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Abstract BACKGROUND Stereotactic radiosurgery (SRS) for benign intracranial meningiomas is an established treatment. OBJECTIVE To summarize the literature and provide evidence-based practice guidelines on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS Articles in English specific to SRS for benign intracranial meningioma, published from January 1964 to April 2018, were systematically reviewed. Three electronic databases, PubMed, EMBASE, and the Cochrane Central Register, were searched. RESULTS Out of the 2844 studies identified, 305 had a full text evaluation and 27 studies met the criteria to be included in this analysis. All but one were retrospective studies. The 10-yr local control (LC) rate ranged from 71% to 100%. The 10-yr progression-free-survival rate ranged from 55% to 97%. The prescription dose ranged typically between 12 and 15 Gy, delivered in a single fraction. Toxicity rate was generally low. CONCLUSION The current literature supporting SRS for benign intracranial meningioma lacks level I and II evidence. However, when summarizing the large number of level III studies, it is clear that SRS can be recommended as an effective evidence-based treatment option (recommendation level II) for grade 1 meningioma.

Purpose To compare treatment results between fractionated gamma knife radiosurgery (f-GKRS) and staged gamma knife radiosurgery (s-GKRS) for mid-to-large brain metastases (BMs). Methods We retrospectively analyzed data of patients with medium (4–10 mL) to large (> 10 mL) BMs who underwent s-GKRS or f-GKRS between March 2008 and September 2022. Patients were treated with (i) s-GKRS before May 2018 and (ii) f-GKRS after May 2018. Patients who underwent follow-up magnetic resonance imaging at least once were enrolled. Case-matched studies were conducted by applying propensity score matching to minimize treatment selection bias and potential confounding. Local control (LC) was set as the primary endpoint and overall survival (OS) as the secondary endpoint. Results This study included 129 patients with 136 lesions and 70 patients with 78 lesions who underwent s-GKRS and f-GKRS, respectively. Overall, 124 lesions (62 lesions in each group) were selected in the case-matched group. No differences were observed in the 6-month and 1-year cumulative incidences of LC failure between the s-GKRS and f-GKRS groups (15.6% vs. 15.9% at 6 months and 25.6% vs. 25.6% at 1 year; p = 0.617). One-year OS rates were 62.6% (95% confidence interval [CI]: 45.4–75.7%) and 73.9% (95% CI: 58.8–84.2%) in the s-GKRS and f-GKRS groups, respectively. The post-GKRS median survival time was shorter in the s-GKRS group than in the f-GKRS group (17 vs. 36 months), without significance (p = 0.202). Conclusions This is the first study to compare f-GKRS and s-GKRS in large BMs. Fractionation is as effective as staged GKRS for treating mid-to-large BMs.

PurposeOutcomes for patients with recurrent high-grade glioma (HGG) progressing on bevacizumab (BEV) are dismal. Fractionated stereotactic radiosurgery (FSRS) has been shown to be feasible and safe when delivered in this setting, but prospective evidence is lacking. This single-institution randomized trial compared FSRS plus BEV-based chemotherapy versus BEV-based chemotherapy alone for BEV-resistant recurrent malignant glioma.Materials and methodsHGG patients on BEV with tumor progression after 2 previous treatments were randomized to 1) FSRS plus BEV-based chemotherapy or 2) BEV-based chemotherapy with irinotecan, etoposide, temozolomide, or carboplatin. FSRS was delivered as 32 Gy (8 Gy × 4 fractions within 2 weeks) to the gross target volume and 24 Gy (6 Gy × 4 fractions) to the clinical target volume (fluid-attenuated inversion recovery abnormality). The primary endpoints were local control (LC) at 2 months and progression-free survival (PFS).ResultsOf the 35 patients enrolled, 29 had glioblastoma (WHO IV) and 6 had anaplastic glioma (WHO III). The median number of prior recurrences was 3. Patients treated with FSRS had significantly improved PFS (5.1 vs 1.8 months, P < .001) and improved LC at 2 months (82% [14/17] vs 27% [4/15], P = .002). The overall median survival was 6.6 months (7.2 months with FSRS vs 4.8 months with chemotherapy alone, P = .11).ConclusionsFSRS combined with BEV-based chemotherapy in recurrent HGG patients progressing on BEV is feasible and improves LC and PFS when compared to treatment with BEV-based chemotherapy alone.

Background The current standard of care for patients with a large brain metastasis and limited intracranial disease burden is surgical resection and post-operative single fraction stereotactic radiosurgery (SRS). However, post-operative SRS can still lead to substantial rates of local failure (LF), radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated treatments may improve local control by allowing delivery of higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) can minimize rates of LF, RN, and MD. Methods A retrospective, multi-institutional analysis was conducted and included patients who had pre-operative FSRT for a large or symptomatic brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. A primary measurement was the rate of a composite endpoint of (1) LF, (2) MD, and/or (3) Grade 2 or higher (symptomatic) RN. Results 53 patients with 55 lesions were eligible for analysis. FSRT was prescribed to a dose of 24–25 Gy in 3–5 fractions. There were 0 LFs, 3 Grade 2–3 RN events, and 1 MD occurrence, which corresponded to an 8% per-patient composite endpoint event rate. Conclusions In this study, the composite endpoint of 8% for pre-operative FSRT was improved compared to previously reported rates with post-operative SRS of 49–60% (N107C, Mahajan etal. JCOG0504) and pre-operative SRS endpoints of 20.6% (PROPS-BM). Pre-operative FSRT appears to be safe, effective, and may decrease the incidence of adverse outcomes. Prospective validation is needed.

