Efficacy and safety of combined anti-vascular and two-staged stereotactic radiosurgery therapy for brain metastases with brainstem compression: a retrospective multicenter study  

Efficacy and safety of combined anti-vascular and two-staged stereotactic radiosurgery therapy for brain metastases with brainstem compression: a retrospective multicenter 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 Research Article Efficacy and safety of combined anti-vascular and two-staged stereotactic radiosurgery therapy for brain metastases with brainstem compression: a retrospective multicenter study Xiuming Zhu, Jia Zhou, Qun Chen, Haining Chen, Renli Li, Yucun Zhu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4467801/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Mar, 2025 Read the published version in Clinical & Experimental Metastasis → Version 1 posted 9 You are reading this latest preprint version Abstract Stereotactic radiosurgery poses a significant risk when treating brain metastases in close proximity to the brainstem. To address this issue, a novel approach known as "combined anti-vascular therapy" has been devised for these metastases. This treatment regimen involves a one-week course of two-staged stereotactic radiosurgery (2-SSRS), supplemented with the administration of the anti-vascular agent bevacizumab during the radiosurgery interval. The objective of this study is to assess the efficacy and safety of a combined anti-vascular and two-staged stereotactic radiosurgery therapy for brain metastases with brainstem compression. A retrospective analysis was conducted on patients treated at five gamma knife treatment centers to assess changes in tumor size and peritumoral edema volume. Clinical symptom changes were evaluated using the Headache Scale (VAS), Dizziness Disorder Inventory (DHI), Vomiting Scale (VS), and Glasgow Coma Scale (GCS). The Karnofsky Task Scale (KPS) and Barthel Index (BI) were used to assess overall physical fitness and physical activity rehabilitation. Tumor local control (TLC) and overall survival (OS) rate were also calculated for the patients. Among the 36 patients with brain metastases with brainstem compression, 36 received combined anti-vascular therapy. Both edema volume and tumor volume significantly decreased during the treatment period and post-treatment 3 months ( p < 0.01). Clinical symptoms, as indicated by median scores of VAS, DHI, VS, and GCS, showed significant improvement during treatment and at the 3-month follow-up ( p < 0.01). Median changes in KPS and BI, reflecting overall physical fitness and physical activity rehabilitation, were also similar and statistically significant ( p < 0.01). The patient cohort exhibited a median overall survival of 14.2 months, with corresponding 6-month and 12-month survival rates of 91.7% and 80.0%, respectively. Tumor local control rates at 6 and 12 months were 94.7% and 78.9%, respectively.The combination of anti-vascular therapy with 2-SSRS demonstrates safety and efficacy in treating patients with brain metastases with brainstem compression. This approach rapidly alleviates patient symptoms, effectively manages tumor progression, extends overall survival, and exhibits manageable adverse effects. 2-staged stereotactic radiosurgery anti-vascular brain metastases brainstem compression Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Stereotactic radiosurgery (SRS) is considered as the primary treatment method for sporadic brain metastases (BM) according to current literature [ 1 – 3 ]. Guidelines recommend staged SRS for larger or high-risk locations, such as large BM (LBM) with a diameter of 2-4cm or BMs near critical structures like the brainstem and optic pathway. Research indicates that two-stage SRS (2-SSRS) not only decreases the occurrence of SRS-related brain radiation necrosis (RN), but also substantially lowers the risk of acute intracranial hypertension in these patients [ 4 – 8 ]. However, the management of brain metastases with brainstem compression poses a significant challenge when utilizing the two-stage stereotactic radiosurgery strategy. The presence of BM volume and peripheral edema contributes to the compression of the brainstem, exacerbating the condition. Additionally, radiation-induced edema following the initial stage of SRS further increase the risk of brainstem compression [ 9 ]. To mitigate these risks, physicians often opt to postpone the second stage of SRS by a period of 30 days [ 4 – 5 ]. Furthermore, the physical symptoms experienced by patients, such as headaches, dizziness, vomiting, and consciousness disturbances resulting from brainstem compression, render their outpatient 2-SSRS treatment impractical. These patients need hospitalization for extended treatment of cerebral dehydration in order to mitigate potential SRS treatment complications and ameliorate clinical manifestations. These are inherent limitations of the 2-SSRS treatment approach. Researchers from four gamma knife treatment centers have previously implemented a ‘combined anti-vascular and 2-SSRS therapy’ for patients who suffered from BM. The anti-vascular therapy was the administration of bevacizumab during the stage interval of 2-SSRS, and the course of combined therapy was one week. The aim of this multicenter retrospective study is to assess the effectiveness and safety of the ‘combined therapy’ strategy for BM with brainstem compression. 2. Methods 2.1 patients Patients who suffered from BMs with brainstem compression and received ‘combined therapy’ were retrospectively studied between Jan 1, 2018, and Dec 31, 2022. The inclusion criteria were patients: (1) without previous whole brain radiation therapy; (2) with arc-shaped displacement of the aqueduct and fourth ventricle; (2) with at least 3 times of follow-up. The exclusion criteria were patients who received surgical intervention during the therapy because of cranial hypertension or cerebral hernia. The ethic approval was obtained from the Institutional Ethics Committee of Zhejiang Provincial People's Hospital (2023-No.066). 2.2 The ‘anti-vascular and 2-SSRS therapy’ The SRS treatment was administered at 1st and 6th day. Patients undergoing stereotactic radiosurgery were immobilized using a Leksell G headrest. In each stage of stereotactic radiosurgery, the 45%-60% isodose line encompassing the entire lesion. Bevacizumab was administered one day following the first-stage SRS at the dosage of 5mg/kg, according to recommended range of 5-10mg/kg [ 10 – 11 ]. The tumor volume was determined using gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI), while the volume of edema was assessed via MRI T2-FLAIR imaging. 2.3 Definition of clinical outcomes Visual Analogue Scale (VAS) to assess headache severity in patients, employing a scale of 0–10 points and categorizing pain levels as follows: 0 for painless; 1–3 for mild pain; 4–6 for moderate pain; and 7–10 for severe pain. The Dizziness Disorder Inventory (DHI) is employed to evaluate symptoms of dizziness and gait instability in patients [ 12 ], with scores ranging from 0–30 indicating mild abnormalities, 30–60 indicating moderate abnormalities, and scores above 60 indicating severe abnormalities and an increased risk of falling. The Vomiting Scale (VS) serves as a standardized assessment tool for adverse events according to CTCAE 4.0, specifically focusing on evaluating vomiting symptoms in patients [ 13 ]. The severity of vomiting can be categorized into five levels: Level 1, consisting of 1–2 episodes within a 24-hour period; Level 2, involving 3–5 episodes within the same timeframe; Level 3, characterized by more than 6 episodes necessitating interventions such as nasogastric feeding, total parenteral nutrition support, or hospitalization; Level 4, indicating life-threatening complications requiring immediate medical attention; and Level 5, representing fatal outcomes. The Glasgow Coma Scale (GCS) should be utilized for patients experiencing consciousness disorders or coma. The physical condition of patients was assessed utilizing the Karnofsky Performance Scale (KPS), while the Barthel index (BI) was employed to evaluate early physical activity recovery following radiotherapy [ 14 ]. In accordance with the updated RANO guidelines, tumor local control failure is characterized by a 25% increase in the vertical diameter product of T1 enhanced MR after combined anti-vascular therapy [15] . Overall survival is defined as the duration between the conclusion of combined anti-vascular therapy and death. 2.4 statistical analysis The mean follows a normal distribution, while the median does not. Continuous data is analyzed using a t-test, while categorical data is expressed as percentages and compared using the Mann-Whitney U-test. Follow-up time and endpoint events are defined as the duration from the completion of the ‘combined therapy’ to the most recent follow-up or event of interest. Kaplan-Meier survival curves are utilized to depict endpoint events, and stratified results are calculated using the log-rank test. 3. Results 3.1 Patient characteristics Thirty-six patients diagnosed with brainstem compression and leptomeningeal metastases received combined anti-vascular therapy. The median age of patients undergoing initial treatment was 61 years, with a range of 35 to 81 years. Of these patients, 17 were female and 19 were male. All patients presented with pre-treatment symptoms such as headache, dizziness, and vomiting. The median Karnofsky Performance Status (KPS) score before treatment was 50 points, ranging from 30 to 80 points. The median doses administered for the first and second stereotactic radiosurgery (SSRS) sessions were 13Gy (ranging from 11 to 13.5Gy) and 12.5Gy (ranging from 11 to 13Gy), respectively. The mean duration of follow-up for the cohort of 36 patients who underwent combined anti-vascular therapy was 24.8 months, with a range of 3.5 to 36.0 months. Further information can be found in Table 1 . Table 1 Patients’ demographic characteristics Characteristics number range age(y) 61 35–81 sex female 17 male 19 Primary tumor lung 25 breast 9 Stomach and Intestine VAS score (median) 2 5 2–9 DHI score (median) 80 60–94 Vomiting score (median) 3 1–4 GCS score (median) 10 6–14 KPS score (median) 50 30–80 BI 50 30–75 peritumoral edema volume (cm 3 ) 13.5 8.9–18.5 tumor volume (cm 3 ) 10.5 4.1–19.6 Follow up time (months) 28.8 2.5–46 3.2 Alterations in tumor size and the presence of edema surrounding the tumor The mean peritumoral edema volume exhibited a significant reduction from 13.5 cm 3 on the initial SSRS scan to 5.5 cm 3 on the subsequent SSRS scan (P < 0.05). Following three months of combined anti-angiogenic therapy, the volume further decreased to 3.0 cm 3 (P < 0.05) (Fig. 1 A). Conversely, the mean tumor volume showed a non-significant decrease from 12.3 cm 3 to 11.8 cm 3 between the first and second SSRS scans. However, after three months of combined anti-vascular treatment, the mean tumor volume significantly decreased from 11.8 cm 3 to 4.2 cm 3 (P < 0.05) (Fig. 1 B). Figure 2 illustrates the dynamic alterations in volume of the lateral brainstem in individuals experiencing compression. 3.3 Symptoms and alterations in physiological movements exhibited by patients Following the combined therapy, the patient experienced significant improvement in symptoms of dizziness, vomiting, and consciousness during and up to 3 months post-treatment. The median Visual Analog Scale (VAS) values after the first and second sessions of stereotactic radiosurgery, as well as at the 3-month mark, were 6, 5, and 2, respectively, with a statistically significant difference (P < 0.05) (Fig. 3 A). Similarly, the median values of the Dizziness Handicap Inventory (DHI) were 78, 70, and 10 (P < 0.05), respectively (Fig. 3 B). Additionally, the median Vertigo Symptom Scale (VS) scores for the first, second, and third months post-SSRS were 2, 1, and 0, respectively, with a significant difference (P < 0.05) (Fig. 3 C). The median values of the first SSRS, second SSRS, and GCS at the 3-month mark were observed to be 11, 12, and 14, respectively, with a statistically significant difference (P < 0.05) as illustrated in Fig. 3 D. Following combined anti-vascular therapy, the patient experienced significant improvements in physical condition and activity. The median values of KPS for the first SSRS, second SSRS, and at the 3-month mark were recorded as 50, 60, and 70, respectively, with a statistically significant difference (P < 0.05) as shown in Fig. 4 A. Similarly, the median BI for the first SSRS, second SSRS, and at the 3-month mark were documented as 50, 55, and 70, respectively, with a statistically significant difference (P < 0.05) as depicted in Fig. 4 B. 3.4 Patient OS and local tumor control The study observed a median follow-up time of 28.8 months following the combined therapy. The median overall survival of the patients was 14.2 months, with survival rates at 6, 12, and 24 months reported as 91.7%, 80.0%, and 30.4%, respectively (Fig. 5 A). Additionally, local tumor control rates at 12 months were found to be 94.7% and 78.9%, as depicted in Fig. 5 B. 3.5 The side effects of combined anti-vascular therapy The adverse effects of concurrent anti-vascular therapy primarily consist of the potential for bleeding associated with bevacizumab and the development of radiation-induced necrosis (RN) following stereotactic radiosurgery. Notably, none of the patients in the study cohort encountered unexpected intracranial hemorrhage following the administration of combined anti-vascular therapy, resulting in a cumulative bleeding incidence of 1.8% (1 out of 36 patients), predominantly manifesting as oral and nasal bleeding. Radiation necrosis typically manifested one to two years post-treatment, with symptoms observed in only 16.7% (6 out of 36 patients) of cases. Further details regarding these six patients are provided in Table 2 . 4. Discussion 4.1 The imperative of implementing the "combined anti-vascular treatment" strategy for brainstem compression due to basilar invagination In recent years, there has been a growing recommendation for the utilization of Stereotactic Radiosurgery, particularly 2-Stage Stereotactic Radiosurgery, in the treatment of large brain metastases and those located in high-risk areas. Angelov et al. conducted a significant study in 2018, employing a 2-SSRS approach with a maximum diameter ranging from 2cm to 4cm in a cohort of 54 patients with LBM. The results demonstrated that 2-SSRS therapy resulted in a substantial reduction in LBM volume, achieving local control rates of 95% and 88% at 3 and 6 months, respectively, with an overall incidence of radiation adverse effects [ 6 ]. The findings of this study were compared to those of 25 prior clinical studies on single stereotactic radiosurgery treatment, revealing that dual SRS treatment is both safe and effective. It demonstrated a favorable local control rate, improved overall survival rate, and reduced incidence of side effects. A notable study by Serizawa T et al. also examined the treatment outcomes of phase 3 and phase 2 gamma knife treatments for large brain metastases, concluding that there were no significant disparities in overall survival, tumor progression, neurological death, or radiation-related adverse events among patients [ 4 ]. Dohm Amoren et al. conducted a study which demonstrated that a 2-SSRS therapy regimen with a 1-month interval is a viable treatment option for patients with LBM [ 16 ]. The researchers established a median dose of 15Gy (range from 10Gy to 21Gy) for the initial SSRS administration, and a median dose of 14Gy (range from 10Gy to 18Gy) for the subsequent SSRS administration. The cumulative incidence of local treatment failure at 6 months and post-treatment 12 months was found to be 3.2% and 13.3%, respectively. Furthermore, Damron E.P. corroborated the efficacy and safety of 2-SRS as a therapeutic approach for LBM patients [ 17 ]. In cases of brain metastasis patients experiencing brainstem compression, the severity of symptoms, including headache, dizziness, vomiting, and mild coma, is significantly heightened compared to those with lesions located above the tentorium. These circumstances amplify the complexity of 2-SSRS treatment approaches, rendering outpatient treatment impractical [ 18 ]. Hospitalization for extended periods is necessary to address dehydration and alleviate symptoms. Prolonged administration of dehydrating agents like mannitol and corticosteroids may result in adverse effects, such as liver and kidney impairment. Prolonged hospitalization may result in deep vein thrombosis, delayed systemic therapy, and increased financial strain on patients. Prior research on LBM 2-SSRS treatment has predominantly examined various primary tumors or the potential impact of different doses of 2-SSRS on treatment efficacy. For instance, a study by Ito Kajima et al. in 2020 found that 2-SSRS treatment yielded comparable outcomes to craniotomy for patients with LBM volumes exceeding 10 cm 3 [ 19 ]. Additionally, the authors noted that LBMs were commonly associated with breast cancer (BC) and non-small cell lung cancer (NSCLC). Anna Cho and colleagues conducted a study to assess the efficacy of different stage doses of LBM 2-SSRS and their impact on clinical outcomes in patients [ 20 ] . The findings suggest that all three dose strategies of 2-SSRS resulted in a high local tumor control rate. Furthermore, the two-stage reduction method was found to be particularly effective in managing brain edema following SRS treatment. It was observed that tumor surrounding edema and radiation edema influenced the timing and dosage of the second - SSRS. Improved edema control during SRS was associated with better patient outcomes with the 2-SSRS strategy. In recent years, an increasing amount of research has been dedicated to exploring the efficacy of the VEGF inhibitor bevacizumab in treating peritumoral edema in brain metastases, as well as edema following SRS radiotherapy [ 21 ]. Studies have indicated that bevacizumab demonstrates promising short-term effectiveness in managing radiation-induced edema in brain metastases post-radiotherapy [ 21 – 23 ]. Li et al. have reported that bevacizumab has the potential to reduce the volume of edema resulting from SRS radiation on T2-FLAIR MRI by a significant percentage [ 24 ]. Previous studies on 2-SSRS LBM have indicated an interval of approximately 4 weeks between treatments. This current study proposes a "combined anti-vascular therapy" approach which significantly reduces the median SRS interval to 6 days, effectively managing patient symptoms, enhancing quality of life, and mitigating psychological distress. These outcomes are essential considerations for healthcare providers treating LBM patients [ 25 ]. Additionally, the anti-angiogenic properties of bevacizumab allow for a synergistic effect with SRS in anti-tumor therapy [ 26 ]. 4.2 The importance of employing a multifaceted scoring system to assess the efficacy of the "combined anti-vascular therapy" approach The traditional assessment of the efficacy of stereotactic radiosurgery for brain metastases primarily relies on the KPS score, which provides an overview of the patient's general health and their potential eligibility for chemotherapy post-SRS. However, there is a notable lack of focus on enhancing the patient's symptomatology and functional capacity throughout the treatment regimen. Relying solely on KPS scores for treatment determinations is incongruent with the contemporary approach of multidisciplinary therapy (MDT) in cancer care, which prioritizes individualized patient management. The advancements in biopharmaceuticals have significantly enhanced the treatment of tumors, offering patients with low physical strength alternative options such as targeted, immune, and anti-vascular therapies when they are unable to tolerate traditional chemotherapy. These treatments have shown promise in increasing the likelihood of long-term survival compared to conventional chemotherapy. Additionally, improvements in symptoms and functional status throughout the course of treatment can greatly improve the quality of life for patients. Moreover, subtle variations in symptoms can hold significant importance in signalling the decline of the patient's health status during the treatment hiatus and recommending prompt medical intervention. Hence, this research incorporates the utilization of various assessment tools such as VAS, DHI, VS, GCS, BI, and KPS to assess the holistic health status, clinical symptom amelioration, and neurological function recovery of patients. A comparative analysis of Combined Anti-vascular Therapy with other 2-SSRS strategies in the study revealed overall survival rates of 91.7% at 6 months and 80.0% at 12 months for patients. In contrast to prior literature documenting the use of 2-SSRS treatment for LBM, the present studies encompassed both infratentorial and supratentorial lesions. The current research findings indicate LC rates of 94.7% and 78.9% at 6 and 12 months, respectively, which are comparable to or higher than those reported in other cohorts in Table 3. The observed incidence of radiation necrosis in this study, while relatively high, is only surpassed by one cohort. The observed variations in outcomes may be attributed to several factors: firstly, the limited duration of follow-up in certain cohort studies (e.g. up to 6.5 months) prior to the recurrence of tumors or the manifestation of symptoms of radiation necrosis in patients; secondly, the positioning of tumors in the brainstem's compressed region in the study, where even minor instances of tumor recurrence or radiation necrosis can result in noticeable symptoms. Based on this comparison, it can be deduced that the efficacy of the "combined anti-vascular therapy strategy" is comparable to that of the 2-SSRS strategy. The primary benefit of implementing a combined anti-vascular treatment approach is the substantial improvement in patient symptoms, significant reduction in treatment duration, and overall enhancement in quality of life[ 27 ]. Additionally, this strategy facilitates a seamless transition to subsequent systemic therapies, including targeted and immune therapies. By adopting the "combined anti-vascular therapy" strategy, patients can potentially extend their life expectancy, enhance their ability to tolerate systemic treatments, and minimize disruptions to future treatment plans. 4.3 Dose selection and prevention of side effects of bevacizumab during combined anti vascular therapy Some patients with impaired coagulation function may experience spontaneous bleeding in their brain metastases. Studies have indicated that low-dose bevacizumab is effective in treating peritumoral edema or radiation edema [ 28 ]. Therefore, a dose of 5mg/kg of bevacizumab is recommended between the two stages of stereotactic radiosurgery. In this study, bevacizumab was typically administered 1 day after the first SSRS treatment. The cumulative incidence of side effects was 2.8% (1/36), primarily attributed to oral and nasal bleeding. However, further evaluation is needed to determine the optimal dosage of bevacizumab during 2-SSRS. This study is subject to limitations, as some patients in the cohort received subsequent systemic treatment, potentially impacting the local control of brain metastases and introducing bias into the statistical analysis. This phenomenon is common in similar studies and warrants further investigation, particularly regarding the individualized dosing and timing of bevacizumab in combination with anti-vascular therapy. 5. Conclusion This study presents the first documented use of the "combined anti-vascular therapy" approach for managing brainstem compression in patients with leptomeningeal metastases. Our findings demonstrate that this strategy is both safe and effective for individuals who are not candidates for or decline surgical intervention. The combined anti-vascular therapy approach effectively inhibits tumor growth and recurrence, extends overall survival, reduces treatment duration, rapidly alleviates symptoms, and has manageable side effects. However, further research is needed to optimize and expand the application of this treatment strategy. Declarations Author contributions Wang Zheng, Chen Ninghai, Chen Qun, Li Renli and Zhu Yucun participated in data collection. Zhu Xiuming and Zhou Jia were involved in writing and reviewing the manuscript. Wang Zheng analyzed all the data and conducted statistics. Wang Zheng supervised the entire project and edited the manuscript. All authors have commented on the previous version of the manuscript. Funding This work was supported by Zhejiang Provincial Department of Education Research Support Project (Y202249332); Zhejiang Provincial Medical and Health Research Project (2023KY475) Data Availability The data will be made available upon reasonable request. Competing interests All authors declare that they have no conflicts of interest. Ethical approval The present study was approved by the Institutional Ethics Committee of Zhejiang Provincial People’s Hospital ( 2022 No. 066) Consent to participate and for publication Informed consent was obtained from all individual participants included in the study. References Arvold ND, Lee EQ, Mehta MP, et al (2016) Updates in the management of brain metastases. Neuro. Oncol. 18:1043–1065 Chao ST, De Salles A, Hayashi M, et al (2018) Stereotactic radiosurgery in the management of limited (1-4) brain metasteses: Systematic review and International Stereotactic Radiosurgery Society practice guideline. Clin. Neurosurg. 83:345–353 Ebner D, Rava P, Gorovets D, et al (2015) Stereotactic radiosurgery for large brain metastases. J Clin Neurosci 22:1650–1654. Serizawa T, Higuchi Y, Yamamoto M, et al (2019) Comparison of treatment results between 3- And 2-stage Gamma Knife radiosurgery for large brain metastases: A retrospective multi-institutional study. J Neurosurg 131:227–237. Dohm AE, Hughes R, Wheless W, et al (2018) Surgical resection and postoperative radiosurgery versus staged radiosurgery for large brain metastases. J Neurooncol 140:749–756. Angelov L, Mohammadi AM, Bennett EE, et al (2018) Impact of 2-staged stereotactic radiosurgery for treatment of brain metastases ≥ 2 cm. J Neurosurg 129:366–382. Hasegawa T, Kato T, Yamamoto T, et al (2017) Multisession gamma knife surgery for large brain metastases. J Neurooncol 131:517–524. Yomo S, Hayashi M (2014) A minimally invasive treatment option for large metastatic brain tumors: Long-term results of two-session Gamma Knife stereotactic radiosurgery. Radiat Oncol 9.: Linskey ME, Andrews DW, Asher AL, et al (2010) The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: A systematic review and evidence-based clinical practice guideline. J. Neurooncol. 96:45–68 Hawasli AH, Rubin JB, Tran DD, et al (2013) Antiangiogenic agents for nonmalignant brain tumors. J Neurol Surgery, Part B Skull Base 74:136–141. Alanin MC, Klausen C, Caye-Thomasen P, et al (2016) Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2 – a retrospective case series. Int J Neurosci 126:1002–1006. Zamyslowska-Szmytke E, Politanski P, Jozefowicz-Korczynska M (2021) Dizziness handicap inventory in clinical evaluation of dizzy patients. Int J Environ Res Public Health 18:1–12. Schiller K, Specht HM, Haller B, et al (2017) Correlation between delivered radiation doses to the brainstem or vestibular organ and nausea & vomiting toxicity in patients with head and neck cancers - an observational clinical trial. Radiat Oncol 12 Hankemeier A, Rollnik JD (2015) The Early Functional Abilities (EFA) scale to assess neurological and neurosurgical early rehabilitation patients. BMC Neurol 15. Lin NU, Lee EQ, Aoyama H, et al (2015) Response assessment criteria for brain metastases: Proposal from the RANO group. Lancet Oncol. 16:e270–e278 Dohm A, McTyre ER, Okoukoni C, et al (2018) Staged Stereotactic Radiosurgery for Large Brain Metastases: Local Control and Clinical Outcomes of a One-Two Punch Technique. Clin Neurosurg 83:114–121. Damron EP, Dono A, Chafi H, et al (2022) Metastatic Neoplasm Volume Kinetics Following 2-Stage Stereotactic Radiosurgery. World Neurosurg 161:e210–e219. Hori Y, Muhsen B, Joshi K, et al (2020) RADT-01. THE EFFICACY AND SAFETY OF TWO-STAGED STEREOTACTIC RADIOSURGERY FOR LARGE POSTERIOR FOSSA METASTASES: POST-TREATMENT VOLUMETRIC CHANGES IN TUMOR SIZE, PERI-TUMORAL EDEMA, AND FOURTH VENTRICLE. Neuro Oncol 22:ii181–ii181. Ito D, Aoyagi K, Nagano O, et al (2020) Comparison of two-stage Gamma Knife radiosurgery outcomes for large brain metastases among primary cancers. J Neurooncol 147:237–246. Cho A, Medvedeva K, Kranawetter B, Untersteiner H, Hirschmann D, Lepilina O, Baulin A, Buschmann M, Ertl A, Marik W, Dorfer C, Rössler K, Gatterbauer B, Ilyalov S FJ (2022) How to dose-stage large or high-risk brain metastases: an alternative two-fraction radiosurgical treatment approach. J Neuro surg 137:1666–1675. Delishaj D, Ursino S, Pasqualetti F, et al (2017) Bevacizumab for the Treatment of Radiation-Induced Cerebral Necrosis: A Systematic Review of the Literature. J Clin Med Res 9:273–280. Erpolat OP, Demircan NV, Sarıbas GS, et al (2020) A Comparison of Ramipril and Bevacizumab to Mitigate Radiation-Induced Brain Necrosis: An Experimental Study. World Neurosurg 144:e210–e220. Lubelski D, Abdullah KG, Weil RJ, Marko NF (2013) Bevacizumab for radiation necrosis following treatment of high grade glioma: A systematic review of the literature. J. Neurooncol. 115:317–322 Juan Li, Jing He, Linbo Cai, Mingyao Lai, Qingjun Hu, Chen Ren, Lei Wen, Jian Wang , Jiangfen Zhou, Zhaoming Zhou, Shaoqun Li, Minting Ye, Changguo Shan, Longhua Chen CZ (2021) Bevacizumab as a treatment for radiation necrosis following stereotactic radio surgery for brain metastases clinical and radiation dosimetric impacts. Ann Palliat Med 10:2018–2026. Kraft J, van Timmeren JE, Frei S, Mayinger M, Borsky K, Kirchner C, Stark LS, Tanadini-Lang S, Wolpert F, Weller M, Woodruff HC, Guckenberger M AN (2022) Comprehensive summary and retrospective evaluation of prognostic scores for patients with newly diagnosed brain metastases treated with upfront radiosurgery in a modern patient collective. Radiother Oncol July:23–31. Tamura R, Tanaka T, Miyake K, et al (2017) Bevacizumab for malignant gliomas: current indications, mechanisms of action and resistance, and markers of response. Brain Tumor Pathol 34:62–77. https://doi.org/10.1007/s10014-017-0284-x Wang Z, Chen H, Chen Q, et al (203) 'Sandwich treatment' for posterior fossa brain metastases with volume larger than 4cm 3 : a multicentric retrospective study. Clin Exp Metastasis. 40(5):415-422. doi: 10.1007/s10585-023-10220-y. Ginalis EE, Cui T, Weiner J, et al (2020) Two-staged stereotactic radiosurgery for the treatment of large brain metastases: Single institution experience and review of literature. J Radiosurgery SBRT 7:105–114 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 29 Mar, 2025 Read the published version in Clinical & Experimental Metastasis → Version 1 posted Editorial decision: Revision requested 07 Jan, 2025 Reviews received at journal 28 Dec, 2024 Reviewers agreed at journal 13 Dec, 2024 Reviewers agreed at journal 06 Dec, 2024 Reviewers agreed at journal 22 Aug, 2024 Reviewers invited by journal 16 Aug, 2024 Editor assigned by journal 24 May, 2024 Submission checks completed at journal 24 May, 2024 First submitted to journal 23 May, 2024 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-4467801","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":309385628,"identity":"52e8bbd1-6f98-4862-b9b8-2f0095ff305a","order_by":0,"name":"Xiuming Zhu","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiuming","middleName":"","lastName":"Zhu","suffix":""},{"id":309385629,"identity":"7f51e7ae-983c-465c-b7dc-67e18417185d","order_by":1,"name":"Jia Zhou","email":"","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Zhou","suffix":""},{"id":309385631,"identity":"174f9ad5-fa6c-4501-8ad3-cd11b5dbbccd","order_by":2,"name":"Qun Chen","email":"","orcid":"","institution":"Jiangsu Province Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qun","middleName":"","lastName":"Chen","suffix":""},{"id":309385633,"identity":"8534428c-e930-4a47-83f0-366d044d49cc","order_by":3,"name":"Haining Chen","email":"","orcid":"","institution":"Anhui Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Haining","middleName":"","lastName":"Chen","suffix":""},{"id":309385637,"identity":"50bb92be-fc39-4f0c-92c9-19206b443ef0","order_by":4,"name":"Renli Li","email":"","orcid":"","institution":"Shanghai 411 Affiliated Hospital of Shanghai University","correspondingAuthor":false,"prefix":"","firstName":"Renli","middleName":"","lastName":"Li","suffix":""},{"id":309385639,"identity":"c31ddcc2-9b9b-474d-ac23-8b55448bdae7","order_by":5,"name":"Yucun Zhu","email":"","orcid":"","institution":"BenQ Hospital Affiliated to Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yucun","middleName":"","lastName":"Zhu","suffix":""},{"id":309385642,"identity":"01634873-5e60-4b29-bc91-c9d78f92ae84","order_by":6,"name":"Zheng Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYLACxgYgwd6DYBOphecMyVokcojUYnD87OGXP3fY5MlHvj264QeDjeyGA8zPHuDVciYvzULyTFqx4e28tJs9DGnGGw6wmRvg02J2IMfMwLDtcOLG2TlmtxkYDiduOMDDJoFXy/k3ZgaJbf8TN848A9LynwgtN3KMHxxsO5A4X4IHpOUAYS32N96YMTa2JSdu4Mkxu9ljkGw88zCbGV4tkv05xh9/ttklzm8/Y3bjR4WdbN/x5md4tQABxBkGB8AkEDMTUA9S8gFEyjcQVjkKRsEoGAUjFAAARM9RG1K4+KAAAAAASUVORK5CYII=","orcid":"","institution":"Zhejiang Provincial People's Hospital","correspondingAuthor":true,"prefix":"","firstName":"Zheng","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-05-23 15:15:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4467801/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4467801/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10585-025-10338-1","type":"published","date":"2025-03-29T15:57:13+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":58076934,"identity":"b53c57e8-9e43-44a7-9ae4-8176482cdcfe","added_by":"auto","created_at":"2024-06-10 22:23:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":37295,"visible":true,"origin":"","legend":"\u003cp\u003eIllustrates the mean peritumoral edema (A) and mean tumor volume (B) in patients with SSRS on day 1, day 2, and 3 months post-combined anti-vascular therapy\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4467801/v1/1f47fd2a6df8e3761f1085e1.jpg"},{"id":58076933,"identity":"3f392802-c10e-48c4-9a71-890b6585df4c","added_by":"auto","created_at":"2024-06-10 22:23:09","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":67243,"visible":true,"origin":"","legend":"\u003cp\u003eDynamic changes of brain metastases in a patients with brainstem compression\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4467801/v1/f0d7d3a62748302484f5d8f1.jpg"},{"id":58076931,"identity":"06240fb4-e8a2-4796-9e5a-2c06e6151976","added_by":"auto","created_at":"2024-06-10 22:23:09","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":100871,"visible":true,"origin":"","legend":"\u003cp\u003eMedian VAS (A), DHI (B), VS (C), and GCS (D) changes in patients after combined anti vascular therapy at 1-SSRS, 2-SSRS, and 3 months.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4467801/v1/4f439817641f350ea9906f42.jpg"},{"id":58076935,"identity":"e81e9b29-52fb-4d35-91d5-3609aff9b5e2","added_by":"auto","created_at":"2024-06-10 22:23:09","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":56544,"visible":true,"origin":"","legend":"\u003cp\u003eMedian changes in KPS (A) and BI (B) of patients on the first day (SSRS), second day (SSRS), and third month after combined anti vascular therapy.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4467801/v1/3aa05e0457a3fc245253c46f.jpg"},{"id":58076936,"identity":"3fd5e275-d5cc-4033-b98f-3bd40f262eb8","added_by":"auto","created_at":"2024-06-10 22:23:09","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":31912,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier curves of patient OS and local tumor control\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4467801/v1/39ffeacacbe2e92b3c09823a.jpg"},{"id":79605157,"identity":"f95be0e1-2a47-4ebe-8039-497946f29c06","added_by":"auto","created_at":"2025-03-31 16:10:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020430,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4467801/v1/9afaf886-4f27-40be-888c-d3fb2eaad754.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of combined anti-vascular and two-staged stereotactic radiosurgery therapy for brain metastases with brainstem compression: a retrospective multicenter study ","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eStereotactic radiosurgery (SRS) is considered as the primary treatment method for sporadic brain metastases (BM) according to current literature [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Guidelines recommend staged SRS for larger or high-risk locations, such as large BM (LBM) with a diameter of 2-4cm or BMs near critical structures like the brainstem and optic pathway. Research indicates that two-stage SRS (2-SSRS) not only decreases the occurrence of SRS-related brain radiation necrosis (RN), but also substantially lowers the risk of acute intracranial hypertension in these patients [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHowever, the management of brain metastases with brainstem compression poses a significant challenge when utilizing the two-stage stereotactic radiosurgery strategy. The presence of BM volume and peripheral edema contributes to the compression of the brainstem, exacerbating the condition. Additionally, radiation-induced edema following the initial stage of SRS further increase the risk of brainstem compression [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. To mitigate these risks, physicians often opt to postpone the second stage of SRS by a period of 30 days [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Furthermore, the physical symptoms experienced by patients, such as headaches, dizziness, vomiting, and consciousness disturbances resulting from brainstem compression, render their outpatient 2-SSRS treatment impractical. These patients need hospitalization for extended treatment of cerebral dehydration in order to mitigate potential SRS treatment complications and ameliorate clinical manifestations. These are inherent limitations of the 2-SSRS treatment approach.\u003c/p\u003e \u003cp\u003eResearchers from four gamma knife treatment centers have previously implemented a \u0026lsquo;combined anti-vascular and 2-SSRS therapy\u0026rsquo; for patients who suffered from BM. The anti-vascular therapy was the administration of bevacizumab during the stage interval of 2-SSRS, and the course of combined therapy was one week. The aim of this multicenter retrospective study is to assess the effectiveness and safety of the \u0026lsquo;combined therapy\u0026rsquo; strategy for BM with brainstem compression.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 patients\u003c/h2\u003e \u003cp\u003ePatients who suffered from BMs with brainstem compression and received \u0026lsquo;combined therapy\u0026rsquo; were retrospectively studied between Jan 1, 2018, and Dec 31, 2022. The inclusion criteria were patients: (1) without previous whole brain radiation therapy; (2) with arc-shaped displacement of the aqueduct and fourth ventricle; (2) with at least 3 times of follow-up. The exclusion criteria were patients who received surgical intervention during the therapy because of cranial hypertension or cerebral hernia. The ethic approval was obtained from the Institutional Ethics Committee of Zhejiang Provincial People's Hospital (2023-No.066).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 The \u0026lsquo;anti-vascular and 2-SSRS therapy\u0026rsquo;\u003c/h2\u003e \u003cp\u003eThe SRS treatment was administered at 1st and 6th day. Patients undergoing stereotactic radiosurgery were immobilized using a Leksell G headrest. In each stage of stereotactic radiosurgery, the 45%-60% isodose line encompassing the entire lesion. Bevacizumab was administered one day following the first-stage SRS at the dosage of 5mg/kg, according to recommended range of 5-10mg/kg [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The tumor volume was determined using gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI), while the volume of edema was assessed via MRI T2-FLAIR imaging.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Definition of clinical outcomes\u003c/h2\u003e \u003cp\u003eVisual Analogue Scale (VAS) to assess headache severity in patients, employing a scale of 0\u0026ndash;10 points and categorizing pain levels as follows: 0 for painless; 1\u0026ndash;3 for mild pain; 4\u0026ndash;6 for moderate pain; and 7\u0026ndash;10 for severe pain. The Dizziness Disorder Inventory (DHI) is employed to evaluate symptoms of dizziness and gait instability in patients [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], with scores ranging from 0\u0026ndash;30 indicating mild abnormalities, 30\u0026ndash;60 indicating moderate abnormalities, and scores above 60 indicating severe abnormalities and an increased risk of falling. The Vomiting Scale (VS) serves as a standardized assessment tool for adverse events according to CTCAE 4.0, specifically focusing on evaluating vomiting symptoms in patients [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The severity of vomiting can be categorized into five levels: Level 1, consisting of 1\u0026ndash;2 episodes within a 24-hour period; Level 2, involving 3\u0026ndash;5 episodes within the same timeframe; Level 3, characterized by more than 6 episodes necessitating interventions such as nasogastric feeding, total parenteral nutrition support, or hospitalization; Level 4, indicating life-threatening complications requiring immediate medical attention; and Level 5, representing fatal outcomes. The Glasgow Coma Scale (GCS) should be utilized for patients experiencing consciousness disorders or coma. The physical condition of patients was assessed utilizing the Karnofsky Performance Scale (KPS), while the Barthel index (BI) was employed to evaluate early physical activity recovery following radiotherapy [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In accordance with the updated RANO guidelines, tumor local control failure is characterized by a 25% increase in the vertical diameter product of T1 enhanced MR after combined anti-vascular therapy \u003csup\u003e[15]\u003c/sup\u003e. Overall survival is defined as the duration between the conclusion of combined anti-vascular therapy and death.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 statistical analysis\u003c/h2\u003e \u003cp\u003eThe mean follows a normal distribution, while the median does not. Continuous data is analyzed using a t-test, while categorical data is expressed as percentages and compared using the Mann-Whitney U-test. Follow-up time and endpoint events are defined as the duration from the completion of the \u0026lsquo;combined therapy\u0026rsquo; to the most recent follow-up or event of interest. Kaplan-Meier survival curves are utilized to depict endpoint events, and stratified results are calculated using the log-rank test.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Patient characteristics\u003c/h2\u003e\n \u003cp\u003eThirty-six patients diagnosed with brainstem compression and leptomeningeal metastases received combined anti-vascular therapy. The median age of patients undergoing initial treatment was 61 years, with a range of 35 to 81 years. Of these patients, 17 were female and 19 were male. All patients presented with pre-treatment symptoms such as headache, dizziness, and vomiting. The median Karnofsky Performance Status (KPS) score before treatment was 50 points, ranging from 30 to 80 points. The median doses administered for the first and second stereotactic radiosurgery (SSRS) sessions were 13Gy (ranging from 11 to 13.5Gy) and 12.5Gy (ranging from 11 to 13Gy), respectively. The mean duration of follow-up for the cohort of 36 patients who underwent combined anti-vascular therapy was 24.8 months, with a range of 3.5 to 36.0 months. Further information can be found in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePatients\u0026rsquo; demographic characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"3\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003enumber\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003erange\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eage(y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35\u0026ndash;81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003esex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePrimary tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elung\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ebreast\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eStomach and Intestine\u003c/p\u003e\n \u003cp\u003eVAS score (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u0026ndash;9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDHI score (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60\u0026ndash;94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVomiting score (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u0026ndash;4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGCS score (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u0026ndash;14\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKPS score (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u0026ndash;80\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u0026ndash;75\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eperitumoral edema volume (cm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.9\u0026ndash;18.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etumor volume (cm\u003csup\u003e3\u003c/sup\u003e )\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.1\u0026ndash;19.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFollow up time (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.5\u0026ndash;46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Alterations in tumor size and the presence of edema surrounding the tumor\u003c/h2\u003e\n \u003cp\u003eThe mean peritumoral edema volume exhibited a significant reduction from 13.5 cm\u003csup\u003e3\u003c/sup\u003e on the initial SSRS scan to 5.5 cm\u003csup\u003e3\u003c/sup\u003e on the subsequent SSRS scan (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Following three months of combined anti-angiogenic therapy, the volume further decreased to 3.0 cm\u003csup\u003e3\u003c/sup\u003e (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). Conversely, the mean tumor volume showed a non-significant decrease from 12.3 cm\u003csup\u003e3\u003c/sup\u003e to 11.8 cm\u003csup\u003e3\u003c/sup\u003e between the first and second SSRS scans. However, after three months of combined anti-vascular treatment, the mean tumor volume significantly decreased from 11.8 cm\u003csup\u003e3\u003c/sup\u003e to 4.2 cm\u003csup\u003e3\u003c/sup\u003e (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB). Figure \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e illustrates the dynamic alterations in volume of the lateral brainstem in individuals experiencing compression.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Symptoms and alterations in physiological movements exhibited by patients\u003c/h2\u003e\n \u003cp\u003eFollowing the combined therapy, the patient experienced significant improvement in symptoms of dizziness, vomiting, and consciousness during and up to 3 months post-treatment. The median Visual Analog Scale (VAS) values after the first and second sessions of stereotactic radiosurgery, as well as at the 3-month mark, were 6, 5, and 2, respectively, with a statistically significant difference (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eA). Similarly, the median values of the Dizziness Handicap Inventory (DHI) were 78, 70, and 10 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), respectively (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eB). Additionally, the median Vertigo Symptom Scale (VS) scores for the first, second, and third months post-SSRS were 2, 1, and 0, respectively, with a significant difference (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eC). The median values of the first SSRS, second SSRS, and GCS at the 3-month mark were observed to be 11, 12, and 14, respectively, with a statistically significant difference (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) as illustrated in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eD. Following combined anti-vascular therapy, the patient experienced significant improvements in physical condition and activity. The median values of KPS for the first SSRS, second SSRS, and at the 3-month mark were recorded as 50, 60, and 70, respectively, with a statistically significant difference (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) as shown in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eA. Similarly, the median BI for the first SSRS, second SSRS, and at the 3-month mark were documented as 50, 55, and 70, respectively, with a statistically significant difference (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) as depicted in Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eB.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Patient OS and local tumor control\u003c/h2\u003e\n \u003cp\u003eThe study observed a median follow-up time of 28.8 months following the combined therapy. The median overall survival of the patients was 14.2 months, with survival rates at 6, 12, and 24 months reported as 91.7%, 80.0%, and 30.4%, respectively (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eA). Additionally, local tumor control rates at 12 months were found to be 94.7% and 78.9%, as depicted in Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eB.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 The side effects of combined anti-vascular therapy\u003c/h2\u003e\n \u003cp\u003eThe adverse effects of concurrent anti-vascular therapy primarily consist of the potential for bleeding associated with bevacizumab and the development of radiation-induced necrosis (RN) following stereotactic radiosurgery. Notably, none of the patients in the study cohort encountered unexpected intracranial hemorrhage following the administration of combined anti-vascular therapy, resulting in a cumulative bleeding incidence of 1.8% (1 out of 36 patients), predominantly manifesting as oral and nasal bleeding. Radiation necrosis typically manifested one to two years post-treatment, with symptoms observed in only 16.7% (6 out of 36 patients) of cases. Further details regarding these six patients are provided in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003e\u003cimg src=\"data:image/png;base64,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\" style=\"width: 884px; height: 384.865px;\" width=\"884\" height=\"384.865\"\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003e \u003cem\u003e4.1 The imperative of implementing the \"combined anti-vascular treatment\" strategy for brainstem compression due to basilar invagination\u003c/em\u003e \u003c/p\u003e \u003cp\u003eIn recent years, there has been a growing recommendation for the utilization of Stereotactic Radiosurgery, particularly 2-Stage Stereotactic Radiosurgery, in the treatment of large brain metastases and those located in high-risk areas. Angelov et al. conducted a significant study in 2018, employing a 2-SSRS approach with a maximum diameter ranging from 2cm to 4cm in a cohort of 54 patients with LBM. The results demonstrated that 2-SSRS therapy resulted in a substantial reduction in LBM volume, achieving local control rates of 95% and 88% at 3 and 6 months, respectively, with an overall incidence of radiation adverse effects [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The findings of this study were compared to those of 25 prior clinical studies on single stereotactic radiosurgery treatment, revealing that dual SRS treatment is both safe and effective. It demonstrated a favorable local control rate, improved overall survival rate, and reduced incidence of side effects. A notable study by Serizawa T et al. also examined the treatment outcomes of phase 3 and phase 2 gamma knife treatments for large brain metastases, concluding that there were no significant disparities in overall survival, tumor progression, neurological death, or radiation-related adverse events among patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Dohm Amoren et al. conducted a study which demonstrated that a 2-SSRS therapy regimen with a 1-month interval is a viable treatment option for patients with LBM [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The researchers established a median dose of 15Gy (range from 10Gy to 21Gy) for the initial SSRS administration, and a median dose of 14Gy (range from 10Gy to 18Gy) for the subsequent SSRS administration. The cumulative incidence of local treatment failure at 6 months and post-treatment 12 months was found to be 3.2% and 13.3%, respectively. Furthermore, Damron E.P. corroborated the efficacy and safety of 2-SRS as a therapeutic approach for LBM patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn cases of brain metastasis patients experiencing brainstem compression, the severity of symptoms, including headache, dizziness, vomiting, and mild coma, is significantly heightened compared to those with lesions located above the tentorium. These circumstances amplify the complexity of 2-SSRS treatment approaches, rendering outpatient treatment impractical [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Hospitalization for extended periods is necessary to address dehydration and alleviate symptoms. Prolonged administration of dehydrating agents like mannitol and corticosteroids may result in adverse effects, such as liver and kidney impairment. Prolonged hospitalization may result in deep vein thrombosis, delayed systemic therapy, and increased financial strain on patients. Prior research on LBM 2-SSRS treatment has predominantly examined various primary tumors or the potential impact of different doses of 2-SSRS on treatment efficacy. For instance, a study by Ito Kajima et al. in 2020 found that 2-SSRS treatment yielded comparable outcomes to craniotomy for patients with LBM volumes exceeding 10 cm\u003csup\u003e3\u003c/sup\u003e [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Additionally, the authors noted that LBMs were commonly associated with breast cancer (BC) and non-small cell lung cancer (NSCLC). Anna Cho and colleagues conducted a study to assess the efficacy of different stage doses of LBM 2-SSRS and their impact on clinical outcomes in patients \u003csup\u003e[\u003c/sup\u003e20\u003csup\u003e]\u003c/sup\u003e. The findings suggest that all three dose strategies of 2-SSRS resulted in a high local tumor control rate. Furthermore, the two-stage reduction method was found to be particularly effective in managing brain edema following SRS treatment. It was observed that tumor surrounding edema and radiation edema influenced the timing and dosage of the second - SSRS. Improved edema control during SRS was associated with better patient outcomes with the 2-SSRS strategy.\u003c/p\u003e \u003cp\u003eIn recent years, an increasing amount of research has been dedicated to exploring the efficacy of the VEGF inhibitor bevacizumab in treating peritumoral edema in brain metastases, as well as edema following SRS radiotherapy [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Studies have indicated that bevacizumab demonstrates promising short-term effectiveness in managing radiation-induced edema in brain metastases post-radiotherapy [\u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Li et al. have reported that bevacizumab has the potential to reduce the volume of edema resulting from SRS radiation on T2-FLAIR MRI by a significant percentage [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Previous studies on 2-SSRS LBM have indicated an interval of approximately 4 weeks between treatments. This current study proposes a \"combined anti-vascular therapy\" approach which significantly reduces the median SRS interval to 6 days, effectively managing patient symptoms, enhancing quality of life, and mitigating psychological distress. These outcomes are essential considerations for healthcare providers treating LBM patients [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Additionally, the anti-angiogenic properties of bevacizumab allow for a synergistic effect with SRS in anti-tumor therapy [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cem\u003e4.2 The importance