Prior Stereotactic Radiosurgery Research Articles

Incidence and imaging characteristics of difficult to detect retrospectively identified brain metastases in patients receiving repeat courses of stereotactic radiosurgery.

During stereotactic radiosurgery (SRS) planning for brain metastases (BM), brain MRIs are reviewed to select appropriate targets based on radiographic characteristics. Some BM are difficult to detect and/or definitively identify and may go untreated initially, only to become apparent on future imaging. We hypothesized that in patients receiving multiple courses of SRS, reviewing the initial planning MRI would reveal early evidence of lesions that developed into metastases requiring SRS. Patients undergoing two or more courses of SRS to BM within 6months between 2016 and 2018 were included in this single-institution, retrospective study. Brain MRIs from the initial course were reviewed for lesions at the same location as subsequently treated metastases; if present, this lesion was classified as a "retrospectively identified metastasis" or RIM. RIMs were subcategorized as meeting or not meeting diagnostic imaging criteria for BM (+ DC or -DC, respectively). Among 683 patients undergoing 923 SRS courses, 98 patients met inclusion criteria. There were 115 repeat courses of SRS, with 345 treated metastases in the subsequent course, 128 of which were associated with RIMs found in a prior MRI. 58% of RIMs were + DC. 17 (15%) of subsequent courses consisted solely of metastases associated with + DC RIMs. Radiographic evidence of brain metastases requiring future treatment was occasionally present on brain MRIs from prior SRS treatments. Most RIMs were + DC, and some subsequent SRS courses treated only + DC RIMs. These findings suggest enhanced BM detection might enable earlier treatment and reduce the need for additional SRS.

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

RADT-07. CLINICAL OUTCOMES OF MELANOMA BRAIN METASTASES TREATED WITH NIVOLUMAB AND IPILIMUMAB ALONE VERSUS NIVOLUMAB AND IPILIMUMAB WITH STEREOTACTIC RADIOSURGERY

Abstract BACKGROUND Upfront dual checkpoint blockade has demonstrated efficacy in new melanoma brain metastases (MBM) of asymptomatic patients. Whether combination stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual checkpoint blockade alone is unknown. We evaluated clinical outcomes of new MBM receiving nivolumab and ipilimumab, with and without SRS. METHODS 52 patients with 171 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and toleration of therapy were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), distant intracranial control (DIC), and intracranial control (ICC). Time-to-event analysis was conducted with the Kaplan-Meier method. RESULTS 25 patients with 74 MBM received nivolumab and ipilimumab alone. 27 patients with 97 MBM received concurrent SRS. No differences in age (p = 0.72), KPS (p = 0.94), presence of symptoms (p = 0.87), prior MBM (p = 0.90), prior MBM-directed surgery (p = 0.77) or SRS (p = 0.65), MBM size (p = 0.36), MBM number (p = 0.36), or treatment completion (p = 0.12) were seen. Median follow-up was 22.7 months. There was a trend towards higher rates of nivolumab and ipilimumab course completion in the combination group (44% vs. 24%; p = 0.12). The combination therapy group received prior immunotherapy more often than the monotherapy group (52% vs. 8.0%; p = 0.0003). OS, DIC, and ICC were similar (p = 0.16, p = 0.32, p = 0.57, respectively) with overall 12-month OS 70.7%, DIC 56.8%, and ICC 49.4%. The combination therapy group had higher 12-month LC compared to the monotherapy group (91% vs. 64%; p = 0.001). CONCLUSION In our analysis, SRS with nivolumab and ipilimumab shows superior LC compared to nivolumab and ipilimumab alone despite our combination cohort being more advanced with higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Patient-Reported Cognitive Outcomes and Survival after Stereotactic Radiosurgery for 15 or More Brain Metastases

Overall survival (OS) in metastatic cancer patients has been improving with continued advancements, necessitating greater attention to treatment related toxicities. Patients with ≥ 15 brain metastases (BM) continue to be treated with whole brain radiation therapy (WBRT), despite poor neurocognitive outcomes. We analyzed our institutional experience of treating these patients with stereotactic radiosurgery (SRS), with the aim of evaluating safety, cognitive outcomes, and survival metrics. Patients who received SRS for ≥ 15 BMs in 1-5 fractions from 2014-2022 using the previously described single isocenter multi-target technique were included. Cognitive outcomes were objectively evaluated using serial Patient-Reported Outcome Measurement Information System (PROMIS) scores. Kaplan-Meier method was used for survival analysis and log-rank test was used for intergroup comparisons. A total of 118 patients underwent 124 courses of LINAC-based SRS. The mean and median number of lesions treated per patient was 24.8 and 20, respectively (range 15 - 94). Most common primary histologies were lung (47.6%), melanoma (21.0%), and breast (14.5%). The median SRS dose was 24 Gy (range 18 - 30 Gy) with 87.9% receiving 3 fraction SRS. At the time of SRS, 19.4% patients had received prior WBRT and 24.2% had received at least one prior SRS course. The rate of any grade radiation necrosis (RN) and ≥ grade 3 RN were 15.3% and 3.2% respectively. New onset seizures were seen in 2.4%, alopecia in 2.4%, and subjective cognitive decline in 4% of patients. Median follow-up by reverse Kaplan-Meier method was 17.8 months (m). Cognitive data was available for 38 patients. Mean PROMIS scores at baseline, 3m, 6m and 9m after SRS were 32.0, 31.6, 30.4 and 28.7 out of 40, respectively. When longitudinal trends were available, 25 of 31 patients had a stable or improved PROMIS score. The 12m local control was 97.6%. Cumulative incidence of distant intracranial failure was 79.2%. One year freedom from neurological death, leptomeningeal disease, and salvage WBRT were 85.6%, 87.6% and 71.7% respectively. Median OS from brain metastases diagnosis was 11.3m (95% CI 7.2m - 15.3m) overall, while it was 9.2m (6.5 - 11.8m) after excluding patients who had prior WBRT or SRS (n = 79). One-year survival was 40% from diagnosis and 38.7% from SRS. On Cox regression analysis, prior WBRT (p = 0.002), higher KPS (p = 0.050), systemic therapy after SRS (p<0.001), and controlled extracranial disease (p = 0.007) predicted for improved OS. We present here the largest study evaluating SRS for patients with ≥ 15 BMs. We found that SRS was safe, had favorable cognitive outcomes, and comparable survival outcomes to contemporary studies evaluating WBRT in this patient population. Treatment-naïve patients had a median survival of > 6 months, long enough to benefit from cognitive sparing with SRS. Our study supports further randomized studies comparing SRS and memory avoidance WBRT approaches for patients with ≥ 15 BMs.

Selected-Lesion Stereotactic Radiosurgery in Treatment of Patients with Multiple Brain Metastases: A Single Institution Retrospective Study

Stereotactic Radiosurgery (SRS) has been increasingly used as first and subsequent-line treatments for brain metastases. While the appropriate cut-off number of lesions for SRS is still being debated nationally in patients with multiple brain metastases, some institutions use an alternate approach particularly for patients with >10-15 lesions. Selected-lesion SRS (SL-SRS) is where only a subset of lesions are chosen for initial SRS treatment leaving small and clinically inconsequential lesions for treatment using alternate or delayed treatments. This study aims to investigate the patient selection criteria, patient and tumor characteristics and analyze the outcomes in patients receiving SL-SRS for brain metastases at our institution. Clinical data from patients treated using the SL-SRS approach from 2012-2022 at our institution were retrospectively reviewed. Patients were divided into cohorts based on overall survival from time of SL-SRS treatment and indications for using SL-SRS. We compared the patient characteristics (age, histology, KPS, dsGPA), tumor characteristics (cumulative tumor volumes, tumor dose, number of brain metastases found, number of metastases treated), treatment characteristics (chemotherapy, immunotherapy, previous SRS/ radiation, previous WBRT) and the reason for decision to recommend SL-SRS across these cohort. A total of 102 patients were treated using the SL-SRS approach. Indications for using SL-SRS were immunotherapy trial (n = 40), CNS penetrating drug options available (n = 18), patient refusing WBRT (n = 6), palliative after prior WBRT/SRS (n = 28), WBRT planned to follow SRS (n = 9). 31 patients were alive at 12 months and 21 patients at 24 months. In patients surviving <12 months - the most common indications for SL-SRS were CNS palliation in the setting of progressive disease after prior WBRT or SRS. Patients in this group had median KPS< = 60 and had predominantly non-small cell carcinoma primary diagnosis. In those patients surviving >12 months - the most common indication for SL-SRS was participation in CNS-penetrant agent clinical trials without WBRT. Patients in this group were more likely to be female, had a median KPS of 90, had predominantly diagnoses of melanoma. Following the SL-SRS treatment, 14 patients required further SRS and 4 patients went on to WBRT in the >12-month survival group. No patients died of CNS progression alone. 10 patients survived 24 months without requiring further CNS radiation. In our institution, SL-SRS has predominantly been used either as palliative treatment at time of disease progression or to facilitate entry onto clinical trial with immunotherapy or potentially CNS-penetrant agents. The latter indication resulted in 47.6% patients surviving >24 month without the need for additional radiation to the CNS and therefore SL-SRS should be considered a feasible, safe and effective alternative to either WBRT or SRS treatment of all radiographically visible brain metastases.

Development of an RPA for Prediction of Radiation Necrosis Following Single Fraction Gamma Knife Radiosurgery for Brain Metastases

Radiation necrosis (RN) is a potential complication following treatment of brain metastases with stereotactic radiosurgery (SRS). Several risk factors for RN have been reported, but to our knowledge there are no recursive partitioning analysis (RPA) models to identify patients at highest risk for RN. We therefore sought to develop a predictive tool to identify patients at highest risk for the development of RN following single fraction SRS. Patients who underwent single fraction SRS for brain metastases from 2017-2021 were identified from a single institutional IRB-approved database. Patients with concern for RN were discussed in a multi-disciplinary setting and a diagnosis of RN was made based on pathologic or radiographic findings. Cox proportional hazards regression was done to identify factors associated with RN. RPA was performed to categorize patients into distinct risk groups for RN. Variables with p<0.1 on univariate analysis from the Cox regression analysis were included in the RPA. Patients with staged SRS, incomplete treatment records, or < 3 months radiographic follow-up were excluded from the analysis. The study population comprised 1,011 lesions from 283 patients with a median follow-up of 9.7 months. The majority of lesions had non-small cell lung cancer (NSCLC) (49%) as the primary site followed by breast (12%) and melanoma (11%). The median prescription dose was 24 Gy (range: 12-24 Gy). RN was diagnosed in 12.2% of lesions, of which 28% (35/123) were symptomatic RN. The median time to RN was 4.9 months. Variables identified for inclusion in the RPA included primary tumor site, use of targeted therapy, tumor location, pre-SRS hemorrhage, post-SRS hemorrhage, prior SRS to other lesions, number of SRS targets, maximum dose, maximum lesion diameter, 70% isodose line, heterogeneity index, conformality index, and gradient index. RPA identified four distinct groups. Group 1 was defined as maximum lesion diameter (MLD) <0.8 cm with primary tumor site other than breast, colorectal (CRC) or NSCLC (n = 174); group 2 was MLD <0.8 cm with breast, CRC, or NSCLC (n = 372). Group 3 was defined as MLD ≥ 0.8 cm without post-SRS hemorrhage (n = 336) and group 4 was MLD ≥0.8 cm with post-SRS hemorrhage (n = 129). Two-year RN free survival for all lesions was 82%, 100% for group 1, 89% for group 2, 76% for group 3, and 58% for group 4. We created the first RPA predictive model for RN following single fraction SRS and identified a subgroup of patients at highest risk. This RPA can help guide clinicians when educating patients on RN risk for brain metastases.

Multi-Institutional Outcomes Following Stereotactic Radiosurgery for Gastrointestinal Brain Metastases

Outcomes following stereotactic radiosurgery (SRS) for gastrointestinal (GI) brain metastases (BM) are poorly defined. We analyzed our multi-institutional database of SRS patients, comparing outcomes between GI and non-GI BM patients after SRS. We retrospectively identified all patients completing an initial SRS course across two institutions from 1/2015-12/2020. Demographic and clinical parameters were manually captured. Intracranial progression (ICP) was defined as any concern on post-SRS imaging for recurrence determined by multidisciplinary consensus. Overall survival (OS) and freedom from ICP (FFICP) were estimated via Kaplan Meier models. Cox proportional hazard models were used to assess associations between ICP and parameters. Among 1383 total patients completing SRS for BM, 102 (7.4%) had GI BM. Among these, 46 (45.1%) were of colorectal (CRC) and 34 (33.3%) esophageal origin. Other GI sites (21.6%) included anal, pancreatic, gastric, GI of unknown origin, and hepatocellular carcinoma. Median follow up was 8.7 mos. GI BM patients were more likely to be younger (mean 59.1 vs 63.5 yrs, p = 0.001), male (56.9% vs 44.3%, p = 0.014 ), have more extracranial metastases (mean 1.9 vs 1.6, p = 0.003), have received systemic therapy (73.5% vs 63.9%, p = 0.049) or resection of BM (45.1% vs 25.0%, p < 0.001) prior to SRS, have larger planned target volumes of all BMs (mean 20.3 ccs vs 15.0 ccs, p = 0.013), and were less likely to receive whole brain radiation therapy (WBRT) prior to SRS (3.9% vs 10.8%, p = 0.028) or systemic therapy after SRS (54.9% vs 68.9%, p = 0.004). Among GI patients, median OS was 28.2 mos (95% CI 16.5-35.3), with no significant differences between GI and non-GI patients (p = 0.220) or among GI subgroups (CRC vs other GI: p = 0.731; esophageal vs other GI: p = 0.478). Median FFICP was significantly worse for GI patients (6.2 mos, 95% CI 4.0-9.6 mos) than for non-GI patients (12.4 mos, 95% CI 10.8-13.9 mos; p = 0.004). After accounting for age, sex, performance status, number of irradiated BMs, extracranial disease burden, extracranial disease control, interval from primary cancer diagnosis to BM diagnosis, resection status, receipt of prior WBRT, and receipt of post-SRS systemic therapy, GI origin was significantly associated with worse FFICP (HR 1.50, 95% CI 1.15-2.02, p = 0.007). FFICP was not significantly different between GI subgroups, with CRC and esophageal patients demonstrating median times to ICP of 5.0 mos (95% CI 3.4-9.6) and 7.2 mos (95% CI 2.7-14.1), respectively. Only 2 GI patients (2.0%) had ICP at site of prior SRS. Across a modern, multi-institutional SRS cohort comparing GI to non-GI primary patients, BMs of GI origin demonstrated inferior FFICP to those of non-GI origin. OS did not vary significantly across GI and non-GI cases. Among GI subtypes, no significant differences were identified across FFICP or OS. These data may help inform treatment decisions and post-SRS surveillance.

