Stereotactic Body Radiotherapy (SBRT) Versus Conventional Palliative Radiotherapy (CRT) for Patients With Painful Spinal Metastases: A Phase 3, Randomized Controlled Trial

Abstract

Background: Conventional external beam radiation (CRT) is standard palliative treatment for spinal metastases; however, complete response rates for pain are low. Stereotactic body radiotherapy (SBRT) delivers high dose ablative radiotherapy. We aimed to compare complete response rates (CR) for pain between SBRT and CRT to painful spinal metastases. \n \nMethods: We did this multicenter, phase 2/3, randomised controlled trial in 13 hospitals in Canada and 5 in Australia and New Zealand. Patients were eligible if they were aged 18 years and older, a spine MRI confirmed painful (pain measured as ≥2 points using the Brief Pain Inventory) site of spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0 to 2, and no frank instability or neurologically symptomatic spinal cord or cauda equina compression. Patients were randomized (1:1) to receive either 24Gy in 2 SBRT fractions or 20Gy in 5 CRT fractions using standard techniques. Treatment assignment was performed centrally using a minimization method to achieve balance for the stratification factors of radioresistant (gastrointestinal, sarcoma, melanoma and renal cell cancer metastases) vs. radiosensitive (all other histologies) histologic type, presence or absence of “Mass” on imaging (extra-osseous paraspinal and/or epidural disease extension), and center. Patients, caregivers and investigators were not masked to the treatment allocation. The primary endpoint was the CR rate for pain at 3 months post-radiation. Final analysis populations included the intent-to-treat (ITT) population for all efficacy endpoints, and the as-treated population for safety and quality assurance analyses. The trial is registered with ClinicalTrials.gov (NCT02512965). \n \nFindings: Patients were enrolled from January 2016 to September 2019. All 229 patients were included in the ITT analyses including 4 of the 114 patients randomized to SBRT who did not initiate the study intervention, 2 of the 115 in the CRT arm that initiated at least one fraction of radiation treatment but withdrew prior to completion, 22 (19%) patients in the CRT arm and 16 (14%) patients in the SBRT arm who were in-evaluable at the primary endpoint assessment at 3 months, and 39 (34%) patients in the CRT arm and 36 (32%) patients in the SBRT arm who were inevaluable at the 6 month endpoint. The median baseline worst pain score was 5 (range, 2-10) in both arms, and the median follow-up was 6.7 months (range, 0.2-8.9). At 3 months, 16/115 (14%) in the CRT arm vs. 40/114 (36%) in the SBRT arm (p=0.0002) achieved a CR for pain. Significance was retained on multivariable analyses (MVA, p=0.0003) and the risk ratio (RR) was 1.33 (95% C.I., 1.14 – 1.55) favoring SBRT. At 6 months, 18/115 (16%) in the CRT arm vs. 37/114 patients (33%) in the SBRT arm achieved a CR (p=0.004), significance was retained on MVA (p=0.007), and the RR was 1.24 (95% C.I., 1.07 – 1.44) favoring SBRT. The 3 month radiation site specific progression-free-survival rates for CRT vs. SBRT were 86% vs. 92% and, at 6 months, 69% vs. 75%, respectively. Quality-of-life outcomes were comparable with only financial perception at 1 month (p=0.03) favoring SBRT. Grade 2+ adverse events were observed in 12% and 11% in the CRT and SBRT arms, respectively. \n \nInterpretation: SBRT is superior to CRT in improving the CR rate for pain in selected patients with spinal metastases. \n \nTrial Registration: (NCT02512965). \n \nFunding: Canadian Cancer Society (CCS) and the National Health and Medical Research Council (NHMRC). \n \nDeclaration of Interests: AS declares prior consulting services and/or honorarium for past educational seminars for Varian Medical Systems, Elekta AB, Astra Zeneca, Medtronic Kyphon, and BrainLAB, and research grants from Elekta AB and Varian Medical Systems. SS declares research grants from Varian Medical Systems, Merck-Sharp-Dohme and Bayer Pharmaceuticals and honorarium for past educational seminars and advisory board participation from Astra Zeneca and Reflexion. SDM declares grant support from Novartis/AAA and honorarium from Ipsen. MF declares grants from Elekta AB and honorarium for past educational seminars from Elekta AB and Varian Medical Systems. JG, IT, MK, MGF, ML, PJM, YL, MB, JB, KD, GLM, RKW, SKL, WRP, and ZG have no conflicts of interests to declare. \n \nEthics Approval Statement: Each participating center obtained approval from their local research ethics board, and each patient provided written informed consent. All data were collected, maintained and analyzed by the Canadian Cancer Trials Group (CCTG) in Kingston, Ontario, Canada. The trial was sponsored in Canada by the CCTG and in Australia and New Zealand by the Trans Tasman Radiation Oncology Group (TROG), and independently monitored by the independent CCTG Data Safety Monitoring Board.