Clinical outcomes of daily 5-fraction Gamma Knife radiosurgery for large brain metastases: a retrospective cohort study

Clinical outcomes of daily 5-fraction Gamma Knife radiosurgery for large brain metastases: a retrospective cohort study | 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 Case Report Clinical outcomes of daily 5-fraction Gamma Knife radiosurgery for large brain metastases: a retrospective cohort study Juhee Jeon, Yukyeng Byeon, Gung Ju Kim, Yuhyun Kwon, Seohmi Jung, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8667314/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 The Gamma Knife Icon has enabled hypofractionated Gamma Knife radiosurgery (GKRS) for large brain metastases (LBMs). We assessed the clinical outcomes and complications of daily 5-fraction GKRS for LBMs. Methods We enrolled 100 patients who underwent daily 5-fraction GKRS for LBMs (> 14 cm 3 ). Forty-six patients were male; the median age was 60 years. The median Karnofsky Performance Status (KPS) was 70 (60–100); 47 patients (47%) had pre-GKRS neurological deficits. The most common primary sites were lung (41), breast (24), and kidney (14). Median tumor volume was 22 cm 3 (14─70 cm 3 ) and the marginal dose was 35.2 Gy (50% isodose line) in 5 fractions. Median follow-up was 18 months (3─72 months). Results Local tumor control was observed in 74 cases (74%). The cumulative 1-, 2-, and 3-year control rates were 73%, 65%, and 60%, respectively. Eighty-six tumors achieved their best magnetic resonance imaging response within 1 year; the median volume reduction was 80% (22%─100%). Thirty patients (30%) had a dramatic volume reduction (> 95%). Median progression-free (PFS) and overall survival (OS) were 7.5 and 16.3 months, respectively. PFS was significantly associated with local tumor control ( p = 0.008). OS was associated with pre-GKRS KPS and neurological deficits ( p = 0.003 and p = 0.025, respectively). Radiation necrosis occurred in 16 patients (16%); 9 (9%) were symptomatic and recovered fully with corticosteroids or bevacizumab. Conclusion Daily 5-fraction GKRS for LBMs yielded favorable local control and PFS with acceptable radiation necrosis rates, but OS benefit was uncertain. Prospective multicenter studies are warranted. Gamma Knife radiosurgery 5-fraction large brain metastases radiation necrosis bevacizumab Figures Figure 1 Figure 2 Introduction Brain metastases are the most common malignant intracranial tumors. Despite this prevalence, optimal treatment remains controversial [ 1 ]. Randomized trials have shown that, in patients with a single brain metastasis, good performance status, and limited extracranial disease, adjuvant radiotherapy after resection improves overall survival (OS) and reduces recurrence [ 2 – 4 ]. More recently, stereotactic radiosurgery (SRS) has been recommended as an effective primary treatment for patients not suitable for surgery [ 5 , 6 ]. According to National Comprehensive Cancer Network guidelines, resection is recommended for patients with mass effect or neurological symptoms, newly diagnosed or stable systemic disease with reasonable systemic options, or when biopsy confirmation is required [ 7 ]. SRS is also preferred for the surgical cavity and as upfront therapy for small tumor volumes (< 2 cm 3 ) [ 7 ]. Although SRS is effective for small to medium-sized metastases, treating large brain metastases (LBMs) remains challenging because of adverse effects including radiation necrosis and neurological decline [ 5 , 6 , 8 ]. The Gamma Knife Icon enables frameless hypo-fractionated SRS; consequently, Gamma Knife radiosurgery (GKRS) is increasingly used for LBMs. However, optimal fraction number and dose for hypofractionated SRS have not been established, and evidence regarding effectiveness, safety, and indications remains limited [ 5 ]. Therefore, we evaluated outcomes and complications of daily 5-fraction GKRS for LBMs (> 14 cm³) and identified clinical parameters associated with favorable outcomes. Methods Study C ohort Between 2017 and 2022, 2,589 patients with 9,211 brain metastases underwent GKRS at our institution. A total of 226 GKRS procedures (2%) targeted LBMs (> 14 cm 3 ). Of the 226 patients, 7 (3%) with single-fraction, 2 (1%) with 2-fraction, 40 (18%) with 3-fraction, 14 (6%) with 4-fraction, and 1 (0%) with 10-fraction GKRS were excluded. Of 162 patients (72%) who received 5-fraction GKRS for LBMs, we excluded 36 (22%) without available radiological follow-up and 26 (16%) who did not undergo primary GKRS. Ultimately, 100 patients were enrolled. The study adhered to the ethical principles of the Declaration of Helsinki, and institutional review board approval was obtained. The median age at GKRS was 60 years (range, 32–91 years), and 54 patients (54%) were female. The pre-GKRS Karnofski Performance Status (KPS) was 60 in 10 patients (10%), 70 in 43 (43%), 80 in 33 (33%), 90 in 12 (12%), and 100 in 2 (2%). Forty-seven patients (47%) had pre-GKRS neurological deficits. The most common primary cancer was non-small cell lung cancer (NSCLC) (41%), followed by breast (24%), genitourinary (16%), gastrointestinal (7%), and small cell lung cancer (4%). Forty-three patients (43%) had extracranial metastases. Four patients (4%) received whole brain radiotherapy (WBRT) before GKRS. The median follow-up duration was 18 months (range, 3─72 months). Demographic and clinical characteristics are summarized in Table 1. Radiosurgical P rotocol Patients underwent GKRS because they were medically ineligible for resection, or their neurological deficits did not warrant surgery. All radiosurgery procedures were performed with a Leksell Gamma Knife Icon system (Elekta, Stockholm, Sweden). A frameless mask was placed on each patient’s face. Patients underwent gadolinium-enhanced magnetic resonance imaging (MRI) with T1- and T2-weighted sequences acquired with 1.0-mm slices. Leksell GammaPlan software (version 10.2.1; Elekta) was used to calculate point doses and generate dose-distance curves [9]. The number of brain metastases was 1 in 33 patients (33%), 2–5 in 48 (48%), and >5 in 19 (19%). The median tumor volume was 22.0 cm 3 (range, 14.1─69.5 cm 3 ). Tumors most commonly involved the frontal lobe (27%), followed by the parietal lobe (20%), cerebellum (18%), occipital lobe (16%), and temporal lobe (13%). All patients received 5 daily fractions. The median marginal dose was 35.2 Gy (range, 24.9─41.5 Gy) at the 50% isodose line; 71 patients (71%) received 35.2 Gy. Radiosurgical parameters are summarized in Tables 1 and Table 2. Gross tumor volume (GTV) was defined as the contrast-enhancing lesion volume on contrast-enhanced T1-weighted. 1.0-mm axial MRI [9]. The clinical target volume equaled to the GTV [10]. The planning target volume (PTV) was created by expanding the contrast-enhancing GTV by 1.0 mm to generate a margin [10, 11]. Radiological and Cli nical E valuation After GKRS, clinical assessments and follow-up MRI were performed every 3 months until last follow-up or death. Lesion volume was measured by outlining the GTV on each thin-section slice of the contrast-enhanced T1-weighted axial images, calculating the area, and summing across slices at each visit. Baseline tumor volume was the volume measured on MRI at the time of GKRS. Percentage change was calculated relative to this baseline on each follow-up MRI. Tumor reduction was defined as a >20% decrease in volume; stabilization as a change within 20%; and progression as a >20% increase without radiation necrosis. Best response was defined as the greatest volume reduction of the GKRS-treated lesion; its timing and magnitude were recorded. Radiation necrosis was diagnosed on clinical and imaging grounds after excluding disease progression, or by histopathology when resection was performed. Radiation necrosis was defined as an enlarging enhancing lesion with geographic intratumoral necrosis and increasing peritumoral