Comparison of outcomes of gamma knife radiosurgery for secondary and de novo grade 2 meningiomas: a single-center retrospective study

Comparison of outcomes of gamma knife radiosurgery for secondary and de novo grade 2 meningiomas: a single-center retrospective 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 Comparison of outcomes of gamma knife radiosurgery for secondary and de novo grade 2 meningiomas: a single-center retrospective study Dili Song, Guangxin Hu, Liping Shen, Jinxiu Yu, Jiaming Fu, Zijing Wang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4877973/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 16 You are reading this latest preprint version Abstract Objective The purpose of this study was to compare outcomes between secondary and de novo grade 2 meningiomas undergoing Gamma Knife radiosurgery (GKRS). Methods Eighteen patients, including secondary grade 2 meningioma group (n = 6) and de novo grade 2 meningioma group (n = 12), treated with GKRS were enrolled in this single-center retrospective study. Results The median tumor volume was 23.4 (range, 5.5–104.0) ml and 9.4 (range, 0.4–24.9) ml in secondary and de novo grade 2 meningioma group respectively ( p = 0.061). Ten patients (55.6%) experienced radiological progression with a median follow-up time of 35.7 (range, 9.4-138.2) months. The median time to radiological progression was 34.5 (range, 14.5–97.7) months. The radiological progression-free survival (PFS) was 74%, 55%, and 15% at 2, 3 and 5 years respectively. The radiological PFS at 2 and 3 years was 60% and 20%, 82% and 82% in secondary and de novo grade 2 group respectively. Secondary grade 2 meningiomas were significantly related with poorer radiological PFS in univariate analysis ( p = 0.021). Nine patients (50%) occurred clinical progression in the study, including headache (n = 7), cranial nerve dysfunction (n = 5), seizure (n = 1) and extremity weakness (n = 1). Secondary grade 2 meningiomas were significantly related with clinical progression in univariate analysis (p = 0.045). Conclusions Secondary grade 2 meningiomas had a shorter radiological and clinical PFS after GKRS than de novo grade 2 meningiomas. Secondary grade 2 meningiomas were an independent risk factor for poor prognosis after GKRS. Gamma knife Stereotactic radiosurgery Meningiomas secondary meningiomas de novo meningiomas Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Meningiomas are the most common primary intracranial tumor, accounting for nearly 37.6% of all intracranial tumors 1 . Almost 17.7% of meningiomas with documented WHO grade are grade 2 1 . As malignant gliomas, Meningiomas can progress from benign to atypical or anaplastic variants 2 , 3 . It is estimated that 20%-40% of meningiomas are secondary tumors which originated from grade 1 meningiomas 4 – 6 . As a consequent, grade 2 meningiomas are categorized as secondary or de novo tumors 7 . Up to now, the treatment for grade 2 meningiomas is challengeable. Surgical resection is still the first choice 8 . Maximal surgical resection is the most important factor related with prediction of prognosis. However, these tumors can demonstrate a higher tumor recurrent rate and poor prognosis despite gross total resection, because of its heterogeneity and unpredictable behavior 9 – 11 . The recurrence of meningiomas can cause significant mortality and morbidity. Thus, in order to reduce tumor recurrence, great effort should be made in the management of grade 2 meningiomas. Gamma knife radiosurgery (GKRS), which can provide a favorable tumor control rate and has advantages of better dose conformity, a less invasive treatment, a highly focused and precise delivery of radiation in a single session, is widely used for postoperative residual or recurrent grade 2 meningiomas. Previous studies have reported stereotactic radiosurgery (SRS) could offer a 3-year tumor control rate of 19%-74% for grade 2 meningiomas 12 – 17 . However, the differences between secondary and de novo grade 2 meningiomas are still unclear. As secondary meningiomas have already undergone surgical resection at least once and/or radiotherapy, they may behave differently and have different prognosis. According to the studies by Zhao et al 18 and Champeaux et al 4 , secondary grade 2 meningiomas had a much shorter surgical recurrence-free survival and overall survival. Because of its rarity, the prognosis of secondary grade 2 meningiomas treated with GKRS are poorly understood. Therefore, in order to compare outcomes between secondary and de novo grade 2 meningiomas undergoing GKRS, we conducted a single-center retrospective study. Methods Patient selection Between December 2008 and December 2017, 6 cases of secondary grade 2 meningiomas (Fig. 1 ) and 12 cases of de novo grade 2 meningiomas (Fig. 2 ) who had complete clinical data and at least once follow-up in our center were retrospectively reviewed. All of the 6 secondary meningiomas had undergone at least twice surgical resection and GKRS in our center. All of the 12 cases of de novo grade 2 meningiomas were residual tumors after the primary treatment of surgery. All of the histological tissue specimens had been confirmed by an experienced pathologist according to the 2016 WHO classification. This retrospective study was approved by the institutional committee of the Second Affiliated Hospital of Guangzhou Medical University. Radiological and clinical evaluations All of these patients were usually followed up with radiological and clinical evaluation every 6 months for the first 3 years and thereafter yearly. Tumor volume was calculated using the following formula: V = anteroposterior diameter × horizontal diameter × vertical diameter × π/6 19 . Tumors shrinking at least 10% in volume was considered shrinkage. Tumor changing within 10% in volume was considered stable. Tumor enlarging at least 10% in volume was considered progression 20 . Radiosurgical techniques Leksell B-type Gamma Knife radiosurgery (Elekta Instruments, Inc, Stockholm, Sweden) was used for these meningioma patients before April 2014 and Perfexion thereafter. After the placement of Leksell stereotactic frame G, stereotactic contrast-enhanced MRI was performed to obtain MRI image for delineating target. GKRS treatment plan was proposed according to experienced neurosurgeons, medical physicist and radiation oncologists. Statistical analysis The comparison of means of continuous variables with normal distribution was performed by independent-sample t test. Wilcoxon rank sum test was used for continuous variables with abnormal distribution. Analysis of categorical variables was performed by Chi-square test and Fisher exact test. Log-rank test statistics and Cox proportional hazard models were used for univariate analysis and multivariate analysis respectively. Kaplan-Meier curves were plotted for progression-free survival. Probability values < 0.05 were considered statistically significant. For statistical analysis, IBM’s SPSS (version 21.0) was used. Results Baseline and treatment characteristics The population in this study consisted of 18 patients, including secondary grade 2 meningioma group (n = 6) and de novo grade 2 meningioma group (n = 12). There were 2 (33.3%) and 8 (66.7%) male patients in secondary and de novo grade 2 meningioma group respectively. There were 6 (50%) non-skull base tumors in de novo grade 2 meningioma group. All of tumors were skull base in secondary grade 2 meningioma group. All the patients had undergone at least once surgical resection in de novo grade 2 meningioma group and at least twice surgical resection in secondary grade 2 meningioma group. The median follow-up was 58.0 (range, 25.5-106.7) months and 29.9 (range, 9.4-138.3) months in secondary and de novo grade 2 meningioma group respectively. The median time to malignant transformation in secondary grade 2 meningioma group was 150.3 (range, 35.0-177.2) months. All of the tumors had undergone GKRS treatment before malignant transformation in secondary grade 2 meningioma group. The median tumor volume, age, margin dose, prescription isodose and max dose were 23.4 ml, 51.8 years, 14.5 Gy, 50%, 30 Gy, and 9.4 ml, 54.5 years, 13.5 Gy, 45%, 32.5 Gy in the secondary and do novo grade 2 meningioma group respectively. All of the treatment and baseline characteristics were similar in the two groups. (Table 1 ) Table 1 Baseline and treatment characteristics of the study group. Characteristic Secondary grade 2 meningiomas De novo grade 2 meningiomas P value No. of patients 6 (33.3) 12 (66.7) NA Male, n (%) 2 (33.3) 8 (66.7) 0.321 Median age, (range), years 51.8 (42.3–60.0) 54.5 (26.5–64.1) 0.921 Median tumor volume at GKRS, (range), ml 23.4 (5.5–104.0) 9.4 (0.4–24.9) 0.061 Median FU duration, (range), months 58.0 (25.5-106.7) 29.9 (9.4-138.3) 0.092 Non-skull base tumors, n (%) 0 6 (50) 0.054 No. of surgery, n (%) Once NA 10 (83.3) NA Twice 5 (83.3) 2 (16.7) NA Three times 1 (16.7) NA NA Tumor histology, n Atypical 5 (83.3) 8 (66.7) NA Chordoid 1 (16.7) 2 (16.7) NA Clear cell 0 2 (16.7) NA Median time to malignant transformation, (range), months 150.3 (35.0-177.2) NA NA Prior GKRS 6 (100) 0 NA Median margin dose, (range), Gy 14.5 (13.0–15.0) 13.5 (12.0–15.0) 0.395 Median maximum dose, (range), Gy 30.0 (26.0–33.0) 32.5 (24.0-32.5) 0.506 Median prescription isodose, (range), % 50 (40–50) 45 (40–50) 0.176 Abbreviations: FU, follow up; GKRS, gamma knife radiosurgery; NA, not available. Treatment outcomes after GKRS Ten patients (55.6%) experienced radiological progression with a median follow-up time of 35.7 (range, 9.4-138.2) months. The median time to radiological progression was 34.5 (range, 14.5–97.7) months. The radiological progression-free survival (PFS) was 74%, 55%, and 15% at 2, 3 and 5 years respectively (Fig. 3 A). There were 5 (83.3%) and 5 (41.7%) patients with tumor progression in secondary and de novo grade 2 meningioma group respectively (Table 2 ). The median time to radiological progression was 31.4 (range, 22.4–41.3) months and 48.9 (range, 14.5–97.7) months in secondary and de novo grade 2 meningioma group respectively. The radiological PFS at 2 and 3 years was 60% and 20%, 82% and 82% in secondary and de novo grade 2 meningioma group respectively. Secondary grade 2 meningiomas were significantly associated with poorer radiological PFS in univariate analysis ( p = 0.021) (Fig. 3 B) (Table 3 ). Table 2 GKRS treatment outcomes in the entire series. Outcomes Secondary grade 2 meningiomas, n (%) De novo grade 2 meningiomas, n (%) Radiological outcomes Tumor control 1 (16.7) 7 (58.3) Tumor shrinkage 0 7 (58.3) Stable tumor 1 (16.7) 0 Progression 5 (83.3) 5 (41.7) Clinical progression 5 (83.3) 4 (33.3) CN dysfunction 5 (83.3) 0 II 5 (83.3) 0 III/IV/VI 1 (16.7) 0 V 1 (16.7) 0 Headache 3 (50) 4 (33.3) Seizure 1 (16.7) 0 Extremity weakness 0 1 (8.3) Abbreviations: CN, cranial nerve. Table 3 Univariate and multivariate Cox proportional hazards regression analyses for radiological progression, and clinical progression in the entire series. Characteristics Radiological progression Clinical progression Univariate, p Univariate, p Age ≥ 55y 0.096 0.196 Gender 0.911 0.539 Tumor volume ≥ 10 ml 0.566 0.343 Non-skull base tumors 0.763 0.529 Margin dose < 15Gy 0.620 0.527 Maximum dose ≤ 32Gy 0.787 0.773 Secondary grade 2 meningiomas 0.021 0.045 ※ Statistically significant ( P < 0.05). Boldface type indicates statistical significance. Nine patients (50%) occurred clinical progression in the study, including headache (n = 7), cranial nerve dysfunction (n = 5), seizure (n = 1) and extremity weakness (n = 1) (Table 2 ). The median time to clinical progression was 34.8 (range, 15.8–72.2) months. There were 5 (83.3%) and 4 (33.3%) patients occurring clinical progression in secondary and de novo grade 2 meningioma group respectively. Secondary grade 2 meningiomas were related with clinical progression in univariate analysis (p = 0.045) (Fig. 4 ) (Table 2 ). Discussion Surgery is the first choice in the management of grade 2 meningiomas. However, grade 2 meningiomas are a heterogeneous group of histologically aggressive tumors, with a high incidence of tumor recurrence and progression as compared to benign meningiomas. Therefore, treatment options for tumor recurrence and progression include repeat surgery and radiotherapy. Given the increased morbidity and poor quality of life after repeat surgical resection 21 , postoperative radiotherapy is advocated in the management of postoperative residual or recurrent grade 2 meningiomas. Radiotherapy for grade 2 meningiomas Although adjuvant radiotherapy for atypical meningiomas after gross total resection is still on controversial, it could significantly improve tumor control rate after subtotal resection 22 . Mair et al 23 analyzed 114 cases of grade 2 atypical meningiomas diagnosed using 2000 WHO criteria, and reported a significant benefit after radiotherapy after subtotal resection. In the study of Jo K et al 24 , for atypical meningiomas with incomplete resection, the median interval to tumor recurrence increased from 17 months for surgery alone to 39 months for adjuvant radiotherapy. SRS and fractionated external beam radiotherapy (fEBRT) are both reasonable options for postoperative residual or recurrent grade 2 meningiomas. Previous studies have reported SRS and fEBRT could offer a 3-year tumor control rate of 19%-74% 12–17 and 45%-71% 12, 17 , 25 for grade 2 meningiomas respectively. However, studies did not find significant difference in tumor control between fEBRT and SRS 17 , 26 . As SRS has the advantage of a highly precise, better dose conformity, minimizing radiation dose to surrounding tissues and shorter duration of treatments, it seems more attractive than fEBRT. Tumor control after SRS and related risk factors Tumor control after SRS and related risk factors have been reported in the literatures. In the study of Choi et al 13 , 25 cases of residual or recurrent atypical meningiomas treated with SRS with a median marginal dose of 22 Gy (range, 16–30) in 1 to 4 fractions, the 3-year local control rate was 74%, the number of recurrences before SRS, late SRS and age at treatment ≥ 60 years were associated with recurrence after SRS on univariate analysis. In the study of Ferraro et al 27 , 31 cases of atypical meningiomas were treated with GKRS, the median time to recurrence was 27.5 months, the 3-year PFS was 70.1%, margin dose was the only significant factor related with recurrence in multivariate analysis. In the study of Pollock et al 14 , 50 cases of grade 2 (= 37) and 3 (n = 13) treat with SRS with a median margin dose of 15 Gy. The 5-year PFS was 40%. In patients who failed prior EBRT, the 3-year PFS was 19%. Having failed EBRT was a negative predictor of PFS. In the study of Kano et al 15 , the authors found the 5-year PFS in lesions treated with SRS below 20 Gy and 20 Gy were 29.4% and 63.1% respectively. The marginal dose < 20 Gy was a significant factor for PFS in