SABR-COMET randomized phase 2 trial: stereotactic ablative radiotherapy (SABR/SBRT) to all oligometastases plus standard palliative care versus standard palliative care alone in oligometastatic cancer

Abstract

Background: The oligometastatic cancer paradigm proposes that selected patients with a limited number of metastatic lesions might be cured if all sites of disease are eradicated. Randomized controlled trial evidence supporting this metastasis-directed approach is scarce. We assessed the effect of stereotactic ablative radiotherapy (SABR; stereotactic body radiotherapy, SBRT) on overall survival, oncological outcomes, toxicity, and quality of life in patients with a controlled primary tumour and one to five oligometastatic lesions. Methods: This randomized, open-label, phase 2 trial was conducted at 10 hospitals in Canada, the Netherlands, Scotland, and Australia. Eligible patients were aged 18 years or older, had a controlled primary tumour, one to five metastatic lesions, an Eastern Cooperative Oncology Group performance status score of 0-1, and a life expectancy of at least 6 months. After stratification by number of metastases (1-3 vs 4-5), patients were randomly assigned (1:2) to palliative standard-of-care treatment alone (control group) or standard of care plus SABR to all metastatic lesions (SABR group), using a computer-generated randomisation list with permuted blocks of nine. Patients and physicians were not masked to treatment allocation. The primary endpoint was overall survival. A randomized phase 2 screening design was used with a two-sided alpha of 0.20, in which p<0.20 designated a positive trial. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01446744. Findings: Between Feb 10, 2012, and Aug 30, 2016, 99 patients were randomized: 33 (33%) to the control group and 66 (67%) to the SABR group. In the SABR group, two (3%) patients did not receive allocated treatment and withdrew; in the control group, two (6%) patients withdrew. Median follow-up was 25 months (IQR 19-54) in the control group and 26 months (23-37) in the SABR group. Median overall survival was 28 months (95% CI 19-33) with standard palliative care alone versus 41 months (26-not reached) with standard care plus SABR to all metastases (hazard ratio 0.57, 95% CI 0.30-1.10; p=0.090). Grade 2 or worse adverse events occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SABR group (p=0.026), an absolute increase of 20% (95% CI 5-34). Treatment-related deaths occurred in three (4.5%) of 66 patients after SABR and in none in the control group. Interpretation: Adding comprehensive SABR to standard palliative treatment was associated with improved overall survival and met the primary endpoint of this randomized phase 2 trial, but three (4.5%) of 66 patients assigned to SABR had treatment-related death. Phase 3 trials are needed to conclusively establish an overall survival benefit and to determine the maximum number of metastatic lesions for which SABR provides benefit. Funding: Ontario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant.