Outcomes of a Third Course of Salvage Spine Stereotactic Radiosurgery for Spinal Metastases

Outcomes of a Third Course of Salvage Spine Stereotactic Radiosurgery for Spinal Metastases | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Outcomes of a Third Course of Salvage Spine Stereotactic Radiosurgery for Spinal Metastases Jessica Bai, Ehsan Balagamwala, Anthony Magnelli, Lilyana Angelov, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8745546/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 22 Apr, 2026 Read the published version in Journal of Neuro-Oncology → Version 1 posted 20 You are reading this latest preprint version Abstract Objective Re-irradiation with salvage spine stereotactic radiosurgery (sSRS) has emerged as a viable strategy for spinal metastases with progressive disease. We report the characteristics and clinical outcomes of spinal segments that received at least three courses of sSRS. Methods 10 spinal segments in 6 patients who received at least three courses of sSRS were evaluated from an IRB-approved retrospective single-institution database. Overall survival (OS) and radiographic progression-free survival (rPFS) were calculated by Kaplan-Meier analysis. Radiographic failure was defined as progression on imaging at the treated segment. Toxicity outcomes were collected. Results Median follow-up was 8.9 months (range, 0.2–46.3). Three patients had died at the time of analysis. Half the patients were female, median age at treatment was 63.2 years (range, 36.9–77.2), and median consult KPS was 80 (range, 70–90). The median cumulative thecal sac EQD2 2 D max after the third course of sSRS was 137.9 Gy (range, 97–227.5). The median third course re-irradiation sSRS thecal sac EQD2 2 D max was 37.15 Gy (range, 21.8–57.8). 30% (3/10) of treated spinal segments had radiographic progression (range of time to radiographic progression, 0.98–14.3 months), with a 1-year radiographic progression-free survival rate of 87.5%. 42.9% (3/7) of treatments resulted in pain flare, which were all adequately treated with steroids. No cases of VCF or radiation myelopathy were reported. Conclusions Three courses of sSRS may be considered for salvage treatment for spinal metastases demonstrating progression. Though it appears to be safe and effective, more investigation is warranted. Since the cumulative doses to the neural structures exceed those established by other studies, great care and review of all treatment options including surgery and other ablative treatments like radiofrequency or cryoablation should be considered in a multidisciplinary setting prior to proceeding with salvage spine SRS. stereotactic radiosurgery metastases central nervous system Figures Figure 1 Figure 2 INTRODUCTION Spine stereotactic radiosurgery (sSRS) delivers high dose conformal radiotherapy in a few fractions, maximizing ablative tumor coverage while sparing adjacent organs at risk (OARs) such as the spinal cord and cauda equina 1 , 2 . Re-irradiation with salvage spine stereotactic radiosurgery (sSRS) has emerged as a viable strategy for spinal metastases with progressive disease, yielding 1-year local control rates of ~ 80% and low rates of vertebral body fracture and radiation-induced myelopathy 3 – 5 . However, epidural tumor progression remains a risk in re-irradiation with sSRS, most likely due to conservative dosing of critical neural structures within the epidural space 1 , 3 , 6 . There is currently limited literature assessing multiple courses of sSRS after local tumor progression. We report the characteristics and clinical outcomes in patients who, after receiving re-irradiation with sSRS and experiencing subsequent radiographic progression, underwent a salvage third course of sSRS to the same spinal segment. METHODS Using an IRB-approved single-institution database, we identified 10 spinal metastases in 6 patients who received at least three courses of sSRS to the same spinal segment. The primary objective was to determine radiographic failure rates after the salvage third sSRS course. Radiographic failure was defined as progression on imaging at the treated segment as determined by the multidisciplinary team including radiology, neurosurgery and radiation oncology. To assess toxicity outcomes, clinical notes and magnetic resonance images (MRI) were reviewed to determine pain flare, radiation-induced vertebral compression fracture (VCF), and radiation myelopathy. Pain flare was defined as an increase in pain within 1 week of treatment, requiring the initiation of steroids. Radiation-induced VCF was defined as fractures that occurred after radiation but before tumor progression, as tumor progression may independently cause destabilization 7 . Our institution’s sSRS technique and setup has been previously described 8 , 9 . All patients underwent CT simulation in the supine position for treatment planning. Patients with spinal metastases at C1 to T4 were immobilized using a 5-point thermoplastic head mask, and those with lesions below T4 were immobilized in a BodyFix mold (Medical Intelligence; Elekta, Stockholm, Sweden) with a vacuum bag. The simulation CT was then fused with high-definition MRI. The target volume was contoured to cover the entire vertebral body for lesions within the vertebral body 10 . For lesions affecting the lamina, pedicles, or spinous process, the target volume included all of the posterior elements. A planning target volume (PTV) margin was not utilized 10 . The spinal cord and thecal sac were contoured with 4.5 mm cranial and caudal margins. Treatment planning was performed using Pinnacle (Philips, Mayfield Heights, OH). sSRS was delivered using the Edge linear accelerator (Varian Medical Systems, Palo Alto, California, USA) equipped with 2.5 mm multi-leaf collimator leaves with cone beam CT (CBCT) image guidance. For patients treated with 5-fraction repeat sSRS, spinal cord was limited to < 0.35 cc receiving ≤ 22 Gy, with a maximum point dose capped at 28 Gy to mitigate the risk of myelitis. The cauda equina was constrained to < 5 cc receiving ≤ 30 Gy, with a maximum point dose of 31.5 Gy to reduce the risk of neuritis. For patients treated with 4-fraction repeat SRS, spinal cord was limited to < 0.35 cc receiving ≤ 18 Gy, with a maximum point dose limited to 25.6 Gy to reduce the risk of myelitis. Clinical records, including consultation, completion, and follow-up notes, were systematically reviewed for each patient. Data were collected on patient age, sex, Karnofsky performance status (KPS), histology, treatment indication (asymptomatic, pain only, neurologic deficit only, or both), prior surgeries, and spinal disease characteristics (epidural or paraspinal disease, location of bony disease, single level or multilevel disease). The treatment plans for each course of sSRS were reviewed for prescription dose, and the Dmax and D10% to the spinal cord and cauda equina for the salvage third course of sSRS were collected. Overall survival (OS), calculated from the start date of salvage third sSRS to death or last follow-up visit, and radiographic progression-free survival (rPFS), defined as the interval from the start date of salvage third sSRS to radiographic progression, death, or last follow-up visit, were calculated by Kaplan–Meier analysis. RESULTS 10 spinal metastases in 6 patients were treated with a salvage third course of sSRS between January 2020 and December 2023 to the same spinal level after radiographic failure. Median time interval to sSRS re-irradiation was 12.1 months (range, 3.6–21.2). One of these segments subsequently received a fourth course of sSRS in December 2023. One patient received prior conventional external beam radiation therapy (EBRT) before their first course of sSRS; therefore, after their salvage third course of sSRS, they had underwent four radiation courses to the same metastatic spinal segment. 50% of patients were female, median age at treatment was 63.2 years (range, 36.9–77.2), and median consult KPS was 80 (range, 70–90). All patients had oligometastatic disease. Of the 10 spinal segments treated with a salvage third course of sSRS, 50% (5/10) were thoracic, 10% (1/10) were lumbar, and 40% (4/10) were sacral. The primary cancers were colorectal adenocarcinoma (40%; 4/10), NUT midline carcinoma (10%; 1/10), lung carcinoid (10%; 1/10), renal clear cell carcinoma (30%; 3/10), and myxoid liposarcoma (10%; 1/10). Median follow-up was 8.9 months (range, 0.2–46.3). Additional clinical characteristics can be found in Table 1. The median dose for the first sSRS course was 30 Gy/3 fractions (range, 16–30 Gy/1–5 fractions). For the second sSRS course, the median dose was 30 Gy/4 fractions (range, 30 Gy/4 fractions – 30 Gy/5 fractions). Median dose for the third course of sSRS was 30 Gy/4 fractions (range, 27–30 Gy/4–5 fractions). Median cumulative Dmax and D10% to the spinal cord was 51 Gy (range, 50.1–71.1) and 45.8 Gy (range, 36.9–55.4), respectively. Median cumulative Dmax and D10% to the cauda equina was 99.5 Gy (range, 58.5–99.5) and 72.4 Gy (range, 34.9–72.4), respectively. A summary of the dosimetric factors can be found in Table 2 . The median cumulative thecal sac EQD2 2 D max after the third course of sSRS was 137.9 Gy (range, 97–227.5). The median third course re-irradiation sSRS thecal sac EQD2 2 D max was 37.15 Gy (range, 21.8–57.8). The median overall survival time was not reached as only 3 out of 7 treatments had an associated patient death at the time of analysis (range, 0.98–46.4 months). The median follow-up for those surviving at the time of analysis was 18.4 months (range, 2.9–46.3). The 1-month, 6-month, and 1-year survival rates were 85.7%, 71.4%, and 53.6%, respectively (Fig. 1 ). 30% (3/10) of treated spinal segments had radiographic progression. The median time to radiographic progression was not reached at the time of analysis (range, 0.98–14.3 months). Median follow-up for treatments that did not result in radiographic progression was 2.5 months (range, 0.98–8.5) (Fig. 2 ). The 1-year rate of radiographic progression-free survival was 87.5%. Of the treatments that had radiographic progression, 33% showed radiographic progression within the paraspinal soft tissues, neural foramen, and pedicles, while 66% showed progression within the epidural space and vertebral body. 42.9% (3/7) of treatments resulted in pain flare, which were all adequately treated with steroids. No cases of VCF or radiation myelopathy were reported after a salvage third course of sSRS. One patient who received 4 total courses of sSRS (4th sSRS dose 30 Gy/4 fractions) to the sacrum/coccyx is currently alive and at time of analysis, 99 days since the last course of sSRS, has not experienced radiographic failure. He has since developed foot drop, thought to be related to repeated sacral SRS, but remains ambulatory with the assistance of a cane and has not become wheelchair dependent. DISCUSSION This study represents one of the first efforts to investigate the efficacy and outcomes of multiple courses of salvage sSRS following local tumor progression. Our experience suggests that a salvage third course of sSRS is potentially safe and feasible in select cases, with pain flare occurring in many patients with complete resolution with steroid use and no instances of VCF or radiation myelopathy, which is surprising given the cumulative doses of radiation given. Pretreatment with steroids to avoid development of pain flare should be a consideration for salvage sSRS. Our outcomes also suggest that salvage third course of sSRS may be effective, as demonstrated by a favorable 1-year radiographic progression-free survival rate of 87.5%. However, these results need to be viewed in the context of the 1-month, 6-month, and 1-year survival rates of 85.7%, 71.4%, and 53.6%, respectively. Our study suggests that a fourth course of salvage sSRS may serve as an option in circumstances where other interventions, such as surgical resection or non-radiation ablative procedures, are not feasible. Epidural radiographic progression was one of the most common patterns of failure after salvage third course sSRS, which is consistent with prior studies 1 , 3 , 6 . Radiographic progression also occurred within the paraspinal soft tissues, neural foramen, and pedicles in 33% of the treatments that showed radiographic progression, while 66% of the treatments had radiographic progression within the vertebral body. This may be attributed to our use of more conservative dosing in fractionated sSRS. The progression may also be due to the inherent radioresistance of the primary tumors within the three patients that showed radiographic progression, as they had colorectal adenocarcinoma, lung carcinoid, and NUT midline carcinoma 11 – 13 . Preclinical studies provide important insight into the kinetics and extent of spinal cord recovery and tolerance after re-irradiation 14 . In rodent models, Ruifrok et al. (1992) demonstrated