edema that subsequently responded to steroids without additional therapy [12, 13]. When differentiation was challenging, experienced radiologists were consulted, and adjunct tests─perfusion and diffusion MRI, MR spectroscopy, and positron emission tomography─were obtained. Initial management was steroid administration; bevacizumab was used when neurological symptoms progressed despite steroids or when adverse effects were severe. Comprehensive clinical and neurological examinations were performed at each follow-up visit. Statistical Analysis Local tumor control (LTC), progression-free survival (PFS), and OS were the primary endpoints. LTC was defined as no progression of GKRS-treated LBMs. PFS was defined as the time from GKRS to any brain metastasis recurrence or progression based on radiological findings. OS was defined as the time from GKRS to death. Cumulative rates of LTC, PFS and OS were estimated using Kaplan–Meier methods. Prognostic factors for LTC, PFS and OS were analyzed using logistic regression and Cox proportional hazards models. A p-value < 0.05 was considered statistically significant. All analyses were conducted using SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY, USA). Results Local Tumor Control During follow-up, 26 GKRS treated LBMs progressed; overall LTC was 74%. Cumulative 1-, 2-, and 3-year LTC rates were 72.7% (95% CI, 62.3%─83.1%), 65.3% (95% CI, 53.5%─ 77.1%), and 59.9% (95% CI, 44.9%─74.9%), respectively. The median time from GKRS to best response was 4 months (range, 1─36 months), and 86 patients (86%) achieved best response within 1 year. Median volume reduction was 80% (range, 22%─100%); 30 patients (30%) had 95% reduction. Patients with NSCLC had significantly higher LTC than those with other primary cancers ( p = 0.030 ). No significant associations were observed with age, sex, KPS, tumor location, tumor volume, or marginal dose ( p = 0.690, 0.440, 0.872, 0.897, 0.909 and 0.645, respectively ). This difference likely reflects the impact of targeted therapies widely used for NSCLC. Progression-Free and Overall Survival During follow-up duration, the median PFS was 7.5 months (range, 1─65 months). The cumulative 1-, 2-, and 3-year PFS rates were 37.2% (95% CI, 26.6─47.8), 17.9% (95% CI, 8.7─27.1), and 14.0% (95% CI, 5.4─22.6), respectively. The median OS was 16.3 months (range, 2─71 months). During follow-up, 52 patients (52%) died. Of these, 27 (27%) deaths were due to progression of the primary cancer or extracranial metastases; 25 (25%) patients resulted from persistent or recurrent brain metastases, or new intracranial lesions despite GKRS. LTC was the only variable significantly associated with improved PFS ( p = 0.008), whereas other factors─including primary cancer type, sex, KPS, pre-GKRS neurologic deficit, pre-GKRS neurologic symptom, tumor volume, marginal dose and radiation necrosis─showed no significant association ( p = 0.801, 0.678, 0.405, 0.610, 0.754, 0.954, 0.110 and 0.126, respectively). Additionally, higher pre-GKRS KPS (> 70) and absence of neurological deficits were significantly associated with longer OS ( p = 0.003 and 0.025, respectively). In contrast, patient age, sex, and primary cancer type were not significantly associated with OS ( p = 0.203, 0.755, and 0.525, respectively). Furthermore, OS did not differ by tumor size or LTC ( p = 0.319 and 0.846, respectively). Radiation Necrosis Radiation necrosis was identified in 16 (16%) patients based on follow-up imaging and outpatient clinical assessments. The median time to diagnosis on follow-up MRI was 8.5 months (range, 1.6─29.8 months) from GKRS. Among the 4 patients who had received prior WBRT, radiation necrosis developed in 2 (50%). By contrast, radiation necrosis occurred in 14 of 96 patients (15%) without prior WBRT. Prior WBRT was not significantly associated with radiation necrosis ( p = 0.180). Of the 16 patients, 7 (7%) remained asymptomatic and 9 (9%) developed neurological symptoms. Based on the CTCAE (Common Terminology Criteria for Adverse Events) central nervous system necrosis grading scale, 5 patients (5%) had grade 2 (moderate) symptoms, and 4 (4%) had grade 3 symptoms, requiring hospitalization and medical intervention [ 14 ]. Neurological symptoms comprised mild headache in 7 patients, nausea and vomiting in 2, and lateralizing signs─partial seizures, cerebellar ataxia, or motor weakness─in 4, depending on lesion location. Of the 9 symptomatic patients, 5 had complete resolution with steroids alone, with marked reduction in peritumoral edema on follow-up MRI. In the 4 patients with grade 3 symptoms, steroids were ineffective and symptoms worsened; after bevacizumab, both clinical and imaging findings improved markedly. Because radiation necrosis responded to bevacizumab, overly conservative GKRS dosing may be unnecessary. Representative Cases The following cases illustrate the spectrum of responses, from durable tumor control to resolution of symptomatic radiation necrosis with bevacizumab. Case 1 A 43-year-old male patient with testis cancer presented with right hemiparesis and a new focal seizure in his right hand. T1-weighted axial MRI showed a 4-cm LBM in the left parietal lobe (Fig. 1A). The tumor volume was 40.6 cm 3 , and 5-fraction GKRS was performed. The marginal prescribed dose was 35.2 Gy. Three months after GKRS, the tumor became nearly undetectable (Fig. 1B), and his neurological symptoms completely resolved. Thereafter, no recurrence occurred through 6 years after GKRS (Fig. 1C). Case 2 A 44-year-old woman with a history of surgery for endometrial cancer, currently undergoing chemotherapy, presented with left-sided hemiparesis. T1-weighted contrast-enhanced (Fig. 2A) and T2-weighted axial MRI (Fig. 2B) revealed a right occipital brain metastasis measuring approximately 67 cm³ in volume, with a substantial internal cystic component. An Ommaya reservoir was placed to evacuate the cystic component, followed by 5-fraction GKRS delivering a marginal dose of 32.5 Gy. Three months after GKRS, the tumor had nearly resolved (Fig. 2C and 2D). One month later, the patient presented to the emergency department with headache and left-sided hemiparesis. MRI revealed severe peritumoral edema with midline shift, consistent with radiation necrosis (Fig. 2E and 2F). After bevacizumab, both neurological symptoms and edema improved markedly (Fig. 2G and 2H). Discussion Single-Fraction GKRS for LBMs Surgical resection is the primary treatment for LBMs, when lesions are accessible and performance status is favorable. When surgery is precluded by poor performance status, uncontrolled primary disease, or progressive systemic disease, SRS provides effective local control [ 15 – 22 ]. LBMs challenge radiosurgical management because safe, effective single-fraction dosing is limited [ 23 ]. In the RTOG (Radiation Therapy Oncology Group) 9005 trial, the maximum tolerated single-fraction dose for 3.1─4.0 cm lesions was 15 Gy; further escalation increased central nervous system toxicity without improving tumor control, yielding a 1-year LTC of approximately 49% [ 24 ]. Subsequent single-fraction dose-escalation studies similarly increased toxicity without improving control, producing suboptimal outcomes. For example, Vogelbaum et al. delivered single-fraction GKRS at 15 Gy and 18 Gy to tumors with median diameters of 3.3 cm (range, 2.9─4.5 cm), and 2.4 cm (range, 2.0─3.0 cm), respectively; the 1-year LTC rates were 45% and 49%, respectively [ 25 ]. These findings underscore the limitations of single-fraction SRS for LBMs. Hypofractionated GKRS for LBMs Constraints of single-fraction SRS have spurred interest in hypofractionated SRS, which distributes the total dose across multiple fractions, enabling higher biologically effective doses with less toxicity. Biologically, fractionation improves the therapeutic ratio via reoxygenation, redistribution into radiosensitive cell-cycle phases, and