Stereotactic radiosurgery for patients with 5 or more brain metastases: Retrospective single-institution analysis with focus on brain metastasis velocity

Stereotactic radiosurgery for patients with 5 or more brain metastases: Retrospective single-institution analysis with focus on brain metastasis velocity | 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 Stereotactic radiosurgery for patients with 5 or more brain metastases: Retrospective single-institution analysis with focus on brain metastasis velocity Michael T. Milano, Dandan Zheng, Jihyung Yoon, Yuwei Zhou, Hyunuk Jung, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7785592/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose We describe patient outcomes following linear accelerator-based stereotactic radiosurgery (SRS) for ≥ 5 brain metastases, without prior or planned whole-brain radiotherapy. Methods We identified 116 eligible patients treated with SRS, from 2019–2024, for newly diagnosed brain metastases. We describe clinical factors associated with survival ≤ 2 months and analyze brain metastasis velocity measured as number (BMV) or volume (vBMV) of new metastases per year. Results The number of treated brain metastases ranged from 5–41 (median 10); net lesion volume ranged from 0.1–59.8 (median 5.2) cc. Primary cancers included non-small cell lung (n = 65), melanoma (n = 20), breast (n = 19), kidney (n = 6), gastrointestinal (n = 4), and other (n = 4) cancers. The 6-, 12- and 24-month overall survivals (OS) were 60.3%, 40.5%, 28.0%, respectively. Progressive extracranial disease at time of brain metastases and lower predicted survival from grade prognostic assessments were significantly adverse factors for OS on multivariable Cox regression, and were associated with ‘poor survivors’ who died ≤ 2 months from SRS (n = 21) or at > 2 months but opting against post-SRS cancer care and follow-up imaging (n = 6; OS = 2.1–5.8 months). Forty-two patients developed new brain metastases after SRS, while 28 (after ≥ 6-months follow-up) did not. Among these patients, OS was significantly associated with BMV and vBMV, though vBMV was not significant on multivariable Cox regressions that included BMV. Conclusions For patients with ≥ 5 brain metastases, clinical factors can potentially aid in selecting patients best-suited for SRS for multiple brain metastases, versus potentially deferring SRS in favor of supportive care. While vBMV is associated with OS, BMV appears more prognostic. Figures Figure 1 Figure 2 Introduction Stereotactic radiosurgery (SRS) is an accepted standard of care for multiple brain metastases, though appropriate selection of patients better-suited for SRS over whole-brain radiotherapy (WBRT), close observation with serial imaging, or supportive care alone are not well-characterized [ 1 ]. Because of adverse effects on neurocognitive function and quality of life (QOL) [ 1 ], delays in systemic therapy, and acute risks (alopecia, fatigue, otitis media, scalp irritation) with WBRT, SRS is often preferred over WBRT. Randomized controlled studies [ 2 – 6 ] along with meta-analyses and systematic reviews [ 7 – 9 ], have demonstrated no detriment in overall survival (OS) and better neurocognitive function and QOL when omitting WBRT in patients with 1–4 brain metastases treated with SRS (with 2 studies also allowing resection). MDACC reported similar findings from a randomized study of SRS vs WBRT among 72 patients with 4–15 brain metastases from non-melanoma cancers [ 10 ]. A multicenter, phase 3 randomized trial of 196 patients with 5–20 (median 14) brain metastases reported fewer symptoms, less functional decline and similar OS with SRS vs hippocampal-avoidant WBRT [ 11 ]. Many other studies, including pooled analyses with thousands of patients [ 12 – 14 ], have examined SRS without WBRT for patients with many brain metastases; these data continue to evolve [ 1 , 15 – 17 ]. The number and (seemingly more so) volume of brain metastases impact outcomes after SRS [ 1 , 18 ], though how these factors impact treatment decision-making remains unclear, particularly in the context of other potentially prognostic factors. As risks of new brain metastases are greater after SRS vs WBRT, salvage therapy (often SRS) is frequently required after SRS [ 1 ]. Researchers from Wake Forest University described brain metastasis velocity (BMV), the cumulative number of new brain metastases over time, as a predictor of OS, neurologic death, and receipt of salvage WBRT; lower BMV, binned into 13 subgroups, was associated with significantly better OS [ 19 ]. A pooled analysis of 2,829 patients from the United States (US) validated these results [ 20 ]. Yamamoto and colleagues from Japan evaluated 833 patients treated with SRS, over 2–4 courses, and showed BMV as prognostic following each SRS course [ 21 ]. In the US studies, most patients initially had 1 brain metastasis (~ 90% initially had ≤ 4) [ 19 , 20 ], while the Japanese study [ 21 ] did not specify numbers of lesions treated during the 1st SRS course. We sought to examine BMV in patients presenting with ≥ 5 lesions, and hypothesized that volume-based brain metastases velocity measures (vBMV) [ 22 ] would also be prognostic. Those who develop new brain metastases amenable to salvage therapies survive long enough to be candidates for additional treatment. At the opposite end of the spectrum are patients who die shortly after SRS. We sought to examine causes of death and factors associated with early death after SRS for ≥ 5 brain metastases. We hypothesized that median OS predicted from grade prognostic assessments (GPA) [ 23 – 28 ] and extracranial progression at time of initial brain metastases diagnosis would be prognostic. Methods Patients Patients who underwent SRS (with no prior WBRT) for ≥ 5 brain metastases, during their first or only course of treatment, were retrospectively identified from a prospective database of patients treated at the University of Rochester from November 2018 through October 2024. We included patients who had undergone brain metastasis resection just prior to SRS and excluded patients with small-cell lung cancer (SCLC). We followed patients through September 2025, for ≥ 1 year or until death. Treatment Treatment with SRS is described in more detail in prior publications [ 17 , 29 , 30 ] and briefly summarized here. Patients were immobilized with a BrainLAB® mask. Planning computed tomography (CT) and magnetic resonance images (MRI) were imported into BrainLAB’s Multi-Metastases Elements (MME)® platform and deformably registered. Gross tumor volumes (GTV) were expanded 1–2 mm to create planning target volumes (PTV). Treatment was planned and delivered in 1, 3 or 5 fractions (at the treating physicians’ discretion) with dynamic conformal arcs using BrainLAB MME® planning software or with volume-modulated arc therapy using Varian Eclipse® planning software, depending on target coverage and brain exposures [ 30 ]. We aimed for > 95% of PTVs receiving prescribed dose (with > 94% considered acceptable). Organ-at-risk considerations were described previously [ 17 ]. Treatment was delivered on a Varian Edge® linear accelerator equipped with BrainLAB ExacTrac® oblique orthogonal x-ray imagers and a 6-degree of freedom robotic couch. Data Analysis We retrospectively reviewed and described characteristics of patients, their cancer, and treatment course (including salvage therapies), along with intracranial control and OS after SRS. T-tests and chi square tests were used to assess potential differences in variables. BMV and vBMV were calculated as the number and volume (net GTV), respectively, of new metastases, divided by duration of time since completion of SRS. For those with innumerable (50+) new lesions, number and volume of brain metastases were estimated. OS, measured from date of SRS to date of death or last follow-up, was calculated by Kaplan-Meier methods. Log-rank tests and Cox regression were used to assess potential factors associated with OS. Serial MRI and clinical follow-up typically occurred every 2–3 months after SRS. Local control was measured from date of SRS completion to date of local recurrence or last brain imaging. Determining local recurrence (vs post-treatment changes) was based on growth on serial imaging, MR perfusion (and occasionally spectroscopy) and consensus opinion in a dedicated brain metastasis tumor board. Results We identified 164 patients who completed SRS for ≥ 5 brain metastases during the study period. Patients were excluded for: prior SRS for brain metastases (n = 29); prior WBRT (n = 6); or SCLC diagnosis (n = 13). Of the remaining 116 patients, with 1,457 brain metastases, primary diagnoses included non-small cell lung (NSCLC; n = 65), melanoma (n = 20), breast (n = 19), kidney (n = 6), gastrointestinal (n = 4), and other (n = 4) cancers. Seven underwent resection of a brain metastasis shortly before SRS. Survival Table 1 outlines patient, cancer, and treatment characteristics. Follow-up after SRS ranged from 0.4–74.7 (median 8.2) months, and 12.1–74.7 (median 39.2) months for 22 patients alive at last follow-up. Among those with NSCLC, 65% (vs. 28% of others) had, at the time of brain metastases diagnosis, either newly diagnosed cancer or newly diagnosed extracranial metastases. There was no discernible relationship between volume and number of brain metastases (Supplemental Fig. 1, showing linear regression R 2 ≈ 0). GPA-predicted median OS increased with increasing Karnofsky performance status (KPS), as expected (since GPAs incorporate KPS), albeit with linear regression R 2 ≈ 0.23 (Supplemental Fig. 2). Median OS was 8.2 months; 6-, 12- and 24-month OS were 60.3%, 40.5%, 28.0%, respectively (Fig. 1 ). GPA-predicted median OS was significantly associated with OS as continuous (HR = 0.905 per month; p < .0001) and discrete variables (p < .00001; Fig. 2 ); KPS and status of extracranial disease at time of brain metastasis diagnosis were also significant factors, whereas number and volume of brain metastases were not (Table 2 ). While those with net GTV > 20 cc fared poorly, this subgroup was small (n = 11). Progressive extracranial disease at the time of brain metastases diagnosis and GPA-predicted median OS remained significant on multivariable Cox regression (Table 2 ). Among 63 patients with GPA-predicted median OS ≤ 6 months, those without (n = 38) vs with (n = 25) progressive extracranial disease at time of brain metastases diagnosis had median OS of 5.7 vs 3.3 months (p = .048), respectively. Twenty-seven patients died ≤ 2 months from SRS (n = 21) or survived > 2 months but opted against post-SRS follow-up imaging and further cancer therapy (n = 6, with OS = 2.1–5.8 months). Causes of deaths among these ‘poor survivors’ included extracranial (n = 16) or intracranial (n = 2) disease progression, infectious (n = 2), renal failure (n = 2), cardiac arrest (n = 1), and unknown (n = 4). ‘Poor survivors’, compared to others, were statistically more likely to have had: poorer KPS (p < .001); progressive extracranial disease (p = .012); and poorer GPA-predicted median OS (p = .004). There were no appreciable differences in numbers or volumes of metastases between these two groups, nor in how many underwent systemic therapy prior to SRS (Table 1 ). Receipt of systemic therapy after SRS is confounded by OS. Toxicity Nine patients developed grade 2 (n = 2) or grade 3–4 (n = 7) radionecrosis/edema, of whom 2 underwent resection for radionecrosis 15 and 19 months after SRS. Radionecrosis vs hemorrhage (vs both) contributed to 2 deaths (grade 5 toxicity) 7–15 months after SRS. New brain metastases Forty-two patients developed new brain metastases 2.3–28.7 (median 5.7) months after initial SRS, with 18 (43%) developing first/only new lesions beyond 6 months. Salvage therapies for new brain metastases included SRS (n = 31 patients), WBRT (n = 7, of whom 4 received WBRT as 1st salvage therapy), resection (n = 1), and no additional therapy (n = 7, of whom 3 had leptomeningeal disease). Seven patients developed leptomeningeal disease (5 as first intracranial occurrence). Specifically for new metastases (i.e., not accounting for treatments of local recurrence), among 31 who received a 2nd SRS, 13 received a 3rd SRS (one who underwent resection prior to 3rd SRS, and another who received WBRT for 3rd treatment/2nd salvage), of whom 5 received a 4th SRS, of whom 2 who received a 5th SRS. These numbers were too small to adequately analyze BMVs following first salvage therapy. Supplemental Fig. 3 depicts cumulative number (panel A) and volume (panel B) of brain metastases vs time since first SRS, with salvage therapies denoted by specific symbols. This figure is intended to be descriptive. BMV and vBMV plateau in some patients. Many with OS < 12 months had high initial BMV (gauged by slopes of lines). However, some patients with initially high BMV or vBMV have relatively long OS. Melanoma vs other sites was not significantly associated with BMV (p = .13) or vBMV (p = .11). Twenty-eight patients with minimum 6-month imaging follow-up developed no new brain metastases (BMV = vBMV = 0) at 8.2–74.7 (median 23.4) months. Thirty-seven patients developed new brain metastases (without leptomeningeal progression for 1st intracranial recurrence). Among these 37, BMV ranged from 0.4-183.6 (median 22.1) lesions/year and vBMV ranged from 0.01–73.5 (median 2.8) cc/year. There were no apparent trends with initial brain metastasis number or net GTV with either BMV or vBMV, with linear and polynomial regressions being relatively flat and R-squared values < 0.1 (Supplemental Fig. 4). BMV and vBMV, as univariable continuous or discrete variables, significantly correlated with OS (Table 3 ). On Cox regression including only BMV and vBMV, BMV remained significant (p = .018) while vBMV did not (p = .74). On multivariable Cox regression with BMV, vBMV, presence of progressive disease and GPA-predicted median OS, no variables were significant. In a separate model omitting vBMV, BMV was significant (p < .0001) with a HR of 1.017 per lesion. vBMV was not significant on any multivariable Cox regression that included BMV (additional data not shown). Specifically for melanoma, BMV (p = .050) and vBMV (p = .046) were significant on univariable Cox regressions, whereas GPA-predicted median OS (p = .13) and extracranial disease progression (p = .94) were not. Local control Among 59 patients (presenting with 1,054 brain metastases), with ≥ 6 months of imaging follow-up, 8 (with 176 initial brain metastases) developed 1 (n = 5) or 2 (n = 3) locally recurrent metastases. Thus, 8/59 (13.5%) patients developed local recurrence of 11/1,054 (1%) brain metastases. Six patients received salvage SRS for local recurrence at 10–22 (median 18.7) months. Two died shortly after developing local recurrences at 8 and 15 months. Three patients, without local recurrence of lesions treated with initial SRS, developed local recurrences of lesions treated with subsequent SRS. Discussion Our retrospective analysis of 116 patients, treated with SRS for ≥ 5 brain metastases, demonstrated that progressive extracranial disease at time of brain metastases diagnosis and lower predicted median OS from GPAs were significantly adverse factors for OS. Among patients evaluable for new brain metastases, numbers of metastases developing over time appeared to be more prognostic than a similar approach using volume. While GPAs were not originally derived specifically from patients treated with SRS, they can reliably classify these patients into prognostic subgroups [ 31 ]. We opted to specifically analyze GPA-predicted median OS (as opposed to GPA score), as GPA-predicted survivals vary across different cancer types. Notably, at the time of brain metastases diagnosis, all but 2 patients in our study had extracranial metastases, which all GPAs consider an adverse prognostic factor (zero points). Furthermore, all patients received zero GPA points for > 4 (for NSCLC, melanoma or RCC), > 3 (for GI cancers, or cancers without disease-specific GPAs) or > 1 (for breast cancer) brain metastases. Consequently, no patients in this study fell into the highest GPA groups (scores of 3.5-4). We generally offered SRS to patients with good KPS (or whose KPS was expected to improve) and with potential systemic options for extracranial disease. Nevertheless, there were (and are in general) patients who did not benefit from SRS and would have been better served with upfront supportive care alone [ 32 ]. Prognostic factors such as GPA-predicted median OS and status of extracranial metastases can inform shared (patient and physician) decision-making (i.e., SRS, supportive care, or reassessing after a short interval), conceding that these factors are probabilistic and not deterministic. In a Polish study, early death after SRS was associated with: classic GPA score 3 lesions with sum-diameters > 3 cm); and serious neurological deficits (not specified) and/or requiring dexamethasone ≥ 4 mg daily. The authors recommended against SRS for patients with all 3 factors [ 33 ]. For our patients, we did not analyze extent of extracranial disease, and neurologic symptoms were not significant for OS (attributable to most early deaths resulting from extracranial progression). Patients presenting with ≥ 5 brain metastases have already demonstrated the propensity to develop multiple metastases. We postulated that vBMV would be more prognostic than BMV in this group, given that volume of brain metastases appears to be more prognostic than number [ 1 , 18 ], However, our results did not demonstrate this. Possibly, BMV reflects underlying biologic aggressiveness and responsiveness to systemic therapy, while vBMV reflects growth rate. Larger studies, not restricted to patients presenting with ≥ 5 brain metastases, may better resolve this. To our knowledge, the only other published study of vBMV focused on patients treated with SRS from 2000–2013 for melanoma brain metastases, showing vBMV to be more prognostic than BMV for OS, new brain metastases, and need for salvage WBRT [ 22 ]. Our patient numbers were too small to separately analyze patients with melanoma. The median OS in our report, subgrouped by BMV 13, are numerically superior to OS reported in other studies [ 19 – 21 , 34 ]. This may reflect more recent treatment (2018–2024) of our patients compared to those in studies by Farris et al. and McTyre et al. (2000–2013/2014) [ 19 , 20 ] and Yamamoto et al. (1998–2017) [ 21 ]. Our patients were treated in the eras of high resolution volumetric MRI and novel systemic agents with potential intracranial efficacy (i.e., immunotherapy, targeted therapies, and drug-antibody conjugates). Immunotherapy has been correlated with lower BMV and improved OS [ 35 ]. A series from U. Pittsburgh reported better OS than what we report here [ 36 ], likely reflecting differences in patient selection. Notably, 15% of their patients had undergone prior WBRT (which was not allowed in early studies on BMV, as WBRT was an endpoint) and all underwent multiple courses of SRS from 2013–2020, thus selecting patients living long enough to develop new metastases. We separately analyzed patients with BMV = 0. The BMV = 0 group contains a mix of patients with low (to possibly no) propensity to develop new brain metastases, and those with no opportunity to develop new brain metastases prior to death. The Wake Forest group showed that, for patients alive > 2 years after SRS, BMV = 0 was significantly associated with single brain metastases and Caucasian race; OS was not specifically analyzed [ 37 ]. In our analysis, BMV = 0 patients did not experience significantly different OS than patients with a 0 < BMV < 4 (Table 3 ), which (to our knowledge) is a new finding. In the aforementioned US studies [ 19 , 20 ], the BMV 0. As in the US studies on BMV [ 19 , 20 ], we did not restrict BMV calculations to those who underwent a 2nd SRS (i.e., we opted to include patients who underwent salvage WBRT or no salvage therapy). Factors associated with increased BMV from the US pooled analysis included melanoma histology and number of initial brain metastases [ 20 ]. Farris et al. [ 19 ] reported that ≥ 2 brain metastases at presentation, number of metastases (continuous variable) and melanoma were associated with higher BMVs, while Her2 + breast cancer was associated with lower BMVs. Melanoma was not significantly associated with a higher BMV in our patients. In the series by Yamamota et al., small cell lung histology (which was excluded from our cohort) was associated with higher BMV. In a study of patients with 5–15 brain metastases, BMV was similar among those presenting with 5–9 vs 10–15 lesions [ 38 ]. In another study of patients with 1–15 brain metastases, BMV was significantly (p < .01) lower among patients with 1 vs 2–4 vs 5–15 brain metastases [ 39 ]. In our series of patients presenting with ≥ 5 brain metastases, there was no discernible relationship between initial number or volume of brain metastases and BMV or vBMV. BMV acceleration or deceleration over multiple time points could also be prognostic [ 19 ], though our patient numbers were too small to evaluate this. Nevertheless, it is evident that BMV and vBMV plateau in some long-term survivors as reported by the Wake Forest group [ 37 ]. Two large studies examined the velocity of brain metastases from time of initial cancer diagnosis to initial brain metastases- termed iBMV [ 40 , 41 ]. We opted against analyzing iBMV since many patients in our cohort presented with newly diagnosed cancer synchronously with brain metastases. Limitations of our study include relatively small numbers of patients (compared to larger institution and pooled databases), single-institution cohort (with potential selection biases), subjectivity in assigning KPS [ 31 ], and retrospective design. Because we selected patients receiving upfront SRS, we could not assess outcomes following upfront WBRT or deferral of radiotherapy in favor of supportive care or CNS-active systemic therapy (a treatment paradigm actively being investigated [ 42 – 44 ]). Conclusions We demonstrated that clinical factors may aid in treatment decision-making for patients with multiple brain metastases. Future studies with larger patient numbers, treated with a variety of upfront approaches, and perhaps incorporating radiomic and genomic factors along with artificial intelligence [ 45 ], would help better refine criteria to aid in treatment decision-making for newly diagnosed brain metastases. Declarations Ethics approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The University of Rochester Research Subjects Review Board approved this study. Funding Declaration There was no funding for this study. Author Contribution MM and KU conceptualized the research idea. MM, KU, SH, and HQ provided patients for the study. JY, YZ and HJ provided treatment planning data. MM and DZ collected data. MM performed data analysis. All authors reviewed and revised earlier draft and approved the final draft. References Milano MT, Chiang VLS, Soltys SG, Wang TJC, Lo SS, Brackett A, Nagpal S, Chao S, Garg AK, Jabbari S, Halasz LM, Gephart MH, Knisely JPS, Sahgal A, Chang EL (2020) Executive summary from American Radium Society's appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases. Neuro Oncol 22:1728–1741. 10.1093/neuonc/noaa192 Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G (2006) Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:2483–2491. 10.1001/jama.295.21.2483 Chang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:1037–1044. 10.1016/S1470-2045(09)70263-3 Kocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Collette S, Collette L, Mueller RP (2011) Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952–26001 study. J Clin Oncol 29:134–141. 10.1200/JCO.2010.30.1655 Brown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, Carrero XW, Barker FG 2nd, Deming R, Burri SH, Menard C, Chung C, Stieber VW, Pollock BE, Galanis E, Buckner JC, Asher AL (2016) Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 316:401–409. 10.1001/jama.2016.9839 Hong AM, Fogarty GB, Dolven-Jacobsen K, Burmeister BH, Lo SN, Haydu LE, Vardy JL, Nowak AK, Dhillon HM, Ahmed T, Shivalingam B, Long GV, Menzies AM, Hruby G, Drummond KJ, Mandel C, Middleton MR, Reisse CH, Paton EJ, Steel V, Williams NC, Scolyer RA, Morton RL, Thompson JF (2019) Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III Trial. J Clin Oncol 37:3132–3141. 10.1200/JCO.19.01414 Sahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, Shaw P, Beyene J, Chang EL (2015) Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 91:710–717. 10.1016/j.ijrobp.2014.10.024 Tsao MN, Xu W, Wong RK, Lloyd N, Laperriere N, Sahgal A, Rakovitch E, Chow E (2018) Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 1:CD003869. 10.1002/14651858.CD003869.pub4 Chao ST, De Salles A, Hayashi M, Levivier M, Ma L, Martinez R, Paddick I, Regis J, Ryu S, Slotman BJ, Sahgal A (2018) Stereotactic Radiosurgery in the Management of Limited (1–4) Brain Metasteses: Systematic Review and International Stereotactic Radiosurgery Society Practice Guideline. Neurosurgery 83:345–353. 10.1093/neuros/nyx522 Li J, Ludmir EB, Wang Y, Guha-Thakurta N, McAleer MF, Settle S, Yeboa DN, Ghia A, McGovern S, Chung C, Woodhouse KD (2020) Stereotactic Radiosurgery versus Whole-brain Radiation Therapy for Patients with 4–15 Brain Metastases: A Phase III Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 108:S21–22 Aizer A, Tanguturi SK, Bengham G, Brown PD, Cagney D, Catalano PJ, Chipodza F, Haas-Kogan DA, Hepel JT, Krishnan M (2025) Stereotactic radiation versus hippocampal avoidance whole brain radiation in patients with 5–20 brain metastases: A multicenter, phase 3 randomized trial. J Clin Oncol 43: 2011 Serizawa T, Higuchi Y, Nagano O, Sato Y, Yamamoto M, Ono J, Saeki N, Miyakawa A, Hirai T (2012) Analysis of 2000 cases treated with gamma knife surgery: validating eligibility criteria for a prospective multi-institutional study of stereotactic radiosurgery alone for treatment of patients with 1–10 brain metastases (JLGK0901) in Japan. J Radiosurg SBRT 2:19–27 Yamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Barfod BE, Kasuya H, Urakawa Y (2013) A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1–4 vs >/= 5 tumors: clinical article. J Neurosurg 118:1258–1268. 10.3171/2013.3.JNS121900 Ali MA, Hirshman BR, Wilson B, Carroll KT, Proudfoot JA, Goetsch SJ, Alksne JF, Ott K, Aiyama H, Nagano O, Carter BS, Fogarty G, Hong A, Serizawa T, Yamamoto M, Chen CC (2017) Survival Patterns of 5750 Stereotactic Radiosurgery-Treated Patients with Brain Metastasis as a Function of the Number of Lesions. World Neurosurg 107:944–951e941. 10.1016/j.wneu.2017.07.062 Ladbury C, Pennock M, Yilmaz T, Ankrah NK, Andraos T, Gogineni E, Kim GG, Gibbs I, Shih HA, Hattangadi-Gluth J, Chao ST, Pannullo SC, Slotman B, Redmond KJ, Lo SS, Schulder M (2024) Stereotactic Radiosurgery in the Management of Brain Metastases: A Case-Based Radiosurgery Society Practice Guideline. Adv Radiat Oncol 9:101402. 10.1016/j.adro.2023.101402 Rozati H, Chen J, Williams M (2023) Overall survival following stereotactic radiosurgery for ten or more brain metastases: a systematic review and meta-analysis. BMC Cancer 23:1004. 10.1186/s12885-023-11452-7 Milano MT, Hardy S, Zheng D, Igwe T, Huang D, Chowdhry AC, Yoon J, Schmidt TM, Walter KA, Jung H, Zhou Y, Usuki KY (2025) Stereotactic radiosurgery alone for patients with 16 or more brain metastases: Retrospective single-institution analysis. World Neurosurg X 26:100432 Hirshman BR, Compton J, Carroll KT, Ali MA, Wang SG, Chen CC (2021) Cumulative Intracranial Tumor Volume as a Prognostic Factor in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery. Acta Neurochir Suppl 128:57–69. 10.1007/978-3-030-69217-9_7 Farris M, McTyre ER, Cramer CK, Hughes R, Randolph DM 2nd, Ayala-Peacock DN, Bourland JD, Ruiz J, Watabe K, Laxton AW, Tatter SB, Zhou X, Chan MD (2017) Brain Metastasis Velocity: A Novel Prognostic Metric Predictive of Overall Survival and Freedom From Whole-Brain Radiation Therapy After Distant Brain Failure Following Upfront Radiosurgery Alone. Int J Radiat Oncol Biol Phys 98:131–141. 10.1016/j.ijrobp.2017.01.201 McTyre ER, Soike MH, Farris M, Ayala-Peacock DN, Hepel JT, Page BR, Shen C, Kleinberg L, Contessa JN, Corso C, Chiang V, Henson-Masters A, Cramer CK, Ruiz J, Pasche B, Watabe K, D'Agostino R, Su J, Laxton AW, Tatter SB, Fiveash JB, Ahluwalia M, Kotecha R, Chao ST, Braunstein SE, Attia A, Chung C, Chan MD (2020) Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery. Radiother Oncol 142:168–174. 10.1016/j.radonc.2019.08.011 Yamamoto M, Aiyama H, Koiso T, Watanabe S, Kawabe T, Sato Y, Higuchi Y, Kasuya H, Barfod BE (2019) Validity of a Recently Proposed Prognostic Grading Index, Brain Metastasis Velocity, for Patients With Brain Metastasis Undergoing Multiple Radiosurgical Procedures. Int J Radiat Oncol Biol Phys 103:631–637. 10.1016/j.ijrobp.2018.10.036 LeCompte MC, McTyre E, Henson A, Farris M, Okoukoni C, Cramer CK, Triozzi P, Ruiz J, Watabe K, Lo HW, Munley MT, Laxton AW, Tatter SB, Zhou X, Chan M (2017) Survival and Failure Outcomes Predicted by Brain Metastasis Volumetric Kinetics in Melanoma Patients Following Upfront Treatment with Stereotactic Radiosurgery Alone. Cureus 9: e1934 10.7759/cureus.1934 Sperduto PW, De B, Li J, Carpenter D, Kirkpatrick J, Milligan M, Shih HA, Kutuk T, Kotecha R, Higaki H, Otsuka M, Aoyama H, Bourgoin M, Roberge D, Dajani S, Sachdev S, Gainey J, Buatti JM, Breen W, Brown PD, Ni L, Braunstein S, Gallitto M, Wang TJC, Shanley R, Lou E, Shiao J, Gaspar LE, Tanabe S, Nakano T, An Y, Chiang V, Zeng L, Soliman H, Elhalawani H, Cagney D, Thomas E, Boggs DH, Ahluwalia MS, Mehta MP (2022) Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors. Int J Radiat Oncol Biol Phys 114:60–74. 10.1016/j.ijrobp.2022.03.020 Sperduto PW, Mesko S, Li J, Cagney D, Aizer A, Lin NU, Nesbit E, Kruser TJ, Chan J, Braunstein S, Lee J, Kirkpatrick JP, Breen W, Brown PD, Shi D, Shih HA, Soliman H, Sahgal A, Shanley R, Sperduto W, Lou E, Everett A, Boggs DH, Masucci L, Roberge D, Remick J, Plichta K, Buatti JM, Jain S, Gaspar LE, Wu CC, Wang TJC, Bryant J, Chuong M, Yu J, Chiang V, Nakano T, Aoyama H, Mehta MP (2020) Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today. Int J Radiat Oncol Biol Phys 107:334–343. 10.1016/j.ijrobp.2020.01.051 Sperduto PW, Jiang W, Brown PD, Braunstein S, Sneed P, Wattson DA, Shih HA, Bangdiwala A, Shanley R, Lockney NA, Beal K, Lou E, Amatruda T, Sperduto WA, Kirkpatrick JP, Yeh N, Gaspar LE, Molitoris JK, Masucci L, Roberge D, Yu J, Chiang V, Mehta M (2017) Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA). Int J Radiat Oncol Biol Phys 99:812–816. 10.1016/j.ijrobp.2017.06.2454 Sperduto PW, Deegan BJ, Li J, Jethwa KR, Brown PD, Lockney N, Beal K, Rana NG, Attia A, Tseng CL, Sahgal A, Shanley R, Sperduto WA, Lou E, Zahra A, Buatti JM, Yu JB, Chiang V, Molitoris JK, Masucci L, Roberge D, Shi DD, Shih HA, Olson A, Kirkpatrick JP, Braunstein S, Sneed P, Mehta MP (2018) Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool. Neuro Oncol 20:1652–1660. 10.1093/neuonc/noy099 Sperduto PW, Fang P, Li J, Breen W, Brown PD, Cagney D, Aizer A, Yu JB, Chiang V, Jain S, Gaspar LE, Myrehaug S, Sahgal A, Braunstein S, Sneed P, Cameron B, Attia A, Molitoris J, Wu CC, Wang TJC, Lockney NA, Beal K, Parkhurst J, Buatti JM, Shanley R, Lou E, Tandberg DD, Kirkpatrick JP, Shi D, Shih HA, Chuong M, Saito H, Aoyama H, Masucci L, Roberge D, Mehta MP (2019) Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA). Clin Transl Radiat Oncol 18:39–45. 