that the ED50 for re-irradiation increases most rapidly within the first month post-treatment in 3 week old rats, with limited additional recovery thereafter; notably, even at 6 months, full recovery to baseline tolerance was not achieved 15 . However, adult rats showed more substantial recovery between 2–6 months, highlighting the influence of developmental stage on spinal cord repair. Knowles et al. (1983), using a guinea pig model, found that the ED50 for paralysis one year after an initial 10 Gy exposure was nearly equivalent to that of previously unirradiated animals (19.5 Gy vs. 20.5 Gy, respectively), suggesting that meaningful recovery is possible over longer intervals 16 . Ang et al. (2001) was a rhesus monkey study that demonstrated substantial recovery of spinal cord tolerance, with results showing up to 76%, 85%, and 101% of the original dose after a 1, 2, and 3-year interval, respectively. Furthermore, swine models in Medin et al. (2012) that were reirradiated with spinal radiosurgery one year after prior fractionated treatment did not exhibit a higher incidence of neurologic injury compared to those that received radiosurgery alone, suggesting no effect from prior radiation at 1 year. In light of these findings, the absence of radiation-induced myelopathy in our cohort receiving three courses of sSRS suggests that, with careful patient selection and appropriate time intervals between treatments, clinically meaningful recovery of spinal cord tolerance may occur, making repeat irradiation a feasible strategy in select cases. Sahgal et al. (2012) reviewed safe spinal cord dosing and suggested the following for re-irradiation SBRT delivered in 1 to 5 fractions 17 : 1) The cumulative thecal sac EQD2 2 D max should not exceed 70 Gy. 2) The re-irradiation SBRT thecal sac EQD2 2 D max should not exceed 25 Gy. 3) The re-irradiation SBRT thecal sac EQD2 2 D max to cumulative EQD2 2 D max ratio should not exceed 0.5. 4) The minimum time interval to re-irradiation should be at least 5 months. For our patients, the median cumulative thecal sac EQD2 2 D max after the third course of sSRS was 137.9 Gy (range, 97–227.5). The median third course re-irradiation sSRS thecal sac EQD2 2 D max was 37.15 Gy (range, 21.8–57.8). Thus, the re-irradiation sSRS thecal sac EQD2 2 D max to cumulative EQD2 2 D max ratio was 0.27, which remains below recommendation of 0.5 from Saghal et al. (2012). Our median time interval from the second course to third course of sSRS was 12.1 months (range, 3.6–21.2), exceeding the recommended 5-month minimum time interval to re-irradiation as outlined. Since the cumulative thecal sac and re-irradiation sSRS thecal sac doses in our cohort exceed the recommendation of 70 Gy and 25 Gy, respectively, great care and multidisciplinary review of all treatment options should be considered in these complex cases to balance disease control with long-term spinal cord safety. Radiation-induced VCF also did not occur after salvage third course sSRS in our cohort. It should be noted that several metastatic spinal segments in our cohort were operated on prior to the salvage third course of sSRS. 2/10 segments received hardware alone and 1/10 segments received both hardware and kyphoplasty. The two patients that received prior surgery both had renal clear cell carcinoma as their primary, which is known to biomechanically weaken bone and contribute to VCF due to its osteolytic properties 18 , 19 . Spinal metastases that are unstable and have significant fracture risk are more likely to be operated on 3 . Therefore, the added stability from hardware or kyphoplasty may have prevented VCF from occurring in the metastatic spinal segments that were operated on in our cohort. Our study has important limitations, most notably is our small sample size, given that very few patients undergo three courses of salvage sSRS. Another important limitation is the study’s retrospective design, which may lead to underreported outcomes such as pain flare. In addition, while the 1-year radiographic progression-free survival rate of 85.7% is encouraging, it must be interpreted with caution, as the median follow-up for segments without progression was only 2.5 months. Longer-term observation is necessary to ascertain the true durability of this approach. A strength of our study was that our patients were followed closely with regular follow-up and imaging, allowing for timely monitoring of radiographic progression, VCF, and radiation myelopathy. Further study is warranted into the clinical characteristics and outcomes of patients who receive at least three courses of sSRS. CONCLUSION Our findings suggest that three courses of salvage stereotactic spine radiosurgery (sSRS) may be a reasonable option for patients with progressive spinal metastases. While this approach appears to be both safe and effective, further study is needed to better define long-term outcomes and toxicity risks. Importantly, because the cumulative radiation dose to adjacent neural structures can exceed thresholds established in prior studies, careful multidisciplinary evaluation is essential. Consideration of surgical management or alternative ablative modalities such as radiofrequency or cryoablation should be undertaken before proceeding with additional salvage spine SRS. Declarations Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Cleveland Clinic Foundation. Consent to participate Informed consent was obtained from all individual participants included in the study. Funding None. Competing Interests STC reports “honorarium” from Varian Medical Systems and Blue Earth Diagnostics, outside the submitted work. JJB, EHB, AM, LA, JHS, ESM, PP have no competing interests to declare. Data availability The data used to support the findings of this study are available from the corresponding author upon request. Author contributions All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: STC Acquisition, analysis, and interpretation of data: All Authors Drafting of the manuscript: JJB, EHB Critical revision of the manuscript for important intellectual content: All Authors Statistical analysis: JJB Administrative, technical, or material support: EHB, STC Study supervision: STC References Sahgal A, Bilsky M, Chang EL et al (2011) Stereotactic body radiotherapy for spinal metastases: current status, with a focus on its application in the postoperative patient. J Neurosurg Spine 14(2):151–166. 