repair of sublethal damage in normal tissue [ 26 – 31 ]. Gamma Knife Icon─based hypofractionated SRS combines the dosimetric precision of the GKRS platform with the radiobiological benefits of fractionation for brain metastases. Multiple series reported improved LTC and reduced toxicity versus single-fraction SRS [ 32 – 36 ]. For example, Samanci et al. treated 76 LBMs with hypofractionated GKRS (median volume, 6.15 cm³; range, 4.0─22.2 cm³), using a median marginal dose of 27 Gy (range, 21─30 Gy) over a median of 3 fractions (range, 3─5). One-year LTC was 96%, and PFS was 66.6%, with no radiation necrosis [ 37 ]. Mishra et al. reported 1-year LTC of 82.4% in LBMs (median volume, 16.0 cm³; range, 10.1─56.0 cm³) treated with 3─5-fraction GKRS, and a 1-year rate of radiation-induced adverse events of 6.5% (Table 3 ) [ 5 ]. Definitions of “large” vary widely across studies, with reported tumor volumes spanning a broad range. Total dose and fraction number also vary substantially among protocols, contributing to heterogeneous outcomes. Standardization is needed to enable evidence-based guidelines for hypofractionated GKRS in managing LBMs. Optimal Radiosurgical Protocol for LBMs Accordingly, we retrospectively analyzed a cohort of patients with LBMs, all using a uniform protocol of 5 daily GKRS fractions. By standardizing fractionation and restricting inclusion to clearly large tumors, we minimized confounding from dose and schedule heterogeneity, enabling a more consistent assessment of efficacy and safety in this setting. The median tumor volume was 22 cm³ (range, 14.1─69.5 cm³), markedly larger than in prior hypofractionated radiosurgery series. Treatment was delivered exclusively to LBMs. Management of Radiation Necrosis Radiation necrosis is the most concerning complication of radiosurgery for LBMs and is dose-limiting. Its incidence correlates with lesion size, dose per fraction, and prescription dose [ 24 , 25 , 38 – 42 ]. Single-fraction SRS for large lesions yields radiation necrosis up to 20%, constraining dose escalation despite suboptimal tumor control [ 25 , 43 – 45 ]. Hypofractionation reduces this risk by permitting normal brain repair between fractions. In our cohort, radiation necrosis occurred in 16% of cases; only 9% were symptomatic, rates comparable with other hypofractionated GKRS series (Table 3 ) [ 5 , 37 , 43 , 46 , 47 ]. All symptomatic cases showed clinical and radiological improvement with corticosteroids alone or with adjunct bevacizumab. Bevacizumab, an anti-VEGF (anti-vascular endothelial growth factor) monoclonal antibody, is increasingly used to treat radiation necrosis because it reduces vascular permeability and cerebral edema. Hypofractionated GKRS with careful dose constraints and close imaging follow-up, coupled with timely bevacizumab when indicated, represents a sound management approach. Although prior studies linked larger tumor volumes and higher doses to increased necrosis risk [ 24 , 25 , 38 – 42 ], chi-square analysis in the present study identified only patient sex─ specifically, female sex─as significant ( p = 0.015). No significant associations were observed for prior WBRT, tumor volume, or marginal dose ( p = 0.393, p = 0.180, and p = 0.530, respectively). The absence of volume- or dose-associations may reflect the uniformly large tumors in this cohort, with all lesions exceeding 14 cm³. In a cohort restricted to uniformly large tumors, volume-based differences in necrosis risk may have been attenuated. Additionally, the marginal dose varied little around a median of 35.0 Gy, which may have limited detectable dose effects on necrosis. Survival Impact of HypoFractionated GKRS for LBMs OS in patients with LBMs is influenced by systemic disease burden, extracranial progression, and performance status. In our study, OS was significantly higher among patients with KPS > 70 and no neurological symptoms or deficits before GKRS. By contrast, OS showed no significant association with other variables, including LTC. The lack of survival improvement despite high LTC underscores the importance of multidisciplinary care that integrates systemic therapies with radiosurgery. Advances in targeted agents and immune checkpoint inhibitors have transformed metastatic cancer management, and combining them with radiosurgery may further improve survival. Nonetheless, improved local control was significantly associated with longer PFS, underscoring the role of radiosurgery in intracranial disease control, symptom relief, and maintenance of quality of life. Prospective studies should evaluate integrated strategies combining hypofractionated radiosurgery with contemporary systemic therapies and investigate biomarkers predictive of intracranial and extracranial responses. Limitations This study had several limitations. The retrospective, single-center design limits generalizability. Retrospective analyses are vulnerable to selection bias and unmeasured confounding─such as variation in patient characteristics, systemic therapies, and follow-up protocols─that may have influenced outcomes. Furthermore, the lack of randomization precludes definitive conclusions about the comparative effectiveness of the hypofractionated GKRS protocol. Although the study achieved favorable LTC rates with a uniform daily 5-fraction regimen for LBMs, no significant survival benefit was observed. This likely reflects the multifactorial determinants of survival in brain metastases, with systemic disease progression remaining the predominant driver of OS. Despite these limitations, these data support the safety and efficacy of hypofractionated GKRS for LBMs. Observed favorable local control and acceptable toxicity underscore the promise of this approach. Prospective, multicenter, randomized trials are needed to confirm these findings and clarify effects on survival outcomes. Conclusions Daily 5-fraction GKRS is a safe and effective treatment for LBMs, achieving robust local control with acceptable toxicity. Compared with staged approaches, our protocol provides comparable oncologic outcomes with greater clinical efficiency and reduced treatment complexity. Bevacizumab has demonstrated efficacy for radiation necrosis, further supporting this protocol. However, given the modest impact on OS, integration with systemic therapy remains critical. Prospective multi-center studies are warranted to validate these findings and optimize treatment sequencing for patients with advanced metastatic disease. Declarations Competing Interests: The authors declare no conflict of interest concerning the materials or methods used in this study. Ethics approval: The study protocol was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2025-0044). Consent to participate: Written informed consent was obtained from all participants enrolled in this study. Funding: The authors declare that no funds, grants, or other support were received during the preparation of this paper. Author Contribution J.J. designed the study, collected and analyzed the data, and wrote the main manuscript. Y.B., G.J.K., Y.K., and S.J. contributed to data collection and analysis. D.H.L., S.W.S., Y.H.C., C.K.H., S.H.H., and J.H.K. contributed to data interpretation and critically revised the manuscript. Y.-H.K. supervised the study and provided critical revisions.All authors reviewed and approved the final version of the manuscript. Acknowledgments: No funding was received for this work, and no benefits from a commercial party were or will be received that are related, directly or indirectly, to the subject of this manuscript. 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Nat Rev Clin Oncol 8:720–734. https://doi.org/10.1038/nrclinonc.2011.160 Tuleasca C, Tripathi M, Starnoni D, Daniel RT, Reyns N, Levivier M (2023) Radiobiology of radiosurgery for neurosurgeons. Neurol India 71:S14–S20. https://doi.org/10.4103/0028-3886.373637 Gill M, Sharma M, Ratan R (2023) Frameless Gamma Knife radiosurgery with leksell ICON: initial experience. Neurol India 71:S68–S73. https://doi.org/10.4103/0028-3886.373646 Hu YH, Hickling SV, Qian J, Blackwell CR, McLemore LB, Tryggestad EJ (2022) Characterization and commissioning of a Leksell Gamma Knife ICON system for framed and frameless stereotactic radiosurgery. J Appl Clin Med Phys 23:e13475. https://doi.org/10.1002/acm2.13475 Noda R, Kawashima M, Segawa M, Tsunoda S, Inoue T, Akabane A (2023) Fractionated versus staged gamma knife radiosurgery for mid-to-large brain metastases: a propensity score-matched analysis. J Neurooncol 164:87–96. https://doi.org/10.1007/s11060-023-04374-8 Kim JW, Park HR, Lee JM, Kim JW, Chung HT, Kim DG, Jung HW, Paek SH (2016) Fractionated stereotactic Gamma Knife radiosurgery for large brain metastases: a retrospective, single center study. PLoS ONE 11:e0163304. https://doi.org/10.1371/journal.pone.0163304 Park HR, Park KW, Lee JM, Kim JH, Jeong SS, Kim JW, Chung HT, Kim DG, Paek SH (2019) Frameless fractionated Gamma Knife radiosurgery with ICON for large metastatic brain tumors. J Korean Med Sci 34:e57. https://doi.org/10.3346/jkms.2019.34.e57 Samanci Y, Sisman U, Altintas A, Sarioglu S, Sharifi S, Atasoy AI, Bolukbasi Y, Peker S (2021) Hypofractionated frameless gamma knife radiosurgery for large metastatic brain tumors. Clin Exp Metastasis 38:31–46. https://doi.org/10.1007/s10585-020-10068-6 Shehata MK, Young B, Reid B et al (2004) Stereotatic radiosurgery of 468 brain metastases < or = 2 cm: implications for SRS dose and whole brain radiation therapy. Int J Radiat Oncol Biol Phys 59:87–93. https://doi.org/10.1016/j.ijrobp.2003.10.009 Jhaveri J, Chowdhary M, Zhang X et al (2019) Does size matter? Investigating the optimal planning target volume margin for postoperative stereotactic radiosurgery to resected brain metastases. J Neurosurg 130:797–803. https://doi.org/10.3171/2017.9.JNS171735 Chin LS, Ma L, DiBiase S (2001) Radiation necrosis following Gamma Knife surgery: a case-controlled comparison of treatment parameters and long-term clinical follow up. J Neurosurg 94:899–904. https://doi.org/10.3171/jns.2001.94.6.0899 Korytko T, Radivoyevitch T, Colussi V, Wessels BW, Pillai K, Maciunas RJ, Einstein DB (2006) 12 Gy gamma knife radiosurgical volume is a predictor for radiation necrosis in non-AVM intracranial tumors. Int J Radiat Oncol Biol Phys 64:419–424. https://doi.org/10.1016/j.ijrobp.2005.07.980 Vellayappan BA, McGranahan T, Graber J et al (2021) Radiation necrosis from stereotactic radiosurgery-how do we mitigate? Curr Treat Options Oncol 22:57. https://doi.org/10.1007/s11864-021-00854-z Minniti G, Scaringi C, Paolini S, Lanzetta G, Romano A, Cicone F, Osti M, Enrici RM, Esposito V (2016) Single-fraction versus multifraction (3 x 9 Gy) stereotactic radiosurgery for large (> 2 cm) brain metastases: a comparative analysis of local control and risk of radiation-induced brain necrosis. Int J Radiat Oncol Biol Phys 95:1142–1148. https://doi.org/10.1016/j.ijrobp.2016.03.013 Prabhu RS, Press RH, Patel KR et al (2017) Single-Fraction Stereotactic Radiosurgery (SRS) alone versus surgical resection and SRS for large brain metastases: a multi-institutional analysis. Int J Radiat Oncol Biol Phys 99:459–467. https://doi.org/10.1016/j.ijrobp.2017.04.006 Minniti G, Clarke E, Lanzetta G, Osti MF, Trasimeni G, Bozzao A, Romano A, Enrici RM (2011) Stereotactic radiosurgery for brain metastases: analysis of outcome and risk of brain radionecrosis. Radiat Oncol 6:48. https://doi.org/10.1186/1748-717X-6-48 Navarria P, Pessina F, Cozzi L et al (2016) Hypo-fractionated stereotactic radiotherapy alone using volumetric modulated arc therapy for patients with single, large brain metastases unsuitable for surgical resection. Radiat Oncol 11:76. https://doi.org/10.1186/s13014-016-0653-3 Yan M, Holden L, Wang M et al (2022) Gamma knife icon based hypofractionated stereotactic radiosurgery (GKI-HSRS) for brain metastases: impact of dose and volume. J Neurooncol 159:705–712. https://doi.org/10.1007/s11060-022-04115-3 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table.docx 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8667314","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":581592953,"identity":"1aea571a-3e8d-4363-95e6-fef66a986a9d","order_by":0,"name":"Juhee Jeon","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Juhee","middleName":"","lastName":"Jeon","suffix":""},{"id":581592954,"identity":"ba0e29c0-b762-4b79-9c97-37161dd586e6","order_by":1,"name":"Yukyeng Byeon","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yukyeng","middleName":"","lastName":"Byeon","suffix":""},{"id":581592960,"identity":"903b5195-2758-46c7-835b-f81ae222a6ae","order_by":2,"name":"Gung Ju Kim","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Gung","middleName":"Ju","lastName":"Kim","suffix":""},{"id":581592961,"identity":"2f12e499-bcd2-4822-852f-c9ca33a3b3b4","order_by":3,"name":"Yuhyun Kwon","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yuhyun","middleName":"","lastName":"Kwon","suffix":""},{"id":581592966,"identity":"924fa991-c9f7-4b4d-9b60-55ad50e44fb1","order_by":4,"name":"Seohmi Jung","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Seohmi","middleName":"","lastName":"Jung","suffix":""},{"id":581592968,"identity":"31e97464-7e61-41ca-be93-4215be41049f","order_by":5,"name":"Do Hee Lee","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Do","middleName":"Hee","lastName":"Lee","suffix":""},{"id":581592970,"identity":"5dc141c5-2692-4e62-bf7e-052d2a465b1e","order_by":6,"name":"Sang Woo Song","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sang","middleName":"Woo","lastName":"Song","suffix":""},{"id":581592971,"identity":"656d15ab-25b0-495b-8ce6-b9b016fab0fa","order_by":7,"name":"Young Hyun Cho","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Young","middleName":"Hyun","lastName":"Cho","suffix":""},{"id":581592972,"identity":"bedaef4c-c4da-4fa5-9e31-cc650ed4bb10","order_by":8,"name":"Chang-Ki Hong","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Chang-Ki","middleName":"","lastName":"Hong","suffix":""},{"id":581592973,"identity":"fbc3ba13-169c-4a13-bc5e-8d86fb2f6eb2","order_by":9,"name":"Seok Ho Hong","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Seok","middleName":"Ho","lastName":"Hong","suffix":""},{"id":581592976,"identity":"3ccaffb0-b2bc-4d2a-aec6-af31c946073d","order_by":10,"name":"Jeong Hoon Kim","email":"","orcid":"","institution":"Asan Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jeong","middleName":"Hoon","lastName":"Kim","suffix":""},{"id":581592978,"identity":"60454731-3061-4fe8-a8eb-a5b660723f4d","order_by":11,"name":"Young-Hoon Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYBACxgYgkcDwT87+eANMjLmBsQGXeogWxoYEhgPGDGcOIMTwaoFadCCx4UYCkVqYZ6Q/f/Bwxx3GxpmPn274wVAnxy+R2MA4cw8eK2bkGDYknnnGzCydZnazh+GwseQMoJYNz/BqYWxIbGNmY5NOMLsNcuGGG0AtDw7g05L+EKSFh0fy+Deglrp6IrQkAB3WdlhCQoIHZAtzggFIywZ8WnreGM5IbEszMODJKbvZY3DYcGbPw4aDM/BoMWxPf/DxZ5tN/Qb249tu/Kiok+dnTz74sAeflgYUrgGEwqOBgUEen+QoGAWjYBSMAjAAABdzXMe5Nw58AAAAAElFTkSuQmCC","orcid":"","institution":"Asan Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Young-Hoon","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2026-01-22 08:40:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8667314/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8667314/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":101751215,"identity":"9072f36b-46da-4977-8a20-eacd0da0cc18","added_by":"auto","created_at":"2026-02-03 10:18:19","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1933557,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative case of a 43-year-old man with testicular cancer presenting with right hemiparesis and focal seizure of the right hand. (A) Pretreatment T1-weighted axial MRI showing a 4-cm left parietal large brain metastasis (tumor volume. 