high-grade meningiomas treated with SRS. Aboukais et al 16 reported 27 cases of grade 2 meningiomas treated with SRS with a median margin dose of 15.2 (range, 12–21) Gy, the 3-year local control was 40%. Age and tumor volume were significantly related with local tumor control in univariate analysis. In the current study, because some tumors were close to optic chiasm and optic nerve or due to the large tumor volume, the median margin dose was 14.5 Gy and 13.5 Gy in secondary and de novo grade 2 meningioma group respectively, which might be a little lower than other studies. The radiological PFS was 74% and 55% at 2 and 3 years respectively, which was similar with other studies. The median time to radiological progression was shorter in secondary grade 2 meningioma group than de novo grade 2 meningioma group (31.4 vs 48.9 months), secondary grade 2 meningiomas were significantly related with poorer prognosis. Meningiomas with multiple recurrences and prior treatment failures are considered more aggressive and difficult to treat. However, in the current study, all of the secondary grade 2 meningiomas had at least twice surgery failures and GKRS treatment failure and were more aggressive and resistant to radiation than those de novo grade 2 meningiomas. Besides, there was no radiation-naïve patient in the secondary grade 2 meningioma group. Therefore, this could be a source of bias. Up to now, there was no standard treatment for secondary grade 2 meningiomas. Due to its poor prognosis, higher radiation dose might be helpful for better tumor control. Secondary grade 2 meningiomas Malignant transformation is not an uncommon phenomenon in benign meningiomas. It is estimated that 20%-40% of meningiomas are secondary tumors which originated from grade 1 meningiomas 4 – 6 . As stepwise genetic progression involving in malignant transformation 3 , 28 , 29 , secondary and de novo grade 2 meningiomas may behave differently. Recent studies indicated secondary meningiomas were associated with poor PFS and overall survival. In the study of Zhao et al 18 , 89 cases of atypical meningiomas were reviewed. Total resection was achieved in 80.9%. Forty (44.9%) patients underwent radiotherapy after surgery. Patients with secondary atypical meningiomas showed a threefold increased risk of recurrence. Secondary atypical meningiomas were related with poor PFS on multivariate analysis. In the study of Champeaux et al 4 , 194 patients with grade 2 meningiomas were reviewed. Thirty-one patients (16%) had a previous history of grade 1 meningiomas. These patients underwent a total of 344 surgical resections and 43.3% received radiotherapy. Secondary grade 2 meningiomas were related with the surgical recurrence-free survival and overall survival. In these studies, only a part of patients underwent radiotherapy for secondary meningiomas. There was no study comparing the outcomes between secondary and de novo grade 2 meningiomas undergoing GKRS. In the current study, we did not investigate molecular markers in this study. CDKN2A/B and TERT promoter have been associated with meningioma behavior and poor prognosis 30 , 31 . The 2021 WHO classification system indicates any meningioma with CDKN2A/B homozygous deletion and/or TERT promoter mutation is allotted to grade 3, irrespective of histological criteria of anaplasia 8 . Thus, future study needed to investigate molecular markers and genetic signatures associated with malignant transformation and prognosis. Study limitations Although this was the first study comparing outcomes between secondary and de novo grade 2 meningiomas undergoing GKRS, there were several limitations in the study. First, it was a single-center retrospective study with selection and treatment biases. Second, because of the rare incidence of secondary meningiomas, only 6 cases of secondary grade 2 meningiomas treated with GKRS were included in this study. The statistical power was limited by the number of cases in the study. Third, the pathological diagnosis was not based on the 2021 WHO classification system. The information of molecular markers was not available in this study. Finally, there was no radiation-naïve patient in the secondary grade 2 meningioma group. This could be a source of bias. Conclusions In this single-center retrospective study, we found secondary grade 2 meningiomas had a shorter radiological and clinical PFS after GKRS than de novo grade 2 meningiomas. The radiological PFS at 3 years was 20% and 82% in secondary and de novo grade 2 group respectively. Secondary grade 2 meningiomas were an independent risk factor for poor prognosis after GKRS. Therefore, further prospective studies should be carried out to investigate the outcomes of GKRS for secondary and de novo grade 2 meningiomas. Abbreviations fEBRT fractionated external beam radiotherapy GRKS Gamma Knife radiosurgery PFS progression-free survival SRS stereotactic radiosurgery Declarations Acknowledgements Not applicable. Declaration of interest Declarations of interest: none. Author contribution Dili Song, Guangxin Hu and Liping Shen made research idea and designed study; Zijing Wang, Jiaming Fu and Lin Chen collected data; Xiaomin Zhou and Xinwu Liu analyzed the data; Dili Song, Jiaming Fu and Jinxiu Yu wrote the paper; Yongguang Cai and Junyi Fu revised the paper. Consent for publication Each author contributed important content during manuscript drafting or revision and accepts accountability for the overall work, and all the authors agreed on the final manuscript. Funding This work was supported by plan on enhancing scientific research in GMU; the Basic and Applied Basic Research Fund of Guangdong Province (2021A1515110596)（2022A1515220024）; the Basic and Applied Basic Research Fund of Guangzhou science project (2024A04J3630). Availability of data and materials The datasets generated and/or analysed during the current study are not publicly available due to part of the data in the study related to other studies, but are available from the corresponding author on reasonable request. Ethics statement The studies involving human participants were reviewed and approved by the institutional committee of the Second Affiliated Hospital of Guangzhou Medical University. The patients/ participants provided their written informed consent to participate in this study. All procedures performed were in accordance with the ethical standards of these committees and with the 1964 Declaration of Helsinki and its later amendments. 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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-4877973","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":347894719,"identity":"dab4a5a9-4a3c-43de-851d-33e2c1bee50d","order_by":0,"name":"Dili Song","email":"","orcid":"","institution":"Guangdong Nongken Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Dili","middleName":"","lastName":"Song","suffix":""},{"id":347894720,"identity":"878c0723-5003-40a5-9da9-eaf899fcc0f3","order_by":1,"name":"Guangxin Hu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guangxin","middleName":"","lastName":"Hu","suffix":""},{"id":347894721,"identity":"88343f5d-e574-4585-8c11-2deb86f4a0dc","order_by":2,"name":"Liping Shen","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Shen","suffix":""},{"id":347894722,"identity":"98bb88fe-b34b-482e-ade3-6f5534d257a5","order_by":3,"name":"Jinxiu Yu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jinxiu","middleName":"","lastName":"Yu","suffix":""},{"id":347894723,"identity":"150c43cb-a534-4cf2-8d77-bc24b3a4b7c5","order_by":4,"name":"Jiaming Fu","email":"","orcid":"","institution":"Guangdong Pharmaceutical University，Guangzhou","correspondingAuthor":false,"prefix":"","firstName":"Jiaming","middleName":"","lastName":"Fu","suffix":""},{"id":347894724,"identity":"57d07ae4-5d62-415e-b37d-7281f230bb82","order_by":5,"name":"Zijing Wang","email":"","orcid":"","institution":"Guilin medical college","correspondingAuthor":false,"prefix":"","firstName":"Zijing","middleName":"","lastName":"Wang","suffix":""},{"id":347894725,"identity":"b1e8b258-8d8a-4784-905a-728adb4c59c7","order_by":6,"name":"Lin Chen","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Chen","suffix":""},{"id":347894726,"identity":"13903c53-8f1a-4572-aed3-8bd6a7d3caf8","order_by":7,"name":"Xinwu Liu","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xinwu","middleName":"","lastName":"Liu","suffix":""},{"id":347894727,"identity":"57f913f9-9907-480d-90c6-514e29759efc","order_by":8,"name":"Xiaomin Zhou","email":"","orcid":"","institution":"The Second Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaomin","middleName":"","lastName":"Zhou","suffix":""},{"id":347894728,"identity":"7429d1a7-5d7f-4b53-acbe-0a26668dbe32","order_by":9,"name":"Yongguang Cai","email":"","orcid":"","institution":"Guangdong Nongken Central Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yongguang","middleName":"","lastName":"Cai","suffix":""},{"id":347894729,"identity":"826ff944-e343-4774-97c0-37db899e36e8","order_by":10,"name":"Junyi Fu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYBAC9gaGBCAlIcfAwAMWYGwgpIXnAESLMUlawCCxgXgtEgnPpAvbLNLn+589upmHwUZ2wwHmZw8IaEmTntkmkbvxwLm02zwMacYbDrCZG+DTYg/SwgvS0thjBtRyOHHDAR42CYK2ALWkGzbzgLT8J15LgjwbWMsBIrTwPEi25jknYbiBh8fs5hyDZOOZh9nM8Gthz0m8zVNWJy/ff8bsxpsKO9m+483P8GoBakpgYGRjYDA4AOKAgooZv3ogYAeq/cPAIN9AUOUoGAWjYBSMVAAAWWFDASfz6lgAAAAASUVORK5CYII=","orcid":"","institution":"The Second Affiliated Hospital of Guangzhou Medical University","correspondingAuthor":true,"prefix":"","firstName":"Junyi","middleName":"","lastName":"Fu","suffix":""}],"badges":[],"createdAt":"2024-08-08 04:12:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4877973/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4877973/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66075986,"identity":"f9737fd2-f34f-4280-8b68-9ff434584a71","added_by":"auto","created_at":"2024-10-07 13:05:19","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":197166,"visible":true,"origin":"","legend":"\u003cp\u003eA 53.8-year-old female patient underwent adjuvant GKRS (margin dose, 12 Gy; maximum dose, 30 Gy) for parasellar grade 1 meningioma. The patient was diagnosed of secondary grade 2 meningioma by repeat surgical resection for tumor progression at 63.9 months after prior surgery. Finally, the patient occurred tumor progression at 31.7 months after repeat GKRS (margin dose, 13.2 Gy; maximum dose, 33 Gy). \u003cstrong\u003eA\u003c/strong\u003e. Contrast-enhanced T1-weighted MRI scans showed parasellar tumor. \u003cstrong\u003eB\u003c/strong\u003e. The patient underwent subtotal resection and was diagnosed of meningothelial meningioma. \u003cstrong\u003eC\u003c/strong\u003e. Postoperative GKRS for residual grade 1 meningioma at 22.4 months after surgical resection. \u003cstrong\u003eD\u003c/strong\u003e. MRI showed tumor progression at 41.1 months after GKRS. \u003cstrong\u003eE\u003c/strong\u003e. The patient underwent repeat GKRS for atypical meningioma confirmed by repeat surgical resection. \u003cstrong\u003eF\u003c/strong\u003e. MRI showed stable tumor at 22.4 months after repeat GKRS. \u003cstrong\u003eG\u003c/strong\u003e. MRI showed tumor progression at 31.7 months after repeat GKRS.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4877973/v1/14cbaf6f4963480d767100d5.jpeg"},{"id":66075627,"identity":"9f258b78-fbcc-407b-a179-902206205af0","added_by":"auto","created_at":"2024-10-07 12:57:19","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":180740,"visible":true,"origin":"","legend":"\u003cp\u003eA 52.8-year-old male patient with parasellar de novo grade 2 meningioma underwent GKRS (margin dose, 12 Gy; maximum dose, 24 Gy) as adjuvant treatment for residual tumor after surgical resection. The patient developed tumor progression at 59.2 months after GKRS. \u003cstrong\u003eA\u003c/strong\u003e. Contrast-enhanced T1-weighted MRI scans showed parasellar tumor. \u003cstrong\u003eB\u003c/strong\u003e. Adjuvant GKRS for residual de novo grade 2 meningioma at 6.7 months after surgical resection. \u003cstrong\u003eC\u003c/strong\u003e. MRI showed stable tumor at 37.1 months after GKRS. \u003cstrong\u003eD\u003c/strong\u003e. MRI showed tumor progression at 59.2 months after GKRS.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4877973/v1/64dec13a5b359162063fe6db.jpeg"},{"id":66075625,"identity":"58db33e5-fe40-49bb-9bc9-e33b8db061a6","added_by":"auto","created_at":"2024-10-07 12:57:19","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":54426,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003e Kaplan-Meier curve of radiological PFS in the entire series. The PFS was 100%, 74%, 55%, 29%, and 15% at 1, 2, 3, 4, and 5 years. \u003cstrong\u003eB\u003c/strong\u003e. Kaplan-Meier curve of radiological PFS of secondary VS de novo grade 2 meningiomas (\u003cem\u003ep\u003c/em\u003e=0.021).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4877973/v1/36a6d560ebcee1eebd5ae5d2.jpeg"},{"id":66075624,"identity":"e67ad1b8-dd04-4033-bd77-27af61440847","added_by":"auto","created_at":"2024-10-07 12:57:19","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":24857,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curve of clinical PFS of secondary VS de novo grade 2 meningiomas (\u003cem\u003ep\u003c/em\u003e=0.045).\u003c/p\u003e","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4877973/v1/017e1bf7925eda8a311f607a.jpeg"},{"id":66075990,"identity":"12c318a4-a90e-4f29-85d6-9ad43d649dd3","added_by":"auto","created_at":"2024-10-07 13:05:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1085101,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4877973/v1/a4808bd3-7cde-4e5f-bb8c-15e984e40e52.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of outcomes of gamma knife radiosurgery for secondary and de novo grade 2 meningiomas: a single-center retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMeningiomas are the most common primary intracranial tumor, accounting for nearly 37.6% of all intracranial tumors\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Almost 17.7% of meningiomas with documented WHO grade are grade 2\u003csup\u003e1\u003c/sup\u003e. As malignant gliomas, Meningiomas can progress from benign to atypical or anaplastic variants\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. It is estimated that 20%-40% of meningiomas are secondary tumors which originated from grade 1 meningiomas\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. As a consequent, grade 2 meningiomas are categorized as secondary or de novo tumors\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eUp to now, the treatment for grade 2 meningiomas is challengeable. Surgical resection is still the first choice\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Maximal surgical resection is the most important factor related with prediction of prognosis. However, these tumors can demonstrate a higher tumor recurrent rate and poor prognosis despite gross total resection, because of its heterogeneity and unpredictable behavior\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The recurrence of meningiomas can cause significant mortality and morbidity. Thus, in order to reduce tumor recurrence, great effort should be made in the management of grade 2 meningiomas.