Ultra-high dose radiation for Liver metastasis using MR-guided TReatment with stereotactic Ablative Single-fraction (ULTRAS): Study protocol for a phase III randomized controlled trial

Abstract

INTRODUCTION: Liver metastases are common in several malignancies, with only 15-20% of patients eligible for surgical resection. For non-surgical candidates, stereotactic body radiation therapy (SBRT) is an effective alternative with acceptable local control (LC) rates. Higher biologically effective doses (BED10 > 100 Gy10) are associated with improved LC, and single-fraction ultra-high dose SBRT (35-40 Gy) has demonstrated excellent LC with minimal toxicity. MR-guided adaptive SBRT enhances precision and may optimizing single-fraction SBRT for liver metastases. METHODS AND ANALYSIS: ULTRAS is a multi-center, phase III randomized trial evaluating whether ultra-high dose MR-guided single-fraction SBRT (38 Gy, BED10 ≈ 180 Gy10) improves LC of liver oligometastases/oligoprogression compared to high-dose MR-guided single-fraction SBRT (27 Gy, BED10 ≈ 100 Gy10). Primary endpoint is LC of treated intrahepatic target lesion(s). Secondary endpoints include overall survival (OS), progression-free survival (PFS), intrahepatic and extrahepatic progression, toxicity (CTCAE v5.0 and PRO-CTCAE v1.0), and quality of life (QOL) (EORTC QLQ-C15-PAL, EORTC QLQ-LM21). Patients will be randomized 1:1 to receive either 27 Gy or 38 Gy, stratified by primary tumor site/histology, lesion characteristics, and prior systemic therapy. A total of 114 patients (57 per arm) will be enrolled over three years, with two years of follow-up. Assessments at predefined intervals will monitor response and toxicity. LC will be analyzed using cumulative incidence function. Widespread and intrahepatic progression will be assessed using Fine & Gray regression; OS and PFS via Cox models; toxicity and QOL via Chi-squared test and mixed-effects model. ETHICS AND DISSEMINATION: The ULTRAS trial obtained ethical approval from the University Health Network and will follow ICMJE reporting standards. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT06362395.