Initial Stereotactic Radiosurgery Research Articles

Comparison of Repeat Versus Initial Stereotactic Radiosurgery for Intracranial Arteriovenous Malformations: A Retrospective Multicenter Matched Cohort Study

BACKGROUND AND OBJECTIVES: Studies comparing neurological and radiographic outcomes of repeat to initial stereotactic radiosurgery (SRS) intracranial arteriovenous malformations are scarce. Our aim was to perform a retrospective matched comparison of patients initially treated with SRS with those undergoing a second radiosurgical procedure. METHODS: We collected data from arteriovenous malformations managed in 21 centers that underwent initial and repeated radiosurgery from 1987 to 2022. Based on arteriovenous malformations volume, margin dose, deep venous drainage, deep, and critical location, we matched 1:1 patients who underwent an initial SRS for treatment-naive arteriovenous malformations and a group with repeated SRS treatment. RESULTS: After the selection process, our sample consisted of 328 patients in each group. Obliteration in the initial SRs group was 35.8% at 3 and 56.7% at 5 years post-SRS, while the repeat SRS group showed obliteration rates of 33.9% at 3 years and 58.6% at 5 years, without statistically significant differences (P = .75 and P = .88, respectively). There were no statistically significant differences between the 2 groups for obliteration rates (hazard ratio = 0.93; 95% CI, 0.77-1.13; P = .5), overall radiation-induced changes (RIC) (OR = 1.1; 95% CI, 0.75-1.6; P = .6), symptomatic RIC (OR = 0.78; 95% CI, 0.4-1.5; P = .4), and post-SRS hemorrhage (OR = 0.68; 95% CI; P = .3). CONCLUSION: In matched cohort analysis, a second SRS provides comparable outcomes in obliteration and RIC compared with the initial SRS. Dose reduction on repeat SRS may not be warranted.

Determinants of Symptomatic Intracranial Progression After an Initial Stereotactic Radiosurgery Course

Purpose: Clinical and imaging surveillance of patients with brain metastases (BMs) is important after stereotactic radiosurgery (SRS), as many will experience intracranial progression (ITCP) requiring multidisciplinary management. The prognostic significance of neurologic symptoms at the time of ITCP is poorly understood. Materials/MethodsThis was a multi-institutional, retrospective cohort study from 2015-2020, including all patients with BMs completing an initial course of SRS. The primary outcome was overall survival (OS) by presence of neurologic symptoms at ITCP. OS, freedom from ITCP (FF-ITCP), and freedom from symptomatic ITCP (FF-SITCP) were assessed via Kaplan-Meier method. Cox proportional hazard models tested parameters impacting FF-ITCP and FF-SITCP. Results: Among 1383 patients, median age was 63.4 years, 55% were female, and common primaries were non-small cell lung (49%), breast (15%), and melanoma (9%). At a median follow up of 8.72 months, asymptomatic and symptomatic ITCP were observed in 504 (36%) and 194 (14%) patients respectively. The majority of ITCP were distant ITCP (79.5%). OS was worse with SITCP (median 10.2 vs 17.9 months, p<0.001). SITCP was associated with clinical factors including total treatment volume (P = 0.012), melanoma histology (P = 0.001), prior WBRT (P = 0.003), number of brain metastases (P < 0.001), interval of 1-2 years from primary and brain metastasis diagnosis (P = 0.012), controlled extracranial disease (P = 0.042), and receipt of pre-SRS chemotherapy (P = 0.015). Patients who were younger and received post-SRS chemotherapy (P = 0.001), immunotherapy (P < 0.001), and targeted or small-molecule inhibitor therapy (P < 0.026) had better FF-SITCP. Conclusions: In this cohort study of BM patients completing SRS, neurologic symptoms at ITCP is prognostic for OS. This data informs post-SRS surveillance in clinical practice as well as future prospective studies needed in the modern management of BMs.

