Re-Irradiation of Anaplastic Meningioma: Higher dose and concomitant Bevacizumab may improve progression-free survival

Re-Irradiation of Anaplastic Meningioma: Higher dose and concomitant Bevacizumab may improve progression-free survival | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Re-Irradiation of Anaplastic Meningioma: Higher dose and concomitant Bevacizumab may improve progression-free survival Ory Haisraely, Alicia Taliansky, Maayan sivan, Yaacov Lawernce This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4313040/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 02 Oct, 2024 Read the published version in Radiation Oncology → Version 1 posted 7 You are reading this latest preprint version Abstract Introduction: Anaplastic meningiomas, categorized as WHO grade 3 tumors, are rare and highly aggressive, accounting for 1%-2% of all meningioma cases. Despite aggressive treatment, including surgery and Radiation, they exhibit a high recurrence rate and poor survival outcomes. The aggressive histopathological features emphasize the urgent need for effective management strategies. Methods: A retrospective multi-institutional analysis was conducted on patients with recurrent anaplastic meningioma who underwent re-irradiation between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed, focusing on local control, progression free survival and treatment-related adverse events. Results: Thirty-four cases were analyzed, with a median follow-up 11 months after re-irradiation. Progression-free survival at 12 months was 61.9%, with higher doses correlating with better outcomes. Concomitant Bevacizumab improves progression-free survival and reduces the risk of radiation necrosis. CDKN2A homozygote deletion correlated with a higher risk of local failure. Symptomatic radiation necrosis occurred in 20.5% of cases, but its incidence was lower with concomitant Bevacizumab treatment. Conclusion: Re-irradiation presents a viable option for recurrent anaplastic meningioma despite the associated risk of radiation necrosis. Higher doses with concomitant Bevacizumab improve clinical outcomes and reduce toxicity. Individualized treatment approaches are necessary, emphasizing the importance of further research to refine management strategies for this challenging disease. Anaplastic meningioma Re-irradiation Dose escalation Bevacizumab Figures Figure 1 Figure 2 Introduction Anaplastic meningiomas, classified as(World Health Organization) WHO grade 3 tumors, represent an uncommon yet highly aggressive subset of meningiomas, constituting only 1%-2% of all meningioma cases. 1 Distinguished by their particularly malignant clinical course, anaplastic meningiomas pose a significant therapeutic challenge, marked by a propensity for local recurrence and an overall poor survival outcome. Despite advancements in neuro-oncology, these tumors exhibit a 3-year progression rate of 59.2%, even following gross total resection and adjuvant Radiation, with an associated overall survival of 78.6%. 2 The histopathological hallmark of anaplastic meningioma is high mitotic activity, cellular atypia, and frequent necrosis, with 2021 WHO incorporating genomics and molecular data into this classification. 3 , 4 These aggressive features underscore the urgent need for effective management strategies, especially in recurrent diseases, where treatment guidelines are notably scarce. Literature on the toxicity associated with re-irradiation in this specific clinical setting is conspicuously limited, accentuating the necessity for a comprehensive evaluation of outcomes related to local control, overall survival, and treatment-related adverse events. In this multi-institutional analysis, we aim to address the existing knowledge gap by systematically examining re-irradiation outcomes in cases of recurrent anaplastic meningioma. Our focus extends beyond survival metrics to encompass factors influencing local control and the potential toxicities associated with re-irradiation. Methods Following institutional review board approval, a retrospective review was conducted on patients undergoing re-irradiation for recurrent or progressive anaplastic meningioma at three major medical centers between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed. The biological effective dose was calculated using an alpha-beta ratio of 10. Kaplan-Meier and Cox regression analyses were performed to describe hazard ratios for local control and survival, utilizing SPSS software (IBM, Chicago, USA version 29). All pathological data were re-analyzed by central evaluation to ensure that both pathologies represented anaplastic meningioma as defined by the WHO 2021 classification. All pathological specimens were also analyzed using fluorescent in-situ hybridization to evaluate 1P del and CDKN2A deletion status (defined as deletion if more than 50%). Local progression was defiend by The Response Assessment in Neuro-Oncology (RANO) 2.0 criteria 5 . Results Thirty-four cases of recurrent anaplastic meningioma that received a second course of Radiation were analyzed. All re-radiation treatments were in field recurrence. The median time from the first radiation course was 11 months (7–25 months). The average age was 57.2, with 55.8% being females. Mitotic rate was the diagnostic criterion for 70% of patients, with 10 exhibiting CDKN2A homozygote deletions. For the initial presentation, 88% underwent gross tumor resection (Simpson 1–3) and received Radiation with a median dose of 60Gy (54-60Gy), translating to a biologically effective dose (using an alpha/beta ratio of 10) of 72Gy (64.8–72). In the recurrent setting, 73% underwent a second surgery (Simpson > 3), and all patients received a second course of Radiation with a median dose of 48.8Gy (range 31.2–56). In 47% of patients, the 2nd(radiation therapy) RT dose was higher than 50Gy biological effective e dose (BED ). In all radiation planning, the clinical target volume (CTV) was defined as the disease identified on a T1 + G MRI with a planning target volume(PTV) between 0.3 cm and 0.5 cm isotropic expansion. Bevacizumab (Bev) was administered concomitantly in 35.3% of cases. The median follow-up from the second Radiation was 13 months (range 5–28), and progression-free survival at 12 months was 61.9%. Impact of dose The average dose was higher for those who achieved local control than those who did not (51.4Gy vs 42.6Gy, p < 0.001). Among patients who achieved local control, 68.1% received a dose higher than 50Gy; in comparison, only one patient who received the 2nd RT dose above 50Gy had a local failure and received a dose lower than 50Gy (p = 0.012). There was no significant difference in other variables between those who received more than 50Gy and those who did not. Patients who received an RT dose above 50Gy (BED) were less likely to progress with an HR = 0.3 {CI95% 0.045-0.8}. higher dose above 50gy improve progression free survival (p = 0.03). Figure 1 . Impact of surgery second surgery did not impact Progreession-free survival outcomes in our cohort with HR 0.36 (0.2–1.27, p = 0.109). Figure 1 . All second surgeries were classified as Simpson grading 1–3. Age (median 51 years VS 69 years) and tumor location (parietal more prevalent in those who underwent second surgery and frontal in those who did not) were the only variables differing between those who underwent second surgery and those who did not. Impact of Bevacizumab Most (66%) of the patients receiving Bevacizumab concomitant with 2nd RT received it because they experienced neurological symptoms related to mass effect secondary to edema. The remaining four patients received it due to physician preference. A statistical trend for improving progression-free survival did not reach statistical significance with using Bevacizumab. All univariable analyses and Kaplan Mair are shown in Table 2 and Fig. 1 . Table 1 patient's characteristics n 34 Age 57.2y (37–74) Location of primary tumor Frontal Parietal Temporal Occipital Base of skull 18 10 4 1 1 Type of resection 1st surgery (Simpson) 1–2 3–4 5 12 20 2 Reason for WHO 3 Histopathology criteria CDKN2A deletion Mitotic > 20 16 10 24 1p loss (more than 50%) 55.8% Karnofsky status 80 (70–100) Total dose deliver 1st 60Gy (54–60) 2nd surgery (yes) 25 (73%) Total dose deliver 2nd 35Gy (25-40.05) Number of fractions 10 (5–15) BED 2nd RT (α/β = 10) Median, range 48.8 (31.2–56) Bed > 50Gy 16 (47%) concomitant Bevacizumab (yes)% 12 (35.3%) PTV 2 ND RT 35cc (11.5-212.4cc) Median follow up (range) 13 (5–28 months) Table 2 Univariable analysis for local progression Variable HR (CI95%) P RT > 50gy 0.3 (0.045-0.8) 0.03 2 ND surgery (yes) 0.39 (0.12–1.2) 0.109 Bevacizumab concomittemt (yes) 0.27 (0.06–1.27) 0.1 CDKN2A homozygous deletion (yes) 11 (3.1–38.4) < 0.001 Multivariable Cox regression model. When incorporating both Bevacziuamb use and dose distribution, we created four different groups. Among the groups, patients who received a dose above 50Gy concomitant with Bevacizumab had no local progression at one year in our cohort. Patients who received a dose above 50Gy and did not receive Bevacizumab had 25% 1-year local Patients who received Bevacizumab with a dose lower than 50Gy had a 40% local progression. Finally, patients who did not receive a dose above 50Gy and did not receive Bevacizumab had 53% local progression at one year. There was a significant change in progression-free survival ( PFS) between groups (p = 0.035). Kaplan Mair curves for all four groups are shown in Fig. 2 . Impact of histopathological data and genetic factors Ten patients had CDK2NA homozygote deletion. Having CDKN2A homozygote deletion increased the hazard ratio for PFS by 11.1 (3.1–38.4), p < 0.001. There was no influence on 1P status or mitotic activity. Toxicity report There was a 20.5% incidence of symptomatic radiation necrosis (RN). Most cases (71.4%) presented with headache. In addition, 1 with seizure, and 1 with confusion and disinhibition. All patients with symptomatic RN improved with dexamethasone treatment. A combined dose for both 1st and 2nd radiation treatment of more than 120Gy (BED) increased the odds for RN (HR-2.4 {1.3–4.1) There were no cases of RN in those who received Bevacizumab concomitant with RT in the recurrent setting. Discussion Reoperation Surgical intervention alleviates the mass effect, relieves associated neurological symptoms, decreases the risk of recurrence, and provides for diagnosis and molecular characterization.5 All of these factors are important when discussing the advantages of reoperation. However, despite plentiful data on the morbidity and mortality associated with initial meningioma resection, information on re-resection in recurrent cases still needs to be determined. A recent analysis found that 48% of the reoperation cases experienced at least one complication in their postoperative care. Pre-radiation tumor location and the experience of the neurosurgical team are essential variables in this context. 6 , 7 Genomic factors In our cohort, ten patients had CDKN2NA homozygote deletion (more than 50%). With the recent 2021 update of the WHO Classification of Central Nervous System Tumors, homozygous deletions of CDKN2A/B are sufficient to classify meningiomas as CNS WHO grade 3 tumors regardless of histological grading. 3 Meningiomas harboring homozygous deletions of CDKN2A/B are characterized by high recurrence rates independent of WHO grade, DNA methylation class, sex, age, and tumor location. 4 Additionally, heterozygous loss, mutations, and promoter methylation of CDKN2A were strongly associated with recurrent meningiomas and a high Ki-67 index. 8 Physiologically, the proteins encoded by CDKN2A/B halt the cell cycle; consequently, homozygous loss leads to dysregulated cell cycle progression and uncontrolled proliferation. 8 In our cohort, a strong relationship was observed between disease recurrence after 2nd RT and CDKN2a Del. Anaplastic meningioma with CDKN2A loss has a poor prognosis, even in re-radiation. Dose regiment and Bevacizumab treatment The optimal RT approach for grade 3 meningioma in the recurrent setting remains controversial regarding clinical target volume (CTV) margins and dose prescription. Regarding dosage regimens for in-field recurrence, data on hypofractionation treatment and stereotactic radiosurgery exist, primarily relating to atypical rather than anaplastic meningioma. The dose-response relationship is more established in anaplastic meningioma, as evidenced by publications in the adjuvant setting. Pontoriero et al. demonstrated that in 16 patients who received 72.5 Gy EQD2, treated with a combination of IMRT and radiosurgery, a 3-year PFS of 75% in sub-totally resected or recurrent grade 2 meningioma. 9 Lee et al., In a cohort of 21 patients who received IMRT to a median GTV dose of 66 Gy (range, 63–69 Gy), reported 3- and 5-year PFS rates of 88.4% and 73.5%. With a mixed photon/proton technique, 10 Chan et al. escalated doses to 68.4 to 72 Gy and found that 5 of the six patients with grade 2 or 3 meningioma achieved long-term local control at a mean follow-up of 145 months. 11 Moreover, most recently, Zhen et al. concluded that the dose-escalation cohort (≥ 66 Gy equivalent dose) improves local control and PFS (HR-0.42). 10 Dose escalation above 50Gy (BED), for example, 40Gy in 10 fractions or 32.5Gy in 5 fractions, appears crucial for improving progression-free survival at the cost of a high RN rate. Concomitant RT with BEV in anaplastic glioma is a rare practice. This practice is an extrapolation from managing recurrent high-grade gliomas, particularly the 1205 RTOG trial, which showed improved progression-regression-free survival with the combination of RT and BEV versus BEV alone. 12 Our data showed improvement in ln progression-free survival with the use of BEV. The group with the best oncology results was the group for which both a higher dose was given and a Bevacizumab concomitant treatment with no progression after one year of follow-up. In addition, an interesting observation was the decreased incidence of RNs using BEV. With Second RT, one of the significant side effects is RN, which has been reported to rise to 25% for cumulative EQD2 > 130 Gy using an α/β ratio of 2Gy for a normal healthy brain. The use of BEV has been shown to improve radiation necrosis. A recent meta-analysis reported that radiographic responses were recorded in 84.7% of patients, and clinical improvement was observed in 91%. 13 One limitation of Bevacizumab is its side effects and the chance of increasing surgical complications. 14 In our cohort, most of the patients who received concomitant Bevacizumab did not undergo a second surgery, so perhaps increasing the dose with concomitant Bevacizumab can be more relevant for patients for whom second surgery is not possible. Strengths and limitations Our study has several limitations. The rarity of this presentation limited Our sample size. Additionally, the retrospective nature of this study identified only patients with complete clinical and dosimetric data, potentially introducing record bias. The small sample size limited our ability to perform multivariable analysis. Nevertheless, the strength of our study lies in collecting data from multiple hospitals, with thorough reviews of surgical reports and plans. All histopathological data underwent review, and genomic analyses were performed to classify anaplastic meningioma according to the WHO 2021 classification. Conclusions Anaplastic meningioma is a rare disease characterized by a poor prognosis and lacks established guidelines for recurrent disease management. Re-irradiation presents a viable option, albeit with a 20% risk of symptomatic RN, particularly if the combined dose exceeds 120Gy. CDKN2A status is pivotal for achieving progression-free survival in the recurrent setting. Concomitant BEV administration improves progression-free survival and reduces the risk of radiation necrosis. Further research is warranted to refine strategies for managing recurrent anaplastic meningioma, emphasizing individualized treatment approaches. . Abbreviations WHO-worls health organization RT-radiation therapy PFS-progression free survival Bev-Bevacizumab CTV-clinical target volume PTV-Planning target volume Declarations IRB approval was given to this study (0265-23-smc) No funding was provided to this study The datasets used and/or analysed during the current study are available from the corresponding author on reasonable reques There is No competing intrests Humen athics and consent to participate:not apllicable. References D Louis E et al, The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathologica, 2016 131(6), 803-820. CL Rogers et al , High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539, Int J Radiat Oncol Biol Phyc, 2020 Mar 15;106(4):790-799. D Louis et al, The 2021 WHO Classification of Tumors of the Central Nervous System: a summary, Neuro Oncol. 2021 Aug; 23(8): 1231–1251. DO Seo et al, Anaplastic Meningioma: Clinical Characteristics, Prognostic Factors and Survival Outcome, Brain Tumor Res Treat. 2022 Oct; 10(4): 244–254 P wen et al, RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults, Journal of Clinical Oncology, Sep, 2023, Volume 41, Number 33 Bi W et al, Oncologic and functional outcomes and complications after reoperation for recurrent skull base meningiomas. Journal of Neurosurgery,2019, 130(1), 25-34 . Karsy M et al, Second Surgery for Recurrent Meningiomas and Outcome Predictors. World Neurosurgery,2017, 107, 378-387. J wach et al, CDKN2A/B deletions are strongly associated with meningioma progression: a meta-analysis of individual patient data, Acta Neuropathol Commun. 2023; 11: 189. Pontorerio A et al, The "Combo" radiotherapy treatment for high-risk grade 2 meningiomas: dose escalation and initial safety and efficacy analysis, J Neurooncol, 2023 Jan;161(2):203-214 Zheng W et al , Intensity-modulated radiotherapy with more than 60 Gy improved the survival of inoperable patients with locally advanced esophageal squamous cell carcinoma: A population-based real-world study, Medicine (Baltimore ( , 2022 Apr 22;101(16):e29166 Chan AW et al, Dose escalation with proton radiation therapy for high-grade meningiomas. Technol Cancer Res Treat. 