Effectiveness of Radiotherapy for Hepatocellular Carcinoma with Lymph Node Metastasis: A Meta-Analysis

Sooyoung Hwang; Seoon Hur; Won Sup Yoon; Sunmin Park; Chai Hong Rim

doi:10.4143/crt.2025.475

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Original Article Gastrointestinal cancer Effectiveness of Radiotherapy for Hepatocellular Carcinoma with Lymph Node Metastasis: A Meta-Analysis: Sooyoung Hwang¹, Seoon Hur¹, Won Sup Yoon^1,2, Sunmin Park², Chai Hong Rim^1,2,3; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2026;58(3):884-896.
DOI: https://doi.org/10.4143/crt.2025.475
Published online: August 12, 2025

¹Korea University College of Medicine, Seoul, Korea

²Department of Radiation Oncology, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea

³CURE Analytics, Korea

Correspondence: Chai Hong Rim, Department of Radiation Oncology, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 15355, Korea
Tel: 82-31-412-6850 E-mail: crusion3@naver.com

^*Sooyoung Hwang and Seoon Hur contributed equally to this work.

• Received: May 2, 2025 • Accepted: August 11, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
Lymph node metastasis (LNM) of hepatocellular carcinoma (HCC) carries a poor prognosis; however, no standard treatment has been established. Radiotherapy (RT) has demonstrated favorable tumor response, with the advantage of being less affected by anatomical hindrances.
Materials and Methods
Databases were searched up to April 2024. The inclusion criteria were ≥ 5 patients with HCC LNM, studies that performed external RT, and reporting survival or response rate (RR). The main effect measures are pooled 1- and 2-year overall survival (OS) rates, RR, and grade ≥ 3 complications.
Results
Twelve studies involving 825 patients were included. The pooled 1-year OS rate and 2-year OS rate were 49.3% (95% confidence interval [CI], 39.2 to 59.4) and 24.5% (95% CI, 17.0 to 34.0), respectively. The median OS ranged from 5.8 to 29.7 months, with a median value of 9.7 months. In one study, 14.7% of patients were prescribed an immunoagent. In other studies, some patients received sorafenib, but no specific systemic therapy was performed for the majority. The pooled RR was 75.1% (95% CI, 66.9 to 81.8). The pooled RR of high dose and low dose groups was 83.8% (95% CI, 76.3 to 89.3) vs. 55.6% (95% CI, 44.4 to 66.3), respectively (p < 0.001). The pooled rate of grade ≥ 3 gastrointestinal toxicity was 3.7% (95% CI, 2.1 to 6.6).
Conclusion
RT is an effective and feasible palliative option for HCC LNM. Further research of combined treatment with novel systemic agents are necessary.
Key words: External beam radiotherapy, Hepatocellular carcinoma, Lymphatic metastasis

Introduction

Lymph node metastasis (LNM) in hepatocellular carcinoma (HCC) occurs in approximately 5%-7% of patients [1,2]. Unlike other solid cancers, LNM of HCC is regarded as an extrahepatic metastasis with a similar prognosis to distant metastasis. In the Barcelona Clinic Liver Cancer (BCLC) staging, LNM is classified as stage C along with distant metastasis, and systemic treatment alone is recommended [3]. However, outcomes for patients with HCC LNM have remained unsatisfactory, prompting investigation into the potential role of local treatments. Due to the frequent presence of poor prognostic factors, such as vascular invasion, cirrhosis, and multiple intrahepatic tumors [1,2], curative surgical resection is feasible only for select patients and has not yet been established as a standard treatment.

Radiotherapy (RT) has demonstrated effective palliative outcomes for HCC, particularly in cases that are challenging to address surgically or have a high risk of recurrence, such as HCC involving major blood vessels [4,5]. Given that RT is less influenced by anatomical constraints [6], it is advantageous for treating LNM from HCC located near major vessels. Studies from the 2000s reported encouraging tumor response rates to RT for HCC LNM, ranging from 60% to 79% [7-9]. More recently, the widespread adoption of advanced RT techniques, including intensity-modulated radiotherapy (IMRT) and stereotactic body radiotherapy (SBRT), has raised expectations for both reduced toxicities and improved therapeutic efficacy.

Recently, several researchers have explored the use of RT to improve oncologic outcomes of HCC LNM. In this context, we conducted a systematic review and meta-analysis to assess the oncological efficacy and feasibility of RT for treating HCC LNM.

Materials and Methods

1. Study design and eligible criteria

This study was conducted in compliance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [10] and AMSTAR (Assessing the methodological quality of systematic reviews) [11]. The hypothetical question of this study is “Can external RT yield better oncologic outcomes (than historical results) for HCC LNM patients?” Inclusion criteria are as follows: (1) including five or more patients with HCC LNM; (2) studies that performed external RT; (3) survival or response rate is reported. External RT included intensity-modulated RT, 3-dimensional conformal RT, stereotactic body RT, cyberknife treatment, and particle therapy.

This study is registered in PROSPERO (CRD42024605660).

2. Data source and collection process

Four databases including PubMed, Embase, MEDLINE, and the Cochrane Library were searched up to April 2, 2024. We used the search terms to enable a broad portal search based on the keywords “hepatocellular carcinoma,” “lymph node,” “metastasis,” and “RT.” Detailed search terms are described in Supplementary Data 1. Conference abstracts were not included in the study. Language restriction was not applied. For multiple studies from a single institution with overlapping patient recruitment, the following selection criteria were prioritized numerically: (1) inclusion of only HCC patients with LNM, not all HCC patients, (2) the study with the largest patient cohort, and (3) the most recent publication. Reference lists of included studies were also searched. We used pre-standardized data sheet for data acquisition, including (1) general information including author names, affiliation, year of publication, patient inclusion period; (2) clinical information including hepatitis B carrier, Child-Pugh class, age, other distant metastases, RT modality and dose, survival (median, 1- and 2-year percentiles), response rates, grade 3 or higher toxicities, and significant factors affecting overall survival (OS). Above processes were performed by at least two independent researchers. Any discrepancies concerning the inclusion of studies and the acquisition of data were resolved through mutual discussion and a reassessment of the literature.

3. Risk of bias assessment

As most researchers included in the study conducted non-randomized studies, we used the Newcastle-Ottawa scale to evaluate study results. Studies scoring 8-9 were categorized as high-quality, while those scoring 6-7 were as moderate-quality. Studies scoring ≤ 5 were classified as low-quality. According to the Cochrane handbook, only observational studies with moderate or low risk of bias are recommended for inclusion in pooled analyses [12]; therefore, low-quality studies were excluded from formal pooled analyses after consent among the authors. Although HCC LNM disease is classified as stage IVA in the American Joint Committee on Cancer staging system, various clinical factors could influence oncologic outcomes. Therefore, significant factors affecting survival in multivariate analyses of included studies were systematically reviewed.