Adjuvant Stereotactic Radiosurgery for Clear Cell Meningiomas

ObjectiveClear cell meningiomas (CCM) are an uncommon meningioma subtype marked by aggressive growth and high rates of recurrence despite initial resection. The present study evaluates the adjuvant benefit of stereotactic radiosurgery (SRS) for residual or recurrent tumors. MethodsAfter review of our prospectively maintained data base, we identified 6 patients (3 female) with histologically confirmed Grade 2 CCMs. The median age of the patients at the time of SRS was 45 years. Five patients had undergone prior gross total surgical resection and 1 patient had subtotal resection before SRS. The median SRS treatment volume was 4.7 cc and the median radiosurgical margin dose was 13 Gy (range: 10 – 15 Gy). ResultsThe median follow-up time was 35.5 months (range 6 – 168 months). Three patients achieved tumor control after the first SRS procedure. Three patients experienced tumor progression at 4, 22, and 32 months after initial SRS. Tumor control was obtained in 2 of these patients after additional SRS. One patient with multiple SRS procedures had suspected adverse radiation effect that was successfully treated with corticosteroids followed by bevacizumab. ConclusionsTumor control was maintained in 5 of 6 patients after one or more SRS procedures. SRS should be considered for early intervention after surgical resection of CCM. To maximize the tumor control rate, patients with diagnosed CCM should be treated more generously and higher margin dose should be prescribed. Patients with CCM should be counselled that more than one SRS may be necessary to provide sustained tumor control.

Delayed Imaging Changes 18 Months or Longer After Stereotactic Radiosurgery for Brain Metastases: Necrosis or Progression

Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment. A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time. The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression. The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression.

Clinical Outcomes Following an Initial Stereotactic Radiosurgery Course for Brain Metastases from Melanoma

Brain metastases (BM) are common in melanoma patients. The effect of gene mutations is not well characterized since first-line metastatic therapy has shifted from chemotherapy (CHT) to molecularly targeted therapies (TT) and immunotherapy (IO). We report outcomes of melanoma BM patients stratified by molecular subtype and pre-stereotactic radiosurgery (SRS) systemic therapy. We identified all patients completing an initial SRS course for BM at two institutions between 1/2015 and 12/2020. Patients who had prior WBRT and/or resection were eligible. Demographic and clinical parameters were collected, along with melanoma tumor molecular characteristics. Intracranial progression (ICP) was defined as any radiographic distant and/or in-field progression per multidisciplinary consensus. Overall survival (OS) and freedom from ICP (FFICP) were estimated via the Kaplan Meier method. From a total of 1383 SRS BM patients, we identified 118 (8.5%) with melanoma. Median follow up was 8.7 months, median age 64 years (IQR 51-72), 81% had cutaneous origin, and 55% had a KPS of 90-100. Molecular subtypes included BRAF (45%), NRAS (9.3%), and c-KIT (3.4%). Overall, 61% received IO prior to SRS, while 25% and 9.3% received TT and CHT prior to SRS respectively. 60% of patients harboring a mutation received IO as first line therapy, 10% received TT, and 30% received both TT and IO prior to SRS. BRAFmut patients more likely to have received TT prior to SRS (43% vs 9.2%, p<0.001) compared to BRAFwt patients. Median OS was 9.7 months (95% CI 7.8-13) and was not significantly different from non-melanoma patients (p = 0.6). Median FFICP was worse for melanoma patients (5.9 mos, 95% CI 3.5-8.5) than non-melanoma patients (8.96 mos, 95% CI 8.2-9.7, p = 0.009). A total of 72 ICP events occurred, with 56 (77.8%) distant ICP cases, 3 (4.2%) in-field ICP, and 13 (18%) ICP events that were radionecrosis (RN) only. RN was associated with the presence of a targetable mutation (18% vs 2%, p = 0.006) and receipt of TT pre-SRS (36% vs 9.8%, p = 0.001). BRAFmut patients had significantly worse FFICP (3.8 mos, 95% CI 3.0-6.8) compared to BRAFwt patients (8.5 mos, 95% CI 5.8-30.2, p = 0.006), although median OS was not significantly different (9.6 mos, 95% CI 6.9-16 vs 10.7 mos, 95% CI 6.7-15.5, p = 0.8). NRASmut was associated with better FFICP (29 mos, 95% CI 2.94-NA, p = 0.02). In this modern, multi-institutional cohort of SRS patients, melanoma BM patients had worse FFICP compared to non-melanoma BM patients, and BRAFmut patients had worse FFICP than BRAFwt patients. RN was associated with mutational status and receipt of TT pre-SRS. OS did not vary significantly across groups. This analysis may help inform systemic therapy decisions and future genomic studies for patients with BMs from melanoma.

Pretreatment Clinical Parameters Associated with Intracranial Progression Burden Following an Initial Stereotactic Radiosurgery Course in a Multi-Institutional Brain Metastases Cohort

While brain metastasis (BM) velocity is a valuable prognostic metric at time of intracranial progression (ICP), pre-SRS risk factors for post-SRS high-burden intracranial progression (ICP) remain poorly characterized. We hypothesized that pre-SRS clinical parameters are associated with subsequent high-burden (ICP), defined as either ≥5 (ICP5) or new/progressive ≥11 BMs (ICP11). All patients completing an initial SRS course for BMs at two institutions from 1/2015-12/2020 were retrospectively identified. Patients with prior whole brain radiation therapy (WBRT) and/or BM resection were eligible. Demographic and clinical parameters were collected. ICP was defined as any radiographic concern for distant and/or in-field progression per multidisciplinary consensus. Overall survival (OS) and freedom from ICP were estimated via the Kaplan Meier method. Cox models assessed association between parameters and freedom from ICP5 and ICP11. We identified 1383 patients completed SRS, with a median follow up of 8.7 months. Patients were 54.8% female, 45.6% with KPS ≥90, and a median of 63.4 years old. Primary tumor types included non-small cell lung (48.7%), breast (14.7%), and melanoma (8.5%). 46.9% had oligometastatic disease (≤5 metastatic foci: including BMs) at SRS, and 53.4% underwent SRS for >1 BM. 10.3% of patients had undergone prior WBRT and 26.1% surgical resection. 555 patients (40.1%) experienced ICP following SRS, of whom 72.6% had 1-4, 11.5% had 5-10, and 15.9% had ≥11 new/progressive BMs. Among patients with ICP, 6-month freedom from ICP was 35.5% (95% CI: 31.1-40.5%) for those with 1-4 BMs at time of ICP, 29.7% (95% CI: 20.4-43.3%) for 5-10 BMs, and 20.5% (95% CI: 13.5-30.1%) for ≥11 BMs (p = 0.016). Respective 12-month OS rates were 56.8% (95% CI: 52.1-61.9%), 46.0% (95% CI: 35.1-60.1%), and 38.7% (95% CI: 29.4-50.9%; p<0.001). Neurologic symptoms at time of ICP were observed in 21.1% of patients with 1-4 BMs, 28.1% with 5-10 BMs, and 50.0% with new/progressive ≥11 BMs (p<0.001). On multivariable analysis, superior freedom from high-burden ICP was associated with the following pre-SRS parameters: oligometastatic burden (ICP5: HR 0.68, 95% CI: 0.47-0.99; ICP11: 0.59; 95% CI: 0.36-0.97), no prior immunotherapy (ICP11: HR 0.57, 95% CI: 0.34-0.57), and a single BM at time of initial SRS (1 vs 2 BM, ICP 5: HR 0.51, 95% CI: 0.31-0.82; ICP11: HR 0.45, 95% CI: 0.24-0.84), while primary tumor type was not associated with ICP5 or ICP11. Pre-SRS parameters including polymetastatic burden, prior receipt of immunotherapy, and >1 BM were associated with post-SRS high-burden ICP. High burden ICP developed earlier following SRS completion and was associated with higher rates of neurologic decline and inferior OS.

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.

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.

EGFR-mutated non-small lung cancer brain metastases and radiosurgery outcomes with a focus on leptomeningeal disease.

Patients with EGFR-mutated NSCLC represent a unique subset of lung cancer patients with distinct clinical and molecular characteristics.Previous studies have showna higherincidence of brain metastases (BM)in this subgroup of patients, and neurologic death has been reported to be as high as 40% and correlates with leptomeningeal disease (LMD). Between 2012 and 2021, a retrospective review of our prospective registry identified 606 patients with BM from NSCLC, with 170 patients having an EGFR mutation. Demographic, clinical, radiographic, and treatment characteristics were correlated to the incidence of LMD and survival. LMD was identified in 22.3% of patients (n = 38) at a median follow-up of 19 (2-98) months from initial SRS. Multivariate regression analysis showed targeted therapy and a cumulative number of metastases as significant predictors of LMD (p = 0.034, HR = 0.44), (p = .04, HR = 1.02). The median survival time after SRS of the 170 patients was 24months (CI 95% 19.1-28.1). In a multivariate Cox regression analysis, RPA, exon 19 deletion, and osimertinib treatment were significant predictors of overall survival. The cumulative incidence of neurological death at 2 and 4years post initial stereotactic radiosurgery (SRS) was 8% and 11%, respectively, and correlated with LMD. The study shows that current-generation targeted therapy for EGFR-mutated NSCLC patients may prevent the development and progression of LMD, leading to improved survival outcomes. Nevertheless, LMD is associated with poor outcomes and neurologic death, making innovative strategies to treat LMD essential.

Pretreatment clinical parameters associated with intracranial progression burden following an initial stereotactic radiosurgery course in a multi-institutional brain metastases cohort.

2013 Background: While brain metastasis (BM) velocity is a valuable prognostic metric at time of intracranial progression (ICP), pre-SRS risk factors for post-SRS high-burden intracranial progression (ICP) remain poorly characterized. We hypothesized that pre-SRS clinical parameters are associated with subsequent high-burden (ICP), defined as either ≥5 (ICP5) or new/progressive ≥11 BMs (ICP11). Methods: All patients completing an initial SRS course for BMs at two institutions from 1/2015-12/2020 were retrospectively identified. Patients with prior whole brain radiation therapy (WBRT) and/or BM resection were eligible. Demographic and clinical parameters were collected. ICP was defined as any radiographic concern for distant and/or in-field progression per multidisciplinary consensus. Overall survival (OS) and freedom from ICP were estimated via the Kaplan Meier method. Cox models assessed association between parameters and freedom from ICP5 and ICP11. Results: We identified 1383 patients completed SRS, with a median follow up of 8.7 months. Patients were 54.8% female, 45.6% with KPS ≥90, and a median of 63.4 years old. Primary tumor types included non-small cell lung (48.7%), breast (14.7%), and melanoma (8.5%). 46.9% had oligometastatic disease (≤5 metastatic foci: including BMs) at SRS, and 53.4% underwent SRS for &gt; 1 BM. 10.3% of patients had undergone prior WBRT and 26.1% surgical resection. 555 patients (40.1%) experienced ICP following SRS, of whom 72.6% had 1-4, 11.5% had 5-10, and 15.9% had ≥11 new/progressive BMs. Among patients with ICP, 6-month freedom from ICP was 35.5% (95% CI: 31.1-40.5%) for those with 1-4 BMs at time of ICP, 29.7% (95% CI: 20.4-43.3%) for 5-10 BMs, and 20.5% (95% CI: 13.5-30.1%) for ≥11 BMs (p = 0.016). Respective 12-month OS rates were 56.8% (95% CI: 52.1-61.9%), 46.0% (95% CI: 35.1-60.1%), and 38.7% (95% CI: 29.4-50.9%; p &lt; 0.001). Neurologic symptoms at time of ICP were observed in 21.1% of patients with 1-4 BMs, 28.1% with 5-10 BMs, and 50.0% with new/progressive ≥11 BMs (p &lt; 0.001). On multivariable analysis, superior freedom from high-burden ICP was associated with the following pre-SRS parameters: oligometastatic burden (ICP5: HR 0.68, 95% CI: 0.47-0.99; ICP11: 0.59; 95% CI: 0.36-0.97), no prior immunotherapy (ICP11: HR 0.57, 95% CI: 0.34-0.57), and a single BM at time of initial SRS (1 vs 2 BM, ICP 5: HR 0.51, 95% CI: 0.31-0.82; ICP11: HR 0.45, 95% CI: 0.24-0.84), while primary tumor type was not associated with ICP5 or ICP11. Conclusions: Pre-SRS parameters including polymetastatic burden, prior receipt of immunotherapy, and &gt; 1 BM were associated with post-SRS high-burden ICP. High burden ICP developed earlier following SRS completion and was associated with higher rates of neurologic decline and inferior OS.

