Most patients with hepatocellular carcinoma (HCC) present with intermediate or advanced stages, for which radiotherapy and chemotherapy serve as the primary palliative interventions. However, owing to substantial tumor heterogeneity at these stages, controversies remain regarding the comparative prognostic benefits of these modalities. Furthermore, there is still a lack of direct comparative evidence from large-scale cohorts.

To investigate the comparative efficacy and prognosis of radiotherapy, chemotherapy and their combination in a large-scale population-based cohort.

Demographic and clinicopathological data of 5 487 patients diagnosed with unresected T3-T4 N0M0 HCC between 2006 and 2016 were retrospectively extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were stratified into four cohorts based on regimens: no treatment (n=2 681), radiotherapy (n=359), chemotherapy (n=2 136), and combined therapy (n=311). The end of follow-up was December 2016. The endpoints were overall survival (OS) and cancer-specific mortality (CSM). Inverse probability of treatment weighting (IPTW) was employed to mitigate baseline confounding. Factors associated with the selection of treatment modalities were identified via multivariate Logistic regression. Survival curves were constructed using the Kaplan-Meier method, and between-group differences were compared using the Log-rank test. Univariate and multivariate Cox proportional hazards regression analyses were utilized to identify factors associated with OS. Univariate and multivariate Fine-Gray competing risk models were applied to analyze factors affecting CSM. Stratified analyses based on different TNM stages were performed to further evaluate the effect of TNM stage on treatment efficacy.

Multivariate Logistic regression analysis revealed that tumor gradeⅡ was an independent predictor for receiving radiotherapy (OR=1.71, 95%CI=1.17-2.51, P<0.05). Predictors associated with chemotherapy included age >70 years (OR=1.56, 95%CI=1.36-1.79), uninsured status (OR=1.89, 95%CI=1.18-3.02), T4N0M0 (OR=1.47, 95%CI=1.19-1.81), tumor gradeⅡ (OR=1.51, 95%CI=1.21-1.89) and gradeⅢ (OR=1.31, 95%CI=1.10-1.56), and AFP positivity (OR=1.84, 95%CI=1.46-2.32)(P<0.05). Factors associated with significantly higher likelihood of receiving combined therapy included age >70 years (OR=2.17, 95%CI=1.60-2.95), T4N0M0 stage (OR=1.60, 95%CI=1.01-2.56), tumor gradeⅡ (OR=2.80, 95%CI=1.93-4.06), AFP positivity (OR=1.76, 95%CI=1.05-2.93), and fibrosis score F5-6 (OR=2.64, 95%CI=1.68-4.16) (P<0.05). Following IPTW adjustment, survival analysis demonstrated significant differences in OS and CSM across the four treatment groups (P<0.001). Patients with T4N0M0 stage exhibited significantly worse OS (P=0.003) and a higher cumulative incidence of CSM (P=0.008) compared with those with T3N0M0. The IPTW-adjusted multivariate Cox proportional hazards regression results showed, radiotherapy (HR=0.31, 95%CI=0.27-0.35), chemotherapy (HR=0.37, 95%CI=0.35-0.40), and combined therapy (HR=0.29, 95%CI=0.26-0.33) were identified as independent protective factors against all-cause mortality(P<0.05). Independent risk factors for all-cause mortality included T4N0M0 (HR=1.18, 95%CI=1.06-1.31), tumor gradeⅡ (HR=1.22, 95%CI=1.06-1.40) and gradeⅢ (HR=1.61, 95%CI=1.38-1.88), AFP positivity (HR=1.55, 95%CI=1.40-1.72), and high fibrosis score (HR=1.27, 95%CI=1.06-1.52) (P<0.05). Multivariate Fine-Gray competing risk analysis indicated that radiotherapy (HR=0.50, 95%CI=0.43-0.58), chemotherapy (HR=0.69, 95%CI=0.64-0.74), combined therapy (HR=0.56, 95%CI=0.49-0.64), and married status (HR=0.91, 95%CI=0.85-0.98) were independent protective factors against CSM. Conversely, T4N0M0 (HR=1.18, 95%CI=1.04-1.33), tumor gradeⅢ (HR=1.43, 95%CI=1.21-1.70), and AFP positivity (HR=1.43, 95%CI=1.29-1.59) were independent risk factors for CSM (P<0.05). Stratified analysis demonstrated that among patients with T3N0M0, both radiotherapy and combined therapy were superior to chemotherapy in terms of favorable OS and CSM outcomes (all P<0.05). However, in patients with T4N0M0, no statistically significant differences in OS and CSM were observed among radiotherapy, chemotherapy, and combined therapy (all P>0.05).

For patients with unresected T3-T4N0M0 stage HCC, radiotherapy alone, chemotherapy alone, and concurrent chemoradiotherapy can all significantly improve OS and reduce CSM. Radiotherapy alone and combined chemoradiotherapy yield more prominent survival benefits, with superior efficacy compared to chemotherapy alone.