4. Statistics

The main effect measures are the pooled 1- and 2-year OS rates as primary outcomes, and response rates and grade ≥ 3 complications as secondary outcomes. (To reduce heterogeneity in toxicity assessment, only grade ≥ 3 toxicity was included. While most studies used Response Evaluation Criteria in Solid Tumors criteria, a few older studies used World Health Organization criteria; however, the authors agreed that the level of heterogeneity was acceptable for meta-analysis inclusion.) We employed a random effects model to conduct pooled analyses of main measures, taking into account the confounding variables inherent in nonrandomized studies, following the recommendation of the Cochrane Handbook that the use of random effects model is considered standard for analyzing nonrandomized studies [13]. For all pooled analyses, heterogeneity was evaluated using Cochrane’s Q statistics [14] and I² statistics [15]; levels of heterogeneity were classified as low, moderate, and high for studies with I² of 25%, 50%, and 75%, respectively. Publication bias was assessed with visual funnel plot analysis and Egger’s test [16]. Significant bias was inferred if visual asymmetry was observed and the two-tailed p-value in Egger’s test was less than 0.1. When publication bias was suspected, trimmed values were computed using Duval and Tweedie’s trim-and-fill method [17]. Subgroup analyses were performed on pooled OS rates based on the clinical factors including the rate of primary disease control, Child-Pugh class (percentage of patients with class A), presence of extra-nodal distant metastasis, and geographic location (Japan [hepatitis C virus dominant] vs. Korea and China [hepatitis B virus dominant]). The cutoff values for subgrouping were selected as round numbers close to the median, rounded to the nearest 10. All statistical meta-analyses were performed with Comprehensive Meta-Analysis ver. 4 (Biostat Inc.).

Results

1. Study characteristics

We searched the database for papers that met the inclusion criteria and identified a total of 969 studies: 798 from Embase/MEDLINE, 158 from PubMed, and 13 from the Cochrane Library. After reviewing the titles and abstracts, 148 duplicate studies were excluded, leaving 821 papers for further assessment. Of these, 73 were selected for full-text review after excluding those with inappropriate subjects or formats. Among the full-text papers, 52 were excluded due to inappropriate subjects, and nine were excluded as they were conducted by the same institution. Ultimately, 12 studies [7-9,18-26] involving 825 HCC patients with LNM were included in the meta-analysis, and the inclusion process is summarized in Fig. 1.

All 12 studies were retrospective in design. Six studies were from South Korea, three from China, and three from Japan. Out of the 12 studies, 10 provided information on the proportion of patients with Child-Pugh classification A, ranging from 33.3% to 100%. Five studies [18,21,22,24,26] reported on the specific use of systemic modality. In the majority of studies, patients also had distant metastases other than LNM, ranging from 0 to 66.1% (median, 22.3%). The rate of primary disease control ranged from 15 to 77.8% (median, 38.2%). Sorafenib was used in four studies, ranging from 1.7%-36.9%. One study reported that 23.0% of patients used targeted therapy, 4.1% used immunotherapy, and 10.8% used both immunotherapy and targeted therapy. None of the included studies reported commercial conflicts of interest, most declared no conflicts, and two were funded by governmental sources. Additional details about the characteristics of the included studies are summarized in Table 1.

2. Risk of bias assessment

The studies included in this meta-analysis investigated a narrow range of diseases, HCC with LNM. All of them used OS or progression-free survival (PFS) as their primary outcomes, so the outcome of interest cannot be present at the start of the study. The studies mainly examined records from tertiary hospitals. Therefore, all studies scored for the questions of representativeness of exposed cohort, ascertainment of exposure, and outcome of interest not present at the start of the study in the selection part of the Newcastle-Ottawa scale. However, no study had a control group that did not receive RT, so no score was given for the question on non-exposed cohort in the selection part and the question on comparability of cohorts in the comparability part. Regarding the three questions in the outcome part, all studies scored for the assessment of outcome question and the adequacy of follow-up question, considering that the studies were based on data from tertiary hospitals, significant follow-up loss was not reported, and the expected time to the outcome of interest was short (i.e., short OS or PFS). For the question on long enough follow-up, considering the median survival value of related studies, studies with follow-up for more than 6 months were scored, while studies with follow-up for less than 6 months or studies without follow-up period information were not scored. All studies were classified as moderate quality studies. Therefore, meta-analysis exclusion for poor quality studies was not discussed.

3. Treatment profiles and clinical outcomes

Ten of the 12 studies (83.3%) used 3-dimensional conformal radiotherapy or IMRT as RT methods, and one study used stereotactic body RT. The median radiation dose ranged from 50 to 100 Gy (median, 60 Gy) when calculated through the BED (biologically effective dose) method, using α/β ratio of 10 (Gy₁₀).

The pooled 1-year and 2-year OS rate were 49.3% (95% confidence interval [CI], 39.2 to 59.4) and 24.5% (95% CI, 17.0 to 34.0), respectively. The heterogeneities among studies were high for both in 1-year OS (p < 0.001, I²=81.5%) and 2-year OS rates (p < 0.001, I²=82.9%). The median OS ranged from 5.8 to 29.7 months (median, 9.7 months). The pooled response rate was 75.1% (95% CI, 66.9 to 81.8), with moderate to high level of heterogeneity (p < 0.001, I²=75.4%). The treatment profiles and clinical outcomes are summarized in Table 2, pooled outcomes were summarized in Fig. 2 as forest plots. In seven studies, the borderline dose was determined based on the BED (54-60 Gy₁₀). Based on the borderline dose of each study, response rates were compared according to RT dose. The pooled response rate of high dose and low dose groups were 83.8% (95% CI, 76.3 to 89.3) and 55.6% (95% CI, 44.4 to 66.3), respectively, with significant intergroup difference (p < 0.001). Heterogeneity was moderate in both subgroups of low dose (p=0.02, I²=60.0%) and high dose (p=0.034, I²=56.0%). Forest plots were shown in Fig. 2 for pooled response rates according to subgroups.

Subgroup analyses were performed for clinical factors including primary disease control, Child-Pugh class, presence of other distant metastases, and geographic region. Among these, the pooled 2-year OS was higher in studies with ≥ 50% primary disease control compared to those with < 50% (32.4% vs. 18.5%, p=0.095) with borderline significance. In some other subgroup analyses, the heterogeneity indices decreased; however, no statistically significant differences were observed in subgroup comparisons. The results of the subgroup analyses are summarized in Table 3 and visualized as forest plots in S1 Fig.

Clinical factors affecting overall survival rates were investigated. Decompensated liver function (Child-Pugh class B) were reported in five studies, with hazard ratio ranged from 2.48 to 71.4. Uncontrolled liver disease, and other distant metastases were reported in four studies. Multiplicity of LNM was reported in two studies. Among treatment-related factors, LNM response to RT was significant factor in three studies. Data on significant factors in multivariable analyses are summarized in Table 4.

4. Publication bias

In funnel plot analyses, no significant visual asymmetry was shown in analysis of 1- and 2-year OS, two-tailed p-values of Egger’s test were 0.55412 and 0.27949, respectively (S2 Fig.)

5. Toxicity

Most commonly reported grade ≥ 3 toxicities were gastrointestinal (GI) toxicity and hematologic toxicity, especially thrombocytopenia. The pooled rate of grade ≥ 3 GI toxicity was 3.7% (95% CI, 2.1 to 6.6), with low to moderate level of heterogeneity (I²=33.1%, p=0.134). The pooled rate of grade ≥ 3 thrombocytopenia was 4.2% (95% CI, 2.0 to 8.6), with moderate amount of heterogeneity (I²=55.3%, p=0.022) (Fig. 3). Other grade ≥ 3 toxicities grade ≥ 3 included hepatic toxicity, anemia, leukopenia, lymphopenia, hyperbilirubinemia, and pneumothorax (S3 Table).

Discussion

1. Oncologic efficacy of RT

The first point of discussion to consider in this study is whether RT provides an oncological benefit for HCC patients with LNM. This should be compared with previous literature, as there are no comparative studies based on whether RT was performed. The present meta-analysis results showed that the median value of median OS for HCC patients with LNM who received RT was 9.7 months, with 1- and 2-year pooled percentiles of 49.3% and 24.5%, despite a substantial proportion of patients having other distant metastases and/or uncontrolled primary diseases. The vast majority of patients in our meta-analysis did not receive any systemic treatment, or received sorafenib, so comparisons with patients in the sorafenib era or who did not receive active oncological treatment could be considered. In the landmark sorafenib trial for the Asian population, the median OS was 6.5 months (1-year survival ~29%) for unresectable HCC patients treated with sorafenib, and 4.2 months (1-year survival ~17%) for those who received a placebo [27]. The survival rates in the present meta-analysis were higher than those in patients who received sorafenib or did not receive active treatment, despite the inclusion of a significant number of patients with other distant metastasis or uncontrolled primary HCC. Lee et al. [26]. conducted a Korean nationwide cohort study diagnosed with BCLC stage C HCC in 2008-2014. Among the subgroup with LNM, the median OS was 3.3 months for patients receiving sorafenib, 1.8 months for those received no treatment, and 7.1 months for those receiving RT and/or other local treatment. Another large Korean study also showed that [28], although they include both RT and surgery as a local modality, added local treatment on systemic treatment yielded significant survival benefit (1-year OS 51.8% vs. 26.6%, p < 0.001), in a propensity-matched analysis. The favorable results in the group that received RT are in line with the results of this meta-analysis.

Another point to consider is the role of RT in the immunotherapy era, of which is the current era. As mentioned earlier, Finn et al. [29] demonstrated that atezolizumab plus bevacizumab showed a significant improvement in survival rates compared to sorafenib in patients with unresectable liver cancer. Among the meta-analysis data, one study combined local RT with immunotherapy [21]; although the study showed the highest median OS (29.7 months), more studies are warranted because only 14.7% of patients underwent immunotherapy. Although the combined role of immunotherapy and RT in the treatment of LNM is yet lacking, several studies are underway for the treatment of HCC. Chiang et al. [30]. reported that, after propensity matching, SBRT combined with atezolizumab and bevacizumab yielded significantly better OS than SBRT alone for unresectable HCCs (3-year OS, 59.8% vs. 42.3%), with an encouraging overall response rate of 88%. Several theories explain the synergistic effects of combination treatment. RT releases tumor antigens and danger-associated molecular patterns while increasing MHC class I and FAS expression on tumor cells, enhancing the efficacy of immune checkpoint inhibitors [31]. Additionally, immune checkpoint inhibitors mitigate the immunosuppressive effects of RT [32]. As shown in the present meta-analysis, since HCC LNM has shown a favorable pooled response rate (76.2%) to RT, the antigen-releasing and microenvironmental modulatory effect due to tumor destruction could be expected. Clinical studies on the combined effect of immunotherapy and radiation therapy on HCC LNM are urgently needed.

2. Feasibility of RT

GI toxicity of grade ≥ 3 was reported in seven studies, with a pooled event rate of 3.7%. The vast majority of GI toxicities were late toxicities (S3 Table), typically occurring more than one month after the completion of RT. In the study by Park et al. [19], GI ulcers were observed between 2 and 7 months post-treatment (median, 4 months). Yoon et al. [7] also reported that GI bleeding occurred within 1 to 2 months after RT. LNM of HCC commonly occurs in the hepatic portal region, making it susceptible to GI complications such as bleeding when exposed to radiation [7,19]. Patients with HCC may exhibit an increased bleeding tendency due to impaired liver function. When administered alongside agents with a bleeding risk, such as bevacizumab, this risk is further elevated, necessitating close collaboration with the gastroenterology department. Although the pooled rate was deemed acceptable, efforts to minimize bystander irradiation to the GI tract through meticulous planning, including methods such as abdominal compression, and respiratory gating are necessary [33,34]. Although radiation-induced liver disease has been a major concern in RT for HCC [35], it is relatively less commonly reported in the treatment of LNM. In the studies in this meta-analysis, liver toxicity of grade ≥ 3 was not specifically reported, except in two studies. RT for LNM necessarily involves the GI tract in the treating field, but bystander irradiation to the liver parenchyme may be less than in the treatment of intrahepatic tumors.

Regarding hematologic toxicity, grade ≥ 3 thrombocytopenia was reported in three studies and pooled rate was 4.2%. In the study by Yamashita et al. [23], thrombocytopenia of grade ≥ 3 was the highest at 14.3%. In that study, anterior-posterior planning with generous margin (2 cm) was applied; therefore, the amount of bystander irradiation of spine and liver could be considerable. Hematologic toxicity is known to be related to radiation exposure to the bone marrow, but a relationship with liver dose of irradiation was also reported [36]. In the modern RT era, using intensity-modulated or stereotactic RT, efforts to reduce bystander irradiation of spine and liver are necessary. However, apart from the studies by Chen et al. [9] and Yamashita et al. [23], the rates of toxicity were low, and the heterogeneity in the pooled analysis was high, which should also be taken into account. Thrombocytopenia may also be influenced by disease progression, such as portal hypertension and hypersplenism [9]. While improving treatment conformality is necessary, the primary concern regarding adverse effects should be directed toward GI toxicity, for which the biological rationale is more clearly established.