Palliative Whole Brain Radiotherapy: International State of Practice 2022

Increasing technology of radiation treatment planning and delivery, better systemic therapies, and randomized trials in the population of patients (pts) with brain metastases have provided robust targeted options. This has resulted in palliative whole brain radiation therapy (WBRT) being used far less frequently than previously. Most centers preferentially use stereotactic radiation surgery (SRS) for pts with several lesions and may reserve WBRT for those with poor performance, with rapidly progressive disease, or with leptomeningeal presentation. We hypothesize that different trends in current WBRT regimens exist across different continents with varying rates of use of hippocampal avoidance (HA) and memantine. Despite differences in dose, fractionation, and treatment technique, we predict that survival post-WBRT will remain poor-indicating appropriate application of whole brain treatment in this era of SRS and improved systemic therapies. A multi-center international analysis of pts receiving WBRT in 2022 was performed. Primary end point was survival after WBRT. Participating centers were located in Belgium, the United Kingdom, Hong Kong, Cyprus, Italy, Germany, Ghana, and the United States. De-identified data were collected and analyzed centrally. Pts receiving WBRT as part of a curative regimen (e.g., medulloblastoma, primary CNS lymphomas), prophylactically in small cell lung cancer, or as bridging prior to CAR-T were excluded. The collected data consisted of pt parameters including prior stereotactic radiosurgery (SRS), prescription dose and fractionation, use of HA technique with or without memantine, and survival after WBRT. Survival was calculated via the Kaplan-Meier method. Of 23,332 RT prescriptions written at these centers in 2022, 399 (1.7%) were for palliative WBRT. Most frequent primary cancers were lung (42%) and breast (28%). Twenty-seven different dose regimens were used. The most common prescriptions were for 3 Gy daily fractions for 10 fractions (45%) and 4 Gy daily for 5 fractions (37%). Prior CNS SRS was delivered in 32 pts (7%). HA technique was used in 44 pts (10%); this technique was almost exclusively used in the United States. Memantine was prescribed in 93 pts (20%). Survival ranged from zero days to still surviving. The global median overall survival was 84 days after completion of treatment (95% CI: 68.0-104.0). Cumulative 3-month and 6-month actuarial survivals were 48% and 32%. This "moment in time" analysis confirms that pts with poor expected survival are being appropriately selected for WBRT and demonstrates the variance in global practice. Since poor survival precludes these pts from deriving much benefit, memantine and HA may be best suited only for carefully selected cases; use of these is not Standard of Care in the participating European, Asian, and African centers.

A Case Series of Stereotactic Radiosurgery First for Trigeminal Neuralgia: A History of Stereotactic Radiosurgery Does Not Complicate Microvascular Decompression.

The influence of prior stereotactic radiosurgery (SRS) on outcomes of subsequent microvascular decompression (MVD) for patients with trigeminal neuralgia (TN) is not well understood. To directly compare pain outcomes in patients undergoing primary MVD vs those undergoing MVD with a history of 1 prior SRS procedure. We retrospectively reviewed all patients undergoing MVD at our institution from 2007 to 2020. Patients were included if they underwent primary MVD or had a history of SRS alone before MVD. Barrow Neurological Institute (BNI) pain scores were assigned at preoperative and immediate postoperative time points and at every follow-up appointment. Evidence of pain recurrence was recorded and compared via Kaplan-Meier analysis. Multivariate Cox proportional hazards regression was used to identify factors associated with worse pain outcomes. Of patients reviewed, 833 met our inclusion criteria. Thirty-seven patients were in the SRS alone before MVD group, and 796 patients were in the primary MVD group. Both groups demonstrated similar preoperative and immediate postoperative BNI pain scores. There were no significant differences between average BNI at final follow-up between the groups. Multiple sclerosis (hazard ratio (HR) = 1.95), age (HR = 0.99), and female sex (HR = 1.43) independently predicted increased likelihood of pain recurrence on Cox proportional hazards analysis. SRS alone before MVD did not predict increased likelihood of pain recurrence. Furthermore, Kaplan-Meier survival analysis demonstrated no relationship between a history of SRS alone and pain recurrence after MVD ( P = .58). SRS is an effective intervention for TN that may not worsen outcomes for subsequent MVD in patients with TN.

Hypofractionated stereotactic radiosurgery (HSRS) as a salvage treatment for brain metastases failing prior stereotactic radiosurgery (SRS)

Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5cc and 37.5Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). Salvage HSRS results in high local control rates and toxicity rates that compare favorably to thosesingle fraction SRS re-irradiationexperiences reported in the literature.

Adverse radiation effect and freedom from progression following repeat stereotactic radiosurgery for brain metastases.

