IMPORTANCE: Most patients with locally advanced hepatocellular carcinoma (HCC) recur within the liver following systemic therapy. OBJECTIVE: To determine whether stereotactic body radiation therapy (SBRT) improves outcomes in patients with locally advanced HCC compared with sorafenib alone. DESIGN, SETTING, AND PARTICIPANTS: This multicenter phase 3 randomized clinical trial randomized patients with HCC 1:1 to sorafenib or SBRT followed by sorafenib, stratified by performance status, liver function, degree of metastases, and macrovascular invasion. Eligible patients had HCC unsuitable for or refractory to standard local-regional therapies and were candidates for first-line systemic therapy. Data were collected from April 2013 to March 2021, and data were analyzed from July 2022 to August 2023. INTERVENTION: Personalized SBRT, 27.5 to 50 Gy in 5 fractions. MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), adverse events, and quality of life. RESULTS: Of 193 patients randomized, 177 were eligible. Accrual was stopped early due to a change in standard-of-care systemic therapy. Of 177 included patients, 150 (84.7%) were male, and the median (IQR) age was 66 (60-72) years. Macrovascular invasion was seen in 131 (74.0%). As of July 1, 2022, the median OS was 12.3 months (90% CI, 10.6-14.3) with sorafenib vs 15.8 months (90% CI, 11.4-19.2) following SBRT and sorafenib (hazard ratio [HR], 0.77
90% CI, 0.59-1.01
1-sided P = .06). Adjusting for stratification factors, OS was improved with SBRT (HR, 0.72
95% CI, 0.52-0.99
2-sided P = .04). Median PFS was improved from 5.5 months (95% CI, 3.4-6.3) with sorafenib to 9.2 months (95% CI, 7.5-11.9) with SBRT and sorafenib (HR, 0.55
95% CI, 0.40-0.75
2-sided P <
.001). Treatment-related grade 3 or higher adverse events were seen in 37 of 88 (42%) and 39 of 83 (47%) of patients treated with sorafenib vs SBRT and sorafenib, respectively (P = .52). There were 2 treatment-related deaths in the sorafenib group (death not otherwise specified and liver failure) and 1 in the SBRT and sorafenib group (lung infection). At 6 months, improved quality of life was seen in 2 of 20 (10%) and 6 of 17 (35%) of patients treated with sorafenib and SBRT and sorafenib, respectively. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial, among patients with locally advanced HCC, SBRT was associated with a clinically important but not statistically significant improved overall survival compared with sorafenib alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01730937.