In summary, the incidence of serious toxicities from RT for HCC LNM remains acceptable. Monitoring for thrombocytopenia and careful treatment planning are essential to reduce bystander irradiation to the bone marrow and liver. GI toxicity is a challenging toxicity difficult to be completely avoided in treating LNM. Meticulous planning, including techniques such as respiratory gating, and abdominal compression should be employed to minimize radiation exposure to the gastrointestinal tract. Close collaboration with the gastroenterology department is crucial.

3. When can we consider RT

In this meta-analysis, the pooled survival analysis were accompanied by moderate to high levels of heterogeneity. This indicates that while HCC LNM is an advanced disease, survival outcomes may be influenced by various clinical factors. Four clinical factors, including decompensated liver function (Child-Pugh class B), uncontrolled liver disease, multiple LNM, and other distant metastases were reported in several multivariate analyses of included studies [9,18-24]. The clinical significance of primary disease control was reaffirmed in our subgroup analysis. The patient group that can be considered as a priority for RT would be the patient with controlled intrahepatic tumors, preserved liver function, and low disease burden of LNM and other metastases. Additionally, the therapeutic factor of RT response has been identified as significant in multivariate analysis [9,18,19]. As discussed, higher RT doses are associated with improved response rates, necessitating the escalation of dosage to the maximum extent permissible, while ensuring organ radiation tolerance is maintained. Given the multiple factors influencing prognosis and the increased risk of side effects with high-dose RT, patient selection must be made through careful multidisciplinary evaluation.

4. Limitations and significance

Although there is no established standard treatment for HCC with LNM, data from randomized studies are still lacking. Due to the lack of control groups in most individual studies, our main outcomes were indirectly compared with previous literature, which is a limitation of this meta-analysis. Since this meta-analysis mainly included observational studies, clinical heterogeneity may have affected the integrated analysis. HCC with LNM is rare and still has a poor prognosis; therefore, research efforts to find the optimal treatment strategy are necessary. Considering the favorable treatment response of external RT, the design of randomized trials may not be ethically sound in the future. Integrating existing observational studies to increase reliability, comparing them with existing literature on different treatment strategies, and providing summarized information through meta-analysis are the best possible ways to help clinical practice. Additionally, the studies included in this meta-analysis were published for academic purposes rather than commercial interests. Therefore, the purpose of this meta-analysis is consistent with Sackett’s definition of evidence-based medicine, which is the conscientious and explicit use of current best evidence in decisions about caring individual patients [37].

When HCC with LNM is diagnosed, most physicians typically prioritize systemic therapy. Among the studies included in this meta-analysis, chemotherapy was rarely administered, if at all, to patients. This limited use is due to several reasons: LNM is regarded to have a poor prognosis and low incidence, so it was not analyzed as a separate subgroup in most major studies. Additionally, previous treatments, such as sorafenib and other chemotherapy drugs, demonstrated a low tumor response rate of less than 3% [27,38], offering minimal expected benefit for patients with LNM. However, the response rate of the recently developed atezolizumab-bevacizumab was 27% [29], and the response rate of durvalumab-tremelimumab was also 20% [39]. As described in the prior discussion, RT for LNM exhibits an impressive response rate and is anticipated to enhance the effects of systemic therapy. We hope that future studies on systemic treatments will specifically explore their effects on patients with LNM.

External RT demonstrated favorable survival and response rates. High-dose RT was associated with better response rates, suggesting benefit of dose escalation. Although serious complications were rare, multidisciplinary management is essential to address gastrointestinal toxicity. Hematological side effects should be closely monitored, and efforts should be made to minimize radiation exposure to the bone marrow and liver. Future studies exploring combination therapies with novel agents, including immunotherapy, are highly warranted.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt-2025-475_S1_Fig.pdf

crt-2025-475_S2_Fig.pdf

crt-2025-475_S3_Table.pdf

crt-2025-475_Supplement-Data-1.pdf

NOTES

Author Contributions

Conceived and designed the analysis: Rim CH.

Collected the data: Rim CH, Hwang SY, Hur S.

Contributed data or analysis tools: Rim CH, Hwang SY, Hur S.

Performed the analysis: Rim CH.

Drafting: Rim CH, Hwang SY, Hur S.

Supervision: Yoon WS, Park S.

Editing: Rim CH.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Funding

This study was supported by national research fund of Korea (NRF-2021R1I1A2047475).

Fig. 1.

A study inclusion plot.

Fig. 2.

Forest plots of overall analyses of 1-year survival (A), 2-year survival (B), response rate (C), and response rate compared to high and low dose radiotherapy (D) [7-9,18-26]. CI, confidence interval; CFRT, conventionally fractionated stereotactic RT; HD, high dose; IG-IMRT, image guided intensity modulated RT; LD, low dose; RT, radiotherapy; OS, overall survival; SBRT, stereotactic body RT.

Fig. 3.

Forest plots of grade ≥ 3 gastrointestinal toxicity (A) and thrombocytopenia (B) [7,9,18-25]. CI, confidence interval; GI, gastrointestinal.

Table 1.

Clinical information of included studies

Study	Affiliation	Nation	Publication year	Patient inclusion	No.	NOS score	HBV (%)	CPC A (%)	Age (M, range)	Other distant mets (%)	Primary controlled (%)	Concomitant systemic Tx
Chen et al. [9]	Fudan Univ.	China	2013	1998-2012	191	6	80.6	94.2	52 (25-83)	22.0	38.2	–
Lee DY et al. [18]	National Cancer Center of Korea	Korea	2015	2002-2014	65	6	83	78.5	59 (37-79)	43.1	64.6	Sorafenib 36.9%
Wee et al. [22]	Seoul National Univ.	Korea	2016	2004-2015	105	5	75.2	71.4	59 (30-81)	39.1	38.1	Sorafenib 22.9%
Park et al. [19]	Samsung Medical Center	Korea	2006	1998-2004	45	5	–	82.2	55 (39-68)	24.4	77.8	–
Yamashita et al. [23]	Tokyo Univ.	Japan	2007	1994-2005	21	5	–	57.1	–	28.5	–	–
Jang et al. [8]	Incheon Catholic Univ.	Korea	2009	2005-2007	20	6	83.3	–	–	–	–	–
Yoon et al. [7]	Asan Hospital	Korea	2004	1997-2001	51	6	–		63% in 50-70s	–	27.0	–
Toya et al. [20]	Kumamoto Hospital	Japan	2009	1998-2006	23	5	–	69.6	68 (44-76)	13	60.9	–
Wang et al. [21]_SBRT group	Sun-Yat Sen Univ.	China	2023	2010-2020	114	5	–	97.4	52 (18-77)	16.7	52.6	43%, targeted or immunotherapy
Wang et al. [21]_CFRT group	–	China	2023	–	34	–	–	97.1	–	20.7	52.9	20.6%, targeted or immunotherapy
Zhang et al. [24]_IG-IMRT group	Fudan Univ.	China	2019	2011-2016	43	5	88.4	95.3	51.7 (35-76)	22.5	27.9	–
Zhang et al [24]_NON-IG-IMRT group	–	China	2019	–	42	–	85.7	100	52.6 (31-74)	18.4	26.2	–
Lee J et al. [26]	Multicenter	Korea	2019	2008-2014	56	5	67.8	71.4	53 (13-85)	66.1	–	1.7% (1 patient) sorafenib
Matoba et al. [25]	Kanazawa Medical Univ.	Japan	2020	2014-2017	15	6	33	33.3	72.7 (64-82)	0	15	Sorafenib 13.3%

CFRT, conventionally fractionated stereotactic RT; CPC, Child-Pugh Class; HBV, hepatitis B virus; IG-IMRT, image guided intensity modulated RT; mets, metastasis; M, median; NOS, Newcastle-Ottawa score; RT, radiotherapy; SBRT, stereotactic body RT; Tx, therapy.

Table 2.

Treatment profiles and clinical outcomes

Study	No.	Modality	Median dose (BED, Gy₁₀)	Dose	Fractionation	MFU	Median OS (mo)	1-Year OS (%)	2-Year OS (%)	Response criteria	Overall response (%)	Low dose		BED borderline	High dose
Study	No.	Modality	Median dose (BED, Gy₁₀)	Dose	Fractionation	MFU	Median OS (mo)	1-Year OS (%)	2-Year OS (%)	Response criteria	Overall response (%)	No.	RR (%)	BED borderline	No.	RR (%)
Chen et al. [9]	191	3DCRT (63.4%) or 2DRT	60	M50 (40–60)	2	7.9	8.0	39.3	18.9	WHO	79.1	42	54.8	60	149	85.9
Lee DY et al. [18]	65	IMRT (33.8%) or 3DCRT	65.5	M52.8 (30–60)	1.8–3	8.1 (1–90.9)	8.1	–	19.6	RECIST	61.5	18	38.9	54	47	70.2
Wee et al. [22]	105	IMRT (23.8%) or 3DCRT	58.5	M45 (30–60)	1.8–3	5.7	5.8	–	–	RECIST	56.7	47	40.0	60	58	75.6
Park et al. [19]	45	3DCRT	50	30–55	1.8–3	–	7.0	35.2	21.7	RECIST	86.7	22	64.7	50	17	90.9
Yamashita et al. [23]	21	3DCRT	60	M50 (46–60)	2	5.2	13.0	53.0	33.0	WHO	81.0
Jang et al. [8]	20	IMRT	75	50	10					RECIST	60.0
Yoon et al. [7]	51	3DCRT	58.5	30–51	2–3	Minimum 6	7.0	31.3	15.7	WHO	76.0	23	56.5	55	28	93.0
Toya et al. [20]	23	3DCRT	58.5	M45 (26–56)	1.8–4	–	19.0	60.0	–	RECIST	83.0	9	56.0	58	14	100
Wang et al. [21]_SBRT group	114	IMRT	64.4	M39 (30-60), 3-8fx.	3.75–13	–	29.7	70.8	53.8	RECIST	85.1	67	73.1	60	81	87.7

Wang et al. [21]_CFRT group	34	3DCRT (44.1%) or IMRT (55.9%)	58.5	M48 (30–60), 8–30fx.	2–4	–	9.9	47.3	37.7	RECIST	67.6	–	–	–	–	–
Zhang et al. [24]_IG-IMRT group	43	IG-IMRT	m 67.23	56.02±7.06	1.8–5.2	–	15.3	69.1	19.3	RECIST	–	–	–	–	–	–
Zhang et al. [24]_NON-IG-IMRT or IMRT group	42	3DCRT (71.4%) or IMRT	m 63.43	52.86±4.17	1.8–2.4	–	9.7	38.1	14.5	RECIST	–	–	–	–	–	–
Lee J et al. [26]	56	Any RT	–	–	–	–	7.1	33.9	18.0	–	–	–	–	–	–	–
Matoba et al. [25]	15	SBRT	78.8	M45 (45–49.5)	5.5–7.5	M18.1 (6–32)	18.6	73.3	28.6	RECIST	100 (CR 67%)	–	–	–	–	–

2DRT, 2-dimensional RT; 3DCRT, 3-dimensional conformal RT; BED, biologically equivalent dose; CFRT, conventionally fractionated stereotactic RT; CR, complete response; IG-IMRT, image guided intensity modulated RT; IMRT, intensity modulated RT; M, median; m, mean; MFU, median follow-up month; OS, overall survival; RECIST, Response Evaluation Criteria in Solid Tumors; RR, response rate; RT, radiotherapy; SBRT, stereotactic body RT; WHO, World Health Organization.

Table 3.

Subgroup analyses of clinical factors

	No. of studies	Pooled 1-year OS (95% CI, %)	Heterogeneity p-value, I² (%)	p of subgroup comparison	No. of studies	Pooled 2-year OS (95% CI, %)	Heterogeneity p-value, I² (%)	p of subgroup comparison
Primary disease controlled < 50%	5	48.0 (34.0–62.4)	0.001, 79.9		5	18.5 (14.7–23.0)	0.785, ~0
Primary disease controlled ≥ 50%	4	53.9 (35.7–71.1)	< 0.001, 83.3	0.626	4	32.4 (17.2–52.4)	< 0.001, 88.0	0.095
Child-Pugh A < 70%	3	60.5 (47.4–72.2)	0.474, ~0		2	31.2 (18.3–47.9)	0.779, ~0
Child-Pugh A ≥ 70%	7	47.9 (35.4–60.6)	< 0.001, 86.3	0.175	8	24.4 (15.5–36.3)	< 0.01, 87.1	0.465
Other DM < 20%	4	60.4 (42.0–76.3)	0.003, 78.5		3	31.0 (10.8–62.5)	< 0.001, 88.9
Other DM ≥ 20%	6	45.2 (35.3–55.5)	0.007, 68.7	0.157	7	22.2 (17.8–27.3)	0.235, 25.4	0.506
China and Korea (HBV dominant)	8	45.7 (34.4–57.6)	< 0.001, 85.6		9	23.4 (15.3–34.1)	< 0.001, 86.1
Japan (HCV dominant)	3	60.5 (47.4–72.2)	0.474, ~0	0.101	2	31.2 (18.3–47.9)	0.779, ~0	0.38

CI, confidence interval; DM, distant metastasis; HBV, hepatitis B virus; HCV, hepatitis C virus; OS, overall survival.