of employing a multifaceted scoring system to assess the efficacy of the \"combined anti-vascular therapy\" approach\u003c/em\u003e \u003c/p\u003e \u003cp\u003eThe traditional assessment of the efficacy of stereotactic radiosurgery for brain metastases primarily relies on the KPS score, which provides an overview of the patient's general health and their potential eligibility for chemotherapy post-SRS. However, there is a notable lack of focus on enhancing the patient's symptomatology and functional capacity throughout the treatment regimen. Relying solely on KPS scores for treatment determinations is incongruent with the contemporary approach of multidisciplinary therapy (MDT) in cancer care, which prioritizes individualized patient management. The advancements in biopharmaceuticals have significantly enhanced the treatment of tumors, offering patients with low physical strength alternative options such as targeted, immune, and anti-vascular therapies when they are unable to tolerate traditional chemotherapy. These treatments have shown promise in increasing the likelihood of long-term survival compared to conventional chemotherapy. Additionally, improvements in symptoms and functional status throughout the course of treatment can greatly improve the quality of life for patients. Moreover, subtle variations in symptoms can hold significant importance in signalling the decline of the patient's health status during the treatment hiatus and recommending prompt medical intervention. Hence, this research incorporates the utilization of various assessment tools such as VAS, DHI, VS, GCS, BI, and KPS to assess the holistic health status, clinical symptom amelioration, and neurological function recovery of patients. A comparative analysis of Combined Anti-vascular Therapy with other 2-SSRS strategies in the study revealed overall survival rates of 91.7% at 6 months and 80.0% at 12 months for patients. In contrast to prior literature documenting the use of 2-SSRS treatment for LBM, the present studies encompassed both infratentorial and supratentorial lesions. The current research findings indicate LC rates of 94.7% and 78.9% at 6 and 12 months, respectively, which are comparable to or higher than those reported in other cohorts in Table\u0026nbsp;3. The observed incidence of radiation necrosis in this study, while relatively high, is only surpassed by one cohort. The observed variations in outcomes may be attributed to several factors: firstly, the limited duration of follow-up in certain cohort studies (e.g. up to 6.5 months) prior to the recurrence of tumors or the manifestation of symptoms of radiation necrosis in patients; secondly, the positioning of tumors in the brainstem's compressed region in the study, where even minor instances of tumor recurrence or radiation necrosis can result in noticeable symptoms. Based on this comparison, it can be deduced that the efficacy of the \"combined anti-vascular therapy strategy\" is comparable to that of the 2-SSRS strategy. The primary benefit of implementing a combined anti-vascular treatment approach is the substantial improvement in patient symptoms, significant reduction in treatment duration, and overall enhancement in quality of life[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Additionally, this strategy facilitates a seamless transition to subsequent systemic therapies, including targeted and immune therapies. By adopting the \"combined anti-vascular therapy\" strategy, patients can potentially extend their life expectancy, enhance their ability to tolerate systemic treatments, and minimize disruptions to future treatment plans.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.3 Dose selection and prevention of side effects of bevacizumab during combined anti vascular therapy\u003c/h2\u003e \u003cp\u003eSome patients with impaired coagulation function may experience spontaneous bleeding in their brain metastases. Studies have indicated that low-dose bevacizumab is effective in treating peritumoral edema or radiation edema [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Therefore, a dose of 5mg/kg of bevacizumab is recommended between the two stages of stereotactic radiosurgery. In this study, bevacizumab was typically administered 1 day after the first SSRS treatment. The cumulative incidence of side effects was 2.8% (1/36), primarily attributed to oral and nasal bleeding. However, further evaluation is needed to determine the optimal dosage of bevacizumab during 2-SSRS.\u003c/p\u003e \u003cp\u003e This study is subject to limitations, as some patients in the cohort received subsequent systemic treatment, potentially impacting the local control of brain metastases and introducing bias into the statistical analysis. This phenomenon is common in similar studies and warrants further investigation, particularly regarding the individualized dosing and timing of bevacizumab in combination with anti-vascular therapy.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study presents the first documented use of the \"combined anti-vascular therapy\" approach for managing brainstem compression in patients with leptomeningeal metastases. Our findings demonstrate that this strategy is both safe and effective for individuals who are not candidates for or decline surgical intervention. The combined anti-vascular therapy approach effectively inhibits tumor growth and recurrence, extends overall survival, reduces treatment duration, rapidly alleviates symptoms, and has manageable side effects. However, further research is needed to optimize and expand the application of this treatment strategy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWang Zheng, Chen Ninghai, Chen Qun, Li Renli and Zhu Yucun participated in data collection. Zhu Xiuming and Zhou Jia were involved in writing and reviewing the manuscript. Wang Zheng analyzed all the data and conducted statistics. Wang Zheng supervised the entire project and edited the manuscript. All authors have commented on the previous version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by Zhejiang Provincial Department of Education Research Support Project (Y202249332); Zhejiang Provincial Medical and Health Research Project (2023KY475)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data will be made available upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe present study was approved by the Institutional Ethics Committee of Zhejiang Provincial People\u0026rsquo;s Hospital ( 2022 No. 066)\u003c/p\u003e\n\u003cp\u003eConsent to participate and for publication Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eArvold ND, Lee EQ, Mehta MP, et al (2016) Updates in the management of brain metastases. Neuro. Oncol. 18:1043\u0026ndash;1065\u003c/li\u003e\n\u003cli\u003eChao ST, De Salles A, Hayashi M, et al (2018) Stereotactic radiosurgery in the management of limited (1-4) brain metasteses: Systematic review and International Stereotactic Radiosurgery Society practice guideline. Clin. Neurosurg. 83:345\u0026ndash;353\u003c/li\u003e\n\u003cli\u003eEbner D, Rava P, Gorovets D, et al (2015) Stereotactic radiosurgery for large brain metastases. J Clin Neurosci 22:1650\u0026ndash;1654. \u003c/li\u003e\n\u003cli\u003eSerizawa T, Higuchi Y, Yamamoto M, et al (2019) Comparison of treatment results between 3- And 2-stage Gamma Knife radiosurgery for large brain metastases: A retrospective multi-institutional study. J Neurosurg 131:227\u0026ndash;237. \u003c/li\u003e\n\u003cli\u003eDohm AE, Hughes R, Wheless W, et al (2018) Surgical resection and postoperative radiosurgery versus staged radiosurgery for large brain metastases. J Neurooncol 140:749\u0026ndash;756. \u003c/li\u003e\n\u003cli\u003eAngelov L, Mohammadi AM, Bennett EE, et al (2018) Impact of 2-staged stereotactic radiosurgery for treatment of brain metastases \u0026ge; 2 cm. J Neurosurg 129:366\u0026ndash;382. \u003c/li\u003e\n\u003cli\u003eHasegawa T, Kato T, Yamamoto T, et al (2017) Multisession gamma knife surgery for large brain metastases. J Neurooncol 131:517\u0026ndash;524. \u003c/li\u003e\n\u003cli\u003eYomo S, Hayashi M (2014) A minimally invasive treatment option for large metastatic brain tumors: Long-term results of two-session Gamma Knife stereotactic radiosurgery. Radiat Oncol 9.: \u003c/li\u003e\n\u003cli\u003eLinskey ME, Andrews DW, Asher AL, et al (2010) The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: A systematic review and evidence-based clinical practice guideline. J. Neurooncol. 96:45\u0026ndash;68\u003c/li\u003e\n\u003cli\u003eHawasli AH, Rubin JB, Tran DD, et al (2013) Antiangiogenic agents for nonmalignant brain tumors. J Neurol Surgery, Part B Skull Base 74:136\u0026ndash;141. \u003c/li\u003e\n\u003cli\u003eAlanin MC, Klausen C, Caye-Thomasen P, et al (2016) Effect of bevacizumab on intracranial meningiomas in patients with neurofibromatosis type 2 \u0026ndash; a retrospective case series. Int J Neurosci 126:1002\u0026ndash;1006. \u003c/li\u003e\n\u003cli\u003eZamyslowska-Szmytke E, Politanski P, Jozefowicz-Korczynska M (2021) Dizziness handicap inventory in clinical evaluation of dizzy patients. Int J Environ Res Public Health 18:1\u0026ndash;12. \u003c/li\u003e\n\u003cli\u003eSchiller K, Specht HM, Haller B, et al (2017) Correlation between delivered radiation doses to the brainstem or vestibular organ and nausea \u0026amp; vomiting toxicity in patients with head and neck cancers - an observational clinical trial. Radiat Oncol 12\u003c/li\u003e\n\u003cli\u003eHankemeier A, Rollnik JD (2015) The Early Functional Abilities (EFA) scale to assess neurological and neurosurgical early rehabilitation patients. BMC Neurol 15.