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

Abstract

Importance: Evidence is lacking from randomized clinical trials to guide the optimal approach for stereotactic ablative body radiotherapy (SABR) in patients with pulmonary oligometastases.

Objective: To assess whether single-fraction or multifraction SABR is more effective for the treatment of patients with pulmonary oligometastases.

Design, setting, and participants: This multicenter, unblinded, phase 2 randomized clinical trial of 90 patients across 13 centers in Australia and New Zealand enrolled patients with 1 to 3 lung oligometastases less than or equal to 5 cm from any nonhematologic malignant tumors located away from the central airways, Eastern Cooperative Oncology Group performance status 0 or 1, and all primary and extrathoracic disease controlled with local therapy. Enrollment was from January 1, 2015, to December 31, 2018, with a minimum patient follow-up of 2 years.

Interventions: Single fraction of 28 Gy (single-fraction arm) or 4 fractions of 12 Gy (multifraction arm) to each oligometastasis.

Main outcomes and measures: The main 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, disease-free survival, and patient-reported outcomes (MD Anderson Symptom Inventory-Lung Cancer and EuroQol 5-dimension visual analog scale).

Results: Ninety participants were randomized, of whom 87 were treated for 133 pulmonary oligometastases. The mean (SD) age was 66.6 [11.6] years; 58 (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% 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. One grade 5 AE occurred in the multifraction arm. No significant differences were found between the multifraction arm and single-fraction arm for 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). There were no significant differences observed in patient-reported outcomes.

Conclusions and relevance: In this randomized clinical trial, neither arm demonstrated evidence of superior safety, efficacy, or symptom burden; however, single-fraction SABR is more efficient to deliver. Therefore, single-fraction SABR, as assessed by the most acceptable outcome profile from all end points, could be chosen to escalate to future studies.

Trial registration: ClinicalTrials.gov Identifier: NCT01965223.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Siva reported receiving grants from Cancer Australia Government and Varian Medical Systems during the conduct of the study and grants from Bayer Pharmaceuticals and Varian Industries, honoraria from Reflexion and AstraZeneca, and personal fees for travel expenses from AstraZeneca outside the submitted work. Dr Hardcastle reported receiving grants from Cancer Australia and Varian Medical Systems during the conduct of the study and grants from Varian Medical Systems outside the submitted work; in addition, Dr Hardcastle had a patent for US20130004034, a patent for WO2012123861, and a patent for WO2012069965 relevant to radiation therapy in general. Dr Pryor reported receiving personal fees from Roche outside the submitted work. Dr Chesson reported receiving grants from Cancer Australia and Varian Medical Systems. Dr Sasso reported receiving grants from Auckland Medical Research Foundation during the conduct of the study. Dr De Abreu Lourenco reported receiving grants from Cancer Australia during the conduct of the study. Dr Kron reported receiving grants from Cancer Australia during the conduct of the study and having an academic appointment at the University of Wollongong outside the submitted work. Dr Ball reported receiving personal fees from AstraZeneca outside the submitted work. Dr Neeson reported receiving grants from Cancer Australia Government and Varian Medical Systems during the conduct of the study and grants from BMS, Roche Genentech, Compugen, Allergan, CRISPR, and Merck Sharp & Dohme outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Patients received 1 dose of 28 Gy (single-fraction arm) or 4 fractions of 12 Gy each (multifraction arm) to each oligometastasis.

Figure 2.. Efficacy Outcomes After Stereotactic Ablative Body Radiotherapy Comparing Each Arm

HR indicates hazard ratio; shaded areas represent 95% CIs.

Figure 3.. Induction of Systemic Immune Activation by Stereotactic Ablative Body Radiotherapy

Blood was collected for plasma and peripheral blood mononuclear cells (PBMCs) from 18 patients at baseline and 1 month after treatment. Cryopreserved PBMCs were analyzed by mass cytometry to define immune lineage, differentiation, or immune checkpoint molecules and ligands. Significant changes from baseline to 1 month are shown. For statistical analysis, all box plots show the median and interquartile range. Whiskers indicate range. The P values were determined by the Wilcoxon rank paired test. CM indicates central memory; CTLA-4, cytotoxic T-lymphocyte–associated antigen; DN, double-negative; EM, effector memory; and Treg, T regulatory.

Figure 4.. Immune Cell Composition and Plasma Cytokine Levels in Responders to Stereotactic Ablative Body Radiotherapy (SABR) Treatment

Nine patients responded to SABR and 9 patients had disease progression within 1 year of follow-up. The baseline to 1-month median change in cluster abundance for patients who responded or progressed are shown. The bar shows the median change in cluster abundance during 1 month. The P values were determined by the Mann-Whitney U test. CTLA-4 indicates cytotoxic T-lymphocyte–associated antigen; EM, effector memory; NK, natural killer; IFN, interferon; PD-1, programmed cell death 1; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain; TNF, tumor necrosis factor; and Treg, T regulatory.