\u003c/p\u003e \u003cp\u003eGamma knife radiosurgery (GKRS), which can provide a favorable tumor control rate and has advantages of better dose conformity, a less invasive treatment, a highly focused and precise delivery of radiation in a single session, is widely used for postoperative residual or recurrent grade 2 meningiomas. Previous studies have reported stereotactic radiosurgery (SRS) could offer a 3-year tumor control rate of 19%-74% for grade 2 meningiomas\u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, the differences between secondary and de novo grade 2 meningiomas are still unclear. As secondary meningiomas have already undergone surgical resection at least once and/or radiotherapy, they may behave differently and have different prognosis. According to the studies by Zhao et al\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e and Champeaux et al\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, secondary grade 2 meningiomas had a much shorter surgical recurrence-free survival and overall survival. Because of its rarity, the prognosis of secondary grade 2 meningiomas treated with GKRS are poorly understood. Therefore, in order to compare outcomes between secondary and de novo grade 2 meningiomas undergoing GKRS, we conducted a single-center retrospective study.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient selection\u003c/h2\u003e \u003cp\u003eBetween December 2008 and December 2017, 6 cases of secondary grade 2 meningiomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and 12 cases of de novo grade 2 meningiomas (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) who had complete clinical data and at least once follow-up in our center were retrospectively reviewed. All of the 6 secondary meningiomas had undergone at least twice surgical resection and GKRS in our center. All of the 12 cases of de novo grade 2 meningiomas were residual tumors after the primary treatment of surgery. All of the histological tissue specimens had been confirmed by an experienced pathologist according to the 2016 WHO classification. This retrospective study was approved by the institutional committee of the Second Affiliated Hospital of Guangzhou Medical University.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eRadiological and clinical evaluations\u003c/h2\u003e \u003cp\u003eAll of these patients were usually followed up with radiological and clinical evaluation every 6 months for the first 3 years and thereafter yearly. Tumor volume was calculated using the following formula: V\u0026thinsp;=\u0026thinsp;anteroposterior diameter \u0026times; horizontal diameter \u0026times; vertical diameter\u0026thinsp;\u0026times;\u0026thinsp;π/6\u003csup\u003e19\u003c/sup\u003e. Tumors shrinking at least 10% in volume was considered shrinkage. Tumor changing within 10% in volume was considered stable. Tumor enlarging at least 10% in volume was considered progression\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eRadiosurgical techniques\u003c/h2\u003e \u003cp\u003eLeksell B-type Gamma Knife radiosurgery (Elekta Instruments, Inc, Stockholm, Sweden) was used for these meningioma patients before April 2014 and Perfexion thereafter. After the placement of Leksell stereotactic frame G, stereotactic contrast-enhanced MRI was performed to obtain MRI image for delineating target. GKRS treatment plan was proposed according to experienced neurosurgeons, medical physicist and radiation oncologists.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe comparison of means of continuous variables with normal distribution was performed by independent-sample t test. Wilcoxon rank sum test was used for continuous variables with abnormal distribution. Analysis of categorical variables was performed by Chi-square test and Fisher exact test. Log-rank test statistics and Cox proportional hazard models were used for univariate analysis and multivariate analysis respectively. Kaplan-Meier curves were plotted for progression-free survival. Probability values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant. For statistical analysis, IBM\u0026rsquo;s SPSS (version 21.0) was used.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline and treatment characteristics\u003c/h2\u003e \u003cp\u003eThe population in this study consisted of 18 patients, including secondary grade 2 meningioma group (n\u0026thinsp;=\u0026thinsp;6) and de novo grade 2 meningioma group (n\u0026thinsp;=\u0026thinsp;12). There were 2 (33.3%) and 8 (66.7%) male patients in secondary and de novo grade 2 meningioma group respectively. There were 6 (50%) non-skull base tumors in de novo grade 2 meningioma group. All of tumors were skull base in secondary grade 2 meningioma group. All the patients had undergone at least once surgical resection in de novo grade 2 meningioma group and at least twice surgical resection in secondary grade 2 meningioma group. The median follow-up was 58.0 (range, 25.5-106.7) months and 29.9 (range, 9.4-138.3) months in secondary and de novo grade 2 meningioma group respectively. The median time to malignant transformation in secondary grade 2 meningioma group was 150.3 (range, 35.0-177.2) months. All of the tumors had undergone GKRS treatment before malignant transformation in secondary grade 2 meningioma group. The median tumor volume, age, margin dose, prescription isodose and max dose were 23.4 ml, 51.8 years, 14.5 Gy, 50%, 30 Gy, and 9.4 ml, 54.5 years, 13.5 Gy, 45%, 32.5 Gy in the secondary and do novo grade 2 meningioma group respectively. All of the treatment and baseline characteristics were similar in the two groups. (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline and treatment characteristics of the study group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSecondary grade 2 meningiomas\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo grade 2 meningiomas\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of patients\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (33.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.321\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian age, (range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51.8 (42.3\u0026ndash;60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e54.5 (26.5\u0026ndash;64.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.921\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian tumor volume at GKRS, (range), ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.4 (5.5\u0026ndash;104.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.4 (0.4\u0026ndash;24.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian FU duration, (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e58.0 (25.5-106.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e29.9 (9.4-138.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.092\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-skull base tumors, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.054\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo. of surgery, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnce\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTwice\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThree times\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor histology, n\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtypical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (66.