40.6 cm³). (B) At 3 months after 5-fraction Gamma Knife radiosurgery (marginal dose, 35.2 Gy), the lesion was almost completely resolved, with full neurological recovery. (C) Follow-up MRI 6 years after treatment demonstrating stable disease without recurrence.\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-8667314/v1/bdfe281502c4f75b3a57dfd5.png"},{"id":101439777,"identity":"9dfdcb19-768e-4b19-ab59-efc035087545","added_by":"auto","created_at":"2026-01-29 16:50:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3637243,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative case of a 64-year-old woman with metastatic endometrial carcinoma. (A) Axial T1-weighted gadolinium-enhanced MRI and (B) axial T2-weighted MRI demonstrating a right occipital metastasis measuring approximately 67 cm³ with a large cystic component. (C, D) Three months after Ommaya reservoir insertion for cyst drainage followed by Gamma Knife radiosurgery (marginal dose, 32.5 Gy in 5 fractions; 50% isodose line), the lesion had markedly regressed. (E, F) One month later, the patient presented with headache and left hemiparesis; MRI demonstrated severe peritumoral edema with midline shift, consistent with radiation necrosis. (G, H) After bevacizumab therapy, both neurological symptoms and edema markedly improved.\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-8667314/v1/833cd09dc0420b42f5b045b4.png"},{"id":102767323,"identity":"dd5e72d2-4b8f-4882-9948-38fd07179e7e","added_by":"auto","created_at":"2026-02-16 11:42:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6437781,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8667314/v1/cbce3ce6-5ca1-4646-b49d-72370760e587.pdf"},{"id":101439776,"identity":"dc0cc518-9201-4a39-97a2-20fc0479d5fe","added_by":"auto","created_at":"2026-01-29 16:50:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":33823,"visible":true,"origin":"","legend":"","description":"","filename":"Table.docx","url":"https://assets-eu.researchsquare.com/files/rs-8667314/v1/15c55a17efaf44619c3cff57.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical outcomes of daily 5-fraction Gamma Knife radiosurgery for large brain metastases: a retrospective cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBrain metastases are the most common malignant intracranial tumors. Despite this prevalence, optimal treatment remains controversial [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Randomized trials have shown that, in patients with a single brain metastasis, good performance status, and limited extracranial disease, adjuvant radiotherapy after resection improves overall survival (OS) and reduces recurrence [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. More recently, stereotactic radiosurgery (SRS) has been recommended as an effective primary treatment for patients not suitable for surgery [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to National Comprehensive Cancer Network guidelines, resection is recommended for patients with mass effect or neurological symptoms, newly diagnosed or stable systemic disease with reasonable systemic options, or when biopsy confirmation is required [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. SRS is also preferred for the surgical cavity and as upfront therapy for small tumor volumes (\u0026lt;\u0026thinsp;2 cm\u003csup\u003e3\u003c/sup\u003e) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough SRS is effective for small to medium-sized metastases, treating large brain metastases (LBMs) remains challenging because of adverse effects including radiation necrosis and neurological decline [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The Gamma Knife Icon enables frameless hypo-fractionated SRS; consequently, Gamma Knife radiosurgery (GKRS) is increasingly used for LBMs. However, optimal fraction number and dose for hypofractionated SRS have not been established, and evidence regarding effectiveness, safety, and indications remains limited [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTherefore, we evaluated outcomes and complications of daily 5-fraction GKRS for LBMs (\u0026gt;\u0026thinsp;14 cm\u0026sup3;) and identified clinical parameters associated with favorable outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003cstrong\u003eohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween 2017 and 2022, 2,589 patients with 9,211 brain metastases underwent GKRS at our institution. A total of 226 GKRS procedures (2%) targeted LBMs (\u0026gt; 14 cm\u003csup\u003e3\u003c/sup\u003e). Of the 226 patients, 7 (3%) with single-fraction, 2 (1%) with 2-fraction, 40 (18%) with 3-fraction, 14 (6%) with 4-fraction, and 1 (0%) with 10-fraction GKRS were excluded. Of 162 patients (72%) who received 5-fraction GKRS for LBMs, we excluded 36 (22%) without available radiological follow-up and 26 (16%) who did not undergo primary GKRS. Ultimately, 100 patients were enrolled. The study adhered to the ethical principles of the Declaration of Helsinki, and institutional review board approval was obtained.\u003c/p\u003e\n\u003cp\u003eThe median age at GKRS was 60 years (range, 32\u0026ndash;91 years), and 54 patients (54%) were female. The pre-GKRS Karnofski Performance Status (KPS) was 60 in 10 patients (10%), 70 in 43 (43%), 80 in 33 (33%), 90 in 12 (12%), and 100 in 2 (2%). Forty-seven patients (47%) had pre-GKRS neurological deficits. The most common primary cancer was non-small cell lung cancer (NSCLC) (41%), followed by breast (24%), genitourinary (16%), gastrointestinal (7%), and small cell lung cancer (4%). Forty-three patients (43%) had extracranial metastases. Four patients (4%) received whole brain radiotherapy (WBRT) before GKRS. The median follow-up duration was 18 months (range, 3─72 months). Demographic and clinical characteristics are summarized in Table 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiosurgical\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003cstrong\u003erotocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients underwent GKRS because they were medically ineligible for resection, or their neurological deficits did not warrant surgery. All radiosurgery procedures were performed with a Leksell Gamma Knife Icon system (Elekta, Stockholm, Sweden). A frameless mask was placed on each patient\u0026rsquo;s face. Patients underwent gadolinium-enhanced magnetic resonance imaging (MRI) with T1- and T2-weighted sequences acquired with 1.0-mm slices. \u0026nbsp;Leksell GammaPlan software (version 10.2.1; Elekta) was used to calculate point doses and generate dose-distance curves [9].\u003c/p\u003e\n\u003cp\u003eThe number of brain metastases was 1 in 33 patients (33%), 2\u0026ndash;5 in 48 (48%), and \u0026gt;5 in 19 (19%). The median tumor volume was 22.0 cm\u003csup\u003e3\u003c/sup\u003e (range, 14.1─69.5 cm\u003csup\u003e3\u003c/sup\u003e). Tumors most commonly involved the frontal lobe (27%), followed by the parietal lobe (20%), cerebellum (18%), occipital lobe (16%), and temporal lobe (13%). All patients received 5 daily fractions. The median marginal dose was 35.2 Gy (range, 24.9─41.5 Gy) at the 50% isodose line; 71 patients (71%) received 35.2 Gy. Radiosurgical parameters are summarized in Tables 1 and Table 2.\u003c/p\u003e\n\u003cp\u003eGross tumor volume (GTV) was defined as the contrast-enhancing lesion volume on contrast-enhanced T1-weighted. 1.0-mm axial MRI [9]. The clinical target volume equaled to the GTV [10]. The planning target volume (PTV) was created by expanding the contrast-enhancing GTV by 1.0 mm to generate a margin [10, 11].