In a phase III NRG/RTOG 0631 randomised study, superiority of stereotactic radiosurgery over conventional radiotherapy for the primary endpoint of patient-reported pain response at 3 months was not found. The study even showed improvement of conventional external beam radiotherapy over stereotactic radiosurgery with no statistical difference. The stereotactic radiosurgery pain relief proportion was only half of the hypothesised rate used to power this study which had been based on single institution spine stereotactic radiosurgery experiences.
This is the first multicentre randomised study to assess the safety and efficacy of technologically advanced stereotactic radiosurgery for the treatment of vertebral metastases. There were no spinal cord complications at 2 years after stereotactic radiosurgery. There was no difference in pain control using stereotactic radiosurgery between radioresistant tumours and tumours with other histologic examination results. The findings are published by Dr. Samuel Ryu of the Department of Radiation Oncology, Stony Brook University Health Science Center in Stony Brook, NY, US and colleagues on 20 April 2023 in the JAMA Oncology.
The NRG/RTOG 0631 was used as a proving ground for centres, including community practices, to carry out more sophisticated and technology intensive radiotherapy treatments under the guidance of rigorous quality assurance. Treatment for spine metastases not requiring or amenable to surgery has been conventional external beam radiotherapy with palliative radiation doses. Previous studies of pain palliation of bone metastases comparing various conventional external beam radiotherapy dose regimens demonstrated equivalent efficacy. Pain relief was modest at 50% to 60%, with a median duration of 4 months.
The authors wrote in the background that with improved image guidance, immobilisation and targeting techniques, and use of intensity or volumetric modulation, stereotactic radiosurgery has been used to deliver a highly conformal dose covering the vertebral metastasis with a steep dose gradient to the spinal cord. Early institutional experiences assessing stereotactic radiosurgery for vertebral metastases have demonstrated safety, rapid and durable pain relief of 80-90%, and long-term tumour control using various dose regimens including. These studies suggested that stereotactic radiosurgery may improve pain relief and local tumour control over conventional external beam radiotherapy.
This phase II and III randomised clinical study assessed whether patient-reported pain relief was improved with stereotactic radiosurgery as compared with conventional external beam radiotherapy for patients with 1 to 3 sites of vertebral metastases. The phase II study results confirmed the feasibility and safety of stereotactic radiosurgery to treat vertebral metastases in the multi-institutional cooperative group setting. The phase III assessed patient reported pain relief and treatment safety on long-term follow-up.
Patients were randomised 2:1 to the stereotactic radiosurgery or conventional external beam radiotherapy groups. Eligibility criteria included solitary vertebral metastasis, 2 contiguous vertebral levels involved, or maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients were enroled in the study, and 339 patients were analyzed. The analysis reported in the JAMA Oncology includes data extracted on 9 March 2020.
Patients randomised to the stereotactic radiosurgery group were treated with a single dose of 16 or 18 Gy (to convert to rad, multiply by 100) given to the involved vertebral level(s) only, not including any additional spine levels. Patients assigned to conventional external beam radiotherapy were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below.
The primary endpoint was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale without worsening in pain at the secondary site(s) or the use of pain medication. Secondary endpoints included treatment-related side effects, quality of life, and long-term effects on vertebral bone and spinal cord.
Among 339 patients analyzed, mean age in stereotactic radiosurgery was 61.9 years versus 63.7 years in conventional external beam radiotherapy group. There were 114 males (54.5%) in stereotactic radiosurgery group versus 70 males (53.8%) in conventional external beam radiotherapy group. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the stereotactic radiosurgery group and 5.88 (2.41) in the conventional external beam radiotherapy group.
The primary endpoint of pain response at 3 months favoured conventional external beam radiotherapy, 41.3% for stereotactic radiosurgery versus 60.5% for conventional external beam radiotherapy with difference −19 percentage points (95% confidence interval −32.9 to −5.5; 1-sided p = 0.99; 2-sided p = 0.01). Zubrod score, a measure of performance status ranging from 0 to 4, with 0 being fully functional and asymptomatic, and 4 being bedridden, was the significant factor influencing pain response.
There were no differences in the proportion of acute or late adverse effects. Vertebral compression fracture at 24 months was 19.5% with stereotactic radiosurgery and 21.6% with conventional external beam radiotherapy (p = 0.59). There were no spinal cord complications reported at 24 months. The authors commented that this finding represents a valuable prospective report of long-term spinal cord tolerance after stereotactic radiosurgery. This information may inform future clinical studies, such as those assessing stereotactic radiosurgery for epidural tumour decompression or for spinal cord compression, and for treating oligometastases where durable local tumour control improves survival.
The authors also commented that stereotactic radiosurgery pain relief proportion was only half of the hypothesised rate used to power this study. It is not clear whether this lower response can be attributed to patient selection, inclusion of occult spine metastases, or study conduct differences as compared with the other reports.
The authors concluded that the results demonstrate prospectively, that 1-year and 2-year survival rates of patients with spine metastases treated with stereotactic radiosurgery are encouraging and underscore the need to continue to find the optimal stereotactic radiosurgery radiation dose and fractionation for patients with vertebral metastases.
Reference
Ryu S, Deshmukh S, Timmerman RD, et al. Stereotactic Radiosurgery vs Conventional Radiotherapy for Localized Vertebral Metastases of the Spine Phase 3 Results of NRG Oncology/RTOG 0631 Randomized Clinical Trial. JAMA Oncology; Published online 20 April 2023. doi:10.1001/jamaoncol.2023.0356.