The authors previously evaluated risk and time course of adverse radiation effects (AREs) following stereotactic radiosurgery (SRS) for brain metastases, excluding lesions treated after prior SRS. In the present analysis they focus specifically on single-fraction salvage SRS to brain metastases previously treated with SRS or hypofractionated SRS (HFSRS), evaluating freedom from progression (FFP) and the risk and time course of AREs. Brain metastases treated from September 1998 to May 2019 with single-fraction SRS after prior SRS or HFSRS were analyzed. Serial follow-up magnetic resonance imaging (MRI) and surgical pathology reports were reviewed to score local treatment failure and AREs. The Kaplan-Meier method was used to estimate FFP and risk of ARE measured from the date of repeat SRS with censoring at the last brain MRI. A total of 229 retreated brain metastases in 124 patients were evaluable. The most common primary cancers were breast, lung, and melanoma. The median interval from prior SRS/HFSRS to repeat SRS was 15.4 months, the median prescription dose was 18 Gy, and the median duration of follow-up imaging was 14.5 months. At 1 year after repeat SRS, FFP was 80% and the risk of symptomatic ARE was 11%. The 1-year risk of imaging changes, including asymptomatic RE and symptomatic ARE, was 30%. Among lesions that demonstrated RE, the median time to onset was 6.7 months (IQR 4.7-9.9 months) and the median time to peak imaging changes was 10.1 months (IQR 5.6-13.6 months). Lesion size by quadratic mean diameter (QMD) showed similar results for QMDs ranging from 0.75 to 2.0 cm (1-year FFP 82%, 1-year risk of symptomatic ARE 11%). For QMD < 0.75 cm, the 1-year FFP was 86% and the 1-year risk of symptomatic ARE was only 2%. Outcomes were worse for QMDs 2.01-3.0 cm (1-year FFP 65%, 1-year risk of symptomatic ARE 24%). The risk of symptomatic ARE was not increased with tyrosine kinase inhibitors or immunotherapy before or after repeat SRS. RE on imaging was common after repeat SRS (30% at 1 year), but the risk of a symptomatic ARE was much less (11% at 1 year). The results of repeat single-fraction SRS were good for brain metastases ≤ 2 cm. The authors recommend an interval ≥ 6 months from prior SRS and a prescription dose ≥ 18 Gy. Alternatives such as HFSRS, laser interstitial thermal therapy, or resection with adjuvant radiation should be considered for recurrent brain metastases > 2 cm.

Stereotactic radiosurgery and local control of brain metastases from triple-negative breast cancer.

Stereotactic radiosurgery (SRS) is an effective treatment for intracranial metastatic disease, but its role in triple-negative breast cancer requires further study. Herein, the authors report overall survival (OS) and local tumor control in a multiinstitutional cohort with triple-negative breast cancer metastases treated with SRS. Patients treated from 2010 to 2019 at 9 institutions were included in this retrospective study if they had biopsy-proven triple-negative breast cancer with intracranial metastatic lesions treated with SRS. Patients were excluded if they had undergone prior SRS, whole-brain radiation therapy, or resection of the metastatic lesions. A retrospective chart review was conducted to determine OS, local control, and treatment efficacy. Sixty-eight patients with 315 treated lesions were assessed. Patients had a median Karnofsky Performance Status of 80 (IQR 70-90) and age of 57 years (IQR 48-67 years). Most treated patients had 5 or fewer intracranial lesions, with 34% of patients having a single lesion. Treated lesions were small, having a median volume owf 0.11 cm3 (IQR 0.03-0.60 cm3). Patients were treated with a median margin dose of 18 Gy (IQR 18-20 Gy) to the median 71% isodose line (IQR 50%-84%). Overall, patients had a 1-year OS of 43% and 2-year OS of 20%. Most patients (88%) were followed until death, by which time local tumor progression had occurred in only 7% of cases. Furthermore, 76% of the lesions demonstrated regression. Tumor volume was correlated with local tumor progression (p = 0.012). SRS was very well tolerated, and only 3 patients (5%) developed symptomatic radiation necrosis. SRS is a safe and efficacious treatment for well-selected patients with triple-negative breast cancer, especially for those with a favorable performance status and small- to moderate-volume metastatic lesions.

Early Imaging Characteristics Associated with Development of Future Brain Metastases in Patients Undergoing Stereotactic Radiosurgery

<h3>Purpose/Objective(s)</h3> Brain MRIs are carefully reviewed during the process of stereotactic radiosurgery (SRS) planning to select targets with radiographic characteristics typical of brain metastases (BM). Some BMs, especially ones that are small, dural-based, appear similar to blood vessels or resemble microinfarcts, are difficult to definitively identify and may go untreated initially, only to become apparent on future imaging. We hypothesized that in patients receiving multiple courses of SRS, retrospective review of the initial planning MRI would reveal early evidence of lesions that would subsequently develop into metastases requiring SRS. <h3>Materials/Methods</h3> Patients undergoing two or more courses of SRS to BMs within a 6-month interval between 2016 and 2018 were included in this single-institution, retrospective study. Exclusion criteria included small cell histology or previous whole-brain radiation therapy. Brain MRIs from the initial treatment course were reviewed for the presence of a contrast enhancing lesion at the same location as a lesion treated in a subsequent course of SRS, which was classified as a "retrospectively identified metastasis" or RIM. <h3>Results</h3> Of the 683 patients who underwent 923 courses of SRS within the study period, 98 patients met inclusion criteria. There were 120 repeat courses of SRS, with 345 treated metastases in the subsequent course, 128 of which were RIMs. 48% were within 5mm of the dura: 12% were abutting blood vessels: 8% became symptomatic. 23% of subsequent courses consisted of metastases that were all identified as RIMs. <h3>Conclusion</h3> Radiographic evidence of lesions requiring future treatment was occasionally present on brain MRIs from prior SRS treatments. RIMs are typically small, often abut blood vessels and/or the dura, and rarely become symptomatic. In some patients undergoing SRS, RIMs alone were treated, suggesting that enhanced detection of RIMs could reduce the need for additional courses of SRS.