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRadiological and\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eCli\u003c/strong\u003e\u003cstrong\u003enical\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eE\u003c/strong\u003e\u003cstrong\u003evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter GKRS, clinical assessments and follow-up MRI were performed every 3 months until last follow-up or death. Lesion volume was measured by outlining the GTV on each thin-section slice of the contrast-enhanced T1-weighted axial images, calculating the area, and summing across slices at each visit. Baseline tumor volume was the volume measured on MRI at the time of GKRS. Percentage change was calculated relative to this baseline on each follow-up MRI. Tumor reduction was defined as a \u0026gt;20% decrease in volume; stabilization as a change within 20%; and progression as a \u0026gt;20% increase without radiation necrosis. Best response was defined as the greatest volume reduction of the GKRS-treated lesion; its timing and magnitude were recorded.\u003c/p\u003e\n\u003cp\u003eRadiation necrosis was diagnosed on clinical and imaging grounds after excluding disease progression, or by histopathology when resection was performed. Radiation necrosis was defined as an enlarging enhancing lesion with geographic intratumoral necrosis and increasing peritumoral edema that subsequently responded to steroids without additional therapy [12, 13]. When differentiation was challenging, experienced radiologists were consulted, and adjunct tests─perfusion and diffusion MRI, MR spectroscopy, and positron emission tomography─were obtained. Initial management was steroid administration; bevacizumab was used when neurological symptoms progressed despite steroids or when adverse effects were severe. Comprehensive clinical and neurological examinations were performed at each follow-up visit.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLocal tumor control (LTC), progression-free survival (PFS), and OS were the primary endpoints. LTC was defined as no progression of GKRS-treated LBMs. PFS was defined as the time from GKRS to any brain metastasis recurrence or progression based on radiological findings. OS was defined as the time from GKRS to death. Cumulative rates of LTC, PFS and OS were estimated using Kaplan\u0026ndash;Meier methods. Prognostic factors for LTC, PFS and OS were analyzed using logistic regression and Cox proportional hazards models. A p-value \u0026lt; 0.05 was considered statistically significant. All analyses were conducted using SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eLocal Tumor Control\u003c/h2\u003e \u003cp\u003eDuring follow-up, 26 GKRS treated LBMs progressed; overall LTC was 74%. Cumulative 1-, 2-, and 3-year LTC rates were 72.7% (95% CI, 62.3%─83.1%), 65.3% (95% CI, 53.5%─ 77.1%), and 59.9% (95% CI, 44.9%─74.9%), respectively. The median time from GKRS to best response was 4 months (range, 1─36 months), and 86 patients (86%) achieved best response within 1 year. Median volume reduction was 80% (range, 22%─100%); 30 patients (30%) had 95% reduction. Patients with NSCLC had significantly higher LTC than those with other primary cancers (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030\u003cb\u003e).\u003c/b\u003e No significant associations were observed with age, sex, KPS, tumor location, tumor volume, or marginal dose (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.690, 0.440, 0.872, 0.897, 0.909 and 0.645, respectively\u003cb\u003e).\u003c/b\u003e This difference likely reflects the impact of targeted therapies widely used for NSCLC.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eProgression-Free and Overall Survival\u003c/h3\u003e\n\u003cp\u003eDuring follow-up duration, the median PFS was 7.5 months (range, 1─65 months). The cumulative 1-, 2-, and 3-year PFS rates were 37.2% (95% CI, 26.6─47.8), 17.9% (95% CI, 8.7─27.1), and 14.0% (95% CI, 5.4─22.6), respectively. The median OS was 16.3 months (range, 2─71 months). During follow-up, 52 patients (52%) died. Of these, 27 (27%) deaths were due to progression of the primary cancer or extracranial metastases; 25 (25%) patients resulted from persistent or recurrent brain metastases, or new intracranial lesions despite GKRS. LTC was the only variable significantly associated with improved PFS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008), whereas other factors─including primary cancer type, sex, KPS, pre-GKRS neurologic deficit, pre-GKRS neurologic symptom, tumor volume, marginal dose and radiation necrosis─showed no significant association (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.801, 0.678, 0.405, 0.610, 0.754, 0.954, 0.110 and 0.126, respectively).\u003c/p\u003e \u003cp\u003eAdditionally, higher pre-GKRS KPS (\u0026gt;\u0026thinsp;70) and absence of neurological deficits were significantly associated with longer OS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003 and 0.025, respectively). In contrast, patient age, sex, and primary cancer type were not significantly associated with OS (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.203, 0.755, and 0.525, respectively). Furthermore, OS did not differ by tumor size or LTC (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.319 and 0.846, respectively).\u003c/p\u003e\n\u003ch3\u003eRadiation Necrosis\u003c/h3\u003e\n\u003cp\u003eRadiation necrosis was identified in 16 (16%) patients based on follow-up imaging and outpatient clinical assessments. The median time to diagnosis on follow-up MRI was 8.5 months (range, 1.6─29.8 months) from GKRS. Among the 4 patients who had received prior WBRT, radiation necrosis developed in 2 (50%). By contrast, radiation necrosis occurred in 14 of 96 patients (15%) without prior WBRT. Prior WBRT was not significantly associated with radiation necrosis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.180). Of the 16 patients, 7 (7%) remained asymptomatic and 9 (9%) developed neurological symptoms. Based on the CTCAE (Common Terminology Criteria for Adverse Events) central nervous system necrosis grading scale, 5 patients (5%) had grade 2 (moderate) symptoms, and 4 (4%) had grade 3 symptoms, requiring hospitalization and medical intervention [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Neurological symptoms comprised mild headache in 7 patients, nausea and vomiting in 2, and lateralizing signs─partial seizures, cerebellar ataxia, or motor weakness─in 4, depending on lesion location. Of the 9 symptomatic patients, 5 had complete resolution with steroids alone, with marked reduction in peritumoral edema on follow-up MRI. In the 4 patients with grade 3 symptoms, steroids were ineffective and symptoms worsened; after bevacizumab, both clinical and imaging findings improved markedly. Because radiation necrosis responded to bevacizumab, overly conservative GKRS dosing may be unnecessary.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRepresentative Cases\u003c/h2\u003e \u003cp\u003eThe following cases illustrate the spectrum of responses, from durable tumor control to resolution of symptomatic radiation necrosis with bevacizumab.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 1\u003c/strong\u003e \u003cp\u003eA 43-year-old male patient with testis cancer presented with right hemiparesis and a new focal seizure in his right hand. T1-weighted axial MRI showed a 4-cm LBM in the left parietal lobe (Fig.\u0026nbsp;1A). The tumor volume was 40.6 cm\u003csup\u003e3\u003c/sup\u003e, and 5-fraction GKRS was performed. The marginal prescribed dose was 35.2 Gy. Three months after GKRS, the tumor became nearly undetectable (Fig.\u0026nbsp;1B), and his neurological symptoms completely resolved. Thereafter, no recurrence occurred through 6 years after GKRS (Fig.\u0026nbsp;1C).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCase 2\u003c/strong\u003e \u003cp\u003eA 44-year-old woman with a history of surgery for endometrial cancer, currently undergoing chemotherapy, presented with left-sided hemiparesis. T1-weighted contrast-enhanced (Fig.\u0026nbsp;2A) and T2-weighted axial MRI (Fig.\u0026nbsp;2B) revealed a right occipital brain metastasis measuring approximately 67 cm\u0026sup3; in volume, with a substantial internal cystic component. An Ommaya reservoir was placed to evacuate the cystic component, followed by 5-fraction GKRS delivering a marginal dose of 32.5 Gy. Three months after GKRS, the tumor had nearly resolved (Fig.