10.1016/j.ctro.2019.06.007 Sperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W (2008) A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:510–514. 10.1016/j.ijrobp.2007.06.074 Zheng D, Yoon J, Jung H, Lemus OMD, Gou L, Zhou Y, Usuki KY, Hardy S, Milano MT (2024) How Does the Number of Brain Metastases Correlate With Normal Brain Exposure in Single-Isocenter Multitarget Multifraction Stereotactic Radiosurgery. Adv Radiat Oncol 9:101499. 10.1016/j.adro.2024.101499 Jung H, Yoon J, Dona Lemus O, Tanny S, Zhou Y, Milano M, Usuki K, Hardy S, Zheng D (2024) Dosimetric evaluation of LINAC-based single-isocenter multi-target multi-fraction stereotactic radiosurgery with more than 20 targets: comparing MME, HyperArc, and RapidArc. Radiat Oncol 19:19. 10.1186/s13014-024-02416-7 Nagtegaal SHJ, Claes A, Suijkerbuijk KPM, Schramel F, Snijders TJ, Verhoeff JJC (2019) Comparing survival predicted by the diagnosis-specific Graded Prognostic Assessment (DS-GPA) to actual survival in patients with 1–10 brain metastases treated with stereotactic radiosurgery. Radiother Oncol 138:173–179. 10.1016/j.radonc.2019.06.033 Mulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE (2016) Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 388:2004–2014. 10.1016/s0140-6736(16)30825-x Harat M, Blok M, Miechowicz I, Kowalewska J (2020) Stereotactic Radiosurgery of Brain Metastasis in Patients with a Poor Prognosis: Effective or Overtreatment? Cancer Manag Res 12:12569–12579. 10.2147/cmar.S272369 Fritz C, Borsky K, Stark LS, Tanadini-Lang S, Kroeze SGC, Krayenbühl J, Guckenberger M, Andratschke N (2018) Repeated Courses of Radiosurgery for New Brain Metastases to Defer Whole Brain Radiotherapy: Feasibility and Outcome With Validation of the New Prognostic Metric Brain Metastasis Velocity. Front Oncol 8:551. 10.3389/fonc.2018.00551 Abdulhaleem M, Scott E, Johnston H, Isom S, Lanier C, LeCompte M, Cramer CK, Ruiz J, Lo HW, Watabe K, O'Neill S, Whitlow C, Tatter SB, A WL, Su J, Chan MD (2022) Upfront immunotherapy leads to lower brain metastasis velocity in patients undergoing stereotactic radiosurgery for brain metastases. J Radiosurg SBRT 8:77–83 Benjamin CG, Gurewitz J, Kavi A, Bernstein K, Silverman J, Mureb M, Donahue B, Kondziolka D (2022) Survival and outcomes in patients with ≥ 25 cumulative brain metastases treated with stereotactic radiosurgery. J Neurosurg 137:571–581. 10.3171/2021.9.Jns21882 Lanier CM, Pearce J, Isom S, Xing F, Lo HW, Whitlow CT, Ruiz J, White JJ, Laxton AW, Tatter SB, Cramer CK, Chan MD (2022) Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero? J Neurooncol 160:643–648. 10.1007/s11060-022-04183-5 Hughes RT, Masters AH, McTyre ER, Farris MK, Chung C, Page BR, Kleinberg LR, Hepel J, Contessa JN, Chiang V, Ruiz J, Watabe K, Su J, Fiveash JB, Braunstein S, Chao S, Attia A, Ayala-Peacock DN, Chan MD (2019) Initial SRS for patients with 5–15 brain metastases: results of a multi-institutional experience. Int J Radiat Oncol Biol Phys. 10.1016/j.ijrobp.2019.03.052 Rogers SJ, Lomax N, Alonso S, Lazeroms T, Riesterer O (2022) Radiosurgery for Five to Fifteen Brain Metastases: A Single Centre Experience and a Review of the Literature. Front Oncol 12:866542. 10.3389/fonc.2022.866542 Soike MH, McTyre ER, Hughes RT, Farris M, Cramer CK, LeCompte MC, Lanier CM, Ruiz J, Su J, Watabe K, Bourland JD, Munley MT, O'Neill S, Laxton AW, Tatter SB, Chan MD (2018) Initial brain metastasis velocity: does the rate at which cancers first seed the brain affect outcomes? J Neurooncol 139:461–467. 10.1007/s11060-018-2888-3 Yamamoto M, Aiyama H, Koiso T, Watanabe S, Kawabe T, Sato Y, Higuchi Y, Kasuya H, Barfod BE (2019) Applicability and limitations of a recently-proposed prognostic grading metric, initial brain metastasis velocity, for brain metastasis patients undergoing stereotactic radiosurgery. J Neurooncol 143:613–621. 10.1007/s11060-019-03199-8 Nagpal S, Milano MT, Chiang VL, Soltys SG, Brackett A, Halasz LM, Garg AK, Sahgal A, Tom M, Palmer JD, Knisely J, Chao ST, Hayden-Gephart M, Wang TJC, Lo SS, Chang EL (2024) Executive Summary of the American Radium Society Appropriate Use Criteria for Brain Metastases in EGFR-mutated and ALK-fusion Non-Small Cell Lung Cancer. Neuro Oncol In press Murphy B, Walker J, Bassale S, Monaco D, Jaboin J, Ciporen J, Taylor M, Dai Kubicky C (2019) Concurrent Radiosurgery and Immune Checkpoint Inhibition: Improving Regional Intracranial Control for Patients With Metastatic Melanoma. Am J Clin Oncol 42:253–257. 10.1097/coc.0000000000000509 Shepard MJ, Xu Z, Donahue J, Eluvathingal Muttikkal TJ, Cordeiro D, Hansen L, Mohammed N, Gentzler RD, Larner J, Fadul CE, Sheehan JP (2019) Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study. J Neurosurg 1–8. 10.3171/2019.4.Jns19822 Cao Y, Cherng HR, Kunaprayoon D, Mishra MV, Ren L (2025) Interpretable AI-assisted clinical decision making for treatment selection for brain metastases in radiation therapy. Med Phys 52:e17844. 10.1002/mp.17844 Tables Table 1 Patient, cancer and treatment characteristics All patients Patients with no imaging follow-up and/or survival ≤ 2 months Patients with imaging follow-up and survival > 2 months p value Number of patients 116 27 89 NA Age : range (median) 33.5–95.2 (66.6) years 41.2–83.5 (68.3) years 33.5–95.2 (65.6) years .22 KPS : range (median) - 40–60 - 70–80 - 90–100 40–100 (80) 20 (17.2%) 51 (44.0%) 45 (38.8%) 50–90 (80) 10 (37.0%) 13 (48.1%) 4 (14.8%) 40–100 (80) 10 (11.2%) 38 (42.7%) 41 (46.1%) .001 .002 .62 .004 Neurologic symptoms : - None - Minor deficits § - dexamethasone ≥ 4mg daily - Major deficits § - Seizure - Major deficits OR dexamethasone ≥ 4mg daily - 52 (44.8%) 37 (31.9%) 25 17 (14.7%) 7 (6.0%) 47 (40.5%) - 11 (40.7%) 11 (40.7%) 8 3 (11.1%) 1 (3.7%) 12 (44.4%) - 41 (4-6.1%) 26 (29.2%) 17 14 (15.7%) 6 (6.7%) 35 (39.3%) - .63 .26 .55 .56 .64 Cancer type and histology - Non-small cell lung cancer - Cutaneous melanoma - Breast adenocarcinoma - Kidney – renal cell carcinoma - Other * - 63 (54.3%) 20 (17.2%) 19 (16.4%) 6 (5.2%) 8 (6.9%) - 11 (40.7%) 5 (18.5%) 3 (11.1%) 3 (11.1%) 5 (18.5%) - 52 (58.4%) 15 (16.9%) 16 (18.0%) 3 (3.3%) 3 (3.3%) - .11 .84 .40 .11 .003 Status of extracranial disease - No evidence of disease - No progression - Progression - New metastatic cancer diagnosis - 2 (1.7%) 17 (14.6%) 41 (35.3%) 56 (48.3%) - 0 2 (7.4%) 15 (55.6%) 10 (37.0%) - 2 (2.2%) 15 (16.8%) 26 (29.2%) 46 (51.7%) - }- .15 .012 .18 Predicted median survival from GPAs range (median) - ≤ 6.0 months - > 6–12 months - > 12 months - 2.0–30.0 (6.0) months 63 (54.3%) 10 (8.6%) 43 (37.0%) - 2.6–15.0 (6.0) months 20 (74.1%) 2 (7.4%) 5 (18.5%) - 2.0–30.0 (8.3) months 43 (48.3%) 8 (9.0%) 38 (42.7%) - .007 .021 .80 .022 Small molecule inhibitor † - none - Before SRS - After SRS - 72 (62.0%) 20 (17.2%) 33 (28.4%) - 17 (63.0%) 7 (25.9%) 3 (11.1%) - 55 (61.8%) 13 (14.6%) 30 (33.7%) - .91 .17 .023 Immune checkpoint inhibitor † - none - Before SRS - After SRS - 42 (36.2%) 44 (37.9%) 57 (49.1%) - 17 (63.0%) 9 (33.3%) 4 (14.8%) - 25 (28.1%) 35 (39.3%) 53 (60.0%) - .001 .57 < .001 CNS penetrant antibody-drug conjugate or chemotherapy † - none - Before SRS - After SRS - 99 (85.3%) 12 (10.3%) 15 (12.9%) - 26 (96.3%) 1 (3.7%) 1 (3.7%) - 73 (82.0%) 11 (12.3%) 14 (15.7%) - .066 .20 .10 SRS – dose and fractionation - 6–7 Gy x 5 - 7–9 Gy x 3 (mostly 9 Gy x 3) - 20 Gy x 1 - 9 (7.7%) 100 (86.2%) 7 (6.0%) - 0 26 (96.3%) 1 (3.7%) - 9 (10.1%) 74 (83.1%) 6 (6.7%) - .085 .083 .56 Number of metastases : range (median) - 5–10 - 11–20 - 20–30 - > 30 5–41 (10) 68 (58.6%) 30 (25.9%) 11 (9.5%) 7 (6.0%) 5–37 (10) 15 (55.6%) 6 (22.2%) 4 (14.8%) 2 (7.4%) 5–41 (9) 53 (59.6%) 24 (26.9%) 7 (7.9%) 5 (5.6%) .31 .71 .62 .28 .73 Net GTV ¥ of metastases : range (median) - ≤ 2 cc - > 2–5 cc - > 5–10 cc - > 10–20 cc - > 20 cc 0.1–59.8 (5.2) cc 28 (24.1%) 29 (25.0%) 26 (22.4%) 22 (19.0%) 11 (9.5%) 0.4–53.3 (5.5) cc 5 (18.5%) 7 (25.9%) 7 (25.9%) 4 (14.8%) 4 (14.8%) 0.1–59.8 (5.0) cc 23 (25.8%) 22 (24.7%) 19 (21.3%) 18 (20.2%) 7 (7.9%) .57 .44 .90 .62 .53 .28 SRS = stereotactic radiosurgery ; KPS = Karnofsky Performance Scale; GPA = graded prognostic assessment; CNS = central nervous system; GTV = gross target volume; NA = not applicable ¥ Net GTV for the initial SRS course * includes duodenum (n = 1), rectum (n = 1) and esophagus (n = 2) for which the gastrointestinal cancer GPA was used; also includes endometrial (n = 2), ovarian (n = 1) and head and neck (n = 1) cancers for which the non-disease site specific GPA was used † some patients received drug prior to and after SRS resulting in net totals > 100% for these cells § major and minor neurologic deficits imply neurologic deficits (including headache but not seizure) requiring vs not requiring (respectively) hospitalization. All those with major deficits received dexamethasone ≥ 4 mg daily, as did all but one who had had seizure. Table 2 Patient, cancer and treatment factors evaluated for potential effect on overall survival Median OS (months) Univariable log rank p value Univariable Cox regression HR [95% CI] (p value) Multivariable Cox regression (model 1) HR [95% CI] (p value) Multivariable Cox regression (model 2) HR [95% CI] (p value) Age : - ≤ 60 years - 60–70 years - > 70 - 11.5 7.1 6.1 .36- - - 1.015 [0.996–1.035] (p = .12) - - - - - - - - - - - KPS : range (median) - 40–60 - 70–80 - 90–100 - 2.2 6.0 18.6 .0001 - - - 0.971 [0.957–0.984] (p < .0001) - - - 0.983 [0.967–0.999] (p = .040) - - - - - - - Neurologic symptoms : - None - Minor deficits (see Table 1 ) - Major deficits (see Table 1 ) - Major deficits OR dexamethasone ≥ 4mg daily - 7.8 7.0 9.0 7.0 - - - .56 .66 - - - - - - - - - - - - - - - Cancer type and histology - Non-small cell lung cancer - Cutaneous melanoma - Breast adenocarcinoma - 8.6 12.1 9.4 - .85 .36 .49 - - - - - - - - - - - - Status of extracranial disease - No progression or NED - Progression - New metastatic cancer diagnosis 26.0 5.1 11.4 - 6–12 months - > 12 months - 5.1 11.0 23.4 < .00001 - - - 0.905 [0.866–0.946] (p 20 - 7.8 7.2 12.1 .84 - - - p = .77 - - - - - - - - Net GTV ¥ of metastases : - ≤ 2 cc - > 2–5 cc - > 5–10 cc - > 10–20 cc - > 20 cc - 9.4 10.0 5.4 9.0 3.0 .32 p = .40 - - - - - - - - - - - - KPS = Karnofsky Performance Scale; GPA = graded prognostic assessment; GTV = gross target volume; HR [95% CI] -hazard ratio with 95% confidence intervals; NED = no evidence of disease (n = 2) ¥ Net GTV for the initial SRS course Table 3 Survival outcomes and factors associated with survival among those evaluable for brain metastases velocity Number of patients Median OS (months) Univariable log rank p value Univariable Cox regression HR [95% CI] (p value) Multivariable Cox regression (model 1) HR [95% CI] (p value) Multivariable Cox regression (model 2) HR [95% CI] (p value) BMV : - 0 per year * - > 0- 13 per year - 28 8 6 23 - 26.5 35.9 14.3 15.0 .003 - - - - 1.022 [1.013–1.032] (p < .0001) - - - - 1.017 [0.996–1.038] (p = .11) - - - - 1.017 [1.008–1.028] (p 0-≤1 cc per year - > 1–5 cc per year - > 5 cc per year 28 10 13 14 26.5 28.5 20.0 7.8 .009 - - - - 1.041 [1.019–1.063] (p 6–12 months - > 12 months - 27 7 31 - 14.3 28.5 29.1 .011 - - - 0.916 [0.863–0.972] (p = .004) - - - 0.941 [0.884–1.003] (p = .061) - - - 0.942 [0.886–1.002] (p = .058) † - - - Status of extracranial disease - NED (n = 2) or No progression - Progression - New metastatic cancer diagnosis - 16 14 35 - 29.0 9.4 26.0 - - .0001 - - - - - - - 1.841 [0.816–4.153] (p = .14) - - - 1.850 [0.824–4.154] (p = .14) † - BMV = brain metastases velocity; CI = confidence intervals; GPA = graded prognostic assessment; HR = hazard ratio; NED = no evidence of disease; OS = overall survival; vBMV = volume-based brain metastases velocity * The survivals between these subgroups was not significantly different on log rank test (p = .99). When these 2 groups merged (as was done in study by Farris et al.) median survival is 35.9 months † Predicted median OS and progressive extracranial disease were each significant (p < .02) in separate two-variable Cox regression analyses with BMV (data not shown), suggesting that they are somewhat interdependent prognostic factors. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7785592","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":532346762,"identity":"5c479822-ad8b-405d-9d79-08973930c57f","order_by":0,"name":"Michael T. Milano","email":"data:image/png;base64,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","orcid":"","institution":"University of Rochester","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"T.","lastName":"Milano","suffix":""},{"id":532346763,"identity":"031e2fce-bd52-4b2d-8651-89d50b6a0aeb","order_by":1,"name":"Dandan Zheng","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Dandan","middleName":"","lastName":"Zheng","suffix":""},{"id":532346764,"identity":"cc22f6d2-7846-4c51-8888-c200b5d0237a","order_by":2,"name":"Jihyung Yoon","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Jihyung","middleName":"","lastName":"Yoon","suffix":""},{"id":532346765,"identity":"040b2584-0365-4337-8c48-2ec43d524a20","order_by":3,"name":"Yuwei Zhou","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Yuwei","middleName":"","lastName":"Zhou","suffix":""},{"id":532346766,"identity":"e25a073d-1dfd-482c-b3ef-8e022d6c1d6b","order_by":4,"name":"Hyunuk Jung","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Hyunuk","middleName":"","lastName":"Jung","suffix":""},{"id":532346767,"identity":"922556e9-aa79-46b7-b59e-7b9f5f0405b9","order_by":5,"name":"Haoming Qiu","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Haoming","middleName":"","lastName":"Qiu","suffix":""},{"id":532346769,"identity":"fcc6ecb1-69d2-4ee4-8d39-4f8b38079f6e","order_by":6,"name":"Terris Igwe","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Terris","middleName":"","lastName":"Igwe","suffix":""},{"id":532346772,"identity":"2a3e51cb-ac99-4673-ae65-b3e4fca04170","order_by":7,"name":"Daniel Huang","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Daniel","middleName":"","lastName":"Huang","suffix":""},{"id":532346774,"identity":"80bd9f62-0659-4f35-a96b-5e766b5ef18b","order_by":8,"name":"Sara Hardy","email":"","orcid":"","institution":"University of Washington","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"","lastName":"Hardy","suffix":""},{"id":532346776,"identity":"641d70ad-1039-4b79-b456-94b9e1228545","order_by":9,"name":"Kenneth Y. Usuki","email":"","orcid":"","institution":"University of Rochester","correspondingAuthor":false,"prefix":"","firstName":"Kenneth","middleName":"Y.","lastName":"Usuki","suffix":""}],"badges":[],"createdAt":"2025-10-05 15:38:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7785592/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7785592/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94048195,"identity":"bfc29896-0258-4874-bf97-73f1232dc70f","added_by":"auto","created_at":"2025-10-21 23:20:55","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":292068,"visible":true,"origin":"","legend":"","description":"","filename":"MMEbrainOct2025FINALJNO.docx","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/811d5274095eb9171e98b05f.docx"},{"id":94047148,"identity":"75cf5ba0-7c66-4ac7-893f-68aa87e6e393","added_by":"auto","created_at":"2025-10-21 23:12:55","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":10786,"visible":true,"origin":"","legend":"","description":"","filename":"c2a9484929174ab9a80586f5a0e4f672.json","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/36bf05864a9619cca8383023.json"},{"id":94047151,"identity":"ba30648e-2a39-4452-afca-457e77b5ba41","added_by":"auto","created_at":"2025-10-21 23:12:55","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":194834,"visible":true,"origin":"","legend":"","description":"","filename":"c2a9484929174ab9a80586f5a0e4f6721enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/51768415e95e403d02e7353c.xml"},{"id":94048194,"identity":"e2775428-1ddd-4671-9e19-c30cfe0a26f9","added_by":"auto","created_at":"2025-10-21 23:20:55","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":49072,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/c598e4e17a94fdb5164df26c.png"},{"id":94047153,"identity":"17dfc4d0-ce14-4c10-9431-9c8ab45dfe1e","added_by":"auto","created_at":"2025-10-21 23:12:55","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":14425,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/0aca38a6004e5ae50f98683a.png"},{"id":94047155,"identity":"d2d4d390-823a-4f82-8bbc-4b80558e24b1","added_by":"auto","created_at":"2025-10-21 23:12:55","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":193438,"visible":true,"origin":"","legend":"","description":"","filename":"c2a9484929174ab9a80586f5a0e4f6721structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/fe6fcb1c909f04cb1bd2b825.xml"},{"id":94047154,"identity":"7ce41773-7554-4d8b-8f17-16885e8a1acd","added_by":"auto","created_at":"2025-10-21 23:12:55","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":202268,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/6eea26f5e0a0643317408945.html"},{"id":94047150,"identity":"1a22b1a8-daba-4a54-b9c2-203ab4b25b34","added_by":"auto","created_at":"2025-10-21 23:12:55","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":263130,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier overall survival of entire cohort of 116 patients treated with stereotactic radiosurgery (SRS) alone for 5 or more brain metastases.