Stereotactic Ablative Fractionated Radiotherapy Versus Radiosurgery for Oligometastatic Neoplasia to the Lung: A Randomized Phase II Trial

The optimal dose and fractionation schedule for SABR to pulmonary oligometastases is unknown. The primary objective of this study is to compare outcomes between single fraction 28Gy (ARM 1, biological equivalent dose [BED10] = 106Gy) and 48Gy in four fractions (ARM 2, BED10 = 106Gy). Trans Tasman Radiation Oncology Group (TROG) 13.01 / Australasian Lung Cancer Trials Group (ALTG) SAFRON II (clinicaltrials.gov ID NCT01965223) was a multicenter randomized screening phase II trial investigating SABR for 1-3 oligometastases to the lung from any non-hematological malignancy. Patients had ECOG performance 0-1 with oligometastases ≤ 5cm and located >2cm away from central airways. Concurrent systemic or targeted therapy was not allowed. The primary endpoint was defined as treatment related toxicity CTCAE V4.0 grade 3 within 1 year of treatment. If either arm is considered safe i.e. if the maximum observed significant toxicity rate is 5% with upper limit of the 80% confidence <17% (one-sided 10% alpha) then the trial would progress to assess secondary endpoints of quality of life, local control (LC), overall survival (OS), time to distant failure, Disease free survival (DFS), Quality of life (QoL), and cost effectiveness. Ninety patients were randomized across 11 centers in Australia and New Zealand of which 87 patients were treated for 133 pulmonary metastases. Two patients received ‘adjuvant’ systemic therapy for less than 6 months after SABR, all other patients had SABR alone. The median age was 68 years, 63% were male and PET staging was used in 72%. Colorectal was the commonest primary (47%), followed by lung (11%) and kidney (10%). Real-time central review necessitated replanning in 18% of cases prior to SABR. Thirteen patients were not assessable for toxicity within 1 year due to early progression or death leaving 74 patients for the late toxicity analysis. The number of grade 3+ toxicities related to treatment within 1 year in ARM 1 and ARM2 were 2 (5% [80% CI: 1-14]) and 1 (3% (80% CI: 0.3% - 10%), respectively. There were two patients with grade 3 events in ARM 1 that lasted <3 months in duration, with no grade 4 or 5 events. There was one patient with a grade 5 event in ARM 2 (pneumonitis within 3 months of SABR, underlying interstitial lung disease), with no grade 3 or 4 events. LC at 1-year (95% CI) between ARM 1 and ARM 2 was 93% (79-98%) versus 95% (81-99%), OS was 95% (83-99%) and 93% (80-98%), and DFS was 59% (43-72%) and 60% (44-73%), respectively. The pre-specified primary endpoint was met both 28Gy/1 fraction and 48Gy/4 fractions of SABR; therefore, comparison of both arms for secondary endpoints will be performed at trial maturation. These findings may have implications for treatment selection in resource-constrained or bundled payment environments.