Table 4.

Clinical factors affecting survival in multivariate analyses

Clinical factor affecting survival	Study author (HR, p-value)
Child-Pugh class B	Chen et al. [9] (2.54, 0.009)
	Lee et al. [18] (2.48, 0.009)
	Wee et al. [22] (2.774, < 0.001)
	Park et al. [19] (NA, 0.1)
	Yamashita et al. [23] (71.4, 0.057)
Uncontrolled liver disease	Chen et al. [9] (1.69, 0.015)
	Lee et al. [18] (5.47, < 0.001)
	Park et al. [19] (NA, < 0.01)
	Toya et al. [20] (NA, 0.03)
LN mets response to RT	Chen et al. [9] (6.8, < 0.001)
	Lee et al. [18] (3.0, < 0.001)
	Park et al. [19] (NA, 0.06)
Multiple LN mets	Lee et al. [18] (1.97, 0027)
	Zhang et al. [24] (2.00, 0.006)
Other distant metastases	Chen et al. [9] (1.82, 0.015)
	Wee et al. [22] (1.62, 0.029)
	Park et al. [19] (NA, 0.01)
	Wang et al. [21] (4.15, < 0.001)

HR, hazard ratio; LN, lymph node; mets, metastasis; NA, not available; RT, radiotherapy.

REFERENCES

1. Xiaohong S, Huikai L, Feng W, Ti Z, Yunlong C, Qiang L. Clinical significance of lymph node metastasis in patients undergoing partial hepatectomy for hepatocellular carcinoma. World J Surg. 2010;34:1028–33. Article PubMed PDF
2. Sun HC, Zhuang PY, Qin LX, Ye QH, Wang L, Ren N, et al. Incidence and prognostic values of lymph node metastasis in operable hepatocellular carcinoma and evaluation of routine complete lymphadenectomy. J Surg Oncol. 2007;96:37–45. Article PubMed
3. European Association for the Study of the Liver. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236. Article PubMed PMC
4. Rim CH, Kim CY, Yang DS, Yoon WS. External beam radiation therapy to hepatocellular carcinoma involving inferior vena cava and/or right atrium: a meta-analysis and systemic review. Radiother Oncol. 2018;129:123–9. Article PubMed
5. Rim CH, Kim CY, Yang DS, Yoon WS. Comparison of radiation therapy modalities for hepatocellular carcinoma with portal vein thrombosis: a meta-analysis and systematic review. Radiother Oncol. 2018;129:112–22. Article PubMed
6. Rim CH, Yoon WS. Leaflet manual of external beam radiation therapy for hepatocellular carcinoma: a review of the indications, evidences, and clinical trials. Onco Targets Ther. 2018;11:2865–74. Article PubMed PMC PDF
7. Yoon SM, Kim JH, Choi EK, Ahn SD, Lee SW, Yi BY, et al. Radioresponse of hepatocellular carcinoma-treatment of lymph node metastasis. Cancer Res Treat. 2004;36:79–84. Article PubMed PMC
8. Jang JW, Kay CS, You CR, Kim CW, Bae SH, Choi JY, et al. Simultaneous multitarget irradiation using helical tomotherapy for advanced hepatocellular carcinoma with multiple extrahepatic metastases. Int J Radiat Oncol Biol Phys. 2009;74:412–8. Article PubMed
9. Chen YX, Zeng ZC, Fan J, Tang ZY, Zhou J, Zeng MS, et al. Defining prognostic factors of survival after external beam radiotherapy treatment of hepatocellular carcinoma with lymph node metastases. Clin Transl Oncol. 2013;15:732–40. Article PubMed PDF
10. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg. 2021;88:105906.Article PubMed PMC
11. Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008.Article PubMed PMC
12. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019. p. 611–3.
13. Reeves BC, Deeks JJ, Higgins JP, Shea B, Tugwell P, Wells GA, et al. Including non-randomized studies on intervention effects. In: Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al., editors. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2019. p. 595–620.
14. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–29. Article
15. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–58. Article PubMed PMC
16. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34. Article PubMed PMC
17. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455–63. Article PubMed PMC
18. Lee DY, Park JW, Kim TH, Lee JH, Kim BH, Woo SM, et al. Prognostic indicators for radiotherapy of abdominal lymph node metastases from hepatocellular carcinoma. Strahlenther Onkol. 2015;191:835–44. Article PubMed PDF
19. Park YJ, Lim DH, Paik SW, Koh KC, Lee JH, Choi MS, et al. Radiation therapy for abdominal lymph node metastasis from hepatocellular carcinoma. J Gastroenterol. 2006;41:1099–106. Article PubMed PDF
20. Toya R, Murakami R, Yasunaga T, Baba Y, Nishimura R, Morishita S, et al. Radiation therapy for lymph node metastases from hepatocellular carcinoma. Hepatogastroenterology. 2009;56:476–80. PubMed
21. Wang Y, Li Q, Zhang L, Liu S, Zhu J, Yang Y, et al. Efficacy and dose-response relationship of stereotactic body radiotherapy for abdominal lymph node metastases from hepatocellular carcinoma. Oncologist. 2023;28:e369–78. Article PubMed PMC PDF
22. Wee CW, Kim K, Chie EK, Yu SJ, Kim YJ, Yoon JH. Prognostic stratification and nomogram for survival prediction in hepatocellular carcinoma patients treated with radiotherapy for lymph node metastasis. Br J Radiol. 2016;89:20160383.Article PubMed PMC
23. Yamashita H, Nakagawa K, Shiraishi K, Tago M, Igaki H, Nakamura N, et al. Radiotherapy for lymph node metastases in patients with hepatocellular carcinoma: retrospective study. J Gastroenterol Hepatol. 2007;22:523–7. Article PubMed
24. Zhang H, Chen Y, Hu Y, Yang P, Wang B, Zhang J, et al. Image-guided intensity-modulated radiotherapy improves short-term survival for abdominal lymph node metastases from hepatocellular carcinoma. Ann Palliat Med. 2019;8:717–27. Article PubMed
25. Matoba M, Tsuchiya H, Kondo T, Ota K. Stereotactic body radiotherapy delivered with IMRT for oligometastatic regional lymph node metastases in hepatocellular carcinoma: a single-institutional study. J Radiat Res. 2020;61:776–83. Article PubMed PMC PDF
26. Lee J, Yoon WS, Koom WS, Rim CH. Role of local treatment including radiotherapy in Barcelona Clinic of Liver Cancer stage C patients: a nationwide cohort analysis in South Korea. Cancer Manag Res. 2019;11:1373–82. PubMed PMC
27. Cheng AL, Guan Z, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III sorafenib Asia-Pacific trial. Eur J Cancer. 2012;48:1452–65. Article PubMed
28. Lee BM, Choi JY, Seong J. Efficacy of local treatment in lymph node metastasis from hepatocellular carcinoma. Liver Cancer. 2023;12:218–28. Article PubMed PMC PDF
29. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894–905. Article PubMed PMC
30. Chiang CL, Lee FA, Chan KS, Lee VW, Chiu KW, Ho RL, et al. Survival outcome analysis of stereotactic body radiotherapy and immunotherapy (SBRT-IO) versus SBRT-alone in unresectable hepatocellular carcinoma. Liver Cancer. 2024;13:265–76. Article PubMed PMC PDF
31. Chen L, Zhang R, Lin Z, Tan Q, Huang Z, Liang B. Radiation therapy in the era of immune treatment for hepatocellular carcinoma. Front Immunol. 2023;14:1100079.Article PubMed PMC
32. Liu Y, Dong Y, Kong L, Shi F, Zhu H, Yu J. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J Hematol Oncol. 2018;11:104.Article PubMed PMC PDF
33. Woo JY, Kim JH, Kim JW, Baek JG, Park KS, Lee JM, et al. Usefulness of abdominal compressor using stereotactic body radiotherapy with hepatocellular carcinoma patients. J Korean Soc Radiat Ther. 2012;24:157–65.
34. Park SH, Kim JC, Kang MK. Technical advances in external radiotherapy for hepatocellular carcinoma. World J Gastroenterol. 2016;22:7311–21. Article PubMed PMC
35. Koay EJ, Owen D, Das P. Radiation-induced liver disease and modern radiotherapy. Semin Radiat Oncol. 2018;28:321–31. Article PubMed PMC
36. Dyer MA, McDonnell EI, Yeap BY, Depauw N, Wolfgang JA, Wo JY, et al. Change in platelet count and normal liver dosimetry in patients receiving proton radiation therapy for unresectable hepatocellular carcinoma or intrahepatic cholangiocarcinoma. Int J Radiat Oncol Biol Phys. 2016;96:E174–5. Article
37. Sackett DL. Evidence-based medicine. Semin Perinatol. 1997;21:3–5. Article PubMed PMC
38. Stuart K, Tessitore J, Huberman M. 5-Fluorouracil and alpha-interferon in hepatocellular carcinoma. Am J Clin Oncol. 1996;19:136–9. Article PubMed
39. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1:EVIDoa2100070.PubMed