\u003c/li\u003e\n\u003cli\u003eLin NU, Lee EQ, Aoyama H, et al (2015) Response assessment criteria for brain metastases: Proposal from the RANO group. Lancet Oncol. 16:e270\u0026ndash;e278\u003c/li\u003e\n\u003cli\u003eDohm A, McTyre ER, Okoukoni C, et al (2018) Staged Stereotactic Radiosurgery for Large Brain Metastases: Local Control and Clinical Outcomes of a One-Two Punch Technique. Clin Neurosurg 83:114\u0026ndash;121. \u003c/li\u003e\n\u003cli\u003eDamron EP, Dono A, Chafi H, et al (2022) Metastatic Neoplasm Volume Kinetics Following 2-Stage Stereotactic Radiosurgery. World Neurosurg 161:e210\u0026ndash;e219. \u003c/li\u003e\n\u003cli\u003eHori Y, Muhsen B, Joshi K, et al (2020) RADT-01. THE EFFICACY AND SAFETY OF TWO-STAGED STEREOTACTIC RADIOSURGERY FOR LARGE POSTERIOR FOSSA METASTASES: POST-TREATMENT VOLUMETRIC CHANGES IN TUMOR SIZE, PERI-TUMORAL EDEMA, AND FOURTH VENTRICLE. Neuro Oncol 22:ii181\u0026ndash;ii181. \u003c/li\u003e\n\u003cli\u003eIto D, Aoyagi K, Nagano O, et al (2020) Comparison of two-stage Gamma Knife radiosurgery outcomes for large brain metastases among primary cancers. J Neurooncol 147:237\u0026ndash;246. \u003c/li\u003e\n\u003cli\u003eCho A, Medvedeva K, Kranawetter B, Untersteiner H, Hirschmann D, Lepilina O, Baulin A, Buschmann M, Ertl A, Marik W, Dorfer C, R\u0026ouml;ssler K, Gatterbauer B, Ilyalov S FJ (2022) How to dose-stage large or high-risk brain metastases: an alternative two-fraction radiosurgical treatment approach. J Neuro surg 137:1666\u0026ndash;1675.\u003c/li\u003e\n\u003cli\u003eDelishaj D, Ursino S, Pasqualetti F, et al (2017) Bevacizumab for the Treatment of Radiation-Induced Cerebral Necrosis: A Systematic Review of the Literature. J Clin Med Res 9:273\u0026ndash;280. \u003c/li\u003e\n\u003cli\u003eErpolat OP, Demircan NV, Sarıbas GS, et al (2020) A Comparison of Ramipril and Bevacizumab to Mitigate Radiation-Induced Brain Necrosis: An Experimental Study. World Neurosurg 144:e210\u0026ndash;e220. \u003c/li\u003e\n\u003cli\u003eLubelski D, Abdullah KG, Weil RJ, Marko NF (2013) Bevacizumab for radiation necrosis following treatment of high grade glioma: A systematic review of the literature. J. Neurooncol. 115:317\u0026ndash;322\u003c/li\u003e\n\u003cli\u003eJuan Li, Jing He, Linbo Cai, Mingyao Lai, Qingjun Hu, Chen Ren, Lei Wen, Jian Wang , Jiangfen Zhou, Zhaoming Zhou, Shaoqun Li, Minting Ye, Changguo Shan, Longhua Chen CZ (2021) Bevacizumab as a treatment for radiation necrosis following stereotactic radio surgery for brain metastases clinical and radiation dosimetric impacts. Ann Palliat Med 10:2018\u0026ndash;2026.\u003c/li\u003e\n\u003cli\u003eKraft J, van Timmeren JE, Frei S, Mayinger M, Borsky K, Kirchner C, Stark LS, Tanadini-Lang S, Wolpert F, Weller M, Woodruff HC, Guckenberger M AN (2022) Comprehensive summary and retrospective evaluation of prognostic scores for patients with newly diagnosed brain metastases treated with upfront radiosurgery in a modern patient collective. Radiother Oncol July:23\u0026ndash;31. \u003c/li\u003e\n\u003cli\u003eTamura R, Tanaka T, Miyake K, et al (2017) Bevacizumab for malignant gliomas: current indications, mechanisms of action and resistance, and markers of response. Brain Tumor Pathol 34:62\u0026ndash;77. https://doi.org/10.1007/s10014-017-0284-x\u003c/li\u003e\n\u003cli\u003eWang Z, Chen H, Chen Q, et al (203) \u0026apos;Sandwich treatment\u0026apos; for posterior fossa brain metastases with volume larger than 4cm\u003csup\u003e3\u003c/sup\u003e: a multicentric retrospective study. Clin Exp Metastasis. 40(5):415-422. doi: 10.1007/s10585-023-10220-y. \u003c/li\u003e\n\u003cli\u003eGinalis EE, Cui T, Weiner J, et al (2020) Two-staged stereotactic radiosurgery for the treatment of large brain metastases: Single institution experience and review of literature. J Radiosurgery SBRT 7:105\u0026ndash;114\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-metastasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clin","sideBox":"Learn more about [Clinical \u0026 Experimental Metastasis](http://link.springer.com/journal/10585)","snPcode":"10585","submissionUrl":"https://submission.nature.com/new-submission/10585/3","title":"Clinical \u0026 Experimental Metastasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"2-staged stereotactic radiosurgery, anti-vascular, brain metastases, brainstem compression","lastPublishedDoi":"10.21203/rs.3.rs-4467801/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4467801/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eStereotactic radiosurgery poses a significant risk when treating brain metastases in close proximity to the brainstem. To address this issue, a novel approach known as \"combined anti-vascular therapy\" has been devised for these metastases. This treatment regimen involves a one-week course of two-staged stereotactic radiosurgery (2-SSRS), supplemented with the administration of the anti-vascular agent bevacizumab during the radiosurgery interval. The objective of this study is to assess the efficacy and safety of a combined anti-vascular and two-staged stereotactic radiosurgery therapy for brain metastases with brainstem compression. A retrospective analysis was conducted on patients treated at five gamma knife treatment centers to assess changes in tumor size and peritumoral edema volume. Clinical symptom changes were evaluated using the Headache Scale (VAS), Dizziness Disorder Inventory (DHI), Vomiting Scale (VS), and Glasgow Coma Scale (GCS). The Karnofsky Task Scale (KPS) and Barthel Index (BI) were used to assess overall physical fitness and physical activity rehabilitation. Tumor local control (TLC) and overall survival (OS) rate were also calculated for the patients. Among the 36 patients with brain metastases with brainstem compression, 36 received combined anti-vascular therapy. Both edema volume and tumor volume significantly decreased during the treatment period and post-treatment 3 months (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Clinical symptoms, as indicated by median scores of VAS, DHI, VS, and GCS, showed significant improvement during treatment and at the 3-month follow-up (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Median changes in KPS and BI, reflecting overall physical fitness and physical activity rehabilitation, were also similar and statistically significant (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01). The patient cohort exhibited a median overall survival of 14.2 months, with corresponding 6-month and 12-month survival rates of 91.7% and 80.0%, respectively. Tumor local control rates at 6 and 12 months were 94.7% and 78.9%, respectively.The combination of anti-vascular therapy with 2-SSRS demonstrates safety and efficacy in treating patients with brain metastases with brainstem compression. This approach rapidly alleviates patient symptoms, effectively manages tumor progression, extends overall survival, and exhibits manageable adverse effects.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of combined anti-vascular and two-staged stereotactic radiosurgery therapy for brain metastases with brainstem compression: a retrospective multicenter study ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-10 22:23:04","doi":"10.21203/rs.3.rs-4467801/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-07T18:06:40+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-28T11:02:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"113439561239844684059804370538748304602","date":"2024-12-13T14:41:18+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"219883334723158507308306275215187105546","date":"2024-12-06T10:54:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"123093730409415613135097551278005690201","date":"2024-08-22T05:35:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-16T12:04:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-05-24T11:13:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-24T10:35:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical \u0026 Experimental Metastasis","date":"2024-05-23T15:14:37+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-and-experimental-metastasis","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"clin","sideBox":"Learn more about [Clinical \u0026 Experimental Metastasis](http://link.springer.com/journal/10585)","snPcode":"10585","submissionUrl":"https://submission.nature.com/new-submission/10585/3","title":"Clinical \u0026 Experimental Metastasis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5e08cc4a-2a76-4f27-8610-93685652cc7c","owner":[],"postedDate":"June 10th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-03-31T16:07:18+00:00","versionOfRecord":{"articleIdentity":"rs-4467801","link":"https://doi.org/10.1007/s10585-025-10338-1","journal":{"identity":"clinical-and-experimental-metastasis","isVorOnly":false,"title":"Clinical \u0026 Experimental Metastasis"},"publishedOn":"2025-03-29 15:57:13","publishedOnDateReadable":"March 29th, 2025"},"versionCreatedAt":"2024-06-10 22:23:04","video":"","vorDoi":"10.1007/s10585-025-10338-1","vorDoiUrl":"https://doi.org/10.1007/s10585-025-10338-1","workflowStages":[]},"version":"v1","identity":"rs-4467801","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4467801","identity":"rs-4467801","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}