10.3171/2010.9.SPINE091005 Sahgal A, Larson DA, Chang EL (2008) Stereotactic body radiosurgery for spinal metastases: a critical review. 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CNS Oncol 2(3):259–270. 10.2217/cns.13.11 Sahgal A, Atenafu EG, Chao S et al (2013) Vertebral compression fracture after spine stereotactic body radiotherapy: a multi-institutional analysis with a focus on radiation dose and the spinal instability neoplastic score. J Clin Oncol Off J Am Soc Clin Oncol 31(27):3426–3431. 10.1200/JCO.2013.50.1411 Balagamwala EH, Cherian S, Angelov L et al (2012) Stereotactic body radiotherapy for the treatment of spinal metastases. J Radiat Oncol 1(3):255–265. 10.1007/s13566-012-0047-6 Balagamwala EH, Naik M, Reddy CA et al (2018) Pain flare after stereotactic radiosurgery for spine metastases. J Radiosurgery SBRT 5(2):99–105 Ryu S, Pugh SL, Gerszten PC et al (2014) RTOG 0631 phase 2/3 study of image guided stereotactic radiosurgery for localized (1–3) spine metastases: phase 2 results. 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Int J Radiat Biol Relat Stud Phys Chem Med 44(5):433–442. 10.1080/09553008314551411 Sahgal A, Ma L, Weinberg V et al (2012) Reirradiation human spinal cord tolerance for stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 82(1):107–116. 10.1016/j.ijrobp.2010.08.021 Balagamwala EH, Angelov L, Koyfman SA et al (2012) Single-fraction stereotactic body radiotherapy for spinal metastases from renal cell carcinoma. J Neurosurg Spine 17(6):556–564. 10.3171/2012.8.SPINE12303 Thibault I, Atenafu EG, Chang E et al (2015) Risk of vertebral compression fracture specific to osteolytic renal cell carcinoma spinal metastases after stereotactic body radiotherapy: A multi-institutional study. J Radiosurgery SBRT 3(4):297–305 Tables Tables 1 to 2 are not available with this version. Additional Declarations Competing interest reported. STC reports “honorarium” from Varian Medical Systems and Blue Earth Diagnostics, outside the submitted work. JJB, EHB, AM, LA, JHS, ESM, PP have no competing interests to declare. Cite Share Download PDF Status: Published Journal Publication published 22 Apr, 2026 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 02 Mar, 2026 Reviews received at journal 02 Mar, 2026 Reviews received at journal 28 Feb, 2026 Reviews received at journal 26 Feb, 2026 Reviews received at journal 21 Feb, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers agreed at journal 20 Feb, 2026 Reviewers agreed at journal 19 Feb, 2026 Reviewers agreed at journal 18 Feb, 2026 Reviews received at journal 18 Feb, 2026 Reviews received at journal 17 Feb, 2026 Reviews received at journal 16 Feb, 2026 Reviewers agreed at journal 16 Feb, 2026 Reviewers agreed at journal 16 Feb, 2026 Reviewers agreed at journal 09 Feb, 2026 Reviewers agreed at journal 04 Feb, 2026 Reviewers invited by journal 04 Feb, 2026 Editor assigned by journal 04 Feb, 2026 Submission checks completed at journal 04 Feb, 2026 First submitted to journal 30 Jan, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8745546","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":586600355,"identity":"d95f0870-87db-4176-a60e-a33986a72052","order_by":0,"name":"Jessica Bai","email":"","orcid":"","institution":"Case Western Reserve University","correspondingAuthor":false,"prefix":"","firstName":"Jessica","middleName":"","lastName":"Bai","suffix":""},{"id":586600357,"identity":"8f5a98fa-50c4-4930-8543-5b89edb06b2e","order_by":1,"name":"Ehsan Balagamwala","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Ehsan","middleName":"","lastName":"Balagamwala","suffix":""},{"id":586600359,"identity":"c3851b6a-12f3-4756-a372-4c2e9386a4e4","order_by":2,"name":"Anthony Magnelli","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Anthony","middleName":"","lastName":"Magnelli","suffix":""},{"id":586600361,"identity":"5e894efd-c110-433d-83ac-b73c41e891db","order_by":3,"name":"Lilyana Angelov","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Lilyana","middleName":"","lastName":"Angelov","suffix":""},{"id":586600362,"identity":"32bb2f64-6e55-4e71-a057-ab101badbabf","order_by":4,"name":"John Suh","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"John","middleName":"","lastName":"Suh","suffix":""},{"id":586600363,"identity":"d43004c5-d887-44ff-9334-149c44386bdb","order_by":5,"name":"Erin Murphy","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Erin","middleName":"","lastName":"Murphy","suffix":""},{"id":586600364,"identity":"48703a26-5982-4a1e-b663-f1888af2309e","order_by":6,"name":"Praveen Pendyala","email":"","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":false,"prefix":"","firstName":"Praveen","middleName":"","lastName":"Pendyala","suffix":""},{"id":586600365,"identity":"70e3373a-8c58-4772-8fe1-67b047129b63","order_by":7,"name":"Samuel Chao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAqElEQVRIiWNgGAWjYDACCRBRwcDA3kCaljMMDDwHSNLC2EaKFv7ZzQ8f/pxnJ8/DwHzs4xeiLLlzzNiYd1uyYQ8DW/JsGWK0GEgkmEkzbjuQYM/AY8wsQZyW9G+SP+ccSOAhQUuOmQRvA0QL4wditEjcyCk25jkG9AszWzIzMToY+Gekb3z4owYYYuzNhxl/EKUHDoBWMPOQpgUISLVlFIyCUTAKRggAAJ30KVFivb3WAAAAAElFTkSuQmCC","orcid":"","institution":"Cleveland Clinic","correspondingAuthor":true,"prefix":"","firstName":"Samuel","middleName":"","lastName":"Chao","suffix":""}],"badges":[],"createdAt":"2026-01-31 01:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8745546/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8745546/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s11060-026-05581-9","type":"published","date":"2026-04-22T15:59:06+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":102211756,"identity":"b374935d-3cb2-40d5-ba5a-f6942f65761a","added_by":"auto","created_at":"2026-02-09 12:28:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":14313,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival after salvage third course spine stereotactic radiosurgery. The y-axis depicts the overall survival rate after salvage third course sSRS, and the x-axis depicts months from salvage third course sSRS. The 1-month, 6-month, and 1-year survival rates were 85.7%, 71.4%, and 53.6%, respectively.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8745546/v1/61d81d753f4e0a6a743cdbd4.png"},{"id":102211766,"identity":"e5350175-bd3a-44c5-a953-8f86050af383","added_by":"auto","created_at":"2026-02-09 12:28:20","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":17104,"visible":true,"origin":"","legend":"\u003cp\u003eRadiographic progression-free survival rates after salvage third course spine stereotactic radiosurgery for the 10 spinal segments treated. The y-axis depicts the radiographic progression-free survival rate after salvage third course sSRS, and the x-axis depicts months from salvage third course sSRS. The 1-year rate of radiographic progression-free survival was 87.5%.