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Effectiveness of Radiotherapy for Hepatocellular Carcinoma with Lymph Node Metastasis: A Meta-Analysis

Cancer Res Treat. 2026;58(3):884-896. Published online August 12, 2025

DOI: https://doi.org/10.4143/crt.2025.475

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Abstract
Introduction
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REFERENCES

Effectiveness of Radiotherapy for Hepatocellular Carcinoma with Lymph Node Metastasis: A Meta-Analysis

Fig. 1. A study inclusion plot.

Fig. 2. Forest plots of overall analyses of 1-year survival (A), 2-year survival (B), response rate (C), and response rate compared to high and low dose radiotherapy (D) [7-9,18-26]. CI, confidence interval; CFRT, conventionally fractionated stereotactic RT; HD, high dose; IG-IMRT, image guided intensity modulated RT; LD, low dose; RT, radiotherapy; OS, overall survival; SBRT, stereotactic body RT.

Fig. 3. Forest plots of grade ≥ 3 gastrointestinal toxicity (A) and thrombocytopenia (B) [7,9,18-25]. CI, confidence interval; GI, gastrointestinal.

Fig. 1.

Fig. 2.

Fig. 3.

Effectiveness of Radiotherapy for Hepatocellular Carcinoma with Lymph Node Metastasis: A Meta-Analysis

Study	Affiliation	Nation	Publication year	Patient inclusion	No.	NOS score	HBV (%)	CPC A (%)	Age (M, range)	Other distant mets (%)	Primary controlled (%)	Concomitant systemic Tx
Chen et al. [9]	Fudan Univ.	China	2013	1998-2012	191	6	80.6	94.2	52 (25-83)	22.0	38.2	–
Lee DY et al. [18]	National Cancer Center of Korea	Korea	2015	2002-2014	65	6	83	78.5	59 (37-79)	43.1	64.6	Sorafenib 36.9%
Wee et al. [22]	Seoul National Univ.	Korea	2016	2004-2015	105	5	75.2	71.4	59 (30-81)	39.1	38.1	Sorafenib 22.9%
Park et al. [19]	Samsung Medical Center	Korea	2006	1998-2004	45	5	–	82.2	55 (39-68)	24.4	77.8	–
Yamashita et al. [23]	Tokyo Univ.	Japan	2007	1994-2005	21	5	–	57.1	–	28.5	–	–
Jang et al. [8]	Incheon Catholic Univ.	Korea	2009	2005-2007	20	6	83.3	–	–	–	–	–
Yoon et al. [7]	Asan Hospital	Korea	2004	1997-2001	51	6	–		63% in 50-70s	–	27.0	–
Toya et al. [20]	Kumamoto Hospital	Japan	2009	1998-2006	23	5	–	69.6	68 (44-76)	13	60.9	–
Wang et al. [21]_SBRT group	Sun-Yat Sen Univ.	China	2023	2010-2020	114	5	–	97.4	52 (18-77)	16.7	52.6	43%, targeted or immunotherapy
Wang et al. [21]_CFRT group	–	China	2023	–	34	–	–	97.1	–	20.7	52.9	20.6%, targeted or immunotherapy
Zhang et al. [24]_IG-IMRT group	Fudan Univ.	China	2019	2011-2016	43	5	88.4	95.3	51.7 (35-76)	22.5	27.9	–
Zhang et al [24]_NON-IG-IMRT group	–	China	2019	–	42	–	85.7	100	52.6 (31-74)	18.4	26.2	–
Lee J et al. [26]	Multicenter	Korea	2019	2008-2014	56	5	67.8	71.4	53 (13-85)	66.1	–	1.7% (1 patient) sorafenib
Matoba et al. [25]	Kanazawa Medical Univ.	Japan	2020	2014-2017	15	6	33	33.3	72.7 (64-82)	0	15	Sorafenib 13.3%