Brain arteriovenous malformation flow after stereotactic radiosurgery: Role of quantitative MRA.

Stereotactic radiosurgery (SRS) is a current therapeutic option for treatment of arteriovenous malformations (AVMs) located in deep or eloquent brain regions. Obliteration usually occurs in a delayed fashion, with an expected latency of 3-5 years. Here, we assess how AVM flow correlates with volume before and after SRS treatment. Patients with supratentorial AVM treated with SRS at our institution between 2012-2022 were retrospectively reviewed. Patients were included if Quantitative Magnetic Resonance Angiography (QMRA) study was performed at baseline and at least at the first follow-up. Correlation between AVM flow and volume before and after treatment was evaluated. AVM flow and volume were additionally assessed for obliteration using the non-parametric receiver operating characteristic (ROC) curve. Twelve patients with radiologic follow-up imaging were included. Eight patients presented AVM rupture, one of which occurred after radiosurgical treatment. Three patients underwent embolization prior SRS. Mean AVM initial volume was 3.8 cc (0.1-12.4 cc), mean initial flow 174 ml/min (11-604 ml/min), both variables showed progressive reduction at follow-up (range 3-57 months); and flow decreased with volume reduction (p < 0.001). Area under the ROC was 0.914 for both AVM flow and volume with obliteration (p = 0.019). AVM flow significantly decreased after SRS treatment, reflecting volume reduction. Baseline AVM flow and volume both predicted obliteration. QMRA provides additional non-invasive information to monitor patients after radiosurgical treatment.

Diagnostic Value of 18 F-FACBC PET/MRI in Brain Metastases.

The study aims to evaluate whether combined 18 F-FACBC PET/MRI could provide additional diagnostic information compared with MRI alone in brain metastases. Eighteen patients with newly diagnosed or suspected recurrence of brain metastases received dynamic 18 F-FACBC PET/MRI. Lesion detection was evaluated on PET and MRI scans in 2 groups depending on prior stereotactic radiosurgery (SRS group) or not (no-SRS group). SUVs, time-activity curves, and volumetric analyses of the lesions were performed. In the no-SRS group, 29/29 brain lesions were defined as "MRI positive." With PET, 19/29 lesions were detected and had high tumor-to-background ratios (TBRs) (D max MR , ≥7 mm; SUV max , 1.2-8.4; TBR, 3.9-25.9), whereas 10/29 lesions were undetected (D max MR , ≤8 mm; SUV max , 0.3-1.2; TBR, 1.0-2.7). In the SRS group, 4/6 lesions were defined as "MRI positive," whereas 2/6 lesions were defined as "MRI negative" indicative of radiation necrosis. All 6 lesions were detected with PET (D max MR , ≥15 mm; SUV max , 1.4-4.2; TBR, 3.6-12.6). PET volumes correlated and were comparable in size with contrast-enhanced MRI volumes but were only partially congruent (mean DSC, 0.66). All time-activity curves had an early peak, followed by a plateau or a decreasing slope. 18 F-FACBC PET demonstrated uptake in brain metastases from cancer of different origins (lung, gastrointestinal tract, breast, thyroid, and malignant melanoma). However, 18 F-FACBC PET/MRI did not improve detection of brain metastases compared with MRI but might detect tumor tissue beyond contrast enhancement on MRI. 18 F-FACBC PET should be further evaluated in recurrent brain metastases.

LOCL-15 PERMANENT CARRIER-EMBEDDED CESIUM-131 BRACHYTHERAPY FOR THE SALVAGE TREATMENT OF PREVIOUSLY IRRADIATED, RECURRENT BRAIN METASTASES

BACKGROUNDSalvage of recurrent of previously-irradiated brain metastases (rBrM) is a significant clinical challenge. High local failure rates are seen following salvage resection without adjuvant re-irradiation, while reirradiation is associated with high radionecrosis rates. Salvage surgery plus intraoperative Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced integral brain dose versus re-irradiation. METHODSA prospective registry of consecutively treated patients with rBrM after prior stereotactic radiosurgery (SRS) was analyzed. Following maximal-safe resection and intraoperative viable-disease confirmation, cavities were implanted with commercially-available, collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies). Prescribed dose was 60Gy at 5mm from the cavity. RESULTSTwenty patients underwent 24 operations with Cs131 implantation in 25 cavities. Previous SRS occurred a median of 358d preoperatively (range=56-1334). Median maximum preoperative diameter was 3.0cm (range=1.1-6.3) and enhancing volume was 9.5cm3 (range=0.6-69.7). Gross- or near-total resection was achieved in 60% of lesions. A median of 16 Cs131 seeds (range=6-30), with a median activity of 3.5U/seed were implanted. Maximal preoperative diameter and enhancing volume were weakly associated with the number of implanted seeds (correlation coefficients=0.50, 0.41, respectively). There was one postoperative wound dehiscence in a multiply resected and irradiated patient with hydrocephalus. With median follow-up of 12.5 months, 2 tumors recurred (one in-field, one marginal) resulting in a 1-year progression incidence of 9.8% (95%CI=0.0-23.2). Radiographic seed migration was identified in 7/25 cavities (28%) on surveillance scans ranging from 1.9-11.7 months post-implantation, without clinical sequelae. CONCLUSIONSWith >1 year of follow-up, intraoperative brachytherapy with commercially-available Cs131 implants was associated with a high rate of local control and a favorable toxicity profile. Modest correlation between preoperative tumor geometry and implanted tiles in the context of high associated cost suggests a need to optimize planning criteria. A randomized trial of salvage resection with or without Cs131 is ongoing (NCT04690348) to assess the incremental benefit of brachytherapy.

