Single-Fraction versus Multifraction Stereotactic Ablative Body Radiotherapy (SABR/SBRT) for Peripheral Pulmonary Oligometastases: SAFRON II Trans Tasman Radiation Oncology Group 13.01 Phase 2 Randomized Clinical Trial

Abstract

Importance: Randomized clinical trial evidence is limited to guide the optimal dose-fractionation approach for stereotactic ablative body radiotherapy (SABR), also known as stereotactic body radiotherapy (SBRT), in patients with pulmonary oligometastases. Objective: To determine whether single-fraction SABR or multifraction SABR is more effective and safe for treating patients with lung oligometastases. Design, Setting, and Participants: SAFRON II was a multicenter, unblinded, phase 2 randomized clinical trial enrolling 90 patients at 13 centers in Australia and New Zealand. Eligible patients had 1 to 3 pulmonary oligometastases measuring 5 cm or smaller from any nonhematologic malignant tumor, lesions located away from the central airways, Eastern Cooperative Oncology Group performance status 0 or 1, and controlled primary and extrathoracic disease after local therapy. Enrollment occurred from January 1, 2015, to December 31, 2018, with a minimum follow-up of 2 years. Interventions: SABR to each oligometastasis delivered as either 28 Gy in 1 fraction (single-fraction arm) or 48 Gy in 4 fractions of 12 Gy (multifraction arm). Main Outcomes and Measures: The primary end point was grade 3 or higher treatment-related adverse events (AEs) within 1 year after SABR. Secondary end points included local control measured as freedom from local failure, overall survival, disease-free survival, and patient-reported outcomes using the MD Anderson Symptom Inventory-Lung Cancer and EuroQol 5-dimension visual analog scale. Results: Of 90 randomized participants, 87 were treated for 133 pulmonary oligometastases. Mean (SD) age was 66.6 (11.6) years, and 58 participants (64%) were male. Median follow-up was 36.5 months (interquartile range, 24.8-43.9 months). Grade 3 or higher treatment-related AEs at 1 year occurred in 2 patients (5%; 80% CI, 1%-13%) in the single-fraction arm and 1 patient (3%; 80% CI, 0%-10%) in the multifraction arm, with no significant difference between arms. One grade 5 AE occurred in the multifraction arm. No significant differences were observed for multifraction versus single-fraction SABR in freedom from local failure (hazard ratio [HR], 0.5; 95% CI, 0.2-1.3; P = .13), overall survival (HR, 1.5; 95% CI, 0.6-3.7; P = .44), or disease-free survival (HR, 1.0; 95% CI, 0.6-1.6; P > .99). Patient-reported outcomes also did not differ significantly. Conclusions and Relevance: In this phase 2 randomized clinical trial of SABR for peripheral pulmonary oligometastatic disease, neither single-fraction nor multifraction treatment demonstrated superior safety, efficacy, or symptom burden outcomes. Because single-fraction SABR is more efficient to deliver, the single-fraction regimen, based on the most acceptable overall outcome profile across end points, could be selected for evaluation in future studies. Trial Registration: ClinicalTrials.gov Identifier: NCT01965223.