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8745546/v1/30186b73b830e0f14d607b50.png"},{"id":107928292,"identity":"9f4c1737-ec10-4105-8e53-50f30dea00cf","added_by":"auto","created_at":"2026-04-27 16:09:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":201405,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8745546/v1/01244f55-5586-4bb4-aa9d-0124d362e7b6.pdf"}],"financialInterests":"Competing interest reported. STC reports “honorarium” from Varian Medical Systems and Blue Earth Diagnostics, outside the submitted work. JJB, EHB, AM, LA, JHS, ESM, PP have no competing interests to declare.","formattedTitle":"Outcomes of a Third Course of Salvage Spine Stereotactic Radiosurgery for Spinal Metastases","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSpine stereotactic radiosurgery (sSRS) delivers high dose conformal radiotherapy in a few fractions, maximizing ablative tumor coverage while sparing adjacent organs at risk (OARs) such as the spinal cord and cauda equina\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Re-irradiation with salvage spine stereotactic radiosurgery (sSRS) has emerged as a viable strategy for spinal metastases with progressive disease, yielding 1-year local control rates of ~\u0026thinsp;80% and low rates of vertebral body fracture and radiation-induced myelopathy\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, epidural tumor progression remains a risk in re-irradiation with sSRS, most likely due to conservative dosing of critical neural structures within the epidural space\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere is currently limited literature assessing multiple courses of sSRS after local tumor progression. We report the characteristics and clinical outcomes in patients who, after receiving re-irradiation with sSRS and experiencing subsequent radiographic progression, underwent a salvage third course of sSRS to the same spinal segment.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eUsing an IRB-approved single-institution database, we identified 10 spinal metastases in 6 patients who received at least three courses of sSRS to the same spinal segment. The primary objective was to determine radiographic failure rates after the salvage third sSRS course. Radiographic failure was defined as progression on imaging at the treated segment as determined by the multidisciplinary team including radiology, neurosurgery and radiation oncology. To assess toxicity outcomes, clinical notes and magnetic resonance images (MRI) were reviewed to determine pain flare, radiation-induced vertebral compression fracture (VCF), and radiation myelopathy. Pain flare was defined as an increase in pain within 1 week of treatment, requiring the initiation of steroids. Radiation-induced VCF was defined as fractures that occurred after radiation but before tumor progression, as tumor progression may independently cause destabilization\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur institution\u0026rsquo;s sSRS technique and setup has been previously described\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. All patients underwent CT simulation in the supine position for treatment planning. Patients with spinal metastases at C1 to T4 were immobilized using a 5-point thermoplastic head mask, and those with lesions below T4 were immobilized in a BodyFix mold (Medical Intelligence; Elekta, Stockholm, Sweden) with a vacuum bag. The simulation CT was then fused with high-definition MRI. The target volume was contoured to cover the entire vertebral body for lesions within the vertebral body\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. For lesions affecting the lamina, pedicles, or spinous process, the target volume included all of the posterior elements. A planning target volume (PTV) margin was not utilized\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The spinal cord and thecal sac were contoured with 4.5 mm cranial and caudal margins. Treatment planning was performed using Pinnacle (Philips, Mayfield Heights, OH). sSRS was delivered using the Edge linear accelerator (Varian Medical Systems, Palo Alto, California, USA) equipped with 2.5 mm multi-leaf collimator leaves with cone beam CT (CBCT) image guidance. For patients treated with 5-fraction repeat sSRS, spinal cord was limited to \u0026lt;\u0026thinsp;0.35 cc receiving\u0026thinsp;\u0026le;\u0026thinsp;22 Gy, with a maximum point dose capped at 28 Gy to mitigate the risk of myelitis. The cauda equina was constrained to \u0026lt;\u0026thinsp;5 cc receiving\u0026thinsp;\u0026le;\u0026thinsp;30 Gy, with a maximum point dose of 31.5 Gy to reduce the risk of neuritis. For patients treated with 4-fraction repeat SRS, spinal cord was limited to \u0026lt;\u0026thinsp;0.35 cc receiving\u0026thinsp;\u0026le;\u0026thinsp;18 Gy, with a maximum point dose limited to 25.6 Gy to reduce the risk of myelitis.\u003c/p\u003e \u003cp\u003eClinical records, including consultation, completion, and follow-up notes, were systematically reviewed for each patient. Data were collected on patient age, sex, Karnofsky performance status (KPS), histology, treatment indication (asymptomatic, pain only, neurologic deficit only, or both), prior surgeries, and spinal disease characteristics (epidural or paraspinal disease, location of bony disease, single level or multilevel disease). The treatment plans for each course of sSRS were reviewed for prescription dose, and the Dmax and D10% to the spinal cord and cauda equina for the salvage third course of sSRS were collected.\u003c/p\u003e \u003cp\u003eOverall survival (OS), calculated from the start date of salvage third sSRS to death or last follow-up visit, and radiographic progression-free survival (rPFS), defined as the interval from the start date of salvage third sSRS to radiographic progression, death, or last follow-up visit, were calculated by Kaplan\u0026ndash;Meier analysis.