Efficacy and Safety of Stereotactic Body Radiation Therapy Modalities for >5 cm Advanced Unresectable Hepatocellular Carcinoma: A Network Meta-Analysis

<b>Objective</b>: Radiotherapy remodels the tumor microenvironment (TME) and may enhance the efficacy of immunotherapy in cancer treatment, particularly in patients with large, unresectable hepatocellular carcinoma (HCC) complicated by portal vein tumor thrombus (PVTT). Because of these unique effects, a growing body of research has found that stereotactic body radiation therapy (SBRT) combined with transcatheter arterial chemoembolization (TACE) or programmed death protein 1 (PD-1) inhibitors has a synergistic impact on unresectable advanced hepatocellular carcinomas (HCCs) larger than 5 cm in diameter. We aim to explore the efficacy of these treatment modalities through a network meta-analysis (NMA). <b>Methods and Analysis</b>: We evaluated the efficacy and safety of different SBRT-based treatment modalities for large advanced HCCs with PVTT (tumor diameter ≥ 5 cm), with primary endpoints including overall survival (OS), progression-free survival (PFS), and grade 3-4 severe adverse events (SAEs). <b>Results:</b> Eighteen studies comprising 2303 patients were included. SBRT combined with transcatheter arterial chemoembolization (SBRT + TACE) demonstrated significantly superior overall survival compared with other monotherapy or combination strategies. Most other treatment regimens showed comparable PFS outcomes. Notably, SBRT alone and SBRT combined with PD 1 inhibitors (SBRT + PD 1) were associated with significantly lower incidences of severe adverse events compared with other treatment modalities; all of these reported SAEs were manageable with appropriate clinical intervention. <b>Conclusions</b>: For patients with large (≥5 cm) advanced HCC with PVTT, SBRT combined with TACE was associated with superior OS and PFS compared with other treatment strategies. These findings suggest potential synergistic interactions between SBRT and TACE or immunotherapy. Further high-quality prospective trials are warranted to validate these observations and clarify the underlying molecular mechanisms. Our results provide evidence to inform therapeutic decision-making in advanced HCC.