A 70-year old male with stage I large cell neuroendocrine carcinoma (LCNEC) of the lung underwent resection of a metachronous 5 cm brain metastasis and received postoperative hypofractionated stereotactic radiotherapy (hfSRT). Five sequential nodular leptomeningeal metastases up to 5.3 cm in diameter were diagnosed on MRI within 10 months and were treated with SRT. Currently the patient has no evidence of intracranial disease 24 months after last irradiation without chemotherapy or whole brain radiotherapy. This is the first report of sustained complete remission of multiple large leptomeningeal metastases achieved with hfSRT, highlighting this brain-sparing approach in selected patients with LCNEC lung cancer.

Abstract BACKGROUND Cavity stereotactic radiotherapy has emerged as a standard option following resection of brain metastases. However, the optimal approach with either single-fraction or hypofractionated stereotactic radiotherapy (HSRT) remains a significant question. OBJECTIVE To report outcomes for 5-fraction HSRT to the surgical cavity, based on contouring according to a recently reported international consensus guideline. METHODS Patients treated with cavity HSRT were identified from a prospective institutional database. Local brain control (LC), distant brain failure (DBF), leptomeningeal disease (LMD), and overall survival rates were determined. Univariate and multivariable analyses were performed on potential predictive factors. RESULTS One hundred thirty-seven cavities in 122 patients were treated at a median total dose of 30 Gy (range, 25-35 Gy). The median follow-up was 16 mo (range, 1-60 mo). Nonsmall cell lung cancer was the most common histology (44%), followed by breast cancer (21%). In 57% of surgical cavities, the preoperative tumor diameter was >3 cm. One-year LC, DBF, LMD, and overall survival rates were 84%, 45%, 22%, and 62%, respectively. Multivariable analyses identified colorectal (hazard ratio [HR] 4.1, P = .0066) and melanoma (HR 2.4, P = .012) metastases as predictors of local recurrence; preoperative tumor diameter >2 cm (HR 8.9, P = .012) and absence of targeted therapy (HR 4.4, P = .03) as predictors of DBF; and breast cancer histology (HR 2.1, P = .05) and subtotal resection (HR 2.6, P = .009) as predictors of LMD. Symptomatic radiation necrosis was observed in 7 patients (6%). CONCLUSION High rates of LC were observed following this 5-fraction HSRT regimen. Superiority as compared to single-fraction SRS requires a randomized trial.

Background Single session radiosurgery represents a widely accepted treatment for intracranial meningiomas. However, this approach could involve a high risk of treatment-related complications when applied to large volume lesions. In these cases and for those not suitable for surgical resection, radiosurgery in multisession setting could represents a viable option. The literature results are reassuring in terms of correlated adverse events as well as in terms of tumor control. However, no prospective long-term results are available. In this scenario, we design a prospective monocentric phase II study, in order to verify the safety of a multisession radiosurgery schedule delivering 25 Gy in 5 daily fractions. Methods Patients diagnosed with large and/or near to critical structures, intracranial meningiomas have been treated by means of multisession radiosurgery in both exclusive and postoperative settings. The primary study aim is safety that has been being prospectively scored based on international scales, including NCI Common Toxicity criteria, version 4.03, Barrow Neurological Institute pain intensity score, Barrow Neurological Institute facial numbness score and House-Brackmann Facial Nerve Grading System for qualitative analysis. Secondary aim is treatment efficacy in terms of local control that has been being assessed on volumetric analysis. Discussion This is the first prospective phase II trial on multisession radiosurgery for large and/or near to critical structures intracranial meningiomas. If positive results will be found, this study could represent the starting point for a phase III trial exploring the role of multisession radiosurgery in the exclusive and postoperative radiation therapy treatment of intracranial meningiomas. Trial registration Trial registration: clinicaltrials.gov platform (Multisession Radiosurgery in Large Meningiomas –MuRaLM- identifier NCT02974127 ). Registered: November 28, 2016. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02974127?term=radiosurgery&cond=Intracranial+Meningioma&draw=2&rank=1