2012;11:607–614. doi: 10.7785/tcrt.2012.500267 CL Tesien et al, NRG Oncology/RTOG1205: A Randomized Phase II Trial of Concurrent Bevacizumab and Reirradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma, J Clin Oncol, 2023 Feb 20;41(6):1285-1295 G Liao et al, Bevacizumab Treatment of Radiation-Induced Brain Necrosis: A Systematic Review, Front Oncol. 2021; 11: 593449 M weller et al, Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults, Neuro-Oncology, Volume 25, Issue 7, July 2023, Pages 1200–1224 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 02 Oct, 2024 Read the published version in Radiation Oncology → Version 1 posted Editorial decision: Accepted 06 Jul, 2024 Reviews received at journal 16 Jun, 2024 Reviewers agreed at journal 14 Jun, 2024 Reviewers invited by journal 04 Jun, 2024 Editor assigned by journal 26 Apr, 2024 Submission checks completed at journal 25 Apr, 2024 First submitted to journal 23 Apr, 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. 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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-4313040","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":295727748,"identity":"efadc8d5-7240-421f-b677-c82d0b78b53a","order_by":0,"name":"Ory Haisraely","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIie2RsYrCQBCGZxmJTby0LnucrzApAyc+S7D1uHuCkCOwaaK1V/kW1hdS2OQBAluojZVF7MKR4jaCYKNJKbhfM1P8H8PwAxgMDwmTANQsGEKph9XvrrCQLRsF289YFzdE+3ytJe+ITO6qr+DTib+leP9bj14QWHma3Vb4wo/dhDJvmadSfCyUKxGQ/6xvK5QzObTpl6DwtZIophULBy0Krymg0XYvhZeoSSdF2IREhV6gUn6rwhOdfKWM3NyPvHmophJZdPcXx+4f+LEO6G2TpUVVq/EqjtLydEe5pjdsam0K6pbXYAl157DBYDA8Ef+eSE1bOS+RjQAAAABJRU5ErkJggg==","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Ory","middleName":"","lastName":"Haisraely","suffix":""},{"id":295727749,"identity":"9e2f3606-e691-4a07-8c0c-8e056155cd7b","order_by":1,"name":"Alicia Taliansky","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Alicia","middleName":"","lastName":"Taliansky","suffix":""},{"id":295727750,"identity":"360aa5da-02b5-4db5-bec9-14875f89997d","order_by":2,"name":"Maayan sivan","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Maayan","middleName":"","lastName":"sivan","suffix":""},{"id":295727751,"identity":"a6e88177-5c90-4a3f-9419-ca98b9f8610a","order_by":3,"name":"Yaacov Lawernce","email":"","orcid":"","institution":"Sheba Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yaacov","middleName":"","lastName":"Lawernce","suffix":""}],"badges":[],"createdAt":"2024-04-23 15:26:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4313040/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4313040/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13014-024-02486-7","type":"published","date":"2024-10-02T15:57:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55639563,"identity":"4df9fe68-8737-4998-be5e-cc1f8f6763e4","added_by":"auto","created_at":"2024-04-30 22:10:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":438565,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4313040/v1/9a37580ceaae72bf321d076c.png"},{"id":55639562,"identity":"a0bccbb0-56ad-4236-877f-62fc0a7c95c3","added_by":"auto","created_at":"2024-04-30 22:10:27","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":220392,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4313040/v1/d882db431bbdf8a3719b493a.png"},{"id":66097112,"identity":"5b9e5ede-be0a-4820-bccf-d783ed83cccf","added_by":"auto","created_at":"2024-10-07 16:13:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1132850,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4313040/v1/cb6f4240-f5a2-47f2-b53a-ff236ed590e4.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRe-Irradiation of Anaplastic Meningioma: Higher dose and concomitant Bevacizumab may improve progression-free survival\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAnaplastic meningiomas, classified as(World Health Organization) WHO grade 3 tumors, represent an uncommon yet highly aggressive subset of meningiomas, constituting only 1%-2% of all meningioma cases.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Distinguished by their particularly malignant clinical course, anaplastic meningiomas pose a significant therapeutic challenge, marked by a propensity for local recurrence and an overall poor survival outcome. Despite advancements in neuro-oncology, these tumors exhibit a 3-year progression rate of 59.2%, even following gross total resection and adjuvant Radiation, with an associated overall survival of 78.6%.\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe histopathological hallmark of anaplastic meningioma is high mitotic activity, cellular atypia, and frequent necrosis, with 2021 WHO incorporating genomics and molecular data into this classification.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e These aggressive features underscore the urgent need for effective management strategies, especially in recurrent diseases, where treatment guidelines are notably scarce. Literature on the toxicity associated with re-irradiation in this specific clinical setting is conspicuously limited, accentuating the necessity for a comprehensive evaluation of outcomes related to local control, overall survival, and treatment-related adverse events.\u003c/p\u003e \u003cp\u003eIn this multi-institutional analysis, we aim to address the existing knowledge gap by systematically examining re-irradiation outcomes in cases of recurrent anaplastic meningioma. Our focus extends beyond survival metrics to encompass factors influencing local control and the potential toxicities associated with re-irradiation.