Intracranial and Extracranial Progression and Their Correlation With Overall Survival After Stereotactic Radiosurgery in a Multi-institutional Cohort With Brain Metastases

Clinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS). To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course. This multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022. Non-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus. The primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach. This study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations. The results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.

Stratified assessment of an FDA-cleared deep learning algorithm for automated detection and contouring of metastatic brain tumors in stereotactic radiosurgery

PurposeArtificial intelligence-based tools can be leveraged to improve detection and segmentation of brain metastases for stereotactic radiosurgery (SRS). VBrain by Vysioneer Inc. is a deep learning algorithm with recent FDA clearance to assist in brain tumor contouring. We aimed to assess the performance of this tool by various demographic and clinical characteristics among patients with brain metastases treated with SRS.Materials and methodsWe randomly selected 100 patients with brain metastases who underwent initial SRS on the CyberKnife from 2017 to 2020 at a single institution. Cases with resection cavities were excluded from the analysis. Computed tomography (CT) and axial T1-weighted post-contrast magnetic resonance (MR) image data were extracted for each patient and uploaded to VBrain. A brain metastasis was considered “detected” when the VBrain- “predicted” contours overlapped with the corresponding physician contours (“ground-truth” contours). We evaluated performance of VBrain against ground-truth contours using the following metrics: lesion-wise Dice similarity coefficient (DSC), lesion-wise average Hausdorff distance (AVD), false positive count (FP), and lesion-wise sensitivity (%). Kruskal–Wallis tests were performed to assess the relationships between patient characteristics including sex, race, primary histology, age, and size and number of brain metastases, and performance metrics such as DSC, AVD, FP, and sensitivity.ResultsWe analyzed 100 patients with 435 intact brain metastases treated with SRS. Our cohort consisted of patients with a median number of 2 brain metastases (range: 1 to 52), median age of 69 (range: 19 to 91), and 50% male and 50% female patients. The primary site breakdown was 56% lung, 10% melanoma, 9% breast, 8% gynecological, 5% renal, 4% gastrointestinal, 2% sarcoma, and 6% other, while the race breakdown was 60% White, 18% Asian, 3% Black/African American, 2% Native Hawaiian or other Pacific Islander, and 17% other/unknown/not reported. The median tumor size was 0.112 c.c. (range: 0.010–26.475 c.c.). We found mean lesion-wise DSC to be 0.723, mean lesion-wise AVD to be 7.34% of lesion size (0.704 mm), mean FP count to be 0.72 tumors per case, and lesion-wise sensitivity to be 89.30% for all lesions. Moreover, mean sensitivity was found to be 99.07%, 97.59%, and 96.23% for lesions with diameter equal to and greater than 10 mm, 7.5 mm, and 5 mm, respectively. No other significant differences in performance metrics were observed across demographic or clinical characteristic groups.ConclusionIn this study, a commercial deep learning algorithm showed promising results in segmenting brain metastases, with 96.23% sensitivity for metastases with diameters of 5 mm or higher. As the software is an assistive AI, future work of VBrain integration into the clinical workflow can provide further clinical and research insights.

876 Significant Survival Improvements for Patients with Melanoma Brain Metastases: Can We Reach Cure in the Current Era?

INTRODUCTION: New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. METHODS: We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012-2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS: Mean age was 63 ± 15 years, 39% were female and 29% had BRAF-mutated tumors. Median overall survival after radiosurgery was 15.7 months (95% Confidence Interval: 11.4-27.7) and 25 months in patients managed since 2015. Thirty-two patients survived 5 years from their initial SRS. BRAF mutation-targeted therapies showed a survival advantage in comparison to chemotherapy (p = 0.009), but not to immunotherapy (p = 0.09). In a multivariable analysis, both immunotherapy and the number of metastases at 1st SRS were predictors of long-term survival (5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for 5 years. CONCLUSIONS: Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.

Stereotactic radiosurgery for intermediate- and high-grade arteriovenous malformations: outcomes stratified by the supplemented Spetzler-Martin grading system.