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChordoid\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClear cell\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian time to malignant transformation, (range), months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150.3 (35.0-177.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior GKRS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian margin dose, (range), Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.5 (13.0\u0026ndash;15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.5 (12.0\u0026ndash;15.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian maximum dose, (range), Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.0 (26.0\u0026ndash;33.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.5 (24.0-32.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.506\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian prescription isodose, (range), %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (40\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45 (40\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: FU, follow up; GKRS, gamma knife radiosurgery; NA, not available.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTreatment outcomes after GKRS\u003c/h2\u003e \u003cp\u003eTen patients (55.6%) experienced radiological progression with a median follow-up time of 35.7 (range, 9.4-138.2) months. The median time to radiological progression was 34.5 (range, 14.5\u0026ndash;97.7) months. The radiological progression-free survival (PFS) was 74%, 55%, and 15% at 2, 3 and 5 years respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). There were 5 (83.3%) and 5 (41.7%) patients with tumor progression in secondary and de novo grade 2 meningioma group respectively (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median time to radiological progression was 31.4 (range, 22.4\u0026ndash;41.3) months and 48.9 (range, 14.5\u0026ndash;97.7) months in secondary and de novo grade 2 meningioma group respectively. The radiological PFS at 2 and 3 years was 60% and 20%, 82% and 82% in secondary and de novo grade 2 meningioma group respectively. Secondary grade 2 meningiomas were significantly associated with poorer radiological PFS in univariate analysis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eGKRS treatment outcomes in the entire series.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcomes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSecondary grade 2 meningiomas, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDe novo grade 2 meningiomas, n (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRadiological outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor control\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (58.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor shrinkage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (58.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStable tumor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProgression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (41.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCN dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIII/IV/VI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeadache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (33.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeizure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtremity weakness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: CN, cranial nerve.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate Cox proportional hazards regression analyses for radiological progression, and clinical progression in the entire series.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRadiological progression\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical progression\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnivariate, \u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUnivariate, \u003cem\u003ep\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;55y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.096\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.196\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.911\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.539\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTumor volume\u0026thinsp;\u0026ge;\u0026thinsp;10 ml\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.566\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.343\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-skull base tumors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.529\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMargin dose\u0026thinsp;\u0026lt;\u0026thinsp;15Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.620\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.527\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaximum dose\u0026thinsp;\u0026le;\u0026thinsp;32Gy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.787\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.773\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary grade 2 meningiomas\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e0.021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.045\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e\u003csup\u003e※\u003c/sup\u003eStatistically significant (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eBoldface type indicates statistical significance.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eNine patients (50%) occurred clinical progression in the study, including headache (n\u0026thinsp;=\u0026thinsp;7), cranial nerve dysfunction (n\u0026thinsp;=\u0026thinsp;5), seizure (n\u0026thinsp;=\u0026thinsp;1) and extremity weakness (n\u0026thinsp;=\u0026thinsp;1) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The median time to clinical progression was 34.8 (range, 15.8\u0026ndash;72.2) months. There were 5 (83.3%) and 4 (33.3%) patients occurring clinical progression in secondary and de novo grade 2 meningioma group respectively. Secondary grade 2 meningiomas were related with clinical progression in univariate analysis (p\u0026thinsp;=\u0026thinsp;0.045) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSurgery is the first choice in the management of grade 2 meningiomas. However, grade 2 meningiomas are a heterogeneous group of histologically aggressive tumors, with a high incidence of tumor recurrence and progression as compared to benign meningiomas. Therefore, treatment options for tumor recurrence and progression include repeat surgery and radiotherapy. Given the increased morbidity and poor quality of life after repeat surgical resection\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, postoperative radiotherapy is advocated in the management of postoperative residual or recurrent grade 2 meningiomas.