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e Following institutional review board approval, a retrospective review was conducted on patients undergoing re-irradiation for recurrent or progressive anaplastic meningioma at three major medical centers between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed. The biological effective dose was calculated using an alpha-beta ratio of 10. Kaplan-Meier and Cox regression analyses were performed to describe hazard ratios for local control and survival, utilizing SPSS software (IBM, Chicago, USA version 29). All pathological data were re-analyzed by central evaluation to ensure that both pathologies represented anaplastic meningioma as defined by the WHO 2021 classification. All pathological specimens were also analyzed using fluorescent in-situ hybridization to evaluate 1P del and CDKN2A deletion status (defined as deletion if more than 50%). Local progression was defiend by The Response Assessment in Neuro-Oncology (RANO) 2.0 criteria\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThirty-four cases of recurrent anaplastic meningioma that received a second course of Radiation were analyzed. All re-radiation treatments were in field recurrence. The median time from the first radiation course was 11 months (7\u0026ndash;25 months). The average age was 57.2, with 55.8% being females. Mitotic rate was the diagnostic criterion for 70% of patients, with 10 exhibiting CDKN2A homozygote deletions. For the initial presentation, 88% underwent gross tumor resection (Simpson 1\u0026ndash;3) and received Radiation with a median dose of 60Gy (54-60Gy), translating to a biologically effective dose (using an alpha/beta ratio of 10) of 72Gy (64.8\u0026ndash;72). In the recurrent setting, 73% underwent a second surgery (Simpson\u0026thinsp;\u0026gt;\u0026thinsp;3), and all patients received a second course of Radiation with a median dose of 48.8Gy (range 31.2\u0026ndash;56). In 47% of patients, the 2nd(radiation therapy) RT dose was higher than 50Gy biological effective e dose (BED ). In all radiation planning, the clinical target volume (CTV) was defined as the disease identified on a T1\u0026thinsp;+\u0026thinsp;G MRI with a planning target volume(PTV) between 0.3 cm and 0.5 cm isotropic expansion.\u003c/p\u003e\n\u003cp\u003eBevacizumab (Bev) was administered concomitantly in 35.3% of cases.\u003c/p\u003e\n\u003cp\u003eThe median follow-up from the second Radiation was 13 months (range 5\u0026ndash;28), and progression-free survival at 12 months was 61.9%.\u003c/p\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n \u003ch2\u003eImpact of dose\u003c/h2\u003e\n \u003cp\u003eThe average dose was higher for those who achieved local control than those who did not (51.4Gy vs 42.6Gy, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Among patients who achieved local control, 68.1% received a dose higher than 50Gy; in comparison, only one patient who received the 2nd RT dose above 50Gy had a local failure and received a dose lower than 50Gy (p\u0026thinsp;=\u0026thinsp;0.012). There was no significant difference in other variables between those who received more than 50Gy and those who did not. Patients who received an RT dose above 50Gy (BED) were less likely to progress with an HR\u0026thinsp;=\u0026thinsp;0.3 {CI95% 0.045-0.8}. higher dose above 50gy improve progression free survival (p\u0026thinsp;=\u0026thinsp;0.03). Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\n \u003ch2\u003eImpact of surgery\u003c/h2\u003e\n \u003cp\u003esecond surgery did not impact Progreession-free survival outcomes in our cohort with HR 0.36 (0.2\u0026ndash;1.27, p\u0026thinsp;=\u0026thinsp;0.109). Figure \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. All second surgeries were classified as Simpson grading 1\u0026ndash;3. Age (median 51 years VS 69 years) and tumor location (parietal more prevalent in those who underwent second surgery and frontal in those who did not) were the only variables differing between those who underwent second surgery and those who did not.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n \u003ch2\u003eImpact of Bevacizumab\u003c/h2\u003e\n \u003cp\u003eMost (66%) of the patients receiving Bevacizumab concomitant with 2nd RT received it because they experienced neurological symptoms related to mass effect secondary to edema. The remaining four patients received it due to physician preference. A statistical trend for improving progression-free survival did not reach statistical significance with using Bevacizumab.\u003c/p\u003e\n \u003cp\u003eAll univariable analyses and Kaplan Mair are shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\u0026nbsp;\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\u003epatient\u0026apos;s characteristics\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e34\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\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57.2y (37\u0026ndash;74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocation of primary tumor\u003c/p\u003e\n \u003cp\u003eFrontal\u003c/p\u003e\n \u003cp\u003eParietal\u003c/p\u003e\n \u003cp\u003eTemporal\u003c/p\u003e\n \u003cp\u003eOccipital\u003c/p\u003e\n \u003cp\u003eBase of skull\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eType of resection 1st surgery (Simpson)\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;2\u003c/p\u003e\n \u003cp\u003e3\u0026ndash;4\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReason for WHO 3\u003c/p\u003e\n \u003cp\u003eHistopathology criteria\u003c/p\u003e\n \u003cp\u003eCDKN2A deletion\u003c/p\u003e\n \u003cp\u003eMitotic\u0026thinsp;\u0026gt;\u0026thinsp;20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1p loss (more than 50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eKarnofsky status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e80 (70\u0026ndash;100)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal dose deliver 1st\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60Gy (54\u0026ndash;60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2nd surgery (yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (73%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTotal dose deliver 2nd\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35Gy (25-40.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNumber of fractions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (5\u0026ndash;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBED 2nd RT (\u0026alpha;/\u0026beta;\u0026thinsp;=\u0026thinsp;10) Median, range\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e48.8 (31.2\u0026ndash;56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBed\u0026thinsp;\u0026gt;\u0026thinsp;50Gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003econcomitant Bevacizumab (yes)%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (35.