\u0026nbsp;2C and 2D). One month later, the patient presented to the emergency department with headache and left-sided hemiparesis. MRI revealed severe peritumoral edema with midline shift, consistent with radiation necrosis (Fig.\u0026nbsp;2E and 2F). After bevacizumab, both neurological symptoms and edema improved markedly (Fig.\u0026nbsp;2G and 2H).\u003c/p\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec13\"\u003e\n \u003ch2\u003eSingle-Fraction GKRS for LBMs\u003c/h2\u003e\n \u003cp\u003eSurgical resection is the primary treatment for LBMs, when lesions are accessible and performance status is favorable. When surgery is precluded by poor performance status, uncontrolled primary disease, or progressive systemic disease, SRS provides effective local control [\u003cspan\u003e15\u003c/span\u003e\u0026ndash;\u003cspan\u003e22\u003c/span\u003e]. LBMs challenge radiosurgical management because safe, effective single-fraction dosing is limited [\u003cspan\u003e23\u003c/span\u003e]. In the RTOG (Radiation Therapy Oncology Group) 9005 trial, the maximum tolerated single-fraction dose for 3.1─4.0 cm lesions was 15 Gy; further escalation increased central nervous system toxicity without improving tumor control, yielding a 1-year LTC of approximately 49% [\u003cspan\u003e24\u003c/span\u003e]. Subsequent single-fraction dose-escalation studies similarly increased toxicity without improving control, producing suboptimal outcomes. For example, Vogelbaum et al. delivered single-fraction GKRS at 15 Gy and 18 Gy to tumors with median diameters of 3.3 cm (range, 2.9─4.5 cm), and 2.4 cm (range, 2.0─3.0 cm), respectively; the 1-year LTC rates were 45% and 49%, respectively [\u003cspan\u003e25\u003c/span\u003e]. These findings underscore the limitations of single-fraction SRS for LBMs.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\"\u003e\n \u003ch2\u003eHypofractionated GKRS for LBMs\u003c/h2\u003e\n \u003cp\u003eConstraints of single-fraction SRS have spurred interest in hypofractionated SRS, which distributes the total dose across multiple fractions, enabling higher biologically effective doses with less toxicity. Biologically, fractionation improves the therapeutic ratio via reoxygenation, redistribution into radiosensitive cell-cycle phases, and repair of sublethal damage in normal tissue [\u003cspan\u003e26\u003c/span\u003e\u0026ndash;\u003cspan\u003e31\u003c/span\u003e]. Gamma Knife Icon─based hypofractionated SRS combines the dosimetric precision of the GKRS platform with the radiobiological benefits of fractionation for brain metastases. Multiple series reported improved LTC and reduced toxicity versus single-fraction SRS [\u003cspan\u003e32\u003c/span\u003e\u0026ndash;\u003cspan\u003e36\u003c/span\u003e]. For example, Samanci et al. treated 76 LBMs with hypofractionated GKRS (median volume, 6.15 cm\u0026sup3;; range, 4.0─22.2 cm\u0026sup3;), using a median marginal dose of 27 Gy (range, 21─30 Gy) over a median of 3 fractions (range, 3─5). One-year LTC was 96%, and PFS was 66.6%, with no radiation necrosis [\u003cspan\u003e37\u003c/span\u003e]. Mishra et al. reported 1-year LTC of 82.4% in LBMs (median volume, 16.0 cm\u0026sup3;; range, 10.1─56.0 cm\u0026sup3;) treated with 3─5-fraction GKRS, and a 1-year rate of radiation-induced adverse events of 6.5% (Table \u003cspan\u003e3\u003c/span\u003e) [\u003cspan\u003e5\u003c/span\u003e]. Definitions of \u0026ldquo;large\u0026rdquo; vary widely across studies, with reported tumor volumes spanning a broad range. Total dose and fraction number also vary substantially among protocols, contributing to heterogeneous outcomes. Standardization is needed to enable evidence-based guidelines for hypofractionated GKRS in managing LBMs.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\"\u003e\n \u003ch2\u003eOptimal Radiosurgical Protocol for LBMs\u003c/h2\u003e\n \u003cp\u003eAccordingly, we retrospectively analyzed a cohort of patients with LBMs, all using a uniform protocol of 5 daily GKRS fractions. By standardizing fractionation and restricting inclusion to clearly large tumors, we minimized confounding from dose and schedule heterogeneity, enabling a more consistent assessment of efficacy and safety in this setting. The median tumor volume was 22 cm\u0026sup3; (range, 14.1─69.5 cm\u0026sup3;), markedly larger than in prior hypofractionated radiosurgery series. Treatment was delivered exclusively to LBMs.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\"\u003e\n \u003ch2\u003eManagement of Radiation Necrosis\u003c/h2\u003e\n \u003cp\u003eRadiation necrosis is the most concerning complication of radiosurgery for LBMs and is dose-limiting. Its incidence correlates with lesion size, dose per fraction, and prescription dose [\u003cspan\u003e24\u003c/span\u003e, \u003cspan\u003e25\u003c/span\u003e, \u003cspan\u003e38\u003c/span\u003e\u0026ndash;\u003cspan\u003e42\u003c/span\u003e]. Single-fraction SRS for large lesions yields radiation necrosis up to 20%, constraining dose escalation despite suboptimal tumor control [\u003cspan\u003e25\u003c/span\u003e, \u003cspan\u003e43\u003c/span\u003e\u0026ndash;\u003cspan\u003e45\u003c/span\u003e]. Hypofractionation reduces this risk by permitting normal brain repair between fractions. In our cohort, radiation necrosis occurred in 16% of cases; only 9% were symptomatic, rates comparable with other hypofractionated GKRS series (Table \u003cspan\u003e3\u003c/span\u003e) [\u003cspan\u003e5\u003c/span\u003e, \u003cspan\u003e37\u003c/span\u003e, \u003cspan\u003e43\u003c/span\u003e, \u003cspan\u003e46\u003c/span\u003e, \u003cspan\u003e47\u003c/span\u003e]. All symptomatic cases showed clinical and radiological improvement with corticosteroids alone or with adjunct bevacizumab.\u003c/p\u003e\n \u003cp\u003eBevacizumab, an anti-VEGF (anti-vascular endothelial growth factor) monoclonal antibody, is increasingly used to treat radiation necrosis because it reduces vascular permeability and cerebral edema. Hypofractionated GKRS with careful dose constraints and close imaging follow-up, coupled with timely bevacizumab when indicated, represents a sound management approach. Although prior studies linked larger tumor volumes and higher doses to increased necrosis risk [\u003cspan\u003e24\u003c/span\u003e, \u003cspan\u003e25\u003c/span\u003e, \u003cspan\u003e38\u003c/span\u003e\u0026ndash;\u003cspan\u003e42\u003c/span\u003e], chi-square analysis in the present study identified only patient sex─ specifically, female sex─as significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015). No significant associations were observed for prior WBRT, tumor volume, or marginal dose (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.393, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.180, and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.530, respectively). The absence of volume- or dose-associations may reflect the uniformly large tumors in this cohort, with all lesions exceeding 14 cm\u0026sup3;. In a cohort restricted to uniformly large tumors, volume-based differences in necrosis risk may have been attenuated. Additionally, the marginal dose varied little around a median of 35.0 Gy, which may have limited detectable dose effects on necrosis.