Repeat stereotactic radiosurgery for cerebral arteriovenous malformations.

The purpose of this retrospective, single-institution study was to evaluate radiological and clinical outcomes of patients managed with repeat stereotactic radiosurgery (SRS) for residual cerebral arteriovenous malformation (AVM) after prior SRS. The authors evaluated the clinical and radiological outcomes of consecutive patients treated with repeat single-session SRS for a residual brain AVM from 1989 to 2021. In total, 170 patients underwent repeat SRS for AVM (90 [52.9%] females; median [interquartile range] age at the first SRS procedure 28 [21.5] years; median [interquartile range] age at the second SRS procedure 32 [22.5] years). After repeat SRS, the actuarial 3-, 5-, and 10-year AVM obliteration rates were 37.6%, 57.3%, and 80.9%, respectively. Higher obliteration rates were associated with margin dose ≥ 19 Gy (p = 0.001). After the second SRS procedure, hemorrhage occurred in 8.2% of patients and was lethal in 1 patient. The risk factors of intracranial hemorrhage were age < 18 years (p = 0.03) and residual AVM diameter > 20 mm (p = 0.004). Lower obliteration rates were noted in patients with residual AVM diameter > 20 mm (p = 0.04) and those < 18 years of age (p = 0.04). Asymptomatic, symptomatic, and permanent radiation-induced changes (RICs) after the second SRS procedure occurred in 25.9%, 8.8%, and 5.3% of patients, respectively, and were associated with RIC after the first SRS procedure (p = 0.006). There was 1 case of a radiation-induced meningioma 12 years after SRS. Repeat SRS is a reasonable therapeutic option, in particular for patients with residual AVM. Repeat SRS was associated with more favorable outcomes in adult patients and those with residual AVM smaller than 20 mm in maximum diameter. To increase the rate of residual AVM obliteration, a prescription dose ≥ 19 Gy should ideally be used for repeat SRS.

Bevacizumab for radiation necrosis of the brain or steroid-refractory edema in patients with melanoma receiving immune checkpoint inhibitors.

e14008 Background: For patients with melanoma brain metastasis (MBM) treated with stereotactic radiosurgery (SRS), 5-6.5% develop radiation necrosis of the brain (RNB), which is commonly treated with corticosteroids (CS). Nonetheless, high-dose CS may reduce efficacy of immunotherapy (IO). Bevacizumab (BV) has been shown to reduce symptoms and peritumoral edema associated with RNB. However, data on the efficacy and toxicity of BV in patients with MBM who also receive IO is limited. We aimed to describe clinical features and outcomes of patients with MBM who received BV and were also treated with IO. Methods: Under an IRB-approved protocol, patients with MBM who developed RNB or steroid-refractory edema (SRE) and were treated with BV were identified. The selection criteria were as follows: (1) one or more MBM; (2) prior SRS for MBM; (3) development of RNB or SRE detected radiographically or based on expert opinion; (4) treatment with one or more cycles of BV; (5) treatment with IO for metastatic melanoma. Results: In this single-center retrospective series, 8 patients received IO and BV: 4 concurrently and 4 patients received IO immediately prior to or after BV. IO therapy included ipilimumab-nivolumab, nivolumab alone or pembrolizumab. Median number of MBM was 3.6 (range, 1-8) and median number of RNB/SRE foci were 1.125 (range, 1-2). Median time from diagnosis of RNB/SRE to initiation of BV was 1.4 months (range, 0.5-3 months). BV dosing regimen was 5 mg/kg every 2 weeks, 7.5 mg/kg every 3 weeks or 10 mg/kg every 2 weeks. 71% (5 of 7) patients who required CS for RNB/peritumoral edema symptoms at the time of starting BV were able to taper CS after receiving BV or stop CS completely. This allowed for 4 of these patients to subsequently start or resume IO. 28% (2 of 7) patients had increasing neurological symptoms during CS taper and required an increase in CS dosing. Only 1 patient was not on CS at the time of BV initiation. 75% (6 of 8) cases attained intracranial radiologic response, with documented decreased edema or tumor size, or resolution of enhancement on MRI; 1 patient had stable disease after BV; and 1 patient had continued clinical deterioration despite BV. 62.5% (5 of 8) patients had no adverse events from BV, but 37.5% (3 of 8) had DVT/PE, 1 requiring a thrombectomy, and 1 additionally had perforated diverticulitis. Median follow-up time from BV administration was 17.94 months (range, 1-58 months), with 75% (6 of 8) patients with survival &gt; 10 months. Conclusions: Treatment of RNB/SRE with BV in patients with MBM receiving IO appears to be effective and relatively well tolerated, though with occasional serious adverse events. BV led to improvement of symptoms and allowed for CS taper in a substantial proportion of patients. By reducing CS requirement, BV may permit continuation of IO, which leads to durable survival in a large proportion of patients.