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRadiotherapy for grade 2 meningiomas\u003c/h2\u003e \u003cp\u003eAlthough adjuvant radiotherapy for atypical meningiomas after gross total resection is still on controversial, it could significantly improve tumor control rate after subtotal resection\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Mair et al\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e analyzed 114 cases of grade 2 atypical meningiomas diagnosed using 2000 WHO criteria, and reported a significant benefit after radiotherapy after subtotal resection. In the study of Jo K et al\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e, for atypical meningiomas with incomplete resection, the median interval to tumor recurrence increased from 17 months for surgery alone to 39 months for adjuvant radiotherapy.\u003c/p\u003e \u003cp\u003eSRS and fractionated external beam radiotherapy (fEBRT) are both reasonable options for postoperative residual or recurrent grade 2 meningiomas. Previous studies have reported SRS and fEBRT could offer a 3-year tumor control rate of 19%-74% \u003csup\u003e12\u0026ndash;17\u003c/sup\u003eand 45%-71% \u003csup\u003e12, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003efor grade 2 meningiomas respectively. However, studies did not find significant difference in tumor control between fEBRT and SRS\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. As SRS has the advantage of a highly precise, better dose conformity, minimizing radiation dose to surrounding tissues and shorter duration of treatments, it seems more attractive than fEBRT.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTumor control after SRS and related risk factors\u003c/h2\u003e \u003cp\u003eTumor control after SRS and related risk factors have been reported in the literatures. In the study of Choi et al\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, 25 cases of residual or recurrent atypical meningiomas treated with SRS with a median marginal dose of 22 Gy (range, 16\u0026ndash;30) in 1 to 4 fractions, the 3-year local control rate was 74%, the number of recurrences before SRS, late SRS and age at treatment\u0026thinsp;\u0026ge;\u0026thinsp;60 years were associated with recurrence after SRS on univariate analysis. In the study of Ferraro et al\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e, 31 cases of atypical meningiomas were treated with GKRS, the median time to recurrence was 27.5 months, the 3-year PFS was 70.1%, margin dose was the only significant factor related with recurrence in multivariate analysis. In the study of Pollock et al\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e, 50 cases of grade 2 (=\u0026thinsp;37) and 3 (n\u0026thinsp;=\u0026thinsp;13) treat with SRS with a median margin dose of 15 Gy. The 5-year PFS was 40%. In patients who failed prior EBRT, the 3-year PFS was 19%. Having failed EBRT was a negative predictor of PFS. In the study of Kano et al\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e, the authors found the 5-year PFS in lesions treated with SRS below 20 Gy and 20 Gy were 29.4% and 63.1% respectively. The marginal dose\u0026thinsp;\u0026lt;\u0026thinsp;20 Gy was a significant factor for PFS in high-grade meningiomas treated with SRS. Aboukais et al\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e reported 27 cases of grade 2 meningiomas treated with SRS with a median margin dose of 15.2 (range, 12\u0026ndash;21) Gy, the 3-year local control was 40%. Age and tumor volume were significantly related with local tumor control in univariate analysis.\u003c/p\u003e \u003cp\u003eIn the current study, because some tumors were close to optic chiasm and optic nerve or due to the large tumor volume, the median margin dose was 14.5 Gy and 13.5 Gy in secondary and de novo grade 2 meningioma group respectively, which might be a little lower than other studies. The radiological PFS was 74% and 55% at 2 and 3 years respectively, which was similar with other studies. The median time to radiological progression was shorter in secondary grade 2 meningioma group than de novo grade 2 meningioma group (31.4 vs 48.9 months), secondary grade 2 meningiomas were significantly related with poorer prognosis. Meningiomas with multiple recurrences and prior treatment failures are considered more aggressive and difficult to treat. However, in the current study, all of the secondary grade 2 meningiomas had at least twice surgery failures and GKRS treatment failure and were more aggressive and resistant to radiation than those de novo grade 2 meningiomas. Besides, there was no radiation-na\u0026iuml;ve patient in the secondary grade 2 meningioma group. Therefore, this could be a source of bias. Up to now, there was no standard treatment for secondary grade 2 meningiomas. Due to its poor prognosis, higher radiation dose might be helpful for better tumor control.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSecondary grade 2 meningiomas\u003c/h2\u003e \u003cp\u003eMalignant transformation is not an uncommon phenomenon in benign meningiomas. It is estimated that 20%-40% of meningiomas are secondary tumors which originated from grade 1 meningiomas\u003csup\u003e\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. As stepwise genetic progression involving in malignant transformation\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, secondary and de novo grade 2 meningiomas may behave differently. Recent studies indicated secondary meningiomas were associated with poor PFS and overall survival. In the study of Zhao et al\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, 89 cases of atypical meningiomas were reviewed. Total resection was achieved in 80.9%. Forty (44.9%) patients underwent radiotherapy after surgery. Patients with secondary atypical meningiomas showed a threefold increased risk of recurrence. Secondary atypical meningiomas were related with poor PFS on multivariate analysis. In the study of Champeaux et al\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e, 194 patients with grade 2 meningiomas were reviewed. Thirty-one patients (16%) had a previous history of grade 1 meningiomas. These patients underwent a total of 344 surgical resections and 43.3% received radiotherapy. Secondary grade 2 meningiomas were related with the surgical recurrence-free survival and overall survival. In these studies, only a part of patients underwent radiotherapy for secondary meningiomas. There was no study comparing the outcomes between secondary and de novo grade 2 meningiomas undergoing GKRS.\u003c/p\u003e \u003cp\u003eIn the current study, we did not investigate molecular markers in this study. CDKN2A/B and TERT promoter have been associated with meningioma behavior and poor prognosis\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. The 2021 WHO classification system indicates any meningioma with CDKN2A/B homozygous deletion and/or TERT promoter mutation is allotted to grade 3, irrespective of histological criteria of anaplasia\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Thus, future study needed to investigate molecular markers and genetic signatures associated with malignant transformation and prognosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStudy limitations\u003c/h2\u003e \u003cp\u003eAlthough this was the first study comparing outcomes between secondary and de novo grade 2 meningiomas undergoing GKRS, there were several limitations in the study. First, it was a single-center retrospective study with selection and treatment biases. Second, because of the rare incidence of secondary meningiomas, only 6 cases of secondary grade 2 meningiomas treated with GKRS were included in this study. The statistical power was limited by the number of cases in the study. Third, the pathological diagnosis was not based on the 2021 WHO classification system. The information of molecular markers was not available in this study. Finally, there was no radiation-na\u0026iuml;ve patient in the secondary grade 2 meningioma group. This could be a source of bias.