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e10 spinal metastases in 6 patients were treated with a salvage third course of sSRS between January 2020 and December 2023 to the same spinal level after radiographic failure. Median time interval to sSRS re-irradiation was 12.1 months (range, 3.6\u0026ndash;21.2). One of these segments subsequently received a fourth course of sSRS in December 2023. One patient received prior conventional external beam radiation therapy (EBRT) before their first course of sSRS; therefore, after their salvage third course of sSRS, they had underwent four radiation courses to the same metastatic spinal segment. 50% of patients were female, median age at treatment was 63.2 years (range, 36.9\u0026ndash;77.2), and median consult KPS was 80 (range, 70\u0026ndash;90). All patients had oligometastatic disease. Of the 10 spinal segments treated with a salvage third course of sSRS, 50% (5/10) were thoracic, 10% (1/10) were lumbar, and 40% (4/10) were sacral. The primary cancers were colorectal adenocarcinoma (40%; 4/10), NUT midline carcinoma (10%; 1/10), lung carcinoid (10%; 1/10), renal clear cell carcinoma (30%; 3/10), and myxoid liposarcoma (10%; 1/10). Median follow-up was 8.9 months (range, 0.2\u0026ndash;46.3). Additional clinical characteristics can be found in \u003cb\u003eTable\u0026nbsp;1.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe median dose for the first sSRS course was 30 Gy/3 fractions (range, 16\u0026ndash;30 Gy/1\u0026ndash;5 fractions). For the second sSRS course, the median dose was 30 Gy/4 fractions (range, 30 Gy/4 fractions \u0026ndash; 30 Gy/5 fractions). Median dose for the third course of sSRS was 30 Gy/4 fractions (range, 27\u0026ndash;30 Gy/4\u0026ndash;5 fractions). Median cumulative Dmax and D10% to the spinal cord was 51 Gy (range, 50.1\u0026ndash;71.1) and 45.8 Gy (range, 36.9\u0026ndash;55.4), respectively. Median cumulative Dmax and D10% to the cauda equina was 99.5 Gy (range, 58.5\u0026ndash;99.5) and 72.4 Gy (range, 34.9\u0026ndash;72.4), respectively. A summary of the dosimetric factors can be found in \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e. The median cumulative thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e after the third course of sSRS was 137.9 Gy (range, 97\u0026ndash;227.5). The median third course re-irradiation sSRS thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e was 37.15 Gy (range, 21.8\u0026ndash;57.8).\u003c/p\u003e \u003cp\u003eThe median overall survival time was not reached as only 3 out of 7 treatments had an associated patient death at the time of analysis (range, 0.98\u0026ndash;46.4 months). The median follow-up for those surviving at the time of analysis was 18.4 months (range, 2.9\u0026ndash;46.3). The 1-month, 6-month, and 1-year survival rates were 85.7%, 71.4%, and 53.6%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e30% (3/10) of treated spinal segments had radiographic progression. The median time to radiographic progression was not reached at the time of analysis (range, 0.98\u0026ndash;14.3 months). Median follow-up for treatments that did not result in radiographic progression was 2.5 months (range, 0.98\u0026ndash;8.5) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The 1-year rate of radiographic progression-free survival was 87.5%. Of the treatments that had radiographic progression, 33% showed radiographic progression within the paraspinal soft tissues, neural foramen, and pedicles, while 66% showed progression within the epidural space and vertebral body.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e42.9% (3/7) of treatments resulted in pain flare, which were all adequately treated with steroids. No cases of VCF or radiation myelopathy were reported after a salvage third course of sSRS. One patient who received 4 total courses of sSRS (4th sSRS dose 30 Gy/4 fractions) to the sacrum/coccyx is currently alive and at time of analysis, 99 days since the last course of sSRS, has not experienced radiographic failure. He has since developed foot drop, thought to be related to repeated sacral SRS, but remains ambulatory with the assistance of a cane and has not become wheelchair dependent.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis study represents one of the first efforts to investigate the efficacy and outcomes of multiple courses of salvage sSRS following local tumor progression. Our experience suggests that a salvage third course of sSRS is potentially safe and feasible in select cases, with pain flare occurring in many patients with complete resolution with steroid use and no instances of VCF or radiation myelopathy, which is surprising given the cumulative doses of radiation given. Pretreatment with steroids to avoid development of pain flare should be a consideration for salvage sSRS. Our outcomes also suggest that salvage third course of sSRS may be effective, as demonstrated by a favorable 1-year radiographic progression-free survival rate of 87.5%. However, these results need to be viewed in the context of the 1-month, 6-month, and 1-year survival rates of 85.7%, 71.4%, and 53.6%, respectively. Our study suggests that a fourth course of salvage sSRS may serve as an option in circumstances where other interventions, such as surgical resection or non-radiation ablative procedures, are not feasible.\u003c/p\u003e \u003cp\u003eEpidural radiographic progression was one of the most common patterns of failure after salvage third course sSRS, which is consistent with prior studies\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Radiographic progression also occurred within the paraspinal soft tissues, neural foramen, and pedicles in 33% of the treatments that showed radiographic progression, while 66% of the treatments had radiographic progression within the vertebral body. This may be attributed to our use of more conservative dosing in fractionated sSRS. The progression may also be due to the inherent radioresistance of the primary tumors within the three patients that showed radiographic progression, as they had colorectal adenocarcinoma, lung carcinoid, and NUT midline carcinoma\u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePreclinical studies provide important insight into the kinetics and extent of spinal cord recovery and tolerance after re-irradiation\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In rodent models, Ruifrok et al. (1992) demonstrated that the ED50 for re-irradiation increases most rapidly within the first month post-treatment in 3 week old rats, with limited additional recovery thereafter; notably, even at 6 months, full recovery to baseline tolerance was not