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/be9042b9e36232d6180cc60f.jpeg"},{"id":94047147,"identity":"ff07446f-df82-4c32-930b-92a66d8943ea","added_by":"auto","created_at":"2025-10-21 23:12:55","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61420,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier overall survival after stereotactic radiosurgery (SRS) alone for 5 or more brain metastases, grouped by predicted survivals from graded prognostic assessments (GPA).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/7f0568788716fd3ba5eedac6.png"},{"id":94473960,"identity":"2fe94a4c-d5a4-47fe-ae14-dbf3189b2725","added_by":"auto","created_at":"2025-10-27 15:46:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1805164,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7785592/v1/eb9ade0b-d82e-40e3-8ce6-65b0a87fcac4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Stereotactic radiosurgery for patients with 5 or more brain metastases: Retrospective single-institution analysis with focus on brain metastasis velocity","fulltext":[{"header":"Introduction","content":"\u003cp\u003eStereotactic radiosurgery (SRS) is an accepted standard of care for multiple brain metastases, though appropriate selection of patients better-suited for SRS over whole-brain radiotherapy (WBRT), close observation with serial imaging, or supportive care alone are not well-characterized [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Because of adverse effects on neurocognitive function and quality of life (QOL) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], delays in systemic therapy, and acute risks (alopecia, fatigue, otitis media, scalp irritation) with WBRT, SRS is often preferred over WBRT. Randomized controlled studies [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] along with meta-analyses and systematic reviews [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], have demonstrated no detriment in overall survival (OS) and better neurocognitive function and QOL when omitting WBRT in patients with 1\u0026ndash;4 brain metastases treated with SRS (with 2 studies also allowing resection). MDACC reported similar findings from a randomized study of SRS vs WBRT among 72 patients with 4\u0026ndash;15 brain metastases from non-melanoma cancers [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A multicenter, phase 3 randomized trial of 196 patients with 5\u0026ndash;20 (median 14) brain metastases reported fewer symptoms, less functional decline and similar OS with SRS vs hippocampal-avoidant WBRT [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Many other studies, including pooled analyses with thousands of patients [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], have examined SRS without WBRT for patients with many brain metastases; these data continue to evolve [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The number and (seemingly more so) volume of brain metastases impact outcomes after SRS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], though how these factors impact treatment decision-making remains unclear, particularly in the context of other potentially prognostic factors.\u003c/p\u003e\u003cp\u003eAs risks of new brain metastases are greater after SRS vs WBRT, salvage therapy (often SRS) is frequently required after SRS [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Researchers from Wake Forest University described brain metastasis velocity (BMV), the cumulative number of new brain metastases over time, as a predictor of OS, neurologic death, and receipt of salvage WBRT; lower BMV, binned into \u0026lt;\u0026thinsp;4, 4\u0026ndash;13, and \u0026gt;\u0026thinsp;13 subgroups, was associated with significantly better OS [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A pooled analysis of 2,829 patients from the United States (US) validated these results [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Yamamoto and colleagues from Japan evaluated 833 patients treated with SRS, over 2\u0026ndash;4 courses, and showed BMV as prognostic following each SRS course [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In the US studies, most patients initially had 1 brain metastasis (~\u0026thinsp;90% initially had\u0026thinsp;\u0026le;\u0026thinsp;4) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], while the Japanese study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] did not specify numbers of lesions treated during the 1st SRS course. We sought to examine BMV in patients presenting with \u0026ge;\u0026thinsp;5 lesions, and hypothesized that volume-based brain metastases velocity measures (vBMV) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] would also be prognostic.\u003c/p\u003e\u003cp\u003eThose who develop new brain metastases amenable to salvage therapies survive long enough to be candidates for additional treatment. At the opposite end of the spectrum are patients who die shortly after SRS. We sought to examine causes of death and factors associated with early death after SRS for \u0026ge;\u0026thinsp;5 brain metastases. We hypothesized that median OS predicted from grade prognostic assessments (GPA) [\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and extracranial progression at time of initial brain metastases diagnosis would be prognostic.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003ePatients who underwent SRS (with no prior WBRT) for \u0026ge;\u0026thinsp;5 brain metastases, during their first or only course of treatment, were retrospectively identified from a prospective database of patients treated at the University of Rochester from November 2018 through October 2024. We included patients who had undergone brain metastasis resection just prior to SRS and excluded patients with small-cell lung cancer (SCLC). We followed patients through September 2025, for \u0026ge;\u0026thinsp;1 year or until death.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eTreatment with SRS is described in more detail in prior publications [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and briefly summarized here. Patients were immobilized with a BrainLAB\u0026reg; mask. Planning computed tomography (CT) and magnetic resonance images (MRI) were imported into BrainLAB\u0026rsquo;s Multi-Metastases Elements (MME)\u0026reg; platform and deformably registered. Gross tumor volumes (GTV) were expanded 1\u0026ndash;2 mm to create planning target volumes (PTV). Treatment was planned and delivered in 1, 3 or 5 fractions (at the treating physicians\u0026rsquo; discretion) with dynamic conformal arcs using BrainLAB MME\u0026reg; planning software or with volume-modulated arc therapy using Varian Eclipse\u0026reg; planning software, depending on target coverage and brain exposures [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. We aimed for \u0026gt;\u0026thinsp;95% of PTVs receiving prescribed dose (with \u0026gt;\u0026thinsp;94% considered acceptable). Organ-at-risk considerations were described previously [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Treatment was delivered on a Varian Edge\u0026reg; linear accelerator equipped with BrainLAB ExacTrac\u0026reg; oblique orthogonal x-ray imagers and a 6-degree of freedom robotic couch.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eData Analysis\u003c/h2\u003e\u003cp\u003eWe retrospectively reviewed and described characteristics of patients, their cancer, and treatment course (including salvage therapies), along with intracranial control and OS after SRS. T-tests and chi square tests were used to assess potential differences in variables. BMV and vBMV were calculated as the number and volume (net GTV), respectively, of new metastases, divided by duration of time since completion of SRS. For those with innumerable (50+) new lesions, number and volume of brain metastases were estimated.\u003c/p\u003e\u003cp\u003eOS, measured from date of SRS to date of death or last follow-up, was calculated by Kaplan-Meier methods. Log-rank tests and Cox regression were used to assess potential factors associated with OS. Serial MRI and clinical follow-up typically occurred every 2\u0026ndash;3 months after SRS. Local control was measured from date of SRS completion to date of local recurrence or last brain imaging. Determining local recurrence (vs post-treatment changes) was based on growth on serial imaging, MR perfusion (and occasionally spectroscopy) and consensus opinion in a dedicated brain metastasis tumor board.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eWe identified 164 patients who completed SRS for \u0026ge;\u0026thinsp;5 brain metastases during the study period. Patients were excluded for: prior SRS for brain metastases (n\u0026thinsp;=\u0026thinsp;29); prior WBRT (n\u0026thinsp;=\u0026thinsp;6); or SCLC diagnosis (n\u0026thinsp;=\u0026thinsp;13). Of the remaining 116 patients, with 1,457 brain metastases, primary diagnoses included non-small cell lung (NSCLC; n\u0026thinsp;=\u0026thinsp;65), melanoma (n\u0026thinsp;=\u0026thinsp;20), breast (n\u0026thinsp;=\u0026thinsp;19), kidney (n\u0026thinsp;=\u0026thinsp;6), gastrointestinal (n\u0026thinsp;=\u0026thinsp;4), and other (n\u0026thinsp;=\u0026thinsp;4) cancers. Seven underwent resection of a brain metastasis shortly before SRS.\u003c/p\u003e\n\u003ch3\u003eSurvival\u003c/h3\u003e\n\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e outlines patient, cancer, and treatment characteristics. Follow-up after SRS ranged from 0.4\u0026ndash;74.7 (median 8.2) months, and 12.1\u0026ndash;74.7 (median 39.2) months for 22 patients alive at last follow-up. Among those with NSCLC, 65% (vs. 28% of others) had, at the time of brain metastases diagnosis, either newly diagnosed cancer or newly diagnosed extracranial metastases. There was no discernible relationship between volume and number of brain metastases (Supplemental Fig.\u0026nbsp;1, showing linear regression R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026asymp;\u0026thinsp;0). GPA-predicted median OS increased with increasing Karnofsky performance status (KPS), as expected (since GPAs incorporate KPS), albeit with linear regression R\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026asymp;\u0026thinsp;0.23 (Supplemental Fig.\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eMedian OS was 8.2 months; 6-, 12- and 24-month OS were 60.3%, 40.5%, 28.0%, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). GPA-predicted median OS was significantly associated with OS as continuous (HR\u0026thinsp;=\u0026thinsp;0.905 per month; p\u0026thinsp;\u0026lt;\u0026thinsp;.0001) and discrete variables (p\u0026thinsp;\u0026lt;\u0026thinsp;.00001; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e); KPS and status of extracranial disease at time of brain metastasis diagnosis were also significant factors, whereas number and volume of brain metastases were not (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). While those with net GTV\u0026thinsp;\u0026gt;\u0026thinsp;20 cc fared poorly, this subgroup was small (n\u0026thinsp;=\u0026thinsp;11). Progressive extracranial disease at the time of brain metastases diagnosis and GPA-predicted median OS remained significant on multivariable Cox regression (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Among 63 patients with GPA-predicted median OS\u0026thinsp;\u0026le;\u0026thinsp;6 months, those without (n\u0026thinsp;=\u0026thinsp;38) vs with (n\u0026thinsp;=\u0026thinsp;25) progressive extracranial disease at time of brain metastases diagnosis had median OS of 5.7 vs 3.3 months (p\u0026thinsp;=\u0026thinsp;.048), respectively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTwenty-seven patients died\u0026thinsp;\u0026le;\u0026thinsp;2 months from SRS (n\u0026thinsp;=\u0026thinsp;21) or survived\u0026thinsp;\u0026gt;\u0026thinsp;2 months but opted against post-SRS follow-up imaging and further cancer therapy (n\u0026thinsp;=\u0026thinsp;6, with OS\u0026thinsp;=\u0026thinsp;2.1\u0026ndash;5.8 months). Causes of deaths among these \u0026lsquo;poor survivors\u0026rsquo; included extracranial (n\u0026thinsp;=\u0026thinsp;16) or intracranial (n\u0026thinsp;=\u0026thinsp;2) disease progression, infectious (n\u0026thinsp;=\u0026thinsp;2), renal failure (n\u0026thinsp;=\u0026thinsp;2), cardiac arrest (n\u0026thinsp;=\u0026thinsp;1), and unknown (n\u0026thinsp;=\u0026thinsp;4). \u0026lsquo;Poor survivors\u0026rsquo;, compared to others, were statistically more likely to have had: poorer KPS (p\u0026thinsp;\u0026lt;\u0026thinsp;.001); progressive extracranial disease (p\u0026thinsp;=\u0026thinsp;.012); and poorer GPA-predicted median OS (p\u0026thinsp;=\u0026thinsp;.004). There were no appreciable differences in numbers or volumes of metastases between these two groups, nor in how many underwent systemic therapy prior to SRS (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Receipt of systemic therapy after SRS is confounded by OS.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eToxicity\u003c/h2\u003e\u003cp\u003eNine patients developed grade 2 (n\u0026thinsp;=\u0026thinsp;2) or grade 3\u0026ndash;4 (n\u0026thinsp;=\u0026thinsp;7) radionecrosis/edema, of whom 2 underwent resection for radionecrosis 15 and 19 months after SRS. Radionecrosis vs hemorrhage (vs both) contributed to 2 deaths (grade 5 toxicity) 7\u0026ndash;15 months after SRS.