In the Trans Tasman Radiation Oncology Group (TROG) 13.01 phase II randomised clinical study that compared single-fraction versus multifraction stereotactic ablative radiation therapy (SABR) in patients with pulmonary metastases, the researchers from Australia and New Zealand demonstrated that neither arm was superior in terms of safety, efficacy, or symptom burden; however, single-fraction SABR is of shorter duration and more efficient to deliver. The study findings are published on 29 August 2021 in the JAMA Oncology by Prof. Shankar Siva of the Department of Radiation Oncology, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne in Victoria, Australia and the Stereotactic Ablative Fractionated Radiotherapy Versus Radiosurgery for Oligometastatic Neoplasia to the Lung (SAFRON) II study investigators.

The authors wrote in the study background about the lack of evidence from the randomised clinical studies to guide the optimal approach for SABR in patients with pulmonary oligometastases. The objective of their study was to determine if single-fraction or multifraction SABR is more effective for the treatment of patients with 1 to 3 oligometastases to the lung.

In this multicentre, unblinded, phase II randomised study, the TROG researchers enrolled 90 patients in 13 centres in Australia and New Zealand. Enrolled patients had 1 to 3 lung oligometastases less than or equal to 5 cm from any solid tumour malignancy located away from the central airways. It was required that patients have ECOG performance status 0 or 1, and primary and extrathoracic disease controlled with local therapy. Patients were enrolled in this study from January 2015 to December 2018, with a minimum follow-up of 2 years.

In the single-fraction arm treatment comprised of 28 Gy and in the multifraction arm 4 fractions were delivered of 12 Gy to each oligometastasis, with biologic effective doses at 10 Gy (BED10) of 106 Gy in the single-fraction arm and 105 Gy in the multifraction arm.

The main study outcome was grade 3 or higher treatment-related adverse events (AEs) occurring within 1 year of SABR. Secondary outcomes were freedom from local failure, overall survival (OS), disease-free survival (DFS), and patient-reported outcomes measured according MD Anderson Symptom Inventory–Lung Cancer and EuroQol 5-dimension visual analogue scale.

From 90 randomised patients, 87 were treated for 133 pulmonary oligometastases. The mean age was 66.6 years; 58 patients (64%) were male. Median follow-up was 36.5 months (interquartile range, 24.8-43.9 months).

The numbers of grade 3 or higher AEs related to treatment at 1 year were 2 (5%; 80% confidence interval [CI] 1%-13%) in the single-fraction arm and 1 (3%; 80% CI 0%-10%) in the multifraction arm, with no significant difference observed between arms. In the multifraction arm, 1 AE of grade 5 occurred.

No significant differences were found between the single-fraction arm and multifraction arm for freedom from local failure (hazard ratio [HR] 0.5; 95% CI 0.2-1.3; p = 0.13), OS (HR 1.5; 95% CI, 0.6-3.7; P = .44), or DFS (HR 1.0; 95% CI 0.6-1.6; p > 0.99).

Patient-reported outcomes were similar between the 2 groups.

The researchers concluded that single-fraction SABR, as assessed by the most acceptable outcome profile from all study endpoints, could be selected for future studies.

Prof. Arya Amini of the Department of Radiation Oncology, City of Hope National Medical Center in Duarte, CA, US wrote in an invited commentary that the landscape in radiation oncology for treatment of patients with metastatic disease has drastically changed during the past decade. Through the combination of stereotactic body radiation therapy (SBRT)/SABR, it is possible to improve PFS, OS and potentially begin flattening Kaplan-Meier curves in metastatic disease.

An additional novelty of the analysis performed by Siva et al. is on the immunogenic effects of SABR in which the TROG investigators demonstrated expected changes in T-regulatory cells, cytotoxic T-lymphocyte–associated antigen, and programmed cell death 1 expression, which all had increased expression levels after SABR. However, differences of expression between the single-fraction and multifraction arms appeared to be similar.

Prof. Amini commented that both single-fraction and multifraction treatments are safe and effective, but the single-fraction treatment is more convenient for patients.


Siva S, Bressel M, Mai T, et al. Single-Fraction vs Multifraction Stereotactic Ablative Body Radiotherapy for Pulmonary Oligometastases (SAFRON II) The Trans Tasman Radiation Oncology Group 13.01 Phase 2 Randomized Clinical Trial. JAMA Oncol. Published online 29 August 2021. doi:10.1001/jamaoncol.2021.2939

Amini A. Managing Pulmonary Oligometastatic Disease with Stereotactic Body Radiation Therapy—Moving the Field Forward 1 Organ at a Time. JAMA Oncol. Published online August 29, 2021. doi:10.1001/jamaoncol.2021.2926