achieved\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, adult rats showed more substantial recovery between 2\u0026ndash;6 months, highlighting the influence of developmental stage on spinal cord repair. Knowles et al. (1983), using a guinea pig model, found that the ED50 for paralysis one year after an initial 10 Gy exposure was nearly equivalent to that of previously unirradiated animals (19.5 Gy vs. 20.5 Gy, respectively), suggesting that meaningful recovery is possible over longer intervals\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Ang et al. (2001) was a rhesus monkey study that demonstrated substantial recovery of spinal cord tolerance, with results showing up to 76%, 85%, and 101% of the original dose after a 1, 2, and 3-year interval, respectively. Furthermore, swine models in Medin et al. (2012) that were reirradiated with spinal radiosurgery one year after prior fractionated treatment did not exhibit a higher incidence of neurologic injury compared to those that received radiosurgery alone, suggesting no effect from prior radiation at 1 year. In light of these findings, the absence of radiation-induced myelopathy in our cohort receiving three courses of sSRS suggests that, with careful patient selection and appropriate time intervals between treatments, clinically meaningful recovery of spinal cord tolerance may occur, making repeat irradiation a feasible strategy in select cases.\u003c/p\u003e \u003cp\u003eSahgal et al. (2012) reviewed safe spinal cord dosing and suggested the following for re-irradiation SBRT delivered in 1 to 5 fractions\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e: \u003cb\u003e1)\u003c/b\u003e The cumulative thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e should not exceed 70 Gy. \u003cb\u003e2)\u003c/b\u003e The re-irradiation SBRT thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e should not exceed 25 Gy. \u003cb\u003e3)\u003c/b\u003e The re-irradiation SBRT thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e to cumulative EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e ratio should not exceed 0.5. \u003cb\u003e4)\u003c/b\u003e The minimum time interval to re-irradiation should be at least 5 months. For our patients, the median cumulative thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e after the third course of sSRS was 137.9 Gy (range, 97\u0026ndash;227.5). The median third course re-irradiation sSRS thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e was 37.15 Gy (range, 21.8\u0026ndash;57.8). Thus, the re-irradiation sSRS thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e to cumulative EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e ratio was 0.27, which remains below recommendation of 0.5 from Saghal et al. (2012). Our median time interval from the second course to third course of sSRS was 12.1 months (range, 3.6\u0026ndash;21.2), exceeding the recommended 5-month minimum time interval to re-irradiation as outlined. Since the cumulative thecal sac and re-irradiation sSRS thecal sac doses in our cohort exceed the recommendation of 70 Gy and 25 Gy, respectively, great care and multidisciplinary review of all treatment options should be considered in these complex cases to balance disease control with long-term spinal cord safety.\u003c/p\u003e \u003cp\u003eRadiation-induced VCF also did not occur after salvage third course sSRS in our cohort. It should be noted that several metastatic spinal segments in our cohort were operated on prior to the salvage third course of sSRS. 2/10 segments received hardware alone and 1/10 segments received both hardware and kyphoplasty. The two patients that received prior surgery both had renal clear cell carcinoma as their primary, which is known to biomechanically weaken bone and contribute to VCF due to its osteolytic properties\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Spinal metastases that are unstable and have significant fracture risk are more likely to be operated on\u003csup\u003e3\u003c/sup\u003e. Therefore, the added stability from hardware or kyphoplasty may have prevented VCF from occurring in the metastatic spinal segments that were operated on in our cohort.\u003c/p\u003e \u003cp\u003eOur study has important limitations, most notably is our small sample size, given that very few patients undergo three courses of salvage sSRS. Another important limitation is the study\u0026rsquo;s retrospective design, which may lead to underreported outcomes such as pain flare. In addition, while the 1-year radiographic progression-free survival rate of 85.7% is encouraging, it must be interpreted with caution, as the median follow-up for segments without progression was only 2.5 months. Longer-term observation is necessary to ascertain the true durability of this approach. A strength of our study was that our patients were followed closely with regular follow-up and imaging, allowing for timely monitoring of radiographic progression, VCF, and radiation myelopathy. Further study is warranted into the clinical characteristics and outcomes of patients who receive at least three courses of sSRS.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eOur findings suggest that three courses of salvage stereotactic spine radiosurgery (sSRS) may be a reasonable option for patients with progressive spinal metastases. While this approach appears to be both safe and effective, further study is needed to better define long-term outcomes and toxicity risks. Importantly, because the cumulative radiation dose to adjacent neural structures can exceed thresholds established in prior studies, careful multidisciplinary evaluation is essential. Consideration of surgical management or alternative ablative modalities such as radiofrequency or cryoablation should be undertaken before proceeding with additional salvage spine SRS.