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePTV 2\u003csup\u003eND\u003c/sup\u003e RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35cc (11.5-212.4cc)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian follow up (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (5\u0026ndash;28 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u0026nbsp;\u0026nbsp;\u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eUnivariable analysis for local progression\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHR (CI95%)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eP\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\u003eRT\u0026thinsp;\u0026gt;\u0026thinsp;50gy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.3 (0.045-0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003csup\u003eND\u003c/sup\u003e surgery (yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.39 (0.12\u0026ndash;1.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.109\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBevacizumab concomittemt (yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.27 (0.06\u0026ndash;1.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDKN2A homozygous deletion (yes)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (3.1\u0026ndash;38.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eMultivariable Cox regression model.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003c/p\u003e\n \u003cp\u003eWhen incorporating both Bevacziuamb use and dose distribution, we created four different groups. Among the groups, patients who received a dose above 50Gy concomitant with Bevacizumab had no local progression at one year in our cohort. Patients who received a dose above 50Gy and did not receive Bevacizumab had 25% 1-year local Patients who received Bevacizumab with a dose lower than 50Gy had a 40% local progression. Finally, patients who did not receive a dose above 50Gy and did not receive Bevacizumab had 53% local progression at one year. There was a significant change in progression-free survival ( PFS) between groups (p\u0026thinsp;=\u0026thinsp;0.035). Kaplan Mair curves for all four groups are shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eImpact of histopathological data and genetic factors\u003c/h2\u003e\n \u003cp\u003eTen patients had CDK2NA homozygote deletion. Having CDKN2A homozygote deletion increased the hazard ratio for PFS by 11.1 (3.1\u0026ndash;38.4), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001. There was no influence on 1P status or mitotic activity.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eToxicity report\u003c/h2\u003e\n \u003cp\u003eThere was a 20.5% incidence of symptomatic radiation necrosis (RN). Most cases (71.4%) presented with headache. In addition, 1 with seizure, and 1 with confusion and disinhibition. All patients with symptomatic RN improved with dexamethasone treatment. A combined dose for both 1st and 2nd radiation treatment of more than 120Gy (BED) increased the odds for RN (HR-2.4 {1.3\u0026ndash;4.1)\u003c/p\u003e\n \u003cp\u003eThere were no cases of RN in those who received Bevacizumab concomitant with RT in the recurrent setting.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eReoperation\u003c/h2\u003e \u003cp\u003eSurgical intervention alleviates the mass effect, relieves associated neurological symptoms, decreases the risk of recurrence, and provides for diagnosis and molecular characterization.5 All of these factors are important when discussing the advantages of reoperation. However, despite plentiful data on the morbidity and mortality associated with initial meningioma resection, information on re-resection in recurrent cases still needs to be determined. A recent analysis found that 48% of the reoperation cases experienced at least one complication in their postoperative care. Pre-radiation tumor location and the experience of the neurosurgical team are essential variables in this context. \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eGenomic factors\u003c/h2\u003e \u003cp\u003eIn our cohort, ten patients had CDKN2NA homozygote deletion (more than 50%). With the recent 2021 update of the WHO Classification of Central Nervous System Tumors, homozygous deletions of \u003cem\u003eCDKN2A/B\u003c/em\u003e are sufficient to classify meningiomas as CNS WHO grade 3 tumors regardless of histological grading.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Meningiomas harboring homozygous deletions of \u003cem\u003eCDKN2A/B\u003c/em\u003e are characterized by high recurrence rates independent of WHO grade, DNA methylation class, sex, age, and tumor location. \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Additionally, heterozygous loss, mutations, and promoter methylation of \u003cem\u003eCDKN2A\u003c/em\u003e were strongly associated with recurrent meningiomas and a high Ki-67 index.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003ePhysiologically, the proteins encoded by \u003cem\u003eCDKN2A/B\u003c/em\u003e halt the cell cycle; consequently, homozygous loss leads to dysregulated cell cycle progression and uncontrolled proliferation.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e In our cohort, a strong relationship was observed between disease recurrence after 2nd RT and CDKN2a Del. Anaplastic meningioma with CDKN2A loss has a poor prognosis, even in re-radiation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDose regiment and Bevacizumab treatment\u003c/h2\u003e \u003cp\u003eThe optimal RT approach for grade 3 meningioma in the recurrent setting remains controversial regarding clinical target volume (CTV) margins and dose prescription. Regarding dosage regimens for in-field recurrence, data on hypofractionation treatment and stereotactic radiosurgery exist, primarily relating to atypical rather than anaplastic meningioma.