Study	No.	Modality	Median dose (BED, Gy₁₀)	Dose	Fractionation	MFU	Median OS (mo)	1-Year OS (%)	2-Year OS (%)	Response criteria	Overall response (%)	Low dose		BED borderline	High dose
Study	No.	Modality	Median dose (BED, Gy₁₀)	Dose	Fractionation	MFU	Median OS (mo)	1-Year OS (%)	2-Year OS (%)	Response criteria	Overall response (%)	No.	RR (%)	BED borderline	No.	RR (%)
Chen et al. [9]	191	3DCRT (63.4%) or 2DRT	60	M50 (40–60)	2	7.9	8.0	39.3	18.9	WHO	79.1	42	54.8	60	149	85.9
Lee DY et al. [18]	65	IMRT (33.8%) or 3DCRT	65.5	M52.8 (30–60)	1.8–3	8.1 (1–90.9)	8.1	–	19.6	RECIST	61.5	18	38.9	54	47	70.2
Wee et al. [22]	105	IMRT (23.8%) or 3DCRT	58.5	M45 (30–60)	1.8–3	5.7	5.8	–	–	RECIST	56.7	47	40.0	60	58	75.6
Park et al. [19]	45	3DCRT	50	30–55	1.8–3	–	7.0	35.2	21.7	RECIST	86.7	22	64.7	50	17	90.9
Yamashita et al. [23]	21	3DCRT	60	M50 (46–60)	2	5.2	13.0	53.0	33.0	WHO	81.0
Jang et al. [8]	20	IMRT	75	50	10					RECIST	60.0
Yoon et al. [7]	51	3DCRT	58.5	30–51	2–3	Minimum 6	7.0	31.3	15.7	WHO	76.0	23	56.5	55	28	93.0
Toya et al. [20]	23	3DCRT	58.5	M45 (26–56)	1.8–4	–	19.0	60.0	–	RECIST	83.0	9	56.0	58	14	100
Wang et al. [21]_SBRT group	114	IMRT	64.4	M39 (30-60), 3-8fx.	3.75–13	–	29.7	70.8	53.8	RECIST	85.1	67	73.1	60	81	87.7

Wang et al. [21]_CFRT group	34	3DCRT (44.1%) or IMRT (55.9%)	58.5	M48 (30–60), 8–30fx.	2–4	–	9.9	47.3	37.7	RECIST	67.6	–	–	–	–	–
Zhang et al. [24]_IG-IMRT group	43	IG-IMRT	m 67.23	56.02±7.06	1.8–5.2	–	15.3	69.1	19.3	RECIST	–	–	–	–	–	–
Zhang et al. [24]_NON-IG-IMRT or IMRT group	42	3DCRT (71.4%) or IMRT	m 63.43	52.86±4.17	1.8–2.4	–	9.7	38.1	14.5	RECIST	–	–	–	–	–	–
Lee J et al. [26]	56	Any RT	–	–	–	–	7.1	33.9	18.0	–	–	–	–	–	–	–
Matoba et al. [25]	15	SBRT	78.8	M45 (45–49.5)	5.5–7.5	M18.1 (6–32)	18.6	73.3	28.6	RECIST	100 (CR 67%)	–	–	–	–	–

	No. of studies	Pooled 1-year OS (95% CI, %)	Heterogeneity p-value, I² (%)	p of subgroup comparison	No. of studies	Pooled 2-year OS (95% CI, %)	Heterogeneity p-value, I² (%)	p of subgroup comparison
Primary disease controlled < 50%	5	48.0 (34.0–62.4)	0.001, 79.9		5	18.5 (14.7–23.0)	0.785, ~0
Primary disease controlled ≥ 50%	4	53.9 (35.7–71.1)	< 0.001, 83.3	0.626	4	32.4 (17.2–52.4)	< 0.001, 88.0	0.095
Child-Pugh A < 70%	3	60.5 (47.4–72.2)	0.474, ~0		2	31.2 (18.3–47.9)	0.779, ~0
Child-Pugh A ≥ 70%	7	47.9 (35.4–60.6)	< 0.001, 86.3	0.175	8	24.4 (15.5–36.3)	< 0.01, 87.1	0.465
Other DM < 20%	4	60.4 (42.0–76.3)	0.003, 78.5		3	31.0 (10.8–62.5)	< 0.001, 88.9
Other DM ≥ 20%	6	45.2 (35.3–55.5)	0.007, 68.7	0.157	7	22.2 (17.8–27.3)	0.235, 25.4	0.506
China and Korea (HBV dominant)	8	45.7 (34.4–57.6)	< 0.001, 85.6		9	23.4 (15.3–34.1)	< 0.001, 86.1
Japan (HCV dominant)	3	60.5 (47.4–72.2)	0.474, ~0	0.101	2	31.2 (18.3–47.9)	0.779, ~0	0.38

Clinical factor affecting survival	Study author (HR, p-value)
Child-Pugh class B	Chen et al. [9] (2.54, 0.009)
	Lee et al. [18] (2.48, 0.009)
	Wee et al. [22] (2.774, < 0.001)
	Park et al. [19] (NA, 0.1)
	Yamashita et al. [23] (71.4, 0.057)
Uncontrolled liver disease	Chen et al. [9] (1.69, 0.015)
	Lee et al. [18] (5.47, < 0.001)
	Park et al. [19] (NA, < 0.01)
	Toya et al. [20] (NA, 0.03)
LN mets response to RT	Chen et al. [9] (6.8, < 0.001)
	Lee et al. [18] (3.0, < 0.001)
	Park et al. [19] (NA, 0.06)
Multiple LN mets	Lee et al. [18] (1.97, 0027)
	Zhang et al. [24] (2.00, 0.006)
Other distant metastases	Chen et al. [9] (1.82, 0.015)
	Wee et al. [22] (1.62, 0.029)
	Park et al. [19] (NA, 0.01)
	Wang et al. [21] (4.15, < 0.001)

Table 1. Clinical information of included studies

Table 2. Treatment profiles and clinical outcomes

Table 3. Subgroup analyses of clinical factors

CI, confidence interval; DM, distant metastasis; HBV, hepatitis B virus; HCV, hepatitis C virus; OS, overall survival.

Table 4. Clinical factors affecting survival in multivariate analyses

HR, hazard ratio; LN, lymph node; mets, metastasis; NA, not available; RT, radiotherapy.