Purpose To investigate the efficacy and safety of concurrent stereotactic radiosurgery (SRS) and ipilimumab or nivolumab in patients with untreated melanoma brain metastases. Patients and Methods Eighty consecutive patients with 326 melanoma brain metastases receiving SRS in combination with ipilimumab or nivolumab were identified from an institutional database and retrospectively evaluated. Patients started systemic treatment with intravenous nivolumab or ipilimumab within one week of receiving SRS. Nivolumab was given at doses of 3 mg/kg every two weeks. Ipilimumab was administered up to four doses of 10 mg/kg, one every 3 weeks, then patients had a maintenance dose of 10 mg/kg every 12 weeks, until disease progression or inacceptable toxicity. Primary endpoint of the study was intracranial progression-free survival (PFS). Secondary endpoints were extracranial PFS, overall survival (OS), and neurological toxicity. Results Eighty patients were analyzed. Forty-five patients received SRS and ipilimumab, and 35 patients received SRS and nivolumab. With a median follow-up of 15 months, the 6-month and 12-month intracranial PFS rates were 69% (95%CI,54–87%) and 42% (95%CI,24–65%) for patients receiving SRS and nivolumab and 48% (95%CI,34–64%) and 17% (95%CI,5–31%) for those treated with SRS and ipilimumab (p = 0.02), respectively. Extracranial PFS and OS were 37 and 78% in SRS and nivolumab group, respectively, and 17 and 68% in SRS and ipilimumab group, respectively, at 12 months. Sub-group analysis showed significantly better intracranial PFS for patients receiving multi-fraction SRS (3 × 9 Gy) compared to single-fraction SRS (70% versus 46% at 6 months, p  = 0.01), especially in combination with nivolumab. Grade 3 treatment-related adverse events occurred in 11 (24%) patients treated with SRS and ipilimumab and 6 (17%) patients who received SRS and nivolumab. Radiation-induced brain necrosis (RN) occurred in 15% of patients. Conclusions Concurrent SRS and ipilimumab or nivolumab show meaningful intracranial activity in patients with either asymptomatic and symptomatic melanoma brain metastases, although a subset of patients may develop symptomatic RN. The combination of nivolumab with SRS is associated with better intracranial control.

Background Stereotactic radiosurgery (SRS) is a frequently chosen treatment for patients with brain metastases and the number of long-term survivors is increasing. Brain necrosis (e.g. radionecrosis) is the most important long-term side effect of the treatment. Retrospective studies show a lower risk of radionecrosis and local tumor recurrence after fractionated stereotactic radiosurgery (fSRS, e.g. five fractions) compared with stereotactic radiosurgery in one or three fractions. This is especially true for patients with large brain metastases. As such, the 2022 ASTRO guideline of radiotherapy for brain metastases recommends more research to fSRS to reduce the risk of radionecrosis. This multicenter prospective randomized study aims to determine whether the incidence of adverse local events (either local failure or radionecrosis) can be reduced using fSRS versus SRS in one or three fractions in patients with brain metastases. Methods Patients are eligible with one or more brain metastases from a solid primary tumor, age of 18 years or older, and a Karnofsky Performance Status ≥ 70. Exclusion criteria include patients with small cell lung cancer, germinoma or lymphoma, leptomeningeal metastases, a contraindication for MRI, prior inclusion in this study, prior surgery for brain metastases, prior radiotherapy for the same brain metastases (in-field re-irradiation). Participants will be randomized between SRS with a dose of 15–24 Gy in 1 or 3 fractions (standard arm) or fSRS 35 Gy in five fractions (experimental arm). The primary endpoint is the incidence of a local adverse event (local tumor failure or radionecrosis identified on MRI scans) at two years after treatment. Secondary endpoints are salvage treatment and the use of corticosteroids, bevacizumab, or antiepileptic drugs, survival, distant brain recurrences, toxicity, and quality of life. Discussion Currently, limiting the risk of adverse events such as radionecrosis is a major challenge in the treatment of brain metastases. fSRS potentially reduces this risk of radionecrosis and local tumor failure. Trial registration ClincalTrials.gov, trial registration number: NCT05346367 , trial registration date: 26 April 2022.

PurposeThis study investigated the interfractional volume changes of large (≥ 10 cm3) brain metastases (BMs) during fractionated gamma knife radiosurgery (FGKRS) to assess its predictive value for tumor control outcomes.MethodsThe patients who underwent FGKRS for large BMs between January 2017 and December 2022 in our center were reviewed. The interfractional volume change was defined as the disparity in tumor volume (TV) measured between the magnetic resonance images acquired on the first treatment day and those obtained after 2 or 3 fractions during the course of FGKRS.ResultsA total of 73 lesions in 70 patients with various primary pathologies were included. Over a median follow-up period of 11 months (range 1–77), the tumor control rate was 63%. Initial TV (cm3) was associated with progression free survival (PFS) and overall survival (OS) in both univariate and multivariate analyses (p = 0.01). Interfractional TV changes revealed an increase in 13 (17.8%) lesions, no change in 14 (19.2%) lesions, and a decrease in 46 (63.0%) lesions, with a mean volume reduction of 5% ± 0.12. Three cut-offs (5%, 10% and 15% volume decrement) were established and patients were divided into two groups based on each reference point. However, there were no significant differences in PFS and OS between the two groups, irrespective of the chosen cut-off value used.ConclusionInterfractional volume changes of large BMs were not found to be associated with tumor control outcomes. Neither significant interfractional volume reduction nor significant volume increase necessarily predicts the tumor control, making early close monitoring essential after FGKRS.