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eNew brain metastases\u003c/h3\u003e\n\u003cp\u003eForty-two patients developed new brain metastases 2.3\u0026ndash;28.7 (median 5.7) months after initial SRS, with 18 (43%) developing first/only new lesions beyond 6 months. Salvage therapies for new brain metastases included SRS (n\u0026thinsp;=\u0026thinsp;31 patients), WBRT (n\u0026thinsp;=\u0026thinsp;7, of whom 4 received WBRT as 1st salvage therapy), resection (n\u0026thinsp;=\u0026thinsp;1), and no additional therapy (n\u0026thinsp;=\u0026thinsp;7, of whom 3 had leptomeningeal disease). Seven patients developed leptomeningeal disease (5 as first intracranial occurrence). Specifically for new metastases (i.e., not accounting for treatments of local recurrence), among 31 who received a 2nd SRS, 13 received a 3rd SRS (one who underwent resection prior to 3rd SRS, and another who received WBRT for 3rd treatment/2nd salvage), of whom 5 received a 4th SRS, of whom 2 who received a 5th SRS. These numbers were too small to adequately analyze BMVs following first salvage therapy. Supplemental Fig.\u0026nbsp;3 depicts cumulative number (panel A) and volume (panel B) of brain metastases vs time since first SRS, with salvage therapies denoted by specific symbols. This figure is intended to be descriptive. BMV and vBMV plateau in some patients. Many with OS\u0026thinsp;\u0026lt;\u0026thinsp;12 months had high initial BMV (gauged by slopes of lines). However, some patients with initially high BMV or vBMV have relatively long OS. Melanoma vs other sites was not significantly associated with BMV (p\u0026thinsp;=\u0026thinsp;.13) or vBMV (p\u0026thinsp;=\u0026thinsp;.11).\u003c/p\u003e\u003cp\u003eTwenty-eight patients with minimum 6-month imaging follow-up developed no new brain metastases (BMV\u0026thinsp;=\u0026thinsp;vBMV\u0026thinsp;=\u0026thinsp;0) at 8.2\u0026ndash;74.7 (median 23.4) months. Thirty-seven patients developed new brain metastases (without leptomeningeal progression for 1st intracranial recurrence). Among these 37, BMV ranged from 0.4-183.6 (median 22.1) lesions/year and vBMV ranged from 0.01\u0026ndash;73.5 (median 2.8) cc/year. There were no apparent trends with initial brain metastasis number or net GTV with either BMV or vBMV, with linear and polynomial regressions being relatively flat and R-squared values\u0026thinsp;\u0026lt;\u0026thinsp;0.1 (Supplemental Fig.\u0026nbsp;4).\u003c/p\u003e\u003cp\u003eBMV and vBMV, as univariable continuous or discrete variables, significantly correlated with OS (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). On Cox regression including only BMV and vBMV, BMV remained significant (p\u0026thinsp;=\u0026thinsp;.018) while vBMV did not (p\u0026thinsp;=\u0026thinsp;.74). On multivariable Cox regression with BMV, vBMV, presence of progressive disease and GPA-predicted median OS, no variables were significant. In a separate model omitting vBMV, BMV was significant (p\u0026thinsp;\u0026lt;\u0026thinsp;.0001) with a HR of 1.017 per lesion. vBMV was not significant on any multivariable Cox regression that included BMV (additional data not shown). Specifically for melanoma, BMV (p\u0026thinsp;=\u0026thinsp;.050) and vBMV (p\u0026thinsp;=\u0026thinsp;.046) were significant on univariable Cox regressions, whereas GPA-predicted median OS (p\u0026thinsp;=\u0026thinsp;.13) and extracranial disease progression (p\u0026thinsp;=\u0026thinsp;.94) were not.\u003c/p\u003e\n\u003ch3\u003eLocal control\u003c/h3\u003e\n\u003cp\u003eAmong 59 patients (presenting with 1,054 brain metastases), with \u0026ge;\u0026thinsp;6 months of imaging follow-up, 8 (with 176 initial brain metastases) developed 1 (n\u0026thinsp;=\u0026thinsp;5) or 2 (n\u0026thinsp;=\u0026thinsp;3) locally recurrent metastases. Thus, 8/59 (13.5%) patients developed local recurrence of 11/1,054 (1%) brain metastases. Six patients received salvage SRS for local recurrence at 10\u0026ndash;22 (median 18.7) months. Two died shortly after developing local recurrences at 8 and 15 months. Three patients, without local recurrence of lesions treated with initial SRS, developed local recurrences of lesions treated with subsequent SRS.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur retrospective analysis of 116 patients, treated with SRS for \u0026ge;\u0026thinsp;5 brain metastases, demonstrated that progressive extracranial disease at time of brain metastases diagnosis and lower predicted median OS from GPAs were significantly adverse factors for OS. Among patients evaluable for new brain metastases, numbers of metastases developing over time appeared to be more prognostic than a similar approach using volume.\u003c/p\u003e\u003cp\u003eWhile GPAs were not originally derived specifically from patients treated with SRS, they can reliably classify these patients into prognostic subgroups [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. We opted to specifically analyze GPA-predicted median OS (as opposed to GPA score), as GPA-predicted survivals vary across different cancer types. Notably, at the time of brain metastases diagnosis, all but 2 patients in our study had extracranial metastases, which all GPAs consider an adverse prognostic factor (zero points). Furthermore, all patients received zero GPA points for \u0026gt;\u0026thinsp;4 (for NSCLC, melanoma or RCC), \u0026gt;\u0026thinsp;3 (for GI cancers, or cancers without disease-specific GPAs) or \u0026gt;\u0026thinsp;1 (for breast cancer) brain metastases. Consequently, no patients in this study fell into the highest GPA groups (scores of 3.5-4).\u003c/p\u003e\u003cp\u003eWe generally offered SRS to patients with good KPS (or whose KPS was expected to improve) and with potential systemic options for extracranial disease. Nevertheless, there were (and are in general) patients who did not benefit from SRS and would have been better served with upfront supportive care alone [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Prognostic factors such as GPA-predicted median OS and status of extracranial metastases can inform shared (patient and physician) decision-making (i.e., SRS, supportive care, or reassessing after a short interval), conceding that these factors are probabilistic and not deterministic. In a Polish study, early death after SRS was associated with: classic GPA score\u0026thinsp;\u0026lt;\u0026thinsp;2; extensive extracranial metastases (\u0026gt;\u0026thinsp;3 lesions with sum-diameters\u0026thinsp;\u0026gt;\u0026thinsp;3 cm); and serious neurological deficits (not specified) and/or requiring dexamethasone\u0026thinsp;\u0026ge;\u0026thinsp;4 mg daily. The authors recommended against SRS for patients with all 3 factors [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. For our patients, we did not analyze extent of extracranial disease, and neurologic symptoms were not significant for OS (attributable to most early deaths resulting from extracranial progression).\u003c/p\u003e\u003cp\u003ePatients presenting with \u0026ge;\u0026thinsp;5 brain metastases have already demonstrated the propensity to develop multiple metastases. We postulated that vBMV would be more prognostic than BMV in this group, given that volume of brain metastases appears to be more prognostic than number [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], However, our results did not demonstrate this. Possibly, BMV reflects underlying biologic aggressiveness and responsiveness to systemic therapy, while vBMV reflects growth rate. Larger studies, not restricted to patients presenting with \u0026ge;\u0026thinsp;5 brain metastases, may better resolve this. To our knowledge, the only other published study of vBMV focused on patients treated with SRS from 2000\u0026ndash;2013 for melanoma brain metastases, showing vBMV to be more prognostic than BMV for OS, new brain metastases, and need for salvage WBRT [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our patient numbers were too small to separately analyze patients with melanoma.\u003c/p\u003e\u003cp\u003eThe median OS in our report, subgrouped by BMV\u0026thinsp;\u0026lt;\u0026thinsp;4, 4\u0026ndash;13 and \u0026gt;\u0026thinsp;13, are numerically superior to OS reported in other studies [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. This may reflect more recent treatment (2018\u0026ndash;2024) of our patients compared to those in studies by Farris et al. and McTyre et al. (2000\u0026ndash;2013/2014) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and Yamamoto et al. (1998\u0026ndash;2017) [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Our patients were treated in the eras of high resolution volumetric MRI and novel systemic agents with potential intracranial efficacy (i.e., immunotherapy, targeted therapies, and drug-antibody conjugates). Immunotherapy has been correlated with lower BMV and improved OS [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. A series from U. Pittsburgh reported better OS than what we report here [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], likely reflecting differences in patient selection. Notably, 15% of their patients had undergone prior WBRT (which was not allowed in early studies on BMV, as WBRT was an endpoint) and all underwent multiple courses of SRS from 2013\u0026ndash;2020, thus selecting patients living long enough to develop new metastases.\u003c/p\u003e\u003cp\u003eWe separately analyzed patients with BMV\u0026thinsp;=\u0026thinsp;0. The BMV\u0026thinsp;=\u0026thinsp;0 group contains a mix of patients with low (to possibly no) propensity to develop new brain metastases, and those with no opportunity to develop new brain metastases prior to death. The Wake Forest group showed that, for patients alive\u0026thinsp;\u0026gt;\u0026thinsp;2 years after SRS, BMV\u0026thinsp;=\u0026thinsp;0 was significantly associated with single brain metastases and Caucasian race; OS was not specifically analyzed [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In our analysis, BMV\u0026thinsp;=\u0026thinsp;0 patients did not experience significantly different OS than patients with a 0\u0026thinsp;\u0026lt;\u0026thinsp;BMV\u0026thinsp;\u0026lt;\u0026thinsp;4 (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), which (to our knowledge) is a new finding. In the aforementioned US studies [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], the BMV\u0026thinsp;\u0026lt;\u0026thinsp;4 group included BMV\u0026thinsp;=\u0026thinsp;0 patients; while in the Japanese study [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], all patients underwent SRS for new lesions and therefore all had BMV\u0026thinsp;\u0026gt;\u0026thinsp;0. As in the US studies on BMV [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], we did not restrict BMV calculations to those who underwent a 2nd SRS (i.e., we opted to include patients who underwent salvage WBRT or no salvage therapy).\u003c/p\u003e\u003cp\u003eFactors associated with increased BMV from the US pooled analysis included melanoma histology and number of initial brain metastases [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Farris et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] reported that \u0026ge;\u0026thinsp;2 brain metastases at presentation, number of metastases (continuous variable) and melanoma were associated with higher BMVs, while Her2\u0026thinsp;+\u0026thinsp;breast cancer was associated with lower BMVs. Melanoma was not significantly associated with a higher BMV in our patients. In the series by Yamamota et al., small cell lung histology (which was excluded from our cohort) was associated with higher BMV. In a study of patients with 5\u0026ndash;15 brain metastases, BMV was similar among those presenting with 5\u0026ndash;9 vs 10\u0026ndash;15 lesions [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In another study of patients with 1\u0026ndash;15 brain metastases, BMV was significantly (p\u0026thinsp;\u0026lt;\u0026thinsp;.01) lower among patients with 1 vs 2\u0026ndash;4 vs 5\u0026ndash;15 brain metastases [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In our series of patients presenting with \u0026ge;\u0026thinsp;5 brain metastases, there was no discernible relationship between initial number or volume of brain metastases and BMV or vBMV. BMV acceleration or deceleration over multiple time points could also be prognostic [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], though our patient numbers were too small to evaluate this. Nevertheless, it is evident that BMV and vBMV plateau in some long-term survivors as reported by the Wake Forest group [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTwo large studies examined the velocity of brain metastases from time of initial cancer diagnosis to initial brain metastases- termed iBMV [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. We opted against analyzing iBMV since many patients in our cohort presented with newly diagnosed cancer synchronously with brain metastases.\u003c/p\u003e\u003cp\u003eLimitations of our study include relatively small numbers of patients (compared to larger institution and pooled databases), single-institution cohort (with potential selection biases), subjectivity in assigning KPS [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], and retrospective design. Because we selected patients receiving upfront SRS, we could not assess outcomes following upfront WBRT or deferral of radiotherapy in favor of supportive care or CNS-active systemic therapy (a treatment paradigm actively being investigated [\u003cspan additionalcitationids=\"CR43\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eWe demonstrated that clinical factors may aid in treatment decision-making for patients with multiple brain metastases. Future studies with larger patient numbers, treated with a variety of upfront approaches, and perhaps incorporating radiomic and genomic factors along with artificial intelligence [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], would help better refine criteria to aid in treatment decision-making for newly diagnosed brain metastases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eEthics approval\u003c/h2\u003e\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The University of Rochester Research Subjects Review Board approved this study.\u003c/p\u003e\u003cp\u003e\u003cb\u003eFunding Declaration\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThere was no funding for this study.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eMM and KU conceptualized the research idea. MM, KU, SH, and HQ provided patients for the study. JY, YZ and HJ provided treatment planning data. MM and DZ collected data. MM performed data analysis. All authors reviewed and revised earlier draft and approved the final draft.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMilano MT, Chiang VLS, Soltys SG, Wang TJC, Lo SS, Brackett A, Nagpal S, Chao S, Garg AK, Jabbari S, Halasz LM, Gephart MH, Knisely JPS, Sahgal A, Chang EL (2020) Executive summary from American Radium Society's appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases. Neuro Oncol 22:1728\u0026ndash;1741. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/neuonc/noaa192\u003c/span\u003e\u003cspan address=\"10.1093/neuonc/noaa192\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G (2006) Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 295:2483\u0026ndash;2491. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.295.21.2483\u003c/span\u003e\u003cspan address=\"10.1001/jama.295.21.2483\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChang EL, Wefel JS, Hess KR, Allen PK, Lang FF, Kornguth DG, Arbuckle RB, Swint JM, Shiu AS, Maor MH, Meyers CA (2009) Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:1037\u0026ndash;1044. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1470-2045(09)70263-3\u003c/span\u003e\u003cspan address=\"10.1016/S1470-2045(09)70263-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKocher M, Soffietti R, Abacioglu U, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Collette S, Collette L, Mueller RP (2011) Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952\u0026ndash;26001 study. J Clin Oncol 29:134\u0026ndash;141. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.2010.30.1655\u003c/span\u003e\u003cspan address=\"10.1200/JCO.2010.30.1655\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBrown PD, Jaeckle K, Ballman KV, Farace E, Cerhan JH, Anderson SK, Carrero XW, Barker FG 2nd, Deming R, Burri SH, Menard C, Chung C, Stieber VW, Pollock BE, Galanis E, Buckner JC, Asher AL (2016) Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial. JAMA 316:401\u0026ndash;409. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jama.2016.9839\u003c/span\u003e\u003cspan address=\"10.1001/jama.2016.9839\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHong AM, Fogarty GB, Dolven-Jacobsen K, Burmeister BH, Lo SN, Haydu LE, Vardy JL, Nowak AK, Dhillon HM, Ahmed T, Shivalingam B, Long GV, Menzies AM, Hruby G, Drummond KJ, Mandel C, Middleton MR, Reisse CH, Paton EJ, Steel V, Williams NC, Scolyer RA, Morton RL, Thompson JF (2019) Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III Trial. J Clin Oncol 37:3132\u0026ndash;3141. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1200/JCO.19.01414\u003c/span\u003e\u003cspan address=\"10.1200/JCO.19.01414\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSahgal A, Aoyama H, Kocher M, Neupane B, Collette S, Tago M, Shaw P, Beyene J, Chang EL (2015) Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 91:710\u0026ndash;717. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2014.10.024\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2014.10.024\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTsao MN, Xu W, Wong RK, Lloyd N, Laperriere N, Sahgal A, Rakovitch E, Chow E (2018) Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 1:CD003869. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/14651858.CD003869.pub4\u003c/span\u003e\u003cspan address=\"10.1002/14651858.CD003869.pub4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChao ST, De Salles A, Hayashi M, Levivier M, Ma L, Martinez R, Paddick I, Regis J, Ryu S, Slotman BJ, Sahgal A (2018) Stereotactic Radiosurgery in the Management of Limited (1\u0026ndash;4) Brain Metasteses: Systematic Review and International Stereotactic Radiosurgery Society Practice Guideline. Neurosurgery 83:345\u0026ndash;353. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/neuros/nyx522\u003c/span\u003e\u003cspan address=\"10.1093/neuros/nyx522\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLi J, Ludmir EB, Wang Y, Guha-Thakurta N, McAleer MF, Settle S, Yeboa DN, Ghia A, McGovern S, Chung C, Woodhouse KD (2020) Stereotactic Radiosurgery versus Whole-brain Radiation Therapy for Patients with 4\u0026ndash;15 Brain Metastases: A Phase III Randomized Controlled Trial. Int J Radiat Oncol Biol Phys 108:S21\u0026ndash;22\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAizer A, Tanguturi SK, Bengham G, Brown PD, Cagney D, Catalano PJ, Chipodza F, Haas-Kogan DA, Hepel JT, Krishnan M (2025) Stereotactic radiation versus hippocampal avoidance whole brain radiation in patients with 5\u0026ndash;20 brain metastases: A multicenter, phase 3 randomized trial. J Clin Oncol 43: 2011\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSerizawa T, Higuchi Y, Nagano O, Sato Y, Yamamoto M, Ono J, Saeki N, Miyakawa A, Hirai T (2012) Analysis of 2000 cases treated with gamma knife surgery: validating eligibility criteria for a prospective multi-institutional study of stereotactic radiosurgery alone for treatment of patients with 1\u0026ndash;10 brain metastases (JLGK0901) in Japan. J Radiosurg SBRT 2:19\u0026ndash;27\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYamamoto M, Kawabe T, Sato Y, Higuchi Y, Nariai T, Barfod BE, Kasuya H, Urakawa Y (2013) A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1\u0026ndash;4 vs \u0026gt;/= 5 tumors: clinical article. J Neurosurg 118:1258\u0026ndash;1268. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3171/2013.3.JNS121900\u003c/span\u003e\u003cspan address=\"10.3171/2013.3.JNS121900\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAli MA, Hirshman BR, Wilson B, Carroll KT, Proudfoot JA, Goetsch SJ, Alksne JF, Ott K, Aiyama H, Nagano O, Carter BS, Fogarty G, Hong A, Serizawa T, Yamamoto M, Chen CC (2017) Survival Patterns of 5750 Stereotactic Radiosurgery-Treated Patients with Brain Metastasis as a Function of the Number of Lesions. World Neurosurg 107:944\u0026ndash;951e941. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.wneu.2017.07.062\u003c/span\u003e\u003cspan address=\"10.1016/j.wneu.2017.07.062\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLadbury C, Pennock M, Yilmaz T, Ankrah NK, Andraos T, Gogineni E, Kim GG, Gibbs I, Shih HA, Hattangadi-Gluth J, Chao ST, Pannullo SC, Slotman B, Redmond KJ, Lo SS, Schulder M (2024) Stereotactic Radiosurgery in the Management of Brain Metastases: A Case-Based Radiosurgery Society Practice Guideline. Adv Radiat Oncol 9:101402. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.adro.2023.101402\u003c/span\u003e\u003cspan address=\"10.1016/j.adro.2023.101402\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRozati H, Chen J, Williams M (2023) Overall survival following stereotactic radiosurgery for ten or more brain metastases: a systematic review and meta-analysis. BMC Cancer 23:1004. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12885-023-11452-7\u003c/span\u003e\u003cspan address=\"10.1186/s12885-023-11452-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMilano MT, Hardy S, Zheng D, Igwe T, Huang D, Chowdhry AC, Yoon J, Schmidt TM, Walter KA, Jung H, Zhou Y, Usuki KY (2025) Stereotactic radiosurgery alone for patients with 16 or more brain metastases: Retrospective single-institution analysis. World Neurosurg X 26:100432\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHirshman BR, Compton J, Carroll KT, Ali MA, Wang SG, Chen CC (2021) Cumulative Intracranial Tumor Volume as a Prognostic Factor in Patients with Brain Metastases Undergoing Stereotactic Radiosurgery. Acta Neurochir Suppl 128:57\u0026ndash;69. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/978-3-030-69217-9_7\u003c/span\u003e\u003cspan address=\"10.1007/978-3-030-69217-9_7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFarris M, McTyre ER, Cramer CK, Hughes R, Randolph DM 2nd, Ayala-Peacock DN, Bourland JD, Ruiz J, Watabe K, Laxton AW, Tatter SB, Zhou X, Chan MD (2017) Brain Metastasis Velocity: A Novel Prognostic Metric Predictive of Overall Survival and Freedom From Whole-Brain Radiation Therapy After Distant Brain Failure Following Upfront Radiosurgery Alone. Int J Radiat Oncol Biol Phys 98:131\u0026ndash;141. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2017.01.201\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2017.01.201\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMcTyre ER, Soike MH, Farris M, Ayala-Peacock DN, Hepel JT, Page BR, Shen C, Kleinberg L, Contessa JN, Corso C, Chiang V, Henson-Masters A, Cramer CK, Ruiz J, Pasche B, Watabe K, D'Agostino R, Su J, Laxton AW, Tatter SB, Fiveash JB, Ahluwalia M, Kotecha R, Chao ST, Braunstein SE, Attia A, Chung C, Chan MD (2020) Multi-institutional validation of brain metastasis velocity, a recently defined predictor of outcomes following stereotactic radiosurgery. Radiother Oncol 142:168\u0026ndash;174. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.radonc.2019.08.011\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2019.08.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYamamoto M, Aiyama H, Koiso T, Watanabe S, Kawabe T, Sato Y, Higuchi Y, Kasuya H, Barfod BE (2019) Validity of a Recently Proposed Prognostic Grading Index, Brain Metastasis Velocity, for Patients With Brain Metastasis Undergoing Multiple Radiosurgical Procedures. Int J Radiat Oncol Biol Phys 103:631\u0026ndash;637. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2018.10.036\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2018.10.036\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLeCompte MC, McTyre E, Henson A, Farris M, Okoukoni C, Cramer CK, Triozzi P, Ruiz J, Watabe K, Lo HW, Munley MT, Laxton AW, Tatter SB, Zhou X, Chan M (2017) Survival and Failure Outcomes Predicted by Brain Metastasis Volumetric Kinetics in Melanoma Patients Following Upfront Treatment with Stereotactic Radiosurgery Alone. Cureus 9: e1934 \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.1934\u003c/span\u003e\u003cspan address=\"10.7759/cureus.1934\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSperduto PW, De B, Li J, Carpenter D, Kirkpatrick J, Milligan M, Shih HA, Kutuk T, Kotecha R, Higaki H, Otsuka M, Aoyama H, Bourgoin M, Roberge D, Dajani S, Sachdev S, Gainey J, Buatti JM, Breen W, Brown PD, Ni L, Braunstein S, Gallitto M, Wang TJC, Shanley R, Lou E, Shiao J, Gaspar LE, Tanabe S, Nakano T, An Y, Chiang V, Zeng L, Soliman H, Elhalawani H, Cagney D, Thomas E, Boggs DH, Ahluwalia MS, Mehta MP (2022) Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors. Int J Radiat Oncol Biol Phys 114:60\u0026ndash;74. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2022.03.020\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2022.03.020\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSperduto PW, Mesko S, Li J, Cagney D, Aizer A, Lin NU, Nesbit E, Kruser TJ, Chan J, Braunstein S, Lee J, Kirkpatrick JP, Breen W, Brown PD, Shi D, Shih HA, Soliman H, Sahgal A, Shanley R, Sperduto W, Lou E, Everett A, Boggs DH, Masucci L, Roberge D, Remick J, Plichta K, Buatti JM, Jain S, Gaspar LE, Wu CC, Wang TJC, Bryant J, Chuong M, Yu J, Chiang V, Nakano T, Aoyama H, Mehta MP (2020) Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today. Int J Radiat Oncol Biol Phys 107:334\u0026ndash;343. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2020.01.051\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2020.01.051\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSperduto PW, Jiang W, Brown PD, Braunstein S, Sneed P, Wattson DA, Shih HA, Bangdiwala A, Shanley R, Lockney NA, Beal K, Lou E, Amatruda T, Sperduto WA, Kirkpatrick JP, Yeh N, Gaspar LE, Molitoris JK, Masucci L, Roberge D, Yu J, Chiang V, Mehta M (2017) Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA). Int J Radiat Oncol Biol Phys 99:812\u0026ndash;816. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2017.06.2454\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2017.06.2454\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSperduto PW, Deegan BJ, Li J, Jethwa KR, Brown PD, Lockney N, Beal K, Rana NG, Attia A, Tseng CL, Sahgal A, Shanley R, Sperduto WA, Lou E, Zahra A, Buatti JM, Yu JB, Chiang V, Molitoris JK, Masucci L, Roberge D, Shi DD, Shih HA, Olson A, Kirkpatrick JP, Braunstein S, Sneed P, Mehta MP (2018) Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool. Neuro Oncol 20:1652\u0026ndash;1660. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1093/neuonc/noy099\u003c/span\u003e\u003cspan address=\"10.1093/neuonc/noy099\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSperduto PW, Fang P, Li J, Breen W, Brown PD, Cagney D, Aizer A, Yu JB, Chiang V, Jain S, Gaspar LE, Myrehaug S, Sahgal A, Braunstein S, Sneed P, Cameron B, Attia A, Molitoris J, Wu CC, Wang TJC, Lockney NA, Beal K, Parkhurst J, Buatti JM, Shanley R, Lou E, Tandberg DD, Kirkpatrick JP, Shi D, Shih HA, Chuong M, Saito H, Aoyama H, Masucci L, Roberge D, Mehta MP (2019) Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA). Clin Transl Radiat Oncol 18:39\u0026ndash;45. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ctro.2019.06.007\u003c/span\u003e\u003cspan address=\"10.1016/j.ctro.2019.06.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSperduto PW, Berkey B, Gaspar LE, Mehta M, Curran W (2008) A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 70:510\u0026ndash;514. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2007.06.074\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2007.06.074\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZheng D, Yoon J, Jung H, Lemus OMD, Gou L, Zhou Y, Usuki KY, Hardy S, Milano MT (2024) How Does the Number of Brain Metastases Correlate With Normal Brain Exposure in Single-Isocenter Multitarget Multifraction Stereotactic Radiosurgery. Adv Radiat Oncol 9:101499. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.adro.2024.101499\u003c/span\u003e\u003cspan address=\"10.1016/j.adro.2024.101499\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJung H, Yoon J, Dona Lemus O, Tanny S, Zhou Y, Milano M, Usuki K, Hardy S, Zheng D (2024) Dosimetric evaluation of LINAC-based single-isocenter multi-target multi-fraction stereotactic radiosurgery with more than 20 targets: comparing MME, HyperArc, and RapidArc. Radiat Oncol 19:19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s13014-024-02416-7\u003c/span\u003e\u003cspan address=\"10.1186/s13014-024-02416-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNagtegaal SHJ, Claes A, Suijkerbuijk KPM, Schramel F, Snijders TJ, Verhoeff JJC (2019) Comparing survival predicted by the diagnosis-specific Graded Prognostic Assessment (DS-GPA) to actual survival in patients with 1\u0026ndash;10 brain metastases treated with stereotactic radiosurgery. Radiother Oncol 138:173\u0026ndash;179. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.radonc.2019.06.033\u003c/span\u003e\u003cspan address=\"10.1016/j.radonc.2019.06.033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMulvenna P, Nankivell M, Barton R, Faivre-Finn C, Wilson P, McColl E, Moore B, Brisbane I, Ardron D, Holt T, Morgan S, Lee C, Waite K, Bayman N, Pugh C, Sydes B, Stephens R, Parmar MK, Langley RE (2016) Dexamethasone and supportive care with or without whole brain radiotherapy in treating patients with non-small cell lung cancer with brain metastases unsuitable for resection or stereotactic radiotherapy (QUARTZ): results from a phase 3, non-inferiority, randomised trial. Lancet 388:2004\u0026ndash;2014. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0140-6736(16)30825-x\u003c/span\u003e\u003cspan address=\"10.1016/s0140-6736(16)30825-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarat M, Blok M, Miechowicz I, Kowalewska J (2020) Stereotactic Radiosurgery of Brain Metastasis in Patients with a Poor Prognosis: Effective or Overtreatment? Cancer Manag Res 12:12569\u0026ndash;12579. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/cmar.S272369\u003c/span\u003e\u003cspan address=\"10.2147/cmar.S272369\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFritz C, Borsky K, Stark LS, Tanadini-Lang S, Kroeze SGC, Krayenb\u0026uuml;hl J, Guckenberger M, Andratschke N (2018) Repeated Courses of Radiosurgery for New Brain Metastases to Defer Whole Brain Radiotherapy: Feasibility and Outcome With Validation of the New Prognostic Metric Brain Metastasis Velocity. Front Oncol 8:551. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2018.00551\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2018.00551\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdulhaleem M, Scott E, Johnston H, Isom S, Lanier C, LeCompte M, Cramer CK, Ruiz J, Lo HW, Watabe K, O'Neill S, Whitlow C, Tatter SB, A WL, Su J, Chan MD (2022) Upfront immunotherapy leads to lower brain metastasis velocity in patients undergoing stereotactic radiosurgery for brain metastases. J Radiosurg SBRT 8:77\u0026ndash;83\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBenjamin CG, Gurewitz J, Kavi A, Bernstein K, Silverman J, Mureb M, Donahue B, Kondziolka D (2022) Survival and outcomes in patients with \u0026ge;\u0026thinsp;25 cumulative brain metastases treated with stereotactic radiosurgery. J Neurosurg 137:571\u0026ndash;581. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3171/2021.9.Jns21882\u003c/span\u003e\u003cspan address=\"10.3171/2021.9.Jns21882\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLanier CM, Pearce J, Isom S, Xing F, Lo HW, Whitlow CT, Ruiz J, White JJ, Laxton AW, Tatter SB, Cramer CK, Chan MD (2022) Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero? J Neurooncol 160:643\u0026ndash;648. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11060-022-04183-5\u003c/span\u003e\u003cspan address=\"10.1007/s11060-022-04183-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHughes RT, Masters AH, McTyre ER, Farris MK, Chung C, Page BR, Kleinberg LR, Hepel J, Contessa JN, Chiang V, Ruiz J, Watabe K, Su J, Fiveash JB, Braunstein S, Chao S, Attia A, Ayala-Peacock DN, Chan MD (2019) Initial SRS for patients with 5\u0026ndash;15 brain metastases: results of a multi-institutional experience. Int J Radiat Oncol Biol Phys. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijrobp.2019.03.052\u003c/span\u003e\u003cspan address=\"10.1016/j.ijrobp.2019.03.052\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRogers SJ, Lomax N, Alonso S, Lazeroms T, Riesterer O (2022) Radiosurgery for Five to Fifteen Brain Metastases: A Single Centre Experience and a Review of the Literature. Front Oncol 12:866542. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fonc.2022.866542\u003c/span\u003e\u003cspan address=\"10.3389/fonc.2022.866542\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSoike MH, McTyre ER, Hughes RT, Farris M, Cramer CK, LeCompte MC, Lanier CM, Ruiz J, Su J, Watabe K, Bourland JD, Munley MT, O'Neill S, Laxton AW, Tatter SB, Chan MD (2018) Initial brain metastasis velocity: does the rate at which cancers first seed the brain affect outcomes? J Neurooncol 139:461\u0026ndash;467. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11060-018-2888-3\u003c/span\u003e\u003cspan address=\"10.1007/s11060-018-2888-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eYamamoto M, Aiyama H, Koiso T, Watanabe S, Kawabe T, Sato Y, Higuchi Y, Kasuya H, Barfod BE (2019) Applicability and limitations of a recently-proposed prognostic grading metric, initial brain metastasis velocity, for brain metastasis patients undergoing stereotactic radiosurgery. J Neurooncol 143:613\u0026ndash;621. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s11060-019-03199-8\u003c/span\u003e\u003cspan address=\"10.1007/s11060-019-03199-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNagpal S, Milano MT, Chiang VL, Soltys SG, Brackett A, Halasz LM, Garg AK, Sahgal A, Tom M, Palmer JD, Knisely J, Chao ST, Hayden-Gephart M, Wang TJC, Lo SS, Chang EL (2024) Executive Summary of the American Radium Society Appropriate Use Criteria for Brain Metastases in EGFR-mutated and ALK-fusion Non-Small Cell Lung Cancer. Neuro Oncol In press\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMurphy B, Walker J, Bassale S, Monaco D, Jaboin J, Ciporen J, Taylor M, Dai Kubicky C (2019) Concurrent Radiosurgery and Immune Checkpoint Inhibition: Improving Regional Intracranial Control for Patients With Metastatic Melanoma. Am J Clin Oncol 42:253\u0026ndash;257. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/coc.0000000000000509\u003c/span\u003e\u003cspan address=\"10.1097/coc.0000000000000509\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShepard MJ, Xu Z, Donahue J, Eluvathingal Muttikkal TJ, Cordeiro D, Hansen L, Mohammed N, Gentzler RD, Larner J, Fadul CE, Sheehan JP (2019) Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study. J Neurosurg 1\u0026ndash;8. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3171/2019.4.Jns19822\u003c/span\u003e\u003cspan address=\"10.3171/2019.4.Jns19822\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCao Y, Cherng HR, Kunaprayoon D, Mishra MV, Ren L (2025) Interpretable AI-assisted clinical decision making for treatment selection for brain metastases in radiation therapy. Med Phys 52:e17844. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/mp.17844\u003c/span\u003e\u003cspan address=\"10.1002/mp.17844\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient, cancer and treatment characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatients with no imaging follow-up and/or survival\u0026thinsp;\u0026le;\u0026thinsp;2 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePatients with imaging follow-up and survival\u0026thinsp;\u0026gt;\u0026thinsp;2 months\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of patients\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e116\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e: range (median)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33.5\u0026ndash;95.2 (66.6) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41.2\u0026ndash;83.5 (68.3) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33.5\u0026ndash;95.2 (65.6) years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKPS\u003c/b\u003e: range (median)\u003c/p\u003e\u003cp\u003e- 40\u0026ndash;60\u003c/p\u003e\u003cp\u003e- 70\u0026ndash;80\u003c/p\u003e\u003cp\u003e- 90\u0026ndash;100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40\u0026ndash;100 (80)\u003c/p\u003e\u003cp\u003e20 (17.2%)\u003c/p\u003e\u003cp\u003e51 (44.0%)\u003c/p\u003e\u003cp\u003e45 (38.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50\u0026ndash;90 (80)\u003c/p\u003e\u003cp\u003e10 (37.0%)\u003c/p\u003e\u003cp\u003e13 (48.1%)\u003c/p\u003e\u003cp\u003e4 (14.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40\u0026ndash;100 (80)\u003c/p\u003e\u003cp\u003e10 (11.2%)\u003c/p\u003e\u003cp\u003e38 (42.7%)\u003c/p\u003e\u003cp\u003e41 (46.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e.001\u003c/p\u003e\u003cp\u003e.002\u003c/p\u003e\u003cp\u003e.62\u003c/p\u003e\u003cp\u003e.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNeurologic symptoms\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- None\u003c/p\u003e\u003cp\u003e- Minor deficits \u0026sect;\u003c/p\u003e\u003cp\u003e- dexamethasone\u0026thinsp;\u0026ge;\u0026thinsp;4mg daily\u003c/p\u003e\u003cp\u003e- Major deficits \u0026sect;\u003c/p\u003e\u003cp\u003e- Seizure\u003c/p\u003e\u003cp\u003e- Major deficits OR dexamethasone\u0026thinsp;\u0026ge;\u0026thinsp;4mg daily\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e52 (44.8%)\u003c/p\u003e\u003cp\u003e37 (31.9%)\u003c/p\u003e\u003cp\u003e25\u003c/p\u003e\u003cp\u003e17 (14.7%)\u003c/p\u003e\u003cp\u003e7 (6.0%)\u003c/p\u003e\u003cp\u003e47 (40.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e11 (40.7%)\u003c/p\u003e\u003cp\u003e11 (40.7%)\u003c/p\u003e\u003cp\u003e8\u003c/p\u003e\u003cp\u003e3 (11.1%)\u003c/p\u003e\u003cp\u003e1 (3.7%)\u003c/p\u003e\u003cp\u003e12 (44.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e41 (4-6.1%)\u003c/p\u003e\u003cp\u003e26 (29.2%)\u003c/p\u003e\u003cp\u003e17\u003c/p\u003e\u003cp\u003e14 (15.7%)\u003c/p\u003e\u003cp\u003e6 (6.7%)\u003c/p\u003e\u003cp\u003e35 (39.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.63\u003c/p\u003e\u003cp\u003e.26\u003c/p\u003e\u003cp\u003e.55\u003c/p\u003e\u003cp\u003e.56\u003c/p\u003e\u003cp\u003e.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCancer type and histology\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- Non-small cell lung cancer\u003c/p\u003e\u003cp\u003e- Cutaneous melanoma\u003c/p\u003e\u003cp\u003e- Breast adenocarcinoma\u003c/p\u003e\u003cp\u003e- Kidney \u0026ndash; renal cell carcinoma\u003c/p\u003e\u003cp\u003e- Other *\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e63 (54.3%)\u003c/p\u003e\u003cp\u003e20 (17.2%)\u003c/p\u003e\u003cp\u003e19 (16.4%)\u003c/p\u003e\u003cp\u003e6 (5.2%)\u003c/p\u003e\u003cp\u003e8 (6.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e11 (40.7%)\u003c/p\u003e\u003cp\u003e5 (18.5%)\u003c/p\u003e\u003cp\u003e3 (11.1%)\u003c/p\u003e\u003cp\u003e3 (11.1%)\u003c/p\u003e\u003cp\u003e5 (18.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e52 (58.4%)\u003c/p\u003e\u003cp\u003e15 (16.9%)\u003c/p\u003e\u003cp\u003e16 (18.0%)\u003c/p\u003e\u003cp\u003e3 (3.3%)\u003c/p\u003e\u003cp\u003e3 (3.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.11\u003c/p\u003e\u003cp\u003e.84\u003c/p\u003e\u003cp\u003e.40\u003c/p\u003e\u003cp\u003e.11\u003c/p\u003e\u003cp\u003e.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStatus of extracranial disease\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- No evidence of disease\u003c/p\u003e\u003cp\u003e- No progression\u003c/p\u003e\u003cp\u003e- Progression\u003c/p\u003e\u003cp\u003e- New metastatic cancer diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2 (1.7%)\u003c/p\u003e\u003cp\u003e17 (14.6%)\u003c/p\u003e\u003cp\u003e41 (35.3%)\u003c/p\u003e\u003cp\u003e56 (48.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e2 (7.4%)\u003c/p\u003e\u003cp\u003e15 (55.6%)\u003c/p\u003e\u003cp\u003e10 (37.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2 (2.2%)\u003c/p\u003e\u003cp\u003e15 (16.8%)\u003c/p\u003e\u003cp\u003e26 (29.2%)\u003c/p\u003e\u003cp\u003e46 (51.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e}- .15\u003c/p\u003e\u003cp\u003e.012\u003c/p\u003e\u003cp\u003e.18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePredicted median survival from GPAs\u003c/b\u003e\u003c/p\u003e\u003cp\u003erange (median)\u003c/p\u003e\u003cp\u003e- \u0026le;\u0026thinsp;6.0 months\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;6\u0026ndash;12 months\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2.0\u0026ndash;30.0 (6.0) months\u003c/p\u003e\u003cp\u003e63 (54.3%)\u003c/p\u003e\u003cp\u003e10 (8.6%)\u003c/p\u003e\u003cp\u003e43 (37.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2.6\u0026ndash;15.0 (6.0) months\u003c/p\u003e\u003cp\u003e20 (74.1%)\u003c/p\u003e\u003cp\u003e2 (7.4%)\u003c/p\u003e\u003cp\u003e5 (18.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2.0\u0026ndash;30.0 (8.3) months\u003c/p\u003e\u003cp\u003e43 (48.3%)\u003c/p\u003e\u003cp\u003e8 (9.0%)\u003c/p\u003e\u003cp\u003e38 (42.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.007\u003c/p\u003e\u003cp\u003e.021\u003c/p\u003e\u003cp\u003e.80\u003c/p\u003e\u003cp\u003e.022\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSmall molecule inhibitor \u0026dagger;\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- none\u003c/p\u003e\u003cp\u003e- Before SRS\u003c/p\u003e\u003cp\u003e- After SRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e72 (62.0%)\u003c/p\u003e\u003cp\u003e20 (17.2%)\u003c/p\u003e\u003cp\u003e33 (28.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e17 (63.0%)\u003c/p\u003e\u003cp\u003e7 (25.9%)\u003c/p\u003e\u003cp\u003e3 (11.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e55 (61.8%)\u003c/p\u003e\u003cp\u003e13 (14.6%)\u003c/p\u003e\u003cp\u003e30 (33.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.91\u003c/p\u003e\u003cp\u003e.17\u003c/p\u003e\u003cp\u003e.023\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eImmune checkpoint inhibitor \u0026dagger;\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- none\u003c/p\u003e\u003cp\u003e- Before SRS\u003c/p\u003e\u003cp\u003e- After SRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e42 (36.2%)\u003c/p\u003e\u003cp\u003e44 (37.9%)\u003c/p\u003e\u003cp\u003e57 (49.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e17 (63.0%)\u003c/p\u003e\u003cp\u003e9 (33.3%)\u003c/p\u003e\u003cp\u003e4 (14.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e25 (28.1%)\u003c/p\u003e\u003cp\u003e35 (39.3%)\u003c/p\u003e\u003cp\u003e53 (60.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.001\u003c/p\u003e\u003cp\u003e.57\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCNS penetrant antibody-drug conjugate or chemotherapy \u0026dagger;\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- none\u003c/p\u003e\u003cp\u003e- Before SRS\u003c/p\u003e\u003cp\u003e- After SRS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e99 (85.3%)\u003c/p\u003e\u003cp\u003e12 (10.3%)\u003c/p\u003e\u003cp\u003e15 (12.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e26 (96.3%)\u003c/p\u003e\u003cp\u003e1 (3.7%)\u003c/p\u003e\u003cp\u003e1 (3.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e73 (82.0%)\u003c/p\u003e\u003cp\u003e11 (12.3%)\u003c/p\u003e\u003cp\u003e14 (15.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.066\u003c/p\u003e\u003cp\u003e.20\u003c/p\u003e\u003cp\u003e.10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eSRS \u0026ndash; dose and fractionation\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- 6\u0026ndash;7 Gy x 5\u003c/p\u003e\u003cp\u003e- 7\u0026ndash;9 Gy x 3 (mostly 9 Gy x 3)\u003c/p\u003e\u003cp\u003e- 20 Gy x 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e9 (7.7%)\u003c/p\u003e\u003cp\u003e100 (86.2%)\u003c/p\u003e\u003cp\u003e7 (6.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e0\u003c/p\u003e\u003cp\u003e26 (96.3%)\u003c/p\u003e\u003cp\u003e1 (3.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e9 (10.1%)\u003c/p\u003e\u003cp\u003e74 (83.1%)\u003c/p\u003e\u003cp\u003e6 (6.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.085\u003c/p\u003e\u003cp\u003e.083\u003c/p\u003e\u003cp\u003e.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of metastases\u003c/b\u003e: range (median)\u003c/p\u003e\u003cp\u003e- 5\u0026ndash;10\u003c/p\u003e\u003cp\u003e- 11\u0026ndash;20\u003c/p\u003e\u003cp\u003e- 20\u0026ndash;30\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u0026ndash;41 (10)\u003c/p\u003e\u003cp\u003e68 (58.6%)\u003c/p\u003e\u003cp\u003e30 (25.9%)\u003c/p\u003e\u003cp\u003e11 (9.5%)\u003c/p\u003e\u003cp\u003e7 (6.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u0026ndash;37 (10)\u003c/p\u003e\u003cp\u003e15 (55.6%)\u003c/p\u003e\u003cp\u003e6 (22.2%)\u003c/p\u003e\u003cp\u003e4 (14.8%)\u003c/p\u003e\u003cp\u003e2 (7.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u0026ndash;41 (9)\u003c/p\u003e\u003cp\u003e53 (59.6%)\u003c/p\u003e\u003cp\u003e24 (26.9%)\u003c/p\u003e\u003cp\u003e7 (7.9%)\u003c/p\u003e\u003cp\u003e5 (5.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e.31\u003c/p\u003e\u003cp\u003e.71\u003c/p\u003e\u003cp\u003e.62\u003c/p\u003e\u003cp\u003e.28\u003c/p\u003e\u003cp\u003e.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNet GTV \u0026yen; of metastases\u003c/b\u003e: range (median)\u003c/p\u003e\u003cp\u003e- \u0026le;\u0026thinsp;2 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;2\u0026ndash;5 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;5\u0026ndash;10 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;10\u0026ndash;20 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;20 cc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.1\u0026ndash;59.8 (5.2) cc\u003c/p\u003e\u003cp\u003e28 (24.1%)\u003c/p\u003e\u003cp\u003e29 (25.0%)\u003c/p\u003e\u003cp\u003e26 (22.4%)\u003c/p\u003e\u003cp\u003e22 (19.0%)\u003c/p\u003e\u003cp\u003e11 (9.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.4\u0026ndash;53.3 (5.5) cc\u003c/p\u003e\u003cp\u003e5 (18.5%)\u003c/p\u003e\u003cp\u003e7 (25.9%)\u003c/p\u003e\u003cp\u003e7 (25.9%)\u003c/p\u003e\u003cp\u003e4 (14.8%)\u003c/p\u003e\u003cp\u003e4 (14.8%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.1\u0026ndash;59.8 (5.0) cc\u003c/p\u003e\u003cp\u003e23 (25.8%)\u003c/p\u003e\u003cp\u003e22 (24.7%)\u003c/p\u003e\u003cp\u003e19 (21.3%)\u003c/p\u003e\u003cp\u003e18 (20.2%)\u003c/p\u003e\u003cp\u003e7 (7.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e.57\u003c/p\u003e\u003cp\u003e.44\u003c/p\u003e\u003cp\u003e.90\u003c/p\u003e\u003cp\u003e.62\u003c/p\u003e\u003cp\u003e.53\u003c/p\u003e\u003cp\u003e.