The supplemented Spetzler-Martin (Supp-SM) grading system was developed to improve the predictive accuracy of surgical risk for patients with brain arteriovenous malformations (AVMs). The aim of this study was to apply the Supp-SM grading system to patients having stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) intermediate- (grade III) or high-grade (grade IV-V) AVMs to enable comparison with published microsurgical series. In 219 patients who underwent SRS during the period from 1990 to 2016, the Supp-SM grade was calculated for SM grade III (n = 154) or SM grade IV-V (n = 65) AVMs. The Supp-SM grades in these patients were 4 (n = 14, 6%), 5 (n = 36, 16%), 6 (n = 67, 31%), 7 (n = 76, 35%), and 8-9 (n = 26, 12%). Sixty patients (27%) had deep AVMs (basal ganglia, thalamus, or brainstem). Thirty-nine patients (18%) had volume-staged SRS; 41 patients (19%) underwent repeat SRS. The median follow-up period was 69 months for SM grade III AVMs and 113 months for SM grade IV-V AVMs. AVM obliteration was confirmed in 163 patients (74%) at a median of 38 months after initial SRS. The obliteration rates at 4 and 8 years were 59% and 76%, respectively. Thirty-one patients (14%) had post-SRS deficits from hemorrhage (n = 7, 3%) or radiation injury (n = 24, 11%). Six patients (3%) died after SRS (hemorrhage, n = 5; radiation injury, n = 1). The rates of neurological decline or death at 4 and 8 years were 11% and 18%, respectively. Factors predictive of nonobliteration were deep location (HR 0.57, 95% CI 0.39-0.82, p = 0.003) and increasing AVM volume (HR 0.96, 95% CI 0.93-0.99, p = 0.002). Increasing AVM volume was the only factor associated with neurological decline (HR 1.05, 95% CI 1.02-1.08, p = 0.002). The Supp-SM grading score did not correlate with either obliteration (HR 0.94, 95% CI 0.82-1.09, p = 0.43) or neurological decline (HR 1.15, 95% CI 0.84-1.56, p = 0.38). The Supp-SM grading system was not predictive of outcomes after SRS of intermediate- or high-grade AVM. In a cohort that included a high percentage (47%) of "inoperable" AVMs according to Supp-SM grade (≥ 7), most patients had obliteration after SRS, although there was a high risk of neurological decline.

Clinical Outcomes of Stereotactic Radiosurgery-Related Radiation Necrosis in Patients with Intracranial Metastasis from Melanoma.

Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero?

Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2years of imaging follow-up without distant brain failure (DBF). Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9years and time to DBF is 1.5years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). Approximately one third of brain metastasis patients who live beyond 2years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Analysis of Survival Outcomes of Patients Treated with Stereotactic Radiosurgery for High Volume Brain Metastases

<h3>Purpose/Objective(s)</h3> To analyze outcomes and assess for factors associated with improved survival in patients with greater than or equal to 20 cumulative brain metastases treated with stereotactic radiosurgery (SRS). <h3>Materials/Methods</h3> This was a single institution, retrospective analysis that included patients with 20 or more cumulative brain metastases treated with SRS. Between December 2015 and February 2022, 96 patients were identified that met the inclusion criteria, and their clinical, tumor, and treatment data were used for analysis. Overall survival outcomes, defined as the time interval from initial SRS treatment until death from any cause, were calculated using the Kaplan-Meier method for various patient, tumor, and treatment factors. The log-rank test was used to compare subgroups and investigate patient characteristics for significance. <h3>Results</h3> The median follow-up time, defined as the interval between date of initial SRS and last recorded physician follow-up, was 8.7 months. Median ages at time of initial cancer diagnosis, initial brain metastases diagnosis, and initial SRS treatment were 60, 57 and 60 years, respectively. The most common primary tumor histologies were lung (48%) and breast (23%), followed by melanoma (10%), and renal cell carcinoma (8%), with the remaining 10% of patients being grouped together due to rare histology. In regard to treatment characteristics, the median cumulative number of brain metastases was 31.5 (range 20-158) with the median of 22 brain metastases treated in a single SRS treatment course. The majority of patients were treated with a distributed SRS technique (86%). The median number of cumulative SRS sessions was 2 (range 1-7). Median overall survival for the entire cohort was 12.6 months. Categorized by primary histology, the median OS for lung, breast, melanoma, RCC, and other was 14.8, 15.5, 8.9, 22.8, and 6.5 months, respectively (NS, p=0.182). Further analysis of factors associated with overall survival found the presence of a targetable mutation (18.4 vs 10.5 months (HR 0.48, 95% CI 0.29-0.78, p=0.004)) and not having received whole brain radiotherapy (15.5 vs 9.3 months (HR 1.92, 95% CI 1.11-3.33, p=0.008)) as significant predictors of overall survival. ECOG performance status at time of initial SRS (0-1 vs 2) was trending toward significance (13.6 vs 9.7 months (HR 0.93, 95% CI 0.54-1.62, p=0.068) but was not statistically relevant. <h3>Conclusion</h3> Treatment of high-volume brain metastases with SRS appears to be safe and is feasible in selected patient populations. Survival rates appear comparable to prospective studies utilizing upfront conventional whole brain and hippocampal sparing radiation. Further studies are needed to validate this approach and identify patients best suited for this treatment paradigm.