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\"\u003e\n \u003ch2\u003eSurvival Impact of HypoFractionated GKRS for LBMs\u003c/h2\u003e\n \u003cp\u003eOS in patients with LBMs is influenced by systemic disease burden, extracranial progression, and performance status. In our study, OS was significantly higher among patients with KPS\u0026thinsp;\u0026gt;\u0026thinsp;70 and no neurological symptoms or deficits before GKRS. By contrast, OS showed no significant association with other variables, including LTC. The lack of survival improvement despite high LTC underscores the importance of multidisciplinary care that integrates systemic therapies with radiosurgery. Advances in targeted agents and immune checkpoint inhibitors have transformed metastatic cancer management, and combining them with radiosurgery may further improve survival. Nonetheless, improved local control was significantly associated with longer PFS, underscoring the role of radiosurgery in intracranial disease control, symptom relief, and maintenance of quality of life. Prospective studies should evaluate integrated strategies combining hypofractionated radiosurgery with contemporary systemic therapies and investigate biomarkers predictive of intracranial and extracranial responses.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\"\u003e\n \u003ch2\u003eLimitations\u003c/h2\u003e\n \u003cp\u003eThis study had several limitations. The retrospective, single-center design limits generalizability. Retrospective analyses are vulnerable to selection bias and unmeasured confounding─such as variation in patient characteristics, systemic therapies, and follow-up protocols─that may have influenced outcomes. Furthermore, the lack of randomization precludes definitive conclusions about the comparative effectiveness of the hypofractionated GKRS protocol. Although the study achieved favorable LTC rates with a uniform daily 5-fraction regimen for LBMs, no significant survival benefit was observed. This likely reflects the multifactorial determinants of survival in brain metastases, with systemic disease progression remaining the predominant driver of OS. Despite these limitations, these data support the safety and efficacy of hypofractionated GKRS for LBMs. Observed favorable local control and acceptable toxicity underscore the promise of this approach. Prospective, multicenter, randomized trials are needed to confirm these findings and clarify effects on survival outcomes.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eDaily 5-fraction GKRS is a safe and effective treatment for LBMs, achieving robust local control with acceptable toxicity. Compared with staged approaches, our protocol provides comparable oncologic outcomes with greater clinical efficiency and reduced treatment complexity. Bevacizumab has demonstrated efficacy for radiation necrosis, further supporting this protocol. However, given the modest impact on OS, integration with systemic therapy remains critical. Prospective multi-center studies are warranted to validate these findings and optimize treatment sequencing for patients with advanced metastatic disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting Interests:\u003c/h2\u003e \u003cp\u003eThe authors declare no conflict of interest concerning the materials or methods used in this study.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval:\u003c/h2\u003e \u003cp\u003eThe study protocol was approved by the Institutional Review Board of Asan Medical Center (IRB No. 2025-0044).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate:\u003c/strong\u003e \u003cp\u003e Written informed consent was obtained from all participants enrolled in this study.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this paper.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJ.J. designed the study, collected and analyzed the data, and wrote the main manuscript. Y.B., G.J.K., Y.K., and S.J. contributed to data collection and analysis. D.H.L., S.W.S., Y.H.C., C.K.H., S.H.H., and J.H.K. contributed to data interpretation and critically revised the manuscript. Y.-H.K. supervised the study and provided critical revisions.All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments:\u003c/h2\u003e \u003cp\u003eNo funding was received for this work, and no benefits from a commercial party were or will be received that are related, directly or indirectly, to the subject of this manuscript. The submitted manuscript does not contain information about any medical devices or drugs.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKalani MY, Filippidis AS, Kalani MA, Sanai N, Brachman D, McBride HL, Shetter AG, Smith KA (2010) Gamma Knife surgery combined with resection for treatment of a single brain metastasis: preliminary results. 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Radiat Oncol 11:76. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13014-016-0653-3\u003c/span\u003e\u003cspan address=\"10.1186/s13014-016-0653-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYan M, Holden L, Wang M et al (2022) Gamma knife icon based hypofractionated stereotactic radiosurgery (GKI-HSRS) for brain metastases: impact of dose and volume. J Neurooncol 159:705\u0026ndash;712. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s11060-022-04115-3\u003c/span\u003e\u003cspan address=\"10.1007/s11060-022-04115-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\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":"Gamma Knife radiosurgery, 5-fraction, large brain metastases, radiation necrosis, bevacizumab","lastPublishedDoi":"10.21203/rs.3.rs-8667314/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8667314/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe Gamma Knife Icon has enabled hypofractionated Gamma Knife radiosurgery (GKRS) for large brain metastases (LBMs). We assessed the clinical outcomes and complications of daily 5-fraction GKRS for LBMs.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe enrolled 100 patients who underwent daily 5-fraction GKRS for LBMs (\u0026gt;\u0026thinsp;14 cm\u003csup\u003e3\u003c/sup\u003e). Forty-six patients were male; the median age was 60 years. The median Karnofsky Performance Status (KPS) was 70 (60\u0026ndash;100); 47 patients (47%) had pre-GKRS neurological deficits. The most common primary sites were lung (41), breast (24), and kidney (14). Median tumor volume was 22 cm\u003csup\u003e3\u003c/sup\u003e (14─70 cm\u003csup\u003e3\u003c/sup\u003e) and the marginal dose was 35.2 Gy (50% isodose line) in 5 fractions. Median follow-up was 18 months (3─72 months).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eLocal tumor control was observed in 74 cases (74%). The cumulative 1-, 2-, and 3-year control rates were 73%, 65%, and 60%, respectively. Eighty-six tumors achieved their best magnetic resonance imaging response within 1 year; the median volume reduction was 80% (22%─100%). Thirty patients (30%) had a dramatic volume reduction (\u0026gt;\u0026thinsp;95%). Median progression-free (PFS) and overall survival (OS) were 7.5 and 16.3 months, respectively. PFS was significantly associated with local tumor control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008). OS was associated with pre-GKRS KPS and neurological deficits (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003 and \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025, respectively). Radiation necrosis occurred in 16 patients (16%); 9 (9%) were symptomatic and recovered fully with corticosteroids or bevacizumab.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eDaily 5-fraction GKRS for LBMs yielded favorable local control and PFS with acceptable radiation necrosis rates, but OS benefit was uncertain. Prospective multicenter studies are warranted.\u003c/p\u003e","manuscriptTitle":"Clinical outcomes of daily 5-fraction Gamma Knife radiosurgery for large brain metastases: a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-29 16:50:30","doi":"10.21203/rs.3.rs-8667314/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":"f66ef26c-c27f-4742-be68-0ef313009e51","owner":[],"postedDate":"January 29th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-16T11:41:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-29 16:50:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8667314","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8667314","identity":"rs-8667314","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}