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSRS\u0026thinsp;=\u0026thinsp;stereotactic radiosurgery ; KPS\u0026thinsp;=\u0026thinsp;Karnofsky Performance Scale; GPA\u0026thinsp;=\u0026thinsp;graded prognostic assessment; CNS\u0026thinsp;=\u0026thinsp;central nervous system; GTV\u0026thinsp;=\u0026thinsp;gross target volume; NA\u0026thinsp;=\u0026thinsp;not applicable\u003c/p\u003e\u003cp\u003e\u0026yen; Net GTV for the initial SRS course\u003c/p\u003e\u003cp\u003e* includes duodenum (n\u0026thinsp;=\u0026thinsp;1), rectum (n\u0026thinsp;=\u0026thinsp;1) and esophagus (n\u0026thinsp;=\u0026thinsp;2) for which the gastrointestinal cancer GPA was used; also includes endometrial (n\u0026thinsp;=\u0026thinsp;2), ovarian (n\u0026thinsp;=\u0026thinsp;1) and head and neck (n\u0026thinsp;=\u0026thinsp;1) cancers for which the non-disease site specific GPA was used\u003c/p\u003e\u003cp\u003e\u003cb\u003e\u0026dagger;\u003c/b\u003e some patients received drug prior to and after SRS resulting in net totals\u0026thinsp;\u0026gt;\u0026thinsp;100% for these cells\u003c/p\u003e\u003cp\u003e\u0026sect; major and minor neurologic deficits imply neurologic deficits (including headache but not seizure) requiring vs not requiring (respectively) hospitalization. All those with major deficits received dexamethasone\u0026thinsp;\u0026ge;\u0026thinsp;4 mg daily, as did all but one who had had seizure.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient, cancer and treatment factors evaluated for potential effect on overall survival\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMedian OS\u003c/p\u003e\u003cp\u003e(months)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eUnivariable\u003c/p\u003e\u003cp\u003elog rank p value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnivariable Cox regression\u003c/p\u003e\u003cp\u003eHR [95% CI] (p value)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMultivariable Cox regression (model 1)\u003c/p\u003e\u003cp\u003eHR [95% CI] (p value)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMultivariable Cox regression (model 2)\u003c/p\u003e\u003cp\u003eHR [95% CI] (p value)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAge\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- \u0026le;\u0026thinsp;60 years\u003c/p\u003e\u003cp\u003e- 60\u0026ndash;70 years\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e11.5\u003c/p\u003e\u003cp\u003e7.1\u003c/p\u003e\u003cp\u003e6.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e.36-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.015 [0.996\u0026ndash;1.035] (p\u0026thinsp;=\u0026thinsp;.12)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKPS\u003c/b\u003e: range (median)\u003c/p\u003e\u003cp\u003e- 40\u0026ndash;60\u003c/p\u003e\u003cp\u003e- 70\u0026ndash;80\u003c/p\u003e\u003cp\u003e- 90\u0026ndash;100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2.2\u003c/p\u003e\u003cp\u003e6.0\u003c/p\u003e\u003cp\u003e18.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e.0001\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.971 [0.957\u0026ndash;0.984] (p\u0026thinsp;\u0026lt;\u0026thinsp;.0001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.983 [0.967\u0026ndash;0.999] (p\u0026thinsp;=\u0026thinsp;.040)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNeurologic symptoms\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- None\u003c/p\u003e\u003cp\u003e- Minor deficits (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e- Major deficits (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e- Major deficits OR dexamethasone\u0026thinsp;\u0026ge;\u0026thinsp;4mg daily\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e7.8\u003c/p\u003e\u003cp\u003e7.0\u003c/p\u003e\u003cp\u003e9.0\u003c/p\u003e\u003cp\u003e7.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.56\u003c/p\u003e\u003cp\u003e.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCancer type and histology\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- Non-small cell lung cancer\u003c/p\u003e\u003cp\u003e- Cutaneous melanoma\u003c/p\u003e\u003cp\u003e- Breast adenocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e8.6\u003c/p\u003e\u003cp\u003e12.1\u003c/p\u003e\u003cp\u003e9.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.85\u003c/p\u003e\u003cp\u003e.36\u003c/p\u003e\u003cp\u003e.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStatus of extracranial disease\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- No progression or NED\u003c/p\u003e\u003cp\u003e- Progression\u003c/p\u003e\u003cp\u003e- New metastatic cancer diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26.0\u003c/p\u003e\u003cp\u003e5.1\u003c/p\u003e\u003cp\u003e11.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.00001\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2.157 [1.384\u0026ndash;3.360] (p\u0026thinsp;=\u0026thinsp;.001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e2.108 [1.358\u0026ndash;3.274] (p\u0026thinsp;=\u0026thinsp;.001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePredicted median survival from GPAs\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- \u0026le;\u0026thinsp;6.0 months\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;6\u0026ndash;12 months\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e5.1\u003c/p\u003e\u003cp\u003e11.0\u003c/p\u003e\u003cp\u003e23.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;.00001\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.905 [0.866\u0026ndash;0.946] (p\u0026thinsp;\u0026lt;\u0026thinsp;.0001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.943 [0.897\u0026ndash;0.991] (p\u0026thinsp;=\u0026thinsp;.020)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.920 [0.880\u0026ndash;0.962] (p\u0026thinsp;=\u0026thinsp;.001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNumber of metastases\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- 5\u0026ndash;10\u003c/p\u003e\u003cp\u003e- 11\u0026ndash;20\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e7.8\u003c/p\u003e\u003cp\u003e7.2\u003c/p\u003e\u003cp\u003e12.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e.84\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eNet GTV \u0026yen; of metastases\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- \u0026le;\u0026thinsp;2 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;2\u0026ndash;5 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;5\u0026ndash;10 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;10\u0026ndash;20 cc\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;20 cc\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e9.4\u003c/p\u003e\u003cp\u003e10.0\u003c/p\u003e\u003cp\u003e5.4\u003c/p\u003e\u003cp\u003e9.0\u003c/p\u003e\u003cp\u003e3.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep\u0026thinsp;=\u0026thinsp;.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eKPS\u0026thinsp;=\u0026thinsp;Karnofsky Performance Scale; GPA\u0026thinsp;=\u0026thinsp;graded prognostic assessment; GTV\u0026thinsp;=\u0026thinsp;gross target volume; HR [95% CI] -hazard ratio with 95% confidence intervals; NED\u0026thinsp;=\u0026thinsp;no evidence of disease (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e\u003cp\u003e\u0026yen; Net GTV for the initial SRS course\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSurvival outcomes and factors associated with survival among those evaluable for brain metastases velocity\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNumber of patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMedian OS\u003c/p\u003e\u003cp\u003e(months)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnivariable\u003c/p\u003e\u003cp\u003elog rank p value\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eUnivariable Cox regression\u003c/p\u003e\u003cp\u003eHR [95% CI] (p value)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMultivariable Cox regression (model 1)\u003c/p\u003e\u003cp\u003eHR [95% CI] (p value)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMultivariable Cox regression (model 2)\u003c/p\u003e\u003cp\u003eHR [95% CI] (p value)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBMV\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- 0 per year *\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;0-\u0026lt;4 per year *\u003c/p\u003e\u003cp\u003e- 4\u0026ndash;13 per year\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;13 per year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e28\u003c/p\u003e\u003cp\u003e8\u003c/p\u003e\u003cp\u003e6\u003c/p\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e26.5\u003c/p\u003e\u003cp\u003e35.9\u003c/p\u003e\u003cp\u003e14.3\u003c/p\u003e\u003cp\u003e15.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.003\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.022 [1.013\u0026ndash;1.032] (p\u0026thinsp;\u0026lt;\u0026thinsp;.0001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.017 [0.996\u0026ndash;1.038] (p\u0026thinsp;=\u0026thinsp;.11)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e1.017 [1.008\u0026ndash;1.028] (p\u0026thinsp;\u0026lt;\u0026thinsp;.0001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003evBMV\u003c/b\u003e:\u003c/p\u003e\u003cp\u003e- 0 cc per year\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;0-\u0026le;1 cc per year\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;1\u0026ndash;5 cc per year\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;5 cc per year\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28\u003c/p\u003e\u003cp\u003e10\u003c/p\u003e\u003cp\u003e13\u003c/p\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.5\u003c/p\u003e\u003cp\u003e28.5\u003c/p\u003e\u003cp\u003e20.0\u003c/p\u003e\u003cp\u003e7.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.009\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.041 [1.019\u0026ndash;1.063] (p\u0026thinsp;\u0026lt;\u0026thinsp;.0001)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.002 [0.955\u0026ndash;1.053] (p\u0026thinsp;=\u0026thinsp;.91)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNot included\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePredicted median OS from GPAs\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- \u0026le;\u0026thinsp;6.0 months\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;6\u0026ndash;12 months\u003c/p\u003e\u003cp\u003e- \u0026gt;\u0026thinsp;12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e27\u003c/p\u003e\u003cp\u003e7\u003c/p\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e14.3\u003c/p\u003e\u003cp\u003e28.5\u003c/p\u003e\u003cp\u003e29.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e.011\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.916 [0.863\u0026ndash;0.972] (p\u0026thinsp;=\u0026thinsp;.004)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.941 [0.884\u0026ndash;1.003] (p\u0026thinsp;=\u0026thinsp;.061)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.942 [0.886\u0026ndash;1.002] (p\u0026thinsp;=\u0026thinsp;.058) \u0026dagger;\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStatus of extracranial disease\u003c/b\u003e\u003c/p\u003e\u003cp\u003e- NED (n\u0026thinsp;=\u0026thinsp;2) or No progression\u003c/p\u003e\u003cp\u003e- Progression\u003c/p\u003e\u003cp\u003e- New metastatic cancer diagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e16\u003c/p\u003e\u003cp\u003e14\u003c/p\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e29.0\u003c/p\u003e\u003cp\u003e9.4\u003c/p\u003e\u003cp\u003e26.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e.0001\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e1.841 [0.816\u0026ndash;4.153] (p\u0026thinsp;=\u0026thinsp;.14)\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003cp\u003e1.850 [0.824\u0026ndash;4.154] (p\u0026thinsp;=\u0026thinsp;.14) \u0026dagger;\u003c/p\u003e\u003cp\u003e-\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eBMV\u0026thinsp;=\u0026thinsp;brain metastases velocity; CI\u0026thinsp;=\u0026thinsp;confidence intervals; GPA\u0026thinsp;=\u0026thinsp;graded prognostic assessment; HR\u0026thinsp;=\u0026thinsp;hazard ratio; NED\u0026thinsp;=\u0026thinsp;no evidence of disease; OS\u0026thinsp;=\u0026thinsp;overall survival; vBMV\u0026thinsp;=\u0026thinsp;volume-based brain metastases velocity\u003c/p\u003e\u003cp\u003e* The survivals between these subgroups was not significantly different on log rank test (p\u0026thinsp;=\u0026thinsp;.99). When these 2 groups merged (as was done in study by Farris et al.) median survival is 35.9 months\u003c/p\u003e\u003cp\u003e\u0026dagger; Predicted median OS and progressive extracranial disease were each significant (p\u0026thinsp;\u0026lt;\u0026thinsp;.02) in separate two-variable Cox regression analyses with BMV (data not shown), suggesting that they are somewhat interdependent prognostic factors.\u003c/p\u003e\u003c/div\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7785592/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7785592/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eWe describe patient outcomes following linear accelerator-based stereotactic radiosurgery (SRS) for \u0026ge;\u0026thinsp;5 brain metastases, without prior or planned whole-brain radiotherapy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe identified 116 eligible patients treated with SRS, from 2019\u0026ndash;2024, for newly diagnosed brain metastases. We describe clinical factors associated with survival\u0026thinsp;\u0026le;\u0026thinsp;2 months and analyze brain metastasis velocity measured as number (BMV) or volume (vBMV) of new metastases per year.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe number of treated brain metastases ranged from 5\u0026ndash;41 (median 10); net lesion volume ranged from 0.1\u0026ndash;59.8 (median 5.2) cc. Primary cancers included non-small cell lung (n\u0026thinsp;=\u0026thinsp;65), melanoma (n\u0026thinsp;=\u0026thinsp;20), breast (n\u0026thinsp;=\u0026thinsp;19), kidney (n\u0026thinsp;=\u0026thinsp;6), gastrointestinal (n\u0026thinsp;=\u0026thinsp;4), and other (n\u0026thinsp;=\u0026thinsp;4) cancers. The 6-, 12- and 24-month overall survivals (OS) were 60.3%, 40.5%, 28.0%, respectively. Progressive extracranial disease at time of brain metastases and lower predicted survival from grade prognostic assessments were significantly adverse factors for OS on multivariable Cox regression, and were associated with \u0026lsquo;poor survivors\u0026rsquo; who died\u0026thinsp;\u0026le;\u0026thinsp;2 months from SRS (n\u0026thinsp;=\u0026thinsp;21) or at \u0026gt;\u0026thinsp;2 months but opting against post-SRS cancer care and follow-up imaging (n\u0026thinsp;=\u0026thinsp;6; OS\u0026thinsp;=\u0026thinsp;2.1\u0026ndash;5.8 months). Forty-two patients developed new brain metastases after SRS, while 28 (after \u0026ge;\u0026thinsp;6-months follow-up) did not. Among these patients, OS was significantly associated with BMV and vBMV, though vBMV was not significant on multivariable Cox regressions that included BMV.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eFor patients with \u0026ge;\u0026thinsp;5 brain metastases, clinical factors can potentially aid in selecting patients best-suited for SRS for multiple brain metastases, versus potentially deferring SRS in favor of supportive care. While vBMV is associated with OS, BMV appears more prognostic.\u003c/p\u003e","manuscriptTitle":"Stereotactic radiosurgery for patients with 5 or more brain metastases: Retrospective single-institution analysis with focus on brain metastasis velocity","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 23:12:50","doi":"10.21203/rs.3.rs-7785592/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"09d490e3-0edf-4f3e-8869-905757a4f1f6","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T14:32:52+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 23:12:50","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7785592","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7785592","identity":"rs-7785592","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}