Phase III Multi-Center, Prospective Randomized Trial Comparing High Dose Single Fraction Radiation Therapy to a 3-Fraction SBRT Regimen in the Treatment of Oligometastatic Human Cancer

Abstract

Pre-clinical and clinical evidence have shown that high single dose radiation therapy (SDRT) is associated with superior tumor control compared to multi-fraction (MF) regimens, due to SDRT’s ability to engage a microvascular response interfering with the ability to repair radiation damage to tumor cell DNA. The primary objective of this study was to compare local control rates with either a single dose of 24Gy versus 27Gy in three 9Gy fractions in patients with oligometastatic disease. A secondary objective was to compare toxicity outcomes between the two cohorts. A total of 174 patients were enrolled at three institutions. 155 patients (75 randomized to the SDRT and 80 to the MF regimen) were assessable for treatment-related toxicities having met protocol criteria. A total of 117 patients with 154 treated lesions, were evaluable for the local disease control end point. Eligibility criteria for enrollment included ≤5 metastatic lesions documented on imaging studies, and no prior radiation therapy to the treated site. Eligible lesions were limited to non-mobile targets (osseous or lymph node metastases). Potential candidates whose target lesions were adjacent to critical organs, precluding treatment with SDRT due to the risk of treatment-induced complications, were excluded. Patients were followed every 6 months for a minimum of 2 years, and imaging evaluation of the treated site at 12 and 24 months post-treatment was mandatory. Responses were measured using standard RECIST criteria. For the assessment of toxicity, a minimum follow-up of 6 months was required. Median follow up was 39 months (range, 11-85). Lesions treated with SDRT demonstrated a significantly lower incidence of local disease progression (LR) compared to those treated with MF (p<0.0005). The 3-year incidence of LR was 6.1% of the lesions compared to 23% for the SDRT and MF regimens, respectively. A reduction in distant metastatic (DM) progression was noted among those treated with SDRT compared to the MF regimen The 3-year incidence of DM progression was 4.1% compared to 17.5% for the SDRT and MF regimens, respectively(p<0.02). There was no significant difference in grade 3+ toxicity between the two arms (SDRT: 10.7%; MF: 5%; p=0.24). The specific incidence of grade 3+ pain, peripheral neuropathy and bone fractures for the SDRT regimen was 5.3%, 2.7% and 1.3%. The corresponding incidence for these toxicities for the MF regimen was 1.3%, 0% and 2.5%. No overall survival differences were observed between the arms. The study provides Level 1 evidence that SDRT was associated with superior tumor control outcomes compared to a standard 3-fraction regimen in a cohort of patients with oligometastatic osseous/nodal disease. SDRT was well tolerated, rendering comparable toxicity outcomes to a current standard-of-care hypofractionated SBRT treatment regimen.