The Impact of Dose on Treatment Outcomes in Patients Treated for Brain Metastases With a Hypofractionated Technique on Gamma Knife

Purpose: Brain metastases are the most common type of diagnosed central nervous system tumours, occurring in approximately 40% of all cancer patients. Historically, treatment consisted of whole brain radiotherapy (WBRT), however current practice for patients with limited intracranial disease, is to offer stereotactic radiosurgery (SRS). In 2016, our centre acquired a Gamma Knife (GK) unit, designed to treat brain metastases with a stereotactic approach, using an invasive frame based immobilization system. In 2017, a mask based frameless system was introduced, expanding indications for patients and allowing for the treatment of hypofractionated courses on this unit. Given the unique dosimetric characteristics of the GK, our research focused on patients treated for intact brain metastases, with hypofractionated doses, and aimed to report adverse radiation effects and local control. Methods: This was a retrospective study, including all patients with intact brain metastases, treated on the GK unit, with hypofractionated (5 fraction) treatments, between 2017-2020. Hypofractionated treatments are generally given to larger lesions (≥2cm) or those lesions situated in eloquent areas of the brain, such as the motor cortex or brainstem. Patients were excluded if the specific metastases received prior SRS or hypofractionated treatment, however those who received previous whole brain radiotherapy were included. Those without post -treatment imaging follow up were also excluded from the analyses. Competing risk methods were used to determine local control and symptomatic adverse radiation effect (ARE) rates per lesion and Kaplan Meier methods were used to determine survival estimates. The Common Terminology Criteria for Adverse events (CTCAE) v 5.0 was used to determine symptomatic ARE. Results: A total of 146 patients and 299 metastases were identified. The most frequent histologies were lung (38.5%), breast (31.4%) and melanoma (13.7%). 53.4% of patients had a KPS > 70% and the majority had multiple lesions treated at the time of their hypofractionated radiosurgery (62.3%). Only 18% had received prior WBRT. Prescribed doses ranged from 20-27.5Gy with the median being 27.5Gy in 5 fractions prescribed in 54.2% of cases. The median volume of the treated lesions was 2.54cc (range 0.004-24.92cc). Clinical follow-up ranged from 0.5 to 49.9 months, with the median being 13.8 months. The 1 year local control was 84.8%, and on multivariable analyses, 1 year local failure rates increased (8.3% (95% CI, 4.6-13.2) vs 23.5% (95%CI,16.6-31)) with decreasing prescribed doses (27.5Gy vs 20-25Gy) respectively. In terms of adverse radiation effects, there were 32 (10.7%) incidents identified, of which 14 (44%) were symptomatic. For symptomatic AREs, the 1 and 2 year rates were 1.7% (95% CI, 0.7-3.8) and 4.5% (95% CI, 2.4-7.7), respectively. Overall survival for this patient population was 12.7 months, with the 1 and 2 year rates being 51.3% (95% CI 42.6-59.2) and 36.8% (95%, CI 28.5-45.1), respectively. Conclusion: For patients with intact brain metastases, GK hypofractionated treatments are a safe and effective treatment modality. A 27.5Gy prescription dose in 5 fractions is associated with improved local control and a low risk of symptomatic ARE at one year.

Optimal management of brainstem metastases: a narrative review.

Brainstem metastases comprise fewer than 7% of all brain metastases. Nonetheless, they present clinicians with unique clinical challenges in symptom management and treatment. No comprehensive review summarizing the management of brainstem metastases exists. This review aims to summarize epidemiology, anatomy, clinical correlation, prognosis, options for management of symptoms, treatment, treatment toxicity, and dose and fractionation for brainstem stereotactic radiosurgery (SRS) as reported in the literature. In July 2021, we searched PubMed and Embase for retrospective studies of brainstem metastasis treatment, as well as case series and case reports describing diagnosis and clinical management of brainstem metastasis. Keywords and MeSH terms searched included "brainstem metastasis", "symptomatic brainstem metastasis", "brain metastasis", "stereotactic radiosurgery brainstem", "whole brain radiation brainstem", "brainstem metastasis resection", "brainstem radiation toxicity", "brainstem radiosurgery toxicity", "brainstem radiosurgery dose", and "radiosurgery dose tolerance". Titles and abstracts were screened for relevant articles and studies. References from full-text articles were screened for additional studies. Single-institution studies and multicenter retrospective analyses from 1993 to 2021 reflect a shift from reliance on whole-brain radiation therapy (WBRT) to SRS for primary treatment of brainstem metastases. Recent multicenter retrospective analyses and single-institution case series support the safety and efficacy of SRS of brainstem metastases in symptom management and preservation of quality of life. Incidence of radiation-induced toxicity following SRS of brainstem metastases is comparable to that of SRS for other brain metastases. Complications following brainstem SRS are most strongly associated with prior WBRT. Radiation oncologists play a central role in the treatment of brainstem metastases due to reliance on SRS. Dose and fractionation of brainstem SRS remain largely institution-dependent. The field would benefit from inclusion of brainstem metastases in prospective trials of SRS and studies of adverse effects of salvage WBRT after prior SRS of brainstem metastases.