\u003c/p\u003e \u003cp\u003eThe dose-response relationship is more established in anaplastic meningioma, as evidenced by publications in the adjuvant setting. Pontoriero et al. demonstrated that in 16 patients who received 72.5 Gy EQD2, treated with a combination of IMRT and radiosurgery, a 3-year PFS of 75% in sub-totally resected or recurrent grade 2 meningioma.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Lee et al., In a cohort of 21 patients who received IMRT to a median GTV dose of 66 Gy (range, 63\u0026ndash;69 Gy), reported 3- and 5-year PFS rates of 88.4% and 73.5%. With a mixed photon/proton technique,\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003eChan et al. escalated doses to 68.4 to 72 Gy and found that 5 of the six patients with grade 2 or 3 meningioma achieved long-term local control at a mean follow-up of 145 months.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e Moreover, most recently, Zhen et al. concluded that the dose-escalation cohort (\u0026ge;\u0026thinsp;66 Gy equivalent dose) improves local control and PFS (HR-0.42). \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDose escalation above 50Gy (BED), for example, 40Gy in 10 fractions or 32.5Gy in 5 fractions, appears crucial for improving progression-free survival at the cost of a high RN rate.\u003c/p\u003e \u003cp\u003eConcomitant RT with BEV in anaplastic glioma is a rare practice. This practice is an extrapolation from managing recurrent high-grade gliomas, particularly the 1205 RTOG trial, which showed improved progression-regression-free survival with the combination of RT and BEV versus BEV alone. \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOur data showed improvement in ln progression-free survival with the use of BEV. The group with the best oncology results was the group for which both a higher dose was given and a Bevacizumab concomitant treatment with no progression after one year of follow-up.\u003c/p\u003e \u003cp\u003eIn addition, an interesting observation was the decreased incidence of RNs using BEV.\u003c/p\u003e \u003cp\u003eWith Second RT, one of the significant side effects is RN, which has been reported to rise to 25% for cumulative EQD2\u0026thinsp;\u0026gt;\u0026thinsp;130 Gy using an α/β ratio of 2Gy for a normal healthy brain. The use of BEV has been shown to improve radiation necrosis. A recent meta-analysis reported that radiographic responses were recorded in 84.7% of patients, and clinical improvement was observed in 91%.\u003csup\u003e13\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eOne limitation of Bevacizumab is its side effects and the chance of increasing surgical complications.\u003csup\u003e14\u003c/sup\u003e In our cohort, most of the patients who received concomitant Bevacizumab did not undergo a second surgery, so perhaps increasing the dose with concomitant Bevacizumab can be more relevant for patients for whom second surgery is not possible.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStrengths and limitations\u003c/h2\u003e \u003cp\u003eOur study has several limitations. The rarity of this presentation limited Our sample size. Additionally, the retrospective nature of this study identified only patients with complete clinical and dosimetric data, potentially introducing record bias. The small sample size limited our ability to perform multivariable analysis. Nevertheless, the strength of our study lies in collecting data from multiple hospitals, with thorough reviews of surgical reports and plans. All histopathological data underwent review, and genomic analyses were performed to classify anaplastic meningioma according to the WHO 2021 classification.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003e\u003cem\u003eAnaplastic meningioma\u003c/em\u003e is a rare disease characterized by a poor prognosis and lacks established guidelines for recurrent disease management. Re-irradiation presents a viable option, albeit with a 20% risk of symptomatic RN, particularly if the combined dose exceeds 120Gy. CDKN2A status is pivotal for achieving progression-free survival in the recurrent setting. Concomitant BEV administration improves progression-free survival and reduces the risk of radiation necrosis. Further research is warranted to refine strategies for managing recurrent anaplastic meningioma, emphasizing individualized treatment approaches.\u003c/p\u003e \u003cp\u003e.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eWHO-worls health organization\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eRT-radiation therapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePFS-progression free survival\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBev-Bevacizumab\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCTV-clinical target volume\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePTV-Planning target volume\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eIRB approval was given to this study (0265-23-smc)\u003c/p\u003e\n\u003cp\u003eNo funding was provided to this study\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable reques\u003c/p\u003e\n\u003cp\u003eThere is No competing intrests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHumen athics and consent to participate:not apllicable.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eD Louis E et al, The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathologica, 2016 131(6), 803-820.\u003c/li\u003e\n\u003cli\u003eCL Rogers et al , High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539, Int J Radiat Oncol Biol Phyc, 2020 Mar 15;106(4):790-799.\u003c/li\u003e\n\u003cli\u003eD Louis et al, The 2021 WHO Classification of Tumors of the Central Nervous System: a summary, Neuro Oncol. 2021 Aug; 23(8): 1231\u0026ndash;1251.\u003c/li\u003e\n\u003cli\u003eDO Seo et al, Anaplastic Meningioma: Clinical Characteristics, Prognostic Factors and Survival Outcome, Brain Tumor Res Treat. 