Long-Term Survivors of Stereotactic Radiosurgery for Brain Metastases: Do Distant Brain Failures Reach a Plateau and what Factors are Associated with a Brain Metastasis Velocity of Zero?

<h3>Purpose/Objective(s)</h3> Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS), and as such, questions regarding how long patients need surveillance imaging have become more relevant. The present study sought to retrospectively analyze brain metastasis patients who have survived two years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of "zero." <h3>Materials/Methods</h3> This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases without prior whole brain radiotherapy (WBRT) who survived greater than two years after first SRS. Clinical outcomes were determined via the Electronic Medical Record. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least two years of imaging follow-up without distant brain failure (DBF). The cumulative incidence of DBF is via the Fine Gray Method and defined from time of first SRS to time of DBF. <h3>Results</h3> Of the 300 patients in this review, median age at first SRS is 61 (IQR: 53, 70). Primary cancers include lung cancer (50%), breast cancer (16%), melanoma (15%), GU primary (11%), GI primary (4%) and other (4%). Median number of metastases at first SRS is one (IQR: 1, 3). Median follow-up is three years (IQR: 2.3, 5.1). Kaplan-Meier estimated median overall survival is 4.9 years. In this patient population, the median Kaplan-Meier estimated time to DBF is 1.5 years (95% CI: 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures appear to reach a plateau at four years where the cumulative incidence of DBF is 82%. Seventy percent of first time DBFs have occurred by two years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). <h3>Conclusion</h3> Approximately one third of brain metastasis patients who live beyond two years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at four years, after which very few patients develop new brain metastases if they have not yet already. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Outcomes of Brain Metastases Managed with Resection and Aggressive Reirradiation after Initial Radiosurgery Failure

<h3>Purpose/Objective(s)</h3> To evaluate local control, overall survival, and toxicity profiles in patients with brain metastases aggressively treated with initial radiation followed by resection and aggressive re-irradiation upon pathological confirmation of failure of prior radiosurgery treatment. <h3>Materials/Methods</h3> A retrospective chart review identified 55 lesions in 51 patients that were initially treated with stereotactic radiosurgery (SRS), then demonstrated evidence of recurrence with pathologic confirmation and underwent high dose re-irradiation either with radiosurgery (n=43, 78.2%) or intracavitary brachytherapy with Cesium-131 seeds (n=12, 21.8%). Toxicity was measured by: steroids initiated or increased within 3 months, imaging evidence of treatment effect vs disease progression at any time point, further intervention for local recurrence or necrosis, and any grade 3/4 neurologic events. Local control (with failure defined by sustained progression on imaging or pathologic confirmation of tumor) was measured from time of re-treatment. Overall survival (OS) and local control were evaluated using the Kaplan-Meier method. <h3>Results</h3> Median follow-up from re-irradiation was 32.5 months (IQR 18-45 months). The majority of cohort patients were female (66.7 %), with median age at first SRS of 56.3 years old. Primary histology was non-small cell lung cancer (NSCLC) in 19 cases (37.2%) and breast cancer in 12 cases (23.53%). Ten individuals had previous WBRT (19.5%) prior to initial stereotactic therapy. The most common dose fractionation for initial SRS was 18 Gy x 1 fraction (18 lesions, 32.7%), and the most common dose fractionation for repeat SRS was 8 Gy in 3 fractions (15 lesions, 27.3%). Twenty-five lesions (45.4%) required use of steroids after re-irradiation. Among all patients, 21.8% experienced evidence of grade 3 or 4 neurotoxicity. There was no statistically significant difference in the rate of steroid use or grade 3-4 neurotoxicity between lesions re-irradiated with SRS vs. brachytherapy (25.6% vs. 8.33% grade 3-4 neurotoxicity; p=0.201 and 51.2% vs 25% steroid use; p=0.108). Forty percent had imaging changes of possible pseudoprogression, radiation necrosis, or true progression. Of patients with imaging changes, 27% (10.9% of all treated patients) were confirmed necrosis by pathology. Median OS was 14.1 months (95% CI 7.63 – 24.3). The 2-year OS was 52% (95% CI 39, 69.3%) and 2-year local control rate was 79.5% (95% CI 61.7, 68.3%). <h3>Conclusion</h3> Aggressive re-irradiation with radiosurgery or brachytherapy after resection for pathologically confirmed progression after prior radiosurgery is appropriately effective and demonstrate similar toxicity profiles.