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval\u0026nbsp;\u003c/strong\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of Cleveland Clinic Foundation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u0026nbsp;\u003c/strong\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u0026nbsp;\u003c/strong\u003eSTC reports \u0026ldquo;honorarium\u0026rdquo; from Varian Medical Systems and Blue Earth Diagnostics, outside the submitted work. JJB, EHB, AM, LA, JHS, ESM, PP have no competing interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003eThe data used to support the findings of this study are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy concept and design:\u003c/em\u003e STC\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcquisition, analysis, and interpretation of data:\u003c/em\u003e \u003cem\u003eAll Authors\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDrafting of the manuscript:\u003c/em\u003e JJB, EHB\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCritical revision of the manuscript for important intellectual content:\u003c/em\u003e \u003cem\u003eAll Authors\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis:\u003c/em\u003e JJB\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAdministrative, technical, or material support:\u003c/em\u003e EHB, STC\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStudy supervision:\u003c/em\u003e STC\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSahgal A, Bilsky M, Chang EL et al (2011) Stereotactic body radiotherapy for spinal metastases: current status, with a focus on its application in the postoperative patient. 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J Radiosurgery SBRT 3(4):297\u0026ndash;305\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 2 are not available with this version.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"stereotactic radiosurgery, metastases, central nervous system","lastPublishedDoi":"10.21203/rs.3.rs-8745546/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8745546/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eRe-irradiation with salvage spine stereotactic radiosurgery (sSRS) has emerged as a viable strategy for spinal metastases with progressive disease. We report the characteristics and clinical outcomes of spinal segments that received at least three courses of sSRS.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e10 spinal segments in 6 patients who received at least three courses of sSRS were evaluated from an IRB-approved retrospective single-institution database. Overall survival (OS) and radiographic progression-free survival (rPFS) were calculated by Kaplan-Meier analysis. Radiographic failure was defined as progression on imaging at the treated segment. Toxicity outcomes were collected.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMedian follow-up was 8.9 months (range, 0.2\u0026ndash;46.3). Three patients had died at the time of analysis. Half the patients were female, median age at treatment was 63.2 years (range, 36.9\u0026ndash;77.2), and median consult KPS was 80 (range, 70\u0026ndash;90). The median cumulative thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e after the third course of sSRS was 137.9 Gy (range, 97\u0026ndash;227.5). The median third course re-irradiation sSRS thecal sac EQD2\u003csub\u003e2\u003c/sub\u003e D\u003csub\u003emax\u003c/sub\u003e was 37.15 Gy (range, 21.8\u0026ndash;57.8). 30% (3/10) of treated spinal segments had radiographic progression (range of time to radiographic progression, 0.98\u0026ndash;14.3 months), with a 1-year radiographic progression-free survival rate of 87.5%. 42.9% (3/7) of treatments resulted in pain flare, which were all adequately treated with steroids. No cases of VCF or radiation myelopathy were reported.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThree courses of sSRS may be considered for salvage treatment for spinal metastases demonstrating progression. Though it appears to be safe and effective, more investigation is warranted. Since the cumulative doses to the neural structures exceed those established by other studies, great care and review of all treatment options including surgery and other ablative treatments like radiofrequency or cryoablation should be considered in a multidisciplinary setting prior to proceeding with salvage spine SRS.\u003c/p\u003e","manuscriptTitle":"Outcomes of a Third Course of Salvage Spine Stereotactic Radiosurgery for Spinal Metastases","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-09 12:26:40","doi":"10.21203/rs.3.rs-8745546/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-03T02:49:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-02T17:12:01+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-28T19:41:05+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-26T13:54:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-21T17:51:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"204461118309769390614513253280593917063","date":"2026-02-20T14:50:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"198360334418475378939764479947735285275","date":"2026-02-20T13:32:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"225905000320862389799848143491006496430","date":"2026-02-19T14:53:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"163237842793450400609812684883680161456","date":"2026-02-18T20:03:45+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-18T15:22:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-17T19:32:00+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-16T19:55:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"157343552509585655615918866631569387857","date":"2026-02-16T15:10:22+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"64663255690631296998728438181995525840","date":"2026-02-16T13:23:48+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"216861364187362244171369097490884756872","date":"2026-02-09T12:17:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"212228561983501920896734537374732857726","date":"2026-02-04T12:05:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-04T11:30:57+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-04T10:56:31+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-04T10:51:18+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2026-01-31T00:51:06+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e6015505-735a-43f4-a58e-1d9628ffe792","owner":[],"postedDate":"February 9th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T16:07:01+00:00","versionOfRecord":{"articleIdentity":"rs-8745546","link":"https://doi.org/10.1007/s11060-026-05581-9","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2026-04-22 15:59:06","publishedOnDateReadable":"April 22nd, 2026"},"versionCreatedAt":"2026-02-09 12:26:40","video":"","vorDoi":"10.1007/s11060-026-05581-9","vorDoiUrl":"https://doi.org/10.1007/s11060-026-05581-9","workflowStages":[]},"version":"v1","identity":"rs-8745546","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8745546","identity":"rs-8745546","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}