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Randomized Controlled Trial
. 2023 Jun 1;9(6):800-807.
doi: 10.1001/jamaoncol.2023.0356.

Stereotactic Radiosurgery vs Conventional Radiotherapy for Localized Vertebral Metastases of the Spine: Phase 3 Results of NRG Oncology/RTOG 0631 Randomized Clinical Trial

Samuel Ryu  1 , Snehal Deshmukh  2   3 , Robert D Timmerman  4 , Benjamin Movsas  5 , Peter Gerszten  6 , Fang-Fang Yin  7 , Adam Dicker  8 , Christopher D Abraham  9 , Jim Zhong  10 , Stephen L Shiao  11 , Richard Tuli  12 , Anand Desai  13 , Loren K Mell  14 , Puneeth Iyengar  4 , Ying J Hitchcock  15 , Aaron Max Allen  16 , Steven Burton  6 , Doris Brown  17 , Hadley J Sharp  18 , Neal E Dunlap  19 , M Salim Siddiqui  5 , Timothy H Chen  20 , Stephanie L Pugh  2   3 , Lisa A Kachnic  21
Affiliations
Randomized Controlled Trial

Stereotactic Radiosurgery vs Conventional Radiotherapy for Localized Vertebral Metastases of the Spine: Phase 3 Results of NRG Oncology/RTOG 0631 Randomized Clinical Trial

Samuel Ryu et al. JAMA Oncol. .

Abstract

Importance: Spine metastasis can be treated with high-dose radiation therapy with advanced delivery technology for long-term tumor and pain control.

Objective: To assess whether patient-reported pain relief was improved with stereotactic radiosurgery (SRS) as compared with conventional external beam radiotherapy (cEBRT) for patients with 1 to 3 sites of vertebral metastases.

Design, setting, and participants: In this randomized clinical trial, patients with 1 to 3 vertebral metastases were randomized 2:1 to the SRS or cEBRT groups. This NRG 0631 phase 3 study was performed as multi-institutional enrollment within NRG Oncology. Eligibility criteria included the following: (1) solitary vertebral metastasis, (2) 2 contiguous vertebral levels involved, or (3) maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients enrolled in the trial, and 339 patients were analyzed. This analysis includes data extracted on March 9, 2020.

Interventions: Patients randomized to the SRS 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 cEBRT were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below.

Main outcomes and measures: The primary end point was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale (NRPS) without worsening in pain at the secondary site(s) or the use of pain medication. Secondary end points included treatment-related toxic effects, quality of life, and long-term effects on vertebral bone and spinal cord.

Results: A total of 339 patients (mean [SD] age of SRS group vs cEBRT group, respectively, 61.9 [13.1] years vs 63.7 [11.9] years; 114 [54.5%] male in SRS group vs 70 [53.8%] male in cEBRT group) were analyzed. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the SRS group and 5.88 (2.41) in the cEBRT group. The primary end point of pain response at 3 months favored cEBRT (41.3% for SRS vs 60.5% for cEBRT; difference, -19 percentage points; 95% CI, -32.9 to -5.5; 1-sided P = .99; 2-sided P = .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 SRS and 21.6% with cEBRT (P = .59). There were no spinal cord complications reported at 24 months.

Conclusions and relevance: In this randomized clinical trial, superiority of SRS for the primary end point of patient-reported pain response at 3 months was not found, and there were no spinal cord complications at 2 years after SRS. This finding may inform further investigation of using spine radiosurgery in the setting of oligometastases, where durability of cancer control is essential.

Trial registration: ClinicalTrials.gov Identifier: NCT00922974.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Timmerman reported grants from Accuray, Inc, Elekta Oncology, and Varian Medical Systems outside the submitted work. Dr Movsas reported grants from Varian Research, Philips Research, and ViewRay Research outside the submitted work; board member positions for ASTRO and ARS; and pending patents for an MRI phantom and a CT simulation phantom. Dr Dicker reported being an employee of Thomas Jefferson University/Jefferson Health; additional support from the National Cancer Institute (NCI), American Society of Clinical Oncology, NRG Oncology, Prostate Cancer Foundation, Prostate Cancer Research Program (DoD); current active advisory activities with Janssen, Oncohost, Oranomed, CVS, IBA, Aptar (Voluntis), Onconova Therapeutics, SBRBio; a patent pending (application No. PCT/US19/37487; Title: Doped BEO Compounds for Optically Stimulated Luminescence (OSL) and Thermoluminescence (TL) Radiation Dosimetry); former activities with Varian, Accordant, Envisino Health Partners, European Commission, Albert Einstein Medical College, Deallus, Roche, Genentech, Alcimed, Self Care Catalyst, and Hengrui Pharmaceuticals; providing expert testimony and consulting regarding intellectual property for Wilson Soncini; and serving as an unpaid advisor for Google LaunchPad Accelerator, Dreamit Ventures, Evolution Road, and 10D. Dr Mell reported grants from Merck and Astra-Zeneca, payment or honoraria from BMS, and participation on both a Data Safety Monitoring Board and an Advisory Board for Astellas. Dr Iyengar reported serving on an advisory board for Astrazeneca and support from Incyte to institution for clinical trial during the conduct of the study. Dr Kachnic reported grants from Varian, Inc, personal fees from New Beta Innovation Limited (Data Safety Monitoring Board) and Radiation Therapy Oncology Group Foundation, and royalties/licenses from UpToDate (editor of Bones Metastasis chapter) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Abbreviations: cEBRT, conventional external beam radiotherapy; RT, radiation therapy; SRS, stereotactic radiosurgery.
Figure 2.
Figure 2.. Numerical Rating Pain Scale Response Proportion at the Index Spine With No Increase in Pain Medication and No Progressive Pain at the Other Treated Spine
The error bars indicate 95% CIs. Abbreviations: cEBRT, conventional external beam radiotherapy; NRPS, Numerical Rating Pain Scale; SRS, stereotactic radiosurgery.
Figure 3.
Figure 3.. Quality of Life Over Time
The error bars indicate 95% CIs. A, Functional Assessment of Cancer Therapy – General (FACT-G) total score. B, Brief Pain Index (BPI) worst pain score. C, EuroQol–5 Dimension (EQ-5D) index score. Abbreviations: cEBRT, conventional external beam radiotherapy; QoL, quality of life; SRS, stereotactic radiosurgery.
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