2022 Oct; 10(4): 244\u0026ndash;254\u003c/li\u003e\n\u003cli\u003eP wen et al, RANO 2.0: Update to the Response Assessment in Neuro-Oncology Criteria for High- and Low-Grade Gliomas in Adults, Journal of Clinical Oncology, Sep, 2023, Volume 41, Number 33\u003c/li\u003e\n\u003cli\u003eBi W et al, Oncologic and functional outcomes and complications after reoperation for recurrent skull base meningiomas. Journal of Neurosurgery,2019, 130(1), 25-34\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eKarsy M et al, Second Surgery for Recurrent Meningiomas and Outcome Predictors. World Neurosurgery,2017, 107, 378-387.\u003c/li\u003e\n\u003cli\u003eJ wach et al, CDKN2A/B deletions are strongly associated with meningioma progression: a meta-analysis of individual patient data, Acta Neuropathol Commun. 2023; 11: 189.\u003c/li\u003e\n\u003cli\u003ePontorerio A et al, The \u0026quot;Combo\u0026quot; radiotherapy treatment for high-risk grade 2 meningiomas: dose escalation and initial safety and efficacy analysis, J Neurooncol, 2023 Jan;161(2):203-214\u003c/li\u003e\n\u003cli\u003eZheng W et al , Intensity-modulated radiotherapy with more than 60 Gy improved the survival of inoperable patients with locally advanced esophageal squamous cell carcinoma: A population-based real-world study, Medicine (Baltimore\u003cspan dir=\"RTL\"\u003e(\u003c/span\u003e, 2022 Apr 22;101(16):e29166\u003c/li\u003e\n\u003cli\u003eChan AW et al, Dose escalation with proton radiation therapy for high-grade meningiomas. \u003cem\u003eTechnol Cancer Res Treat. \u003c/em\u003e2012;11:607\u0026ndash;614. doi: 10.7785/tcrt.2012.500267\u003c/li\u003e\n\u003cli\u003eCL Tesien et al, NRG Oncology/RTOG1205: A Randomized Phase II Trial of Concurrent Bevacizumab and Reirradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma, J Clin Oncol, 2023 Feb 20;41(6):1285-1295\u003c/li\u003e\n\u003cli\u003eG Liao et al, Bevacizumab Treatment of Radiation-Induced Brain Necrosis: A Systematic Review, Front Oncol. 2021; 11: 593449\u003c/li\u003e\n\u003cli\u003eM weller et al, Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults, Neuro-Oncology, Volume 25, Issue 7, July 2023, Pages 1200\u0026ndash;1224\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":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anaplastic meningioma, Re-irradiation, Dose escalation, Bevacizumab ","lastPublishedDoi":"10.21203/rs.3.rs-4313040/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4313040/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction:\u003c/p\u003e \u003cp\u003eAnaplastic meningiomas, categorized as WHO grade 3 tumors, are rare and highly aggressive, accounting for 1%-2% of all meningioma cases. Despite aggressive treatment, including surgery and Radiation, they exhibit a high recurrence rate and poor survival outcomes. The aggressive histopathological features emphasize the urgent need for effective management strategies.\u003c/p\u003e \u003cp\u003eMethods:\u003c/p\u003e \u003cp\u003eA retrospective multi-institutional analysis was conducted on patients with recurrent anaplastic meningioma who underwent re-irradiation between 2017 and 2023. Clinical, dosimetric, and outcome data were collected and analyzed, focusing on local control, progression free survival and treatment-related adverse events.\u003c/p\u003e \u003cp\u003eResults:\u003c/p\u003e \u003cp\u003eThirty-four cases were analyzed, with a median follow-up 11 months after re-irradiation. Progression-free survival at 12 months was 61.9%, with higher doses correlating with better outcomes. Concomitant Bevacizumab improves progression-free survival and reduces the risk of radiation necrosis. CDKN2A homozygote deletion correlated with a higher risk of local failure. Symptomatic radiation necrosis occurred in 20.5% of cases, but its incidence was lower with concomitant Bevacizumab treatment.\u003c/p\u003e \u003cp\u003eConclusion:\u003c/p\u003e \u003cp\u003eRe-irradiation presents a viable option for recurrent anaplastic meningioma\u003c/p\u003e \u003cp\u003edespite the associated risk of radiation necrosis. Higher doses with concomitant Bevacizumab improve clinical outcomes and reduce toxicity. Individualized treatment approaches are necessary, emphasizing the importance of further research to refine management strategies for this challenging disease.\u003c/p\u003e","manuscriptTitle":"Re-Irradiation of Anaplastic Meningioma: Higher dose and concomitant Bevacizumab may improve progression-free survival","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-30 22:10:23","doi":"10.21203/rs.3.rs-4313040/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-07-06T09:11:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-16T21:06:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87291648553743142307739974537445989357","date":"2024-06-14T15:30:00+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-04T07:36:03+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-26T08:09:13+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-25T08:44:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Radiation Oncology","date":"2024-04-23T14:51:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"radiation-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"raon","sideBox":"Learn more about [Radiation Oncology](http://ro-journal.biomedcentral.com/)","snPcode":"13014","submissionUrl":"https://submission.nature.com/new-submission/13014/3","title":"Radiation Oncology","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7eaf5185-f476-497d-bd50-ba39778777a7","owner":[],"postedDate":"April 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-10-07T16:07:18+00:00","versionOfRecord":{"articleIdentity":"rs-4313040","link":"https://doi.org/10.1186/s13014-024-02486-7","journal":{"identity":"radiation-oncology","isVorOnly":false,"title":"Radiation Oncology"},"publishedOn":"2024-10-02 15:57:34","publishedOnDateReadable":"October 2nd, 2024"},"versionCreatedAt":"2024-04-30 22:10:23","video":"","vorDoi":"10.1186/s13014-024-02486-7","vorDoiUrl":"https://doi.org/10.1186/s13014-024-02486-7","workflowStages":[]},"version":"v1","identity":"rs-4313040","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4313040","identity":"rs-4313040","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}