Stratified Assessment of a Commercial Deep Learning Algorithm for Automated Detection and Contouring of Metastatic Brain Tumors in Stereotactic Radiosurgery

<h3>Purpose/Objective(s)</h3> Artificial intelligence-based tools can be leveraged to improve detection and segmentation of brain metastases for stereotactic radiosurgery (SRS). This study explores a deep learning algorithm with recent FDA clearance to assist in brain tumor contouring. In this study, we aimed to assess the performance of this tool by various demographic and clinical characteristics among patients with brain metastases treated with SRS. <h3>Materials/Methods</h3> We randomly selected 100 patients with brain metastases who underwent initial SRS on a frameless robotic radiosurgery system from 2017 to 2020 at a single institution. Cases with resection cavities were excluded from the analysis. Computed tomography (CT) and axial T1-weighted post-contrast magnetic resonance (MR) image data were extracted for each patient and uploaded to VBrain. A brain metastasis was considered "detected" when the VBrain "predicted" contours overlapped with the corresponding physician contours ("ground-truth" contours). We evaluated performance of VBrain against ground-truth contours using the following metrics: lesion-wise Dice similarity coefficient (DSC), lesion-wise average Hausdorff distance (AVD), false positive count (FP), and lesion-wise sensitivity (%). Wilcoxon rank-sum tests were performed to assess the relationships between patient characteristics including sex, race, primary histology, age, and size and number of brain metastases, and performance metrics such as DSC, AVD, FP, and sensitivity. <h3>Results</h3> We analyzed 100 patients with 422 intact brain metastases treated with SRS. Our cohort consisted of patients with a median number of 2 brain metastases (range: 1 to 47), median age of 79 (range: 19 to 91), and 50% male and 50% female patients. The primary site breakdown was 56% lung, 10% melanoma, 9% breast, 8% gynecological, 5% gastrointestinal, 2% prostate, and 5% other, while the race breakdown was 60% White, 18% Asian, 3% Black/African American, 2% Native Hawaiian or other Pacific Islander, and 17% other/unknown/not reported. The median tumor size was 0.118 c.c. (range: 0.003-28.838 c.c.). We found mean lesion-wise DSC to be 0.714, mean lesion-wise AVD to be 8.44% of lesion size (0.796 mm), mean FP count to be 0.17 tumors per case, and lesion-wise sensitivity to be 83.65% for all lesions. Moreover, mean sensitivity was found to be 98%, 91.93%, and 79.87% for lesions with diameter equal to and greater than 10 mm, 5 mm, and 3 mm, respectively. No other significant differences in performance metrics were observed across demographic or clinical characteristic groups. <h3>Conclusion</h3> A commercial deep learning algorithm showed promising results in segmenting brain metastases, with 98% sensitivity for metastases with diameters of 1 cm or higher. Performance declined for smaller lesions. As advances in imaging and radiosurgery enable the detection and treatment of smaller brain metastases, future work is ongoing to develop and improve these tools to assist in radiosurgical treatment planning.