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn this single-center retrospective study, we found secondary grade 2 meningiomas had a shorter radiological and clinical PFS after GKRS than de novo grade 2 meningiomas. The radiological PFS at 3 years was 20% and 82% in secondary and de novo grade 2 group respectively. Secondary grade 2 meningiomas were an independent risk factor for poor prognosis after GKRS. Therefore, further prospective studies should be carried out to investigate the outcomes of GKRS for secondary and de novo grade 2 meningiomas.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003efEBRT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efractionated external beam radiotherapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGRKS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGamma Knife radiosurgery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eprogression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSRS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estereotactic radiosurgery\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDeclarations of interest: none.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDili Song, Guangxin Hu and Liping Shen made research idea and designed study; Zijing Wang, Jiaming Fu and Lin Chen collected data; Xiaomin Zhou and Xinwu Liu analyzed the data; Dili Song, Jiaming Fu and Jinxiu Yu wrote the paper; Yongguang Cai and Junyi Fu revised the paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEach author contributed important content during manuscript drafting or revision and accepts accountability for the overall work, and all the authors agreed on the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by plan on enhancing scientific research in GMU; the \u0026nbsp;Basic and Applied Basic Research Fund of Guangdong Province (2021A1515110596)（2022A1515220024）; the Basic and Applied Basic Research Fund of Guangzhou science project (2024A04J3630).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are not publicly available due to part of the data in the study related to other studies, but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were reviewed and approved by the institutional committee of the Second Affiliated Hospital of Guangzhou Medical University. The patients/ participants provided their written informed consent to participate in this study. All procedures \u0026nbsp; performed were in accordance with the ethical standards of these committees and with the 1964 Declaration of Helsinki and its later amendments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eOstrom QT, Cioffi G, Gittleman H, et al. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012\u0026ndash;2016. 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Brain Pathol. 2021;31(1):61\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/bpa.12892\u003c/span\u003e\u003cspan address=\"10.1111/bpa.12892\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Gamma knife, Stereotactic radiosurgery, Meningiomas, secondary meningiomas, de novo meningiomas","lastPublishedDoi":"10.21203/rs.3.rs-4877973/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4877973/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThe purpose of this study was to compare outcomes between secondary and de novo grade 2 meningiomas undergoing Gamma Knife radiosurgery (GKRS).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eEighteen patients, including secondary grade 2 meningioma group (n\u0026thinsp;=\u0026thinsp;6) and de novo grade 2 meningioma group (n\u0026thinsp;=\u0026thinsp;12), treated with GKRS were enrolled in this single-center retrospective study.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe median tumor volume was 23.4 (range, 5.5\u0026ndash;104.0) ml and 9.4 (range, 0.4\u0026ndash;24.9) ml in secondary and de novo grade 2 meningioma group respectively (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.061). Ten patients (55.6%) experienced radiological progression with a median follow-up time of 35.7 (range, 9.4-138.2) months. The median time to radiological progression was 34.5 (range, 14.5\u0026ndash;97.7) months. The radiological progression-free survival (PFS) was 74%, 55%, and 15% at 2, 3 and 5 years respectively. The radiological PFS at 2 and 3 years was 60% and 20%, 82% and 82% in secondary and de novo grade 2 group respectively. Secondary grade 2 meningiomas were significantly related with poorer radiological PFS in univariate analysis (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021). Nine patients (50%) occurred clinical progression in the study, including headache (n\u0026thinsp;=\u0026thinsp;7), cranial nerve dysfunction (n\u0026thinsp;=\u0026thinsp;5), seizure (n\u0026thinsp;=\u0026thinsp;1) and extremity weakness (n\u0026thinsp;=\u0026thinsp;1). Secondary grade 2 meningiomas were significantly related with clinical progression in univariate analysis (p\u0026thinsp;=\u0026thinsp;0.045).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eSecondary grade 2 meningiomas had a shorter radiological and clinical PFS after GKRS than de novo grade 2 meningiomas. Secondary grade 2 meningiomas were an independent risk factor for poor prognosis after GKRS.\u003c/p\u003e","manuscriptTitle":"Comparison of outcomes of gamma knife radiosurgery for secondary and de novo grade 2 meningiomas: a single-center retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-07 12:57:14","doi":"10.21203/rs.3.rs-4877973/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-06T14:03:12+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-25T20:00:15+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-03-21T07:29:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"251355571623964604030012307018853215185","date":"2025-03-19T06:55:34+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"284141486597326579627472828940816077092","date":"2025-03-17T13:42:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"151320009716877863353630826721442594226","date":"2025-03-12T10:10:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"180587170332839588641944006782516036976","date":"2024-12-09T12:35:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-26T12:43:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-15T10:56:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"91000281183890425802207972955552890949","date":"2024-09-09T06:16:44+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"157954716593951267822424637133799172985","date":"2024-09-06T12:46:53+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-06T12:25:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-08-09T07:52:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-08-09T03:57:35+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-09T03:56:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2024-08-08T04:10:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eabe1856-ca80-4366-864c-f7bff82212b4","owner":[],"postedDate":"October 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-01T07:38:15+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-07 12:57:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4877973","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4877973","identity":"rs-4877973","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}