
      • Li L.Q.
      • Chen M.S.
      • Wen T.F.
      • et al.
      Actual long-term survival in HCC patients with portal vein tumor thrombus after liver resection: a nationwide study.
      ]. In an open-label randomized RCT, Sun et al [
      • Sun J.
      • Yang L.
      • Shi J.
      • Liu C.
      • Zhang X.
      • Chai Z.
      • et al.
      Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial.
      ] reported that the median DFS of PVTT patients receiving adjuvant IMRT was significantly longer than those receiving partial hepatectomy plus thrombectomy (9.1 ± 1.6 months vs 4.1 ± 0.5 months, P < 0.05); in addition, the former group also showed longer OS (18.9 ± 1.8 months vs 10.8 ± 1.3 months, P < 0.05). In the current systematic review, two studies included patients with PVTT, and the pooled HR for median DFS and OS were both in favor of adjuvant EBRT to surgery alone (P < 0.05 for both). However, in a subgroup analysis of a previous RCT, the survival advantage conferred by adjuvant EBRT was not observed among patients with PVTT type III and IV; this was likely attributable to the occurrence of recurrence or metastasis before adjuvant EBRT. Novel adjuvant modalities such as combination with systemic treatment should be considered for this population.
      TACE is the preferred adjuvant treatment for HCC patients, especially in the East Asia, although international consensus has not been reached [
      • Wang Z.
      • Ren Z.
      • Chen Y.
      • Hu J.
      • Yang G.
      • Yu L.
      • et al.
      Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study.
      ,
      • Wang L.
      • Ke Q.
      • Lin K.
      • Chen J.
      • Wang R.
      • Xiao C.
      • et al.
      Not all hepatocellular carcinoma patients with microvascular invasion after R0 resection could be benefited from prophylactic transarterial chemoembolization: a propensity score matching study.
      ]. Adjuvant TACE for HCC was first reported in 1995 [
      • Li J.Q.
      • Zhang Y.Q.
      • Zhang W.Z.
      • Yuan Y.F.
      • Li G.H.
      Randomized study of chemoembolization as an adjuvant therapy for primary liver carcinoma after hepatectomy.
      ], and since then several retrospective and prospective studies have demonstrated its efficacy in preventing recurrence, especially among patients with MVI, narrow margin, and PVTT [
      • Peng B.G.
      • He Q.
      • Li J.P.
      • Zhou F.
      Adjuvant transcatheter arterial chemoembolization improves efficacy of hepatectomy for patients with hepatocellular carcinoma and portal vein tumor thrombus.
      ,
      • Wei W.
      • Jian P.E.
      • Li S.H.
      • Guo Z.X.
      • Zhang Y.F.
      • Ling Y.H.
      • et al.
      Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety.
      ,
      • Qi X.
      • Liu L.
      • Wang D.
      • Li H.
      • Su C.
      • Guo X.
      Hepatic resection alone versus in combination with pre- and post-operative transarterial chemoembolization for the treatment of hepatocellular carcinoma: a systematic review and meta-analysis.
      ]. With the development of RT techniques, adjuvant EBRT has been tried in the management of HCC. However, there is a paucity of studies comparing the anti-recurrence efficacy of adjuvant EBRT versus TACE for HCC. Bai et al [
      • Bai T.
      • Chen J.
      • Xie Z.B.
      • Wu F.X.
      • Wang S.D.
      • Liu J.J.
      • et al.
      The efficacy and safety of postoperative adjuvant transarterial embolization and radiotherapy in hepatocellular carcinoma patients with portal vein tumor thrombus.
      ] first compared the efficacy of adjuvant EBRT versus TACE for patients with PVTT. They found no significant difference between the two groups in terms of DFS or OS (P > 0.05 for both). However, a subsequent study demonstrated the advantage of EBRT among patients with MVI [
      • Wang L.
      • Wang W.
      • Yao X.
      • Rong W.
      • Wu F.
      • Chen B.
      • et al.
      Postoperative adjuvant radiotherapy is associated with improved survival in hepatocellular carcinoma with microvascular invasion.
      ]. In the current review, three studies had compared adjuvant EBRT versus TACE, and the pooled HR for the median DFS and OS were both in favor of adjuvant EBRT (P < 0.001 for both). Nonetheless, it is too early to draw a definitive conclusion about the optimal adjuvant treatment for HCC.
      Safety is one of the decision-making factors in cancer management. Liver was considered as a contraindication for RT, and radiation-induced liver disease (RILD), regardless of classic or non-classic, is a common and fatal adverse event [
      • Roberts H.J.
      • Wo J.Y.
      Stereotactic body radiation therapy for primary liver tumors: an effective liver-directed therapy in the toolbox.
      ]. Owing to rapid advances in RT techniques (such as 3DCRT, IMRT and SBRT), EBRT has been adopted for treatment of all stages of HCC. In addition, advances in breathing-motion management strategies such as four-dimensional computed tomography, and real-time target tracking and continuous patient position adjustment with robotic treatment couches have also facilitated the application of RT [
      • Chen W.
      • Chiang C.L.
      • Dawson L.A.
      Efficacy and safety of radiotherapy for primary liver cancer.
      ]. In the present study, the pooled incidence of total treatment-related AEs was 65.3%, but the rate of severe AEs was only 12.2%. The top three common AEs were myeloid suppression, RILD, and fatigue, but the corresponding severe rates were 3.9%, 2.4%, and 0.5%, respectively. Notably, no fatal AE related to adjuvant EBRT was reported in the included studies. These findings indicate the feasibility and safety of adjuvant EBRT in the management of HCC.
      In addition, radiation-immunity is a growing concern in recent years. Preclinical studies have found that radiation can induce remodeling of the tumor immune microenvironment via multiple mechanisms, such as exosomes and stromal cells [
      • Lin W.
      • Xu Y.
      • Chen X.
      • Liu J.
      • Weng Y.
      • Zhuang Q.
      • et al.
      Radiation-induced small extracellular vesicles as “carriages” promote tumor antigen release and trigger antitumor immunity.
      ,
      • Berg T.J.
      • Pietras A.
      Radiotherapy-induced remodeling of the tumor microenvironment by stromal cells.
      ]. In the study by Du et al [
      • Du S.S.
      • Chen G.W.
      • Yang P.
      • Chen Y.X.
      • Hu Y.
      • Zhao Q.Q.
      • et al.
      Radiation therapy promotes hepatocellular carcinoma immune cloaking via PD-L1 upregulation induced by cGAS-STING activation.
      ], RT was found to promote HCC immune cloaking through PD-L1 upregulation, which offered theoretical support for the combination of RT and immune check-point inhibitors (ICIs). In 2019, Yu et al [
      • Yu J.I.
      • Lee S.J.
      • Lee J.
      • Lim H.Y.
      • Paik S.W.
      • Yoo G.S.
      • et al.
      Clinical significance of radiotherapy before and/or during nivolumab treatment in hepatocellular carcinoma.
      ] first identified the survival gain conferred by addition of RT to ICI therapy, which was further confirmed by the subsequent reports [
      • Xiang Y.J.
      • Wang K.
      • Zheng Y.T.
      • Feng S.
      • Yu H.M.
      • Li X.W.
      • et al.
      Effects of stereotactic body radiation therapy plus PD-1 inhibitors for patients with transarterial chemoembolization refractory.
      ,
      • Manzar G.S.
      • De B.S.
      • Abana C.O.
      • Lee S.S.
      • Javle M.
      • Kaseb A.O.
      • et al.
      Outcomes and toxicities of modern combined modality therapy with atezolizumab plus bevacizumab and radiation therapy for hepatocellular carcinoma.
      ]. Moreover, Sung et al [
      • Sung W.
      • Hong T.S.
      • Poznansky M.C.
      • Paganetti H.
      • Grassberger C.
      Mathematical modeling to simulate the effect of adding radiation therapy to immunotherapy and application to hepatocellular Carcinoma.
      ] established a mathematical model to simulate the effect of adding RT to ICIs, which was verified in patients with HCC. Considering that local recurrence is still the main mode of treatment failure in HCC, aggressive adjuvant treatment modality, such as RT and ICIs, would be an alternative option.
      More consensus can be reached over the role and modalities of adjuvant EBRT. First, adjuvant EBRT can be an option for patients with MVI, narrow margin, or PVTT to decrease recurrence. Second, 4–6 weeks after surgery might be the optimal interval time for adjuvant EBRT. Third, 3D-CRT or IMRT using conventional fractions with total dose of 50–60 Gy was strongly recommended, but SBRT can also be adopted as an alternative option. Fourth, CTV should consist of tumor bed indicated by silver markers, but there is controversy regarding the expand distance. The main trunk and branch of portal vein should also be incorporated in case of PVTT. Last but not the least, organs at risk (OARs) including normal liver, stomach and duodenum, colon, cord, and kidney should be treated with caution.
      However, due caution should be exercised while interpreting the results of our study. All the studies included in this review were conducted in China. Thus, the conclusions may not be entirely applicable to Western population because of differences in the pathogenesis between the East and the West. Secondly, almost half of the included studies were retrospective observational studies which would weaken the conclusion of the current study. However, the results of subgroup analysis stratified by study design (retrospective and prospective) were consistent. Besides, there were apparent differences among the included studies with respect to study population (MVI, narrow margin, or PVTT) and EBRT techniques (3DCRT, IMRT, or SBRT), although no significant heterogeneity was found among the included studies in this respect. Moreover, the results of corresponding subgroup analysis were consistent with the overall results. Finally, the long-term survival benefit of adjuvant EBRT has not been verified with unimproved DFS and OS at 5-year (P > 0.05 for both), which should weaken the clinical value of adjuvant EBRT.

      Conclusion

      The available evidence suggests that adjuvant EBRT can be considered for HCC patients, especially those with MVI, narrow margin, or PVTT. However, more attention should be paid to the management of adjuvant EBRT, such as RT modality, fraction/dose, and delineation of CTV. Considering the promising results of adjuvant EBRT for HCC, international multi-center RCTs with larger sample size are required to obtain more definitive evidence.

      Disclosure

      The author reports no conflicts of interest in this work.

      Acknowledgement

      This research was funded by the Science and Technology Program of Fujian Province, China (Nos. 2019L3018 and 2019YZ016006 ); the Fujian Province Finance Department Project (No. (2019) 827 ); the Fujian Province Natural Science Foundation ( 2021J01438 ); the Fujian Provincial Clinical Research Center for Cancer Radiotherapy and Immunotherapy ( 2020Y2012 ); the National Clinical Key Specialty Construction Program .

      Author contributions

      Lei Wang, Lu Qiu, and Qiao Ke acquisition of data, analyzing and interpretation of data, drafting